case study a patient with uncontrolled type 2 diabetes

• DOI: 10.2337/DIASPECT.16.1.32
• Corpus ID: 73083750

Case Study: A Patient With Uncontrolled Type 2 Diabetes and Complex Comorbidities Whose Diabetes Care Is Managed by an Advanced Practice Nurse

• G. Spollett
• Published 2003
• Diabetes Spectrum

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Management of ketosis-prone type 2 diabetes mellitus., integrating a pico clinical questioning to the ql4pomr framework for building evidence-based clinical case reports, nursing practice guideline for foot care for patients with diabetes in thailand, goal-driven structured argumentation for patient management in a multimorbidity setting, logic and argumentation: third international conference, clar 2020, hangzhou, china, april 6–9, 2020, proceedings, 18 references, using a primary nurse manager to implement dcct recommendations in a large pediatric program, diabetes in urban african americans. iii. management of type ii diabetes in a municipal hospital setting., primary care outcomes in patients treated by nurse practitioners or physicians: a randomized trial., caring for a child with diabetes: the effect of specialist nurse care on parents' needs and concerns., standards of medical care for patients with diabetes mellitus, management of patients with diabetes by nurses with support of subspecialists., a practical approach to type 2 diabetes., the diabetes control and complications trial (dcct): the trial coordinator perspective, oral antihyperglycemic therapy for type 2 diabetes: scientific review., caring for feet: patients and nurse practitioners working together., related papers.

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Case Study: A Patient With Uncontrolled Type 2 Diabetes and Complex Comorbidities Whose Diabetes Care Is Managed by an Advanced Practice Nurse

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Nutrient patterns and risk of diabetes mellitus type 2: a case-control study

• Morteza haramshahi 1 ,
• Thoraya Mohamed Elhassan A-Elgadir 2 ,
• Hamid Mahmood Abdullah Daabo 3 ,
• Yahya Altinkaynak 4 ,
• Ahmed Hjazi 5 ,
• Archana Saxena 6 ,
• Mazin A.A. Najm 7 ,
• Abbas F. Almulla 8 ,
• Ali Alsaalamy 9 &
• Mohammad Amin Kashani 10  

BMC Endocrine Disorders volume  24 , Article number:  10 ( 2024 ) Cite this article

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Backgrounds

Although the significance of diet in preventing or managing diabetes complications is highlighted in current literature, there is insufficient evidence regarding the correlation between nutrient patterns and these complications. The objective of this case-control study is to investigate this relationship by analyzing the dietary intake of nutrients in participants with and without type 2 diabetes (T2D).

A case-control study was conducted at the Tabriz Center of Metabolism and Endocrinology to investigate the relationship between nutrient patterns and type 2 diabetes (T2D). The study enrolled 225 newly diagnosed cases of T2D and 225 controls. The dietary intake of nutrients was assessed using a validated semi-quantitative food frequency questionnaire (FFQ). Principal component analysis using Varimax rotation was used to obtain nutrient patterns. Logistic regression analysis was performed to estimate the risk of T2D.

The participants’ mean (SD) age and BMI were 39.8 (8.8) years and 27.8 (3.6) kg/m2, respectively. The results identified three major nutrient patterns. The first nutrient pattern was characterized by high consumption of sucrose, animal protein, vitamin E, vitamin B1, vitamin B12, calcium, phosphorus, zinc, and potassium. The second nutrient pattern included fiber, plant protein, vitamin D, Riboflavin, Vitamin B5, copper, and Magnesium. The third nutrient pattern was characterized by fiber, plant protein, vitamin A, riboflavin, vitamin C, calcium, and potassium. Individuals in the highest tertile of nutrient pattern 3 (NP3) had a lower risk of T2D compared to those in the lowest tertile after adjusting for confounders. The odds ratio was 0.52 with a 95% confidence interval of 0.30–0.89 and a P_trend of 0.039.

This study found that conforming to a nutrient pattern consisting of plant protein, vitamin C, vitamin A, vitamin B2, potassium, and calcium is linked to a lower likelihood of developing T2D.The initial results suggest that following a nutrient pattern that includes these nutrients may reduce the risk of T2D. However, further research is required to confirm the relationship between nutrient patterns and T2D.

Peer Review reports

Type 2 diabetes is a significant concern for public health in developed nations. It leads to high rates of illness and death and places a significant financial burden on healthcare systems [ 1 , 2 ]. In the past few decades, there has been a sharp increase in the occurrence of diabetes, and is expected to continue increasing, with an estimated 693 million people living with the disease by 2045 [ 1 ]. Complications associated with type 2 diabetes can also contribute to premature death. A concerning aspect of the disease is that a significant proportion of cases (40%) go undetected [ 3 ], and there is also an increasing prevalence of prediabetes, which raises the risk of developing type 2 diabetes and other chronic diseases [ 1 ].

The connection between diet and type 2 diabetes has been extensively studied, including the examination of dietary patterns and individual foods or nutrient patterns [ 4 , 5 , 6 , 7 ]. Various sources have suggested that chronic diseases may be influenced by a combination of nutrients [ 8 ]. In the field of nutritional epidemiology, the examination of dietary patterns has emerged as a viable approach to investigate the correlation between diet and disease. This method involves using statistical techniques to combine multiple foods or nutrients into dietary or nutrient patterns, which are believed to provide a more detailed understanding of the connection between diet and disease. It has been suggested that the impact of individual nutrients or foods on chronic disease may be too subtle to detect, but their collective effect within a pattern may be more indicative [ 9 ].

There have been some recent studies examining the effect of nutrient patterns on chronic disease such as, non-alcoholic fatty liver, breast and gastric cancer, Polycystic Ovary Syndrome (PCOs) and metabolic syndrome [ 10 , 11 , 12 , 13 , 14 ]. For example, it was found that a nutrient pattern consisting mainly of protein, carbohydrates, and various sugars was linked to a higher risk of Metabolic Syndrome (MetS) in both men and women, whereas a pattern characterized by copper, selenium, and several vitamins was linked to greater odds of MetS [ 14 ]. A prospective study conducted among participants of the Tehran Lipid and Glucose Study indicates that a nutrient pattern rich in vitamin A, vitamin C, vitamin B6, potassium, and fructose is associated with a reduced risk of insulin-related disorders [ 15 ]. Although there have been limited investigations on the connection between nutrient patterns and the likelihood of developing diabetes, the present study seeks to explore this relationship by analyzing the adherence to different nutrient patterns and its effect on the risk of type 2 diabetes.

Study population

This study utilized a case-control design and involved participants between the ages of 18 and 60 who had been diagnosed with type 2 diabetes within the previous six months based on specific glucose level criteria (FBS levels of ≥ 126 mg/dl and 2 h-PG levels of ≥ 200 mg/dl [ 17 ]). Healthy individuals within the same age range were also included, with specific glucose level criteria (FBS levels of < 100 mg/dl and 2 h-PG levels of < 200 mg/dl [ 17 ]). The study excluded individuals with certain chronic diseases, Type 1 Diabetes, gestational diabetes, those following specific dietary patterns or taking certain medications, pregnant and breastfeeding women, those with a family history of diabetes or hypertension, and those who did not complete the food frequency questionnaire (more than 35 items) or whose reported energy intake was outside of a specific range (range of 800–4200 kcal [ 18 ]).

This study enrolled 450 adult participants, with 225 individuals in the case group and 225 in the control group. The case group was selected using a simple sampling method from patients diagnosed with diabetes at the Tabriz Center of Metabolism and Endocrinology as a referral center affiliated to tabriz University of Medical Sciences from January 2021 to March 2022, as well as through a two-stage cluster sampling method among patients referred to private endocrinologists to enhance the sample’s external validity. Participants in the control group were also selected through a two-stage cluster sampling method from individuals who had undergone blood glucose checkups at the Tabriz Center of Metabolism and Endocrinology, a referral center affiliated with Tabriz University of Medical Sciences, within the past six months. All participants provided informed consent at the beginning of the study. The study was financially supported by Tabriz University of Medical Sciences and is related to project NO. 1400/63,145.

Dietary assessment

To collect dietary intake information, personal interviews and a semi-quantitative food frequency questionnaire (FFQ) consisting of 168 food items were used [ 16 ]. The FFQ asked about the frequency of consumption for each item over the course of one year, with the year before diagnosis for the case group and the year before the interview for the control group. Participants were also asked about the frequency of consumption (per day, week, month, or year) for each type of food. to ensure consistency in measurements, a nutritionist provided instructions on converting the size of reported food items from household measures to grams using four scales. The quantity of food consumed by each individual was calculated based on their intake in grams and reported on a daily basis. The nutrient composition of all foods was derived by using modified nutritionist IV software.

Nutrient pattern assessment

We conducted factor analyses using a comprehensive set of 34 nutrients, encompassing various macronutrients, micronutrients, and other dietary components. These included sucrose, lactose, fructose, fiber, animal protein, plant protein, saturated fatty acids, monounsaturated fatty acids, polyunsaturated fatty acids, cholesterol, as well as an array of vitamins and minerals such as A, D, E, K, C, thiamine (B1), riboflavin (B2), niacin (B3), pantothenic acid (B5), pyridoxine (B6), folate (B9), B12, calcium, phosphorus, iron, zinc, copper, magnesium, manganese, chromium, selenium, sodium, potassium, and caffeine. The dietary intake of these 34 nutrients per 1,000 Kcal of energy intake was computed and utilized as input variables. Subsequently, nutrient patterns (NPs) were derived through principal component analysis (PCA) with varimax rotation, based on the correlation matrix. Factor scores for each participant were then calculated by aggregating the frequency of consumption and multiplying it by the factor loadings across all 34 nutrients. To assess the statistical correlation between variables and evaluate the adequacy of the sample size, we employed the Bartlett test of sphericity ( P  < 0.001) and the Kaiser-Mayer-Olkin test (0.71), respectively.

Assessment of other variables

To obtain the participants’ anthropometric measurements, weight and height were measured using a seca scale, and the participants’ BMI was determined by dividing their weight in kilograms by the square of their height in meters. Waist circumference was measured using a metal anthropometric tape, and the participants’ hip circumference was measured using a metal anthropometric tape while standing [ 17 ]. Daily physical activity was measured using a physical activity questionnaire [ 18 ], and personal questioning was employed to gather information on population and socioeconomic characteristics, including marital status, academic degree, and smoking.

Statistical analysis

Statistical analysis was performed using the Statistical Package Software for Social Science, version 21. The normality of the data was assessed using Kolmogorov-Smirnov’s test and histogram chart. The characteristics and dietary intakes of the case and control groups were presented as mean ± SD or median and frequency (percentages). Independent sample t-tests and chi-square tests were used to compare continuous and categorical variables, respectively, between the case and control groups.

The participants’ mean (SD) age and BMI were 39.8 (8.8) years and 27.8 (3.6) kg/m2, respectively. The mean (SD) BMI in the case group was 30.5 ± 4.1, and in the control group, it was 25.2 ± 3.2 kg/m2. The mean (SD) physical activity in the case group was 1121 ± 611 MET/min/week, and in the control group, it was 1598 ± 940 MET/min/week. There were significant differences in BMI and physical activity between the two groups. The mean (SD) waist circumference in the case group was 109.32 ± 10.28 cm, and in the control group, it was 87.25 ± 9.35 cm. The mean (SD) hip circumference in the case group was 107.25 ± 8.61 cm, and in the control group, it was 91.44 ± 6.17 cm. The study identified three primary nutrient patterns (NPs) with eigenvalues greater than 2. Table  1 displays the factor loadings for nutrient patterns, which accounted for 56.11% of the total nutrient variation. The high intake of sucrose, animal protein, phosphorus, zinc, potassium, calcium, vitamin E, vitamin B1 and vitamin B12 were the distinguishing features of the first pattern. The second nutrient pattern was positively associated with copper, magnesium, fiber, vitamin D, B2, B5 and plant protein but had a negative correlation with lactose and saturated fatty acids. On the other hand, the high intake of fiber, vitamin A, B2, vitamin C, plant protein and potassium were the distinguishing features of the third pattern.

The following are the characteristics of T2D patients compared to the control group, as shown in Table  2 : Higher BMI, More likely to be smokers, Lower physical activity levels, higher FBS, HbA1C, Insulin ( p  < 0.05). Other variables did not differ significantly between the two groups ( p  > 0.05). Additionally, T2D patients had a greater intake of energy and vitamin B3 but consumed less plant protein, vitamin A, vitamin E, vitamin B2, and zinc ( p  < 0.05).

Table  3 summarizes the partial correlation coefficient between NPs and food sources, with NP1 showing a strong positive correlation with low-fat dairy, NP2 with refined grains, and NP3 with fruits and vegetables.

Table  4 demonstrates the relationships between NPs and T2D. After adjusting for age and sex, there was no significant link between each nutrient pattern (NP) and T2D. However, when adjusting for other factors such as BMI, physical activity, smoking, and energy intake, individuals in the highest tertile of NP1 and NP2 did not show a significant association with T2D compared to those in the lowest tertile. On the other hand, those in the highest tertile of NP3 had a lower probability of developing T2D than those in the lowest tertile (OR: 0.52, 95%CI: 0.30–0.89, P_trend = 0.039).

In this study, three major NPs were identified. After adjusting for potential confounders, we observed a significant inverse association between the Third NP and the odds of T2D. The high intake of fiber, vitamin A, B2, vitamin C, plant protein and potassium were the distinguishing features of the third pattern.

Dietary patterns, such as healthy, Mediterranean, traditional, and Western dietary patterns, have recently received significant attention in studying the connection between diet and health. When looking at the relationship between nutrients and disease incidence, it is more challenging to evaluate when considering individual foods and the metabolism of all nutrients together [ 19 ]. It is therefore more effective to take a broader view and consider diet as a whole. Dietary and nutrient patterns can have a greater impact on health than specific nutrients or nutritional groups. There is supporting evidence that links high calorie or high glycemic index foods with an increased risk of T2D. The quality of one’s diet is also associated with the risk, progression, and side effects of T2D [ 20 ]. Establishing a desirable food pattern has become a priority in public health efforts to prevent T2D. By studying dietary and nutrient patterns, we can gain a comprehensive understanding of an individual’s overall diet beyond just the consumption of specific nutrients and food groups. Moreover, it is easier for people to understand health recommendations when presented as dietary patterns rather than focusing solely on individual nutrients [ 19 ].

A previous cross-sectional study investigated the relationship between NPs and fasting glucose and glycated hemoglobin levels among apparently healthy black South Africans. The study stratified 2,010 participants by gender and urban/rural status and identified three nutrient patterns per stratum. In rural women, a nutrient pattern driven by starch, dietary fiber, and B vitamins was significantly associated with lower fasting glucose and glycated hemoglobin levels. A nutrient pattern that included vitamin B1, zinc, and plant protein was linked to notable decreases in glycated hemoglobin and fasting glucose levels in rural men. These findings suggest that nutrient patterns that are plant-based are linked to lower levels of fasting glucose and glycated hemoglobin [ 21 ].

Iwasaki et al. found that specific nutrient patterns were associated with lower risks of MetS. One nutrient pattern high in potassium, fiber, and vitamins, while another pattern high in vitamin B2, saturated fatty acids and calcium [ 22 ]. A recent study found that a nutrient pattern characterized by high intake of calcium, potassium, fats, cholesterol, vitamins B2, B12, A, D, K and C was positively linked to MetS [ 23 ]. Salehi-Sahlabadi et al. found that adhering to a nutrient pattern rich in potassium, vitamin A, fructose, vitamin C and vitamin B6 was negatively associated with the likelihood of NAFLD [ 11 ]. A nutrient pattern high in potassium, vitamin A, vitamin B6, vitamin C and fructose was associated with a reduced risk of hyperinsulinemia, IR, and dyslipidemia among participants in Tehran, according to a prospective study [ 11 , 24 , 25 ].

Due to several variations among studies exploring NPs linked to chronic diseases, including differences in the number of nutrients, populations, study designs and outcomes there has been a considerable diversity in the identified NPs, with only a few NPs being replicated across studies. Our study is the first of its kind to explore the correlation between nutrient patterns and T2D in this context.

In our study, there was no association between NPs 1 and 2 and T2D. This lack of correlation may be attributed to the absence of harmful nutrients or food categories linked to diabetes in these NPs. NP3 in this study, unlike other NPs, is positively associated with beneficial food groups such as nuts, fruits, plant oil and vegetables, and negatively associated with unhealthy food groups like red-processed meat, snacks, high-fat dairy and refined grains. A recent systematic review and meta-analysis found that individuals who consumed higher amounts of fruits and vegetables had a lower risk of developing type 2 diabetes [ 26 ]. Moreover, the consumption of vegetables was found to have an inverse relationship with ALT, TC and LDL levels among adults, while fruit consumption was associated with a positive reduction in visceral fat [ 27 , 28 ]. Another study suggested that an increased intake of vegetables and fruits could potentially lower the risk of MetS [ 29 ]. According to a study, greater nut consumption was significantly linked to a reduced prevalence of T2D [ 30 ]. Consuming fruits and vegetables is a crucial component of a healthful dietary pattern that can lower the risk of type 2 diabetes [ 31 ]. On the other hand, Consuming a Western dietary pattern, which primarily consists of fast foods, high-fat dairy, refined grains, soft drinks and processed meat has been found to be correlated with an increased risk of type 2 diabetes [ 31 ].

Several mechanisms have been identified that explain the positive associations between the components of NP 3 and T2D or its risk factors. Vitamin intake has been shown to play a role in the development of T2D through various pathways. Consuming vitamin C has been found to have beneficial effects in reducing the risk of type 2 diabetes mellitus. These effects can be attributed to the following actions of vitamin C: vasodilator, cytoprotective, platelet anti-aggregator and anti-mutagenic. To achieve this, the body increases the production of several substances including prostaglandin E1, PGI2, endothelial nitric oxide, and lipoxin A4. Additionally, the body restores the Arachidonic Acid content to normal levels [ 32 ]. Vitamin A has a multifaceted role in cell regulation beyond its antioxidant function. It contributes to gene regulation, epithelial cell integrity, and resistance to infection. Research suggests that vitamin A also enhances antioxidant enzyme function in the body. Research has indicated a link between vitamin A deficiency and type 2 diabetes mellitus (T2DM), which suggests that vitamin A may have a role in the biology of T2DM [ 33 ]. Moreover, a meta-analysis has found that replacing animal protein with plant protein can lead to minor improvements in glycemic control for individuals with diabetes [ 34 ]. According to a recent meta-analysis, increasing the consumption of fruits, especially berries, yellow vegetables, cruciferous vegetables, green leafy vegetables is associated with a lower risk of developing type 2 diabetes. These results support the recommendation to incorporate more fruits and vegetables into the diet as a way to prevent various chronic diseases, including type 2 diabetes [ 35 ]. A study showed that maintaining adequate potassium intake could regulate insulin secretion and carbohydrate metabolism, leading to the prevention of obesity and metabolic syndrome (MetS) [ 36 ].

A number of research studies conducted in the Western societies have shown that Western dietary pattern including higher intake of red meat, processed meat, and refined grains is significantly associated with increased risk of T2D [ 37 , 38 ]. For example, in the 12-years cohort prospective study, van Dam et al. investigated dietary pattern of 42,504 American white men at the age range of 40–75 years old using the FFQ. After controlling the confounders, the risk of T2D increased 60% in people adherent to the western-like dietary pattern [ 38 ]. The rapid process of change in lifestyle, diets, and physical activity that have been occurred as a result of extended urbanization, improved economic status, change of work pattern toward jobs, and change in the processes of producing and distributing nutrients during the recent years in developing countries have led people to more consumption of fast food and processed foods [ 20 ].

Significant research has been conducted on the impact of nutrient type and sequence on glucose tolerance. Multiple studies have shown that manipulating the sequence of food intake can enhance glycemic control in individuals with type 2 diabetes in real-life situations. The glucose-lowering effect of preload-based nutritional strategies has been found to be more pronounced in type 2 diabetes patients compared to healthy individuals. Moreover, consuming carbohydrates last, as part of meal patterns, has been proven to improve glucose tolerance and reduce the risk of weight gain [ 39 ]. Recent findings on meal sequence further emphasize the potential of this dietary approach in preventing and managing type 2 diabetes [ 40 ].

Several studies have shown that food from a short supply chain has a significant impact on metabolic syndrome. The length of the food supply chain is important in determining the risk of metabolic syndrome in a population [ 41 ]. Research indicates that people who consume food from short supply chains have a lower prevalence of metabolic syndrome compared to those who consume food from long supply chains. Specifically, food from short supply chains is associated with lower levels of triglycerides and glucose, which leads to a reduced occurrence of metabolic syndrome [ 42 ]. Adhering to the Mediterranean diet with a short supply chain is also found to significantly reduce the prevalence of metabolic syndrome. Therefore, these studies provide evidence that food from short supply chains positively affects metabolic parameters and the occurrence of metabolic syndrome [ 41 ].

The study we conducted presented several advantages. It was the first case-control research to investigate the correlation between nutrient patterns and the likelihood of developing type 2 diabetes (T2D). While numerous studies have explored the relationship between dietary patterns and diabetes, there is a scarcity of research specifically focusing on nutrient patterns in individuals with type 2 diabetes. Furthermore, the collection of dietary intake data was carried out through face-to-face interviews conducted by trained dieticians to minimize measurement errors. However, this study also had some limitations. Case-control studies are susceptible to selection and recall biases. Additionally, the use of factor analysis to identify patterns, and the potential influence of research decisions on the number of factors and nutrient factor loadings in each pattern, should be considered. Lastly, despite the use of a validated semi-quantitative FFQ (food frequency questionnaire), there remains a possibility of measurement error due to dietary recall. The study’s findings and limitations contribute to the ongoing discourse on the role of nutrient patterns in the development of T2D and the importance of considering these factors in future research and preventive strategies.

Conclusions

The results of this study indicate that conforming to a nutrient pattern consisting of plant protein, vitamin C, vitamin A, vitamin B2, potassium, and calcium is linked to a lower likelihood of developing T2D. Our investigation did not reveal any significant correlation between other nutrient patterns and T2D risk. However, additional research is necessary to authenticate these initial findings and establish the correlation between nutrient patterns and T2D.

Data availability

Upon reasonable request, the corresponding author can provide the datasets that were produced and analyzed during the current study.

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The researchers express their gratitude towards all the individuals who volunteered to take part in the study.

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The study’s protocol was designed by M.K., M.H., and T.E., while H.A., Y.A., and A.H. carried out the research. A.S. analyzed the data and prepared the initial draft of the manuscript. M.N., A.FA., and A.A. interpreted the data and provided critical feedback on the manuscript. All authors reviewed and approved the final version of the manuscript.

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haramshahi, M., A-Elgadir, T.M.E., Daabo, H.M.A. et al. Nutrient patterns and risk of diabetes mellitus type 2: a case-control study. BMC Endocr Disord 24 , 10 (2024). https://doi.org/10.1186/s12902-024-01540-5

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Impact of Gender on Patient Experiences of Self-Management in Type 2 Diabetes: A Qualitative Study

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Authors Ramírez-Morros A   , Berenguera A   , Millaruelo L , Buil-Cosiales P , Gomez Garcia C , Cos X , Ávila Lachica L , Artola S , Millaruelo JM , Mauricio D   , Franch-Nadal J  

Received 2 March 2024

Accepted for publication 16 August 2024

Published 13 September 2024 Volume 2024:18 Pages 1885—1896

DOI https://doi.org/10.2147/PPA.S466931

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Editor who approved publication: Dr Michael Ortiz

Anna Ramírez-Morros, 1– 3, * Anna Berenguera, 4, * Laura Millaruelo, 3 Pilar Buil-Cosiales, 3, 5– 7 Carmen Gomez Garcia, 3, 8 Xavier Cos, 3, 9, 10 Luis Ávila Lachica, 3, 8 Sara Artola, 3, 11 Jose Manuel Millaruelo, 3, 12 Didac Mauricio, 1, 9, 13– 15 Josep Franch-Nadal 1, 3, 9, 16 1 DAP-Cat Group, Unitat de Suport a la Recerca de la Catalunya Central, Institut Universitari d’Investigació en Atenció Primària Jordi Gol (IDIAP Jordi Gol), Sant Fruitós de Bages, Spain; 2 Gerència Territorial de la Catalunya Central, Institut Català de la Salut, Sant Fruitós de Bages, Spain; 3 red GDPS Foundation, Sabadell, Spain; 4 Institut Universitari d’Investigació en Atenció Primària Jordi Gol (IDIAP Jordi Gol), Barcelona, Spain; 5 Centro de Investigación Biomédica en Red Fisiopatología de la Obesidad y la Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain; 6 Atención Primaria, Servicio Navarro de Salud, Navarra, Spain; 7 IdiSNA, Instituto de Investigación Sanitaria de Navarra, Navarra, Spain; 8 Unidad de Gestión Clínica Vélez Norte, Vélez-Málaga, Servicio Andaluz de Salud, Vélez-Málaga, Spain; 9 Center for Biomedical Research on Diabetes and Associated Metabolic Diseases (CIBERDEM), Instituto de Salud Carlos III, Barcelona, Spain; 10 EAP Sant Martí, Institut Catalá de la Salut, Barcelona, Spain; 11 Centro de Salud José Marvá, Madrid, Spain; 12 Centro de Salud Torrero La Paz, Zaragoza, Spain; 13 Institut de Recerca Hospital de la Santa Creu i Sant Pau, Barcelona, Spain; 14 Department of Endocrinology and Nutrition, Hospital Universitari de la Santa Creu i Sant Pau, Barcelona, Spain; 15 Department of Medicine, University of Vic – Central University of Catalonia, Vic, Spain; 16 Equip d’Atenció Primària (EAP) Raval Sud-Gerencia Territorial Barcelona, Institut Català de la Salut, Barcelona, Spain *These authors contributed equally to this work Correspondence: Anna Ramírez-Morros, Unitat de Suport a la Recerca de la Catalunya Central, Gerència Territorial de la Catalunya Central, Institut Català de la Salut, Sant Fruitós de Bages, 08272, Spain, Tel +34 936 930 040, Email [email protected] Josep Franch-Nadal, Unitat de Suport a la Recerca de Barcelona, Barcelona, 08025, Spain, Tel +34 932 073 760, Email [email protected] Purpose: This study aims to identify gender disparities in knowledge, attitudes and behaviors related to self-management and control of Type 2 diabetes Mellitus (T2DM) among primary care patients. The research was conducted across multiple Spanish cities. Patients and Methods: The study involved 8 Primary Care Centres located in four distinct regions of Spain: East (Barcelona), Centre (Madrid), North (Pamplona and Zumaia) and South (Vélez-Málaga and Málaga). A total of 111 individuals diagnosed with T2DM, comprising 52 women and 59 men, participated in 12 group discussions at these primary healthcare centers from February to June 2015. Participation was voluntary, and all participants provided informed consent by signing the consent form. A qualitative hermeneutic phenomenological study with a maximum variation sample was done. Participant profiles were defined based on gender, age, place of residence, type of treatment, years living with T2DM and the presence or absence of a cardiovascular event. Thematic analysis was used to analyze the data. Results: Participants were aware that diabetes is a chronic condition, with varied levels of concern regarding the diagnosis. Participants’ locus of control influenced their perception of the disease’s cause, with women attributing it to stress and emotional situations, while men linked it to risky behaviors. Self-management strategies were shaped by beliefs about diabetes, with both genders facing challenges in implementing recommended practices. Gender differences were also evident in caregiving roles, with men receiving more family support for diet adherence, while women prioritized family needs over their self-care. Participants expressed satisfaction with professional-patient interactions but highlighted the need for more accessible information and specialist care, suggesting support groups for women and clear health guidelines for men. Conclusion: Gender differences significantly influence how patients perceive and manage type 2 diabetes, with women experiencing greater concern and care burden compared to men. Effective diabetes management requires tailored support that addresses these gender-specific challenges. Enhancing healthcare services with clear guidelines and support groups can improve self-management outcomes in both men and women. Keywords: gender, type 2 diabetes mellitus, self-care, personal experience

Introduction

Type 2 diabetes mellitus (T2DM) is a chronic disease that requires a lifelong commitment to complex lifestyle adjustments. These include dietary control, maintenance of a physically active lifestyle, regular self-monitoring of blood glucose levels, and adherence to oral and/or injectable treatments to control and prevent or delay diabetes complications. 1–3 Cardiovascular disease is the most important complication, is a leading cause of death and disability among people with diabetes and has a higher prevalence rate compared to their counterparts without diabetes. 4 Among women, diabetes has a greater impact on cardiovascular disease than among men. It has been estimated that the relative risk of coronary heart disease is 44% higher in women compared to men, 27% higher in stroke and 19% higher in vascular dementia. 5–7 However, despite these higher risks, women are less frequently prescribed medications aimed at preventing cardiovascular disease. 8 , 9 Existing studies indicate that gender may play an important role in disease self-management, 3 , 8 , 10 as well as differences in how men and women experience and manage diabetes. 11 , 12

According to the existing literature, some hypotheses could explain this phenomenon. First, there is limited representation of women in studies focused on cardiovascular disease. Second, healthcare professionals tend to assign lower cardiovascular risk ratings to women, 13 an aspect that has received minimal research. Finally, there is a notable lack of awareness among women of the importance and risks associated with cardiovascular disease, potentially influenced by the perception that breast and cervical cancer are more pressing health concerns. 10 , 14 , 15

Perception of the disease is considered very important, as disease severity has been shown to be associated with patients’ perception of severity. 16 Perceptions of the disease could be shaped by gender-constructed social roles and expectations. 17 The aim of this study is to identify gender differences in knowledge, attitudes, and behaviors related to the control and self-management of T2DM in primary care patients. The study was conducted in Primary Care Centers in different Spanish cities.

Materials and Methods

This was a qualitative study, specifically adopting the Heideggerian hermeneutics phenomenological methodology, 18 to delve into individual experiences related to control and self-management of T2DM within the primary care setting. We used an interpretive approach, aiming to understand discourses emerging from personal experiences and to identify the social context through the exploration of language.

Study manuscript follows the consolidated criteria for reporting qualitative research (COREQ) ( Supplementary Table 1 ). The COREQ guide includes a reporting checklist for in-depth interviews and focus groups to promote complete and transparent reporting and to improve the rigor, completeness and credibility of these two data collection methods. The checklist contains 32 items with a description for each criterion and is made up of three domains: research team and reflexivity, study design, and analysis and findings. 19

Conceptual Framework

This study was guided by a conceptual framework for self- and family management of chronic conditions, developed at Yale School of Nursing. 20 This framework includes risk and protective factors, as well as outcomes that potentially influence individuals’ and families’ capacity to manage chronic illness. The factors and outcomes included in this framework are categorized into four dimensions: 1) health status; 2) individual-level factors/outcomes; 3) family-related factors/outcomes; and 4) environmental context. According to this mode, self- and family management behaviors act as mediators between risk/protective factors and ultimate outcomes. Accordingly, health interventions can strategically target either the modification of risk/protective factors, or shaping self- and family management behaviors.

Participant and Recruitment

Subjects with a diagnosis of T2DM and age over 35 years were recruited by their general practitioner (GP) or nurse to participate in the study and to explain the structure and the purpose of the study. The research was conducted from February to June 2015 in 8 Primary Care Centers from four regions of Spain: East (Barcelona), Centre (Madrid), North (Pamplona and Zumaia) and South (Vélez-Málaga and Málaga). Employing a theoretical sampling approach with maximum variation strategy, participants were selected based on gender, age, place of residence, type of treatment, years with T2DM and presence/absence of previous cardiovascular event. Thus, the eligibility criteria for the study were to have a diagnosis of DM2, 35 years of age or older and to belong to one of the participating health centers.

Data Collection

Data were obtained through discussion groups from 7 to 13 people. In each area, 3 focus groups were set up, one with men, one with women and one with both men and women. All groups consisted of people of different ages from 35 years old onward, taking different treatments for diabetes and with the absence/presence of cardiovascular event. A female moderator (AB) and a female observer (LM), both with previous experience in qualitative research, were present in all groups. Data were collected until saturation was reached. 21

Prior to data collection, the interview guide was pilot tested with 3 individuals with T2DM who did not participate in the study. The guide explored 10 main components: 1) Coexistence with the disease and moment of diagnosis; 2) Knowledge about diabetes at the moment of diagnosis; 3) Communication and relationship with the health institution (locus of control, shared responsibility, individual responsibility in self-care); 4) Adherence to treatment and medical prescriptions, and perceived treatment benefits; 5) Coping strategies; 6) Support received/perceived; 7) States of mind and their effect on health. Contents of emotional variability; 8) Work environment; 9) Leisure and free time; and 10) Areas for improvement in the management of diabetes.

The dynamics of the discussion groups were designed to create a space where participants could openly share their experiences among peers (homogeneity criteria) while fostering significant discursive variability (heterogeneity criteria). These group sessions, held at the primary care centers to which the patients were affiliated, extended for approximately 90 to 120 minutes. Following the acquisition of informed consent, the sessions were both video and audio-recorded. A literal and systematic transcription of the audio and video recordings was undertaken, conducted by an experienced member of the research team. To ensure confidentiality, all data were anonymized. Additionally, observational field notes, capturing contextual characteristics, the overall atmosphere, and pertinent non-verbal expressions, were included in the analyses. The moderator actively recorded field notes during the focus group discussions. Data saturation was achieved in each discussion group. The field notebook, the saturation of information and the reflexivity of the research team regarding the entire research process are criteria of quality and rigor for qualitative studies.

Data Analysis

A thematic analysis 21–23 was performed based on the transcriptions 24 and the moderator’s notes obtained during the group discussions. The entire analytical process was carried out by two researchers. First of all, relevant subjects and texts were identified; text was fragmented into units of meaning and labeled with a code. Secondly, the categories were created by grouping the codes by similarity. This categorization was done in a mixed way, starting from the predefined categories in the focus group script (Additional file 1) based on the self- and family management framework 20 and expanded with the themes emerged from the discussion groups. Thirdly, the entirely text was fragmented by categories and analyzed each of them in detail. Finally, an explanatory framework with a new text was created after establishing the relationships between categories. NVivo v10 was used for the analysis.

The findings and discrepancies were discussed with the entire research team until consensus was reached. This consensus-seeking process (triangulation) 25 is a method used in qualitative research to ensure validity. The research team also shared the findings with a subset of 10 participants as part of the validation process. No objections were raised. This validation process added important insights to the analysis and facilitated consensus on the interpretation of results.

Ethical Considerations

The study was conducted according to the guidelines of the Declaration of Helsinki and Good Clinical Research Practice. Approval was granted by the Ethics and Clinical Research Committee of the Primary Care Research Institute Jordi Gol (P14/131). Comprehensive information about the study’s objectives and procedures was communicated to all participants, and their informed consent form, including the publication of anonymous responses, was obtained before engaging in the group discussions. All transcripts were coded and anonymized and data were securely stored to maintain confidentiality. The audio and video recordings will be securely deleted five years after the study’s completion, in accordance with our data retention policy.

Impact of the Diagnosis

“I felt overwhelming fear when my general practitioner informed me that I had diabetes”. (Female, 39 years old, treated with insulin without cardiovascular disease)

“My general practitioner delivered the diagnosis in a very calm manner, leading me to believe that it was a common disease (…). Surprisingly, my feelings have worsened over time, and I now find myself in a more challenging emotional state than at the moment of the initial diagnosis (…). (Male, 68 years old, treated with insulin with cardiovascular disease)

It is noteworthy that, for the majority of participants, diabetes was considered a socially accepted condition.

Attribution of Responsibility

“I lost my dad, and two years later, I was diagnosed with diabetes”. (Female, 52 years old, treated with insulin with cardiovascular disease)

“(…) I am paying the consequences (…)”. (Male, 35 years old, noninsulin antidiabetic drugs without cardiovascular disease)

Diabetes-Related Beliefs and Self-Management

“I pass by a bakery, spot a chocolate croissant, and indulge. If I had to walk for one hour, I’ll walk for two hours to burn off the calories (…). The philosophy is simple — ‘Poison doesn’t kill; the dosage kills.’ It’s all about moderation. Overindulging is what poses a threat”. (Female, 65 years old, insulin treatment without cardiovascular disease)

“(…) Diabetes is a disease that does not kill you (…)”. (Male, 55 years old, insulin treatment with cardiovascular disease)

These alternatives tended to justify sedentary behavior and poorly-balanced diets, hindering positive diabetes self-management. Notably, there was no observed variability between genders in this category.

Emotions and Self-Management

“I can’t take on more responsibilities. I already care for my mom and my sons, and adding things like different diets and exercise is simply impossible for me (…)”. (Female, 42 years old, noninsulin antidiabetic drugs without cardiovascular disease)

“But since I live alone, well, I kind of sense that sometimes you’re a bit down, and you just throw everything away, what they tell you to do (…)”. (Female, 69 years old, insulin treatment without cardiovascular disease)

Conversely, men generally emphasized that mood, motivation, and fatigue were not as critical for them. Instead, they underscored the difficulties of balancing self-care and work responsibilities.

“When I go through stress or nerves at work, call it whatever you want (.) and those days, when I take my sugar mid-morning, instead of having 125 I have 142. (Male, 63 years old, noninsulin antidiabetic drugs without cardiovascular disease)

“When I am very stressed by work, and on top of that I have to take care of my diabetes, and (.) There are times when I send it to hell, I’m fed up with diabetes, with work (.) Of course, because you end up desperate”. (Male, 45 years old, insulin treatment without cardiovascular disease)

Overall, participants stressed the importance of maintaining a positive attitude towards the disease for effective self-management. Both men and women acknowledged the impact of mood on glycemic levels. This category is closely interconnected with the following one.

Self-Care and Carer’ Support

“At times, my wife serves as a guardian, saving me from temptations”. (Male, 67 years old, noninsulin antidiabetic drugs without cardiovascular disease)

“I go to work in the morning, and in the afternoon, I spend time with my daughter. Obviously, I’m not taking her for a walk”. (Female, 40 years old with insulin treatment and cardiovascular disease)

Variability in women’s discourses emerges, with some expressing explicit awareness of the burden of caring for their families. Those who view household chores as work and recognize their role within family networks tend to prioritize their self-care more. On the other hand, some women, while discussing housework, see caring for others “for love” and “as always” as their natural role as mothers or grandmothers, embracing gender-constructed expectations. These women may be less inclined to prioritize themselves over their families’ needs. Generally, the awareness of inequities in the distribution of household responsibilities and family care emanates more strongly from the discourse of the first group of women.

Professional-Patient Interactions

There was significant variability in discourse concerning institutions and the difficulties associated with health service cuts due to financial crises. Interestingly, individuals expressed contradictory opinions along the satisfaction-dissatisfaction spectrum on this matter.

“I have a good general practitioner, but I have numerous doubts that I need to address (…) concerns about the future, my relationships, and even aspects related to sex (…). Sometimes, the visit feels like a mere review of medical tests”. (Male, 58 years old, insulin treatment and without cardiovascular disease)

“I would appreciate motivation from the nurse or general practitioner”. (Female, 38 years old, noninsulin antidiabetic drugs without cardiovascular disease)

Conversely, a too strict approach in medical instructions or an “alarmist attitude” was perceived as counterproductive to promoting good self-management.

Sources of Information and Resources

“I would like to know the best places to find good information”. (Female, 50 years old, insulin treatment with cardiovascular disease)

“I need more information (.) my family doctor only showed me the results of the lab test (.) I need to know what my near future will be (.) what will be the consequences of this (.)”. (Male, 40 years old, noninsulin treatment without cardiovascular disease)

Suggestions for Improvement

“I wish for a group like this, where I can share experiences with people who have gone through similar situations and can understand me”. (Female, 40 years old, insulin treatment without cardiovascular disease)

“I would like to discover recipes that are suitable for me and easy to cook”. (Male, 40 years old, noninsulin antidiabetic drugs without cardiovascular disease; Male, 72 years old, noninsulin antidiabetic drugs without cardiovascular disease)

In the present study, we explored the experiences of people diagnosed with T2DM. The aim was to understand gender differences in the knowledge, attitudes, and behaviors of people with diabetes in relation to self-management of the disease. Gender differences were observed in several dimensions of the experiences of patients with T2DM, especially in aspects related to emotions, feelings, and self-care.

One of the main gender differences observed in the study was the emotional reactions following the diagnosis of T2DM. Women tended to express greater feelings of sadness and anxiety, whereas men showed relatively calm behavior in response to the diagnosis. Women have been considered to be more emotional than men, specifically with respect to negative emotions which are experienced with greater intensity and frequency. 26 , 27 Gender differences have also been found in the way emotions are expressed. Women have been attributed a greater facility in using emotional language and expressing it verbally, whereas men tended to express themselves more through behavior. 28 , 29 These distinctions may be influenced by social roles based on traditional constructs of femininity and masculinity, along with variations in emotional intensity. 30 In accordance with these constructs, men are often reluctant to engage in emotional discourse, presenting themselves as “strong”, resilient, and self-sufficient in order to maintain their perceived masculinity. In contrast, women are expected to be emotional and. 17

The diagnosis of a chronic disease requires patients to seek help and support, both from healthcare professionals and their family environment. Men may more often experience internal conflicts in having to act in a way that goes against their perceived social role as men defined as the provider of subsistence resources. 17 On the other hand, although women tend to communicate their emotions more openly, they also face self-care challenges. Indeed, in this study, a tendency was observed among women to neglect their own needs and prioritize the needs of others, especially family members. This tendency can again be explained by socially constructed gender roles and norms, in which women are often seen as “caregivers” and men as “providers” within the family context. 17

Regarding the attribution of responsibility for the conditions that contribute to the development of diabetes, women attributed the onset of the disease more to stressful and highly emotional situations, while men attributed it mostly to the performance of risky behaviors or poor health habits. This fact can be related to the concept of locus of control, which refers to the perceived ability to control an event depending on whether the control is perceived as internal or external. 31 Internal locus of control is when responsibility is attributed to one’s own behavior (eg, poor health habits). In this case, the individual feels capable of controlling the event. Conversely, when responsibility is attributed to external factors such as the death of a family member (external locus of control), the outcome is considered random. Studies on locus of control and health have indicated that internal locus of control buffers the effects of physical and emotional symptoms of illness, 32 while external locus of control can be seen as a predictor of illness. 33 In this study, women aligned more with external locus of control and men with internal locus of control, consistent with a study conducted with patients with T2DM in what men were significantly more likely to have internal locus of control than women and it was found that having internal locus of control had positive effects on self-care activities. 34

The American and European guidelines advocate lifestyle changes as the first step in the management of DM 35–38 and maintain that good self-care habits, such as a balanced diet and exercise, are essential for good diabetes control. In this regard, gender differences were observed in the factors that hinder the adoption of good self-care habits. Women identified lack of time, probably related to the role of caregiver associated with the female gender, and low mood as the main obstacles, while men identified the difficulty of combining work and self-care as the main problem. Men may strive to maintain their pre-diagnosis public identity to preserve traditional masculine values such as independence, autonomy, and control of decision-making that may be threatened by a diagnosis of diabetes. Traditional masculine characteristics of autonomy, dominance, and stoicism may make self-care, glycemic control, and treatment compliance difficult, and it becomes difficult to cope with working, reflecting public identity, with the disease when it is perceived as threatening to masculinity. 39 These findings are consistent with previous studies; both men and women identified their emotional state and existing complications of the disease as influencing their health and attitude toward self-care. 39–42 In women, mood was associated with conflict and emotional distress, whereas in men it was related to stress problems. As for work-related stress and the resulting negative emotional states, they have been shown to contribute to negative health behaviors, such as decreased levels of physical activity, eating more food than usual, and increased substance abuse, all conditions that worsen diabetes control. 43

Regarding the category of “self-care” and caregiver support, many men acknowledge receiving support from their families and/or partners, especially with regard to dietary aspects. In this regard, single men expressed more difficulties in self-care, especially in maintaining motivation for a healthy diet. In contrast, women with diabetes express that they are caregivers for their families, prioritizing the care of their family over their own self-care due to lack of time. 44 This often leads to neglect of dietary requirements and the need for physical activity. Women often consider caring for their family a priority, 45 , 46 even at the expense of their own health. 46 , 47 Social and family support has been shown to be a critical aspect of diabetes self-management. 42 Women caregivers neglect themselves in order to provide care, diminishing their own time to dedicate to others. 45 On the other hand, patriarchal culture encourages the fulfillment of caregiving duties in women and the social and economic need to participate in educational, labor and political processes to survive in patriarchal society, trapping women between duty and development. 45 However, there are individual differences in women’s awareness of the barriers to self-care due to their role in the family. Some women were fully aware of the time and effort they devoted to their unpaid occupation of caring for their family, and how this commitment left little time for self-care. When women were more aware of these challenges, they tended to seek alternatives to prioritize self-care. However, women who considered self-care secondary to family care often expressed that they were unable to find other options for managing diabetes. This aspect could be related to the fact that women often have access to a wider support network that includes other family members (sisters, daughters, etc) and friends as an alternative resource. 39

According to Lazarus and Folkman’s theory, the way individuals cope with events such as the onset of a chronic illness can affect their health. In an initial assessment of the situation, it is determined whether it is perceived as a threat or as a challenge. If the situation is perceived as a threat, it may trigger a stress response. In a second assessment, the resources and abilities to cope with the situation and carry out a response are assessed. When the assessment of the situation and available resources is overwhelming, toxic stress is experienced, which can have serious effects on the individual’s physical and mental health. 48 According to the results of the study, women perceive the available resources as more deficient than men, which, together with the external locus of control, may help us to better understand the difficulties they face in self-managing the disease.

Both genders evaluated the discussion groups and diabetes education positively, specifically because they had a space in which they could talk with people in similar situations about their concerns and their experience in diabetes self-management. There is evidence that patient groups can provide emotional support and understanding of the disease experience, as well as motivation regarding self-care practices. 46 , 47

Regarding interactions with health professionals, although they perceived their care as good, they felt that they did not have enough time during appointments to ask questions and express their concerns. They also considered that positive reinforcement was more useful than a pessimistic or alarmist attitude. The lack of time needed in primary care physicians’ offices has been highlighted in previous studies. 39 , 41 This time would be necessary for patients to ask diabetes-related questions, discuss their own experiences with T2DM, and seek emotional support. 39 , 49 Of note, participants only mentioned their primary care physician in relation to their disease-related needs, but not primary care nurses. Primary care nurses, in fact, play a key role in empowering patients in their self-care. 50

The participants expressed the need to understand how T2DM originates and progresses and how they should modify their habits, aspects that agree with the studies of Andrade and Guinea. 40 , 41 Beliefs related to the disease are an important factor in the daily practice of self-care and patient empowerment. 42 Lack of understanding inevitably shifts the responsibility for care to health care professionals. This can lead to the development of paternalistic relationships between healthcare professionals and patients, rather than collaborative, patient-centered interaction. This is a critical issue, as recent research supports the relevance of patient involvement in personal and family decision-making and self-management, especially in the context of chronic disease. 51–53

This study has some limitations. First, the sampling strategy was not fully planned from the outset, as opportunistic rather than theoretical sampling had to be used. Second, there were difficulties in recruitment, so that the experiences of younger individuals with cardiovascular events could not be included. Finally, it was not possible to include variables related to socioeconomic level, a factor that influences self-management of the disease. The study also has strengths. First, it allowed us to observe the reality of self-care experiences in the focus groups through the discourse of the participants and their constructed realities. A wide range of discursive variability was captured, reflecting the cultural diversity of Spain and reaching data saturation. This variability is essential to avoid cultural bias in a country as diverse as Spain. Secondly, given the scarce evidence on this topic in the literature, this study can serve as a starting point for future research on specific differences in self-management among patients with T2DM.

Empowering patients to self-care is an important factor in improving health. The importance of understanding gender differences and barriers to self-care lies in the need to tailor healthcare and encourage patients to take care of their own health. This means empowering patients to act beyond gender roles and social expectations. This has important implications not only for clinical practice, but also for health policy and service development. First, there is a need to improve training programs for healthcare professionals to raise awareness of the relationship between gender and health. Health professionals must be able to tailor health information to the needs and experiences of each individual. The primary care professional is the one who knows the patient best, making it essential to personalize care from the primary care center. It is important to work with the patient to identify the barriers they face in self-care, conduct a joint analysis of the social determinants affecting them, provide available resources at the center to minimize these obstacles, and help establish a support network with others facing similar challenges. Gender differences and underlying social determinants should be taken into account when developing health policies and services for people with T2DM. Given the gender differences highlighted in this study, it would also be essential for the entire family unit to understand and cooperate to optimize self-care among women living with T2DM.

Abbreviations

T2DM, type 2 diabetes mellitus; GP, general practitioner.

Acknowledgments

The authors acknowledge the Territorial Management of Central Catalonia of Institut Català de la Salut (ICS) and the Primary Healthcare University Research Institute (IDIAP) Jordi Gol for the grant for intensification of researchers (grant code: 7z22/005). This project was developed within the framework of the Doctorate in the Department of Medicine of the University of Barcelona. Additionally, authors acknowledge the study participants and the healthcare professionals who helped in recruitment tasks.

The author reports no conflicts of interest in this work.

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• PMC10166362

A Rare and Unique Complication of Uncontrolled Type 2 Diabetes Mellitus: A Case Report and Literature Review of Spontaneous Diabetic Myonecrosis

Adejoke m johnson.

1 Medicine, Jacobi Medical Center/North Central Bronx Hospital, Bronx, USA

Zin Thawdar Oo

2 Internal Medicine, Jacobi Medical Center/North Central Bronx Hospital, Bronx, USA

Thar Sann Oo

3 Internal Medicine, Albert Einstein College of Medicine, Jacobi Medical Center, Bronx, USA

Damion A Hunter

4 Internal Medicine, Jacobi Medical Center, Bronx, USA

5 Internal Medicine, James J. Peters Veterans Affairs (VA) Medical Center, Bronx, USA

Vishal Reddy Bejugam

Gabriel purice.

6 Internal Medicine, North Central Bronx Hospital, Bronx, USA

There are many microvascular and macrovascular complications regarding uncontrolled diabetes mellitus (DM). Among them, diabetes myonecrosis is one of the complications but rarely seen in the uncontrolled DM patient population. Here, we present a rare case of DM myonecrosis in a patient with elevated hemoglobin A1c (HbA1c) of 18.2% and discuss the literature review of diabetes myonecrosis. A 48-year-old male with hypertension and uncontrolled type 2 diabetes mellitus (T2DM) with hemoglobin A1c of 18.2% presented with progressive swelling and pain in the right thigh for two days. Physical examination demonstrated swollen and tense tender right thigh with a circumference five inches larger than the left. Computed tomography (CT) and magnetic resonance imaging (MRI) results revealed severe myositis of the right leg, likely myonecrosis, and associated fascial edema/fasciitis. The patient was also complicated with diffuse anasarca, which was corrected with albumin transfusion and furosemide. Aspirin and lisinopril were also started for antithrombotic and cardioprotective effects. The right thigh swelling improved, and the patient could ambulate with supportive measures and regular physical therapy (PT). He was discharged home after 45 days of hospitalization. Diabetic myonecrosis is a rare condition and hence is underdiagnosed. In patients with uncontrolled diabetes, especially with diabetic complications, physicians should have high clinical suspicion to diagnose diabetic myonecrosis when patients present with an acute unilateral painful swollen limb. Our case highlights the complicated course of diabetes myonecrosis with anasarca, improved with supportive measures.

Introduction

Diabetes is associated with vascular complications, typically microvascular complications such as retinopathy, nephropathy, and peripheral neuropathy and macrovascular complications such as cardiovascular disease, cerebrovascular disease, and peripheral vascular disease. Poor glycemic control increases the risk of some of these complications, especially microvascular complications, and diabetic myonecrosis is one of them but relatively rare [ 1 ]. Diabetic myonecrosis is a spontaneous skeletal muscle infarction frequently reported in patients with poorly controlled type 1 and 2 diabetes mellitus (DM) with a sub-optimized hemoglobin A1c (HbA1c) level [ 1 ].

Case presentation

A 48-year-old male with a history of hypertension and poorly controlled type 2 diabetes mellitus (T2DM) presents to the emergency department with complaints of progressive right thigh swelling and pain (Figure 1 ).

The patient had been experiencing intermittent swelling and stabbing right thigh pain for two months, which had worsened over the course of two days and resulted in difficulty with ambulation. He also reported intermittent chills and shortness of breath due to intractable pain, numbness, and tingling of both upper and lower extremities. He denied a history of falls, trauma, injury to his lower extremities, fever, night sweat, nausea, vomiting, abdominal pain, change of urinary or bowel habits, and weakness of his arms and legs. The patient was diagnosed with T2DM 15 years ago and missed insulin treatment for a year before he came to the hospital. Physical examination revealed swollen and tense right thigh with tenderness, and the thigh circumference was five inches larger than the left. Vitals were significant for blood pressure of 170/74 mmHg. Laboratory results were significant for elevated glucose, hemoglobin A1c, leukocytosis, thrombocytosis, and increased creatinine kinase (Table ​ (Table1 1 ).

BNP, brain natriuretic peptide; CPK, creatine phosphokinase

Blood cultures obtained throughout hospitalization had no growth; the antinuclear antibody (ANA)-extractable nuclear antigen (ENA) antibody panel was positive only for the SCL-70 antibody. All rheumatological workups were negative. Bilateral lower extremity ultrasound showed subcutaneous edema without acute deep vein thrombosis. A computed tomography (CT) of the abdomen and pelvis also demonstrated soft tissue swelling and fat stranding, most prominent within the right thigh. CT angiogram of the right thigh was done to rule peripheral vascular disease, which revealed diffuse subcutaneous fat stranding and edema in the interfascial plane of the right thigh, relative hypo-enhancement of the adductor magnus muscle suggestive of myositis with likely myonecrosis, and associated fascial edema/fasciitis. Magnetic resonance imaging (MRI) findings of the right femur were also compatible with severe myositis with associated superficial and deep fasciitis and the area of myonecrosis of the right leg (Figures ​ (Figures2 2 - ​ -5). 5 ). At the same time, left thigh MRI results revealed significantly less pronounced myositis than the right thigh.

MRI: magnetic resonance imaging

General surgery was consulted for high suspicions of compartment syndrome but suggested that no surgical intervention was needed. The patient was started on aspirin and pain control, and physical therapy (PT) was started intermittently when his thigh swelling and pain had improved. Endocrinology was consulted for glycemic control. The patient was symptomatically treated with pain management, physical therapy as tolerated, and glycemic control with three units of basal and corrective insulin scales. Unfortunately, on day 8, the hospital course was complicated by diffuse anasarca in the setting of low albumin levels and intravenous (IV) fluid. The nephrology team was consulted, and they recommended starting with IV Lasix 40 mg twice daily, hydrochlorothiazide 12.5 mg daily, and 25 g of 25% albumin transfusion for two days. The patient became euvolemic on day 11 of hospitalization with gradual resolution of myositis.

Since the patient also had nephrotic range proteinuria of 4.6 g, a renal biopsy was done to rule out other causes of nephrotic range proteinuria. The renal biopsy results show moderate nodular diabetic glomerulosclerosis, mild tubular atrophy, and interstitial fibrosis, and he was eventually started on lisinopril 40 mg and Lasix 20 mg for fluid overload. He spent a total of 45 days in the hospital due to poor pain management, diffuse anasarca secondary to nephrotic syndrome that required further renal workup, and symptomatic COVID-19 infection. Some social factors also affected the patient's safe discharge during the last 10 days of hospitalization. After 45 days in the hospital, he was able to ambulate with assistance and was discharged with home physical therapy.

Diabetes mellitus is a complex metabolic disease associated with multiple systemic complications, primarily when the condition is poorly controlled. The complications can be acute or chronic, but chronic complications are associated with higher morbidity and mortality in diabetes mellitus [ 2 ]. Chronic complications can be divided into microvascular and macrovascular [ 3 ]. The report from 1999-2004 National Health and Nutrition Examination Survey (NHANES) revealed that microvascular complications, including peripheral neuropathy, retinopathy, and nephropathy, are more common compared to macrovascular complications such as coronary artery disease, heart failure, and stroke [ 4 ]. Other microvascular complications of diabetes mellitus not routinely discussed in the literature are diabetic myonecrosis and diabetic amyotrophy.

Diabetic myonecrosis is also known as diabetic skeletal muscle infarction, aseptic or ischemic myonecrosis, and tumoriform focal muscular degeneration. It was first reported in 1965 as a rare microangiopathic complication of poorly managed type 1 or type 2 diabetes [ 5 ]. A systematic review was done in 2003, including 115 patients with diabetic myonecrosis. It was observed that the disease is commonly diagnosed in middle-aged females (61.53%) and patients with an average A1C of 9% [ 5 ].

The exact pathophysiology of diabetic myonecrosis is not well established, although several theories suggest that vasculopathic changes in the muscles drive it. These changes are similar to the pathogenesis of coronary artery disease induced by prolonged exposure to hyperglycemia. It is highlighted as a significant factor in accelerated atherosclerosis in microvascular endothelium leading to ischemia and reperfusion injury [ 6 ]. The mechanisms for accelerated atherosclerosis occur through the nonenzymatic glycosylation of lipids and proteins in blood vessels, oxidative stress, and pro-inflammatory response. Hypercoagulation by alterations in the coagulation-fibrinolysis system has also been involved in the pathophysiology of diabetic myonecrosis [ 1 , 6 ].

The primary clinical presentation of diabetic myonecrosis is ipsilateral proximal lower limb acute or subacute pain with muscle swelling, weakness, and tenderness without a history of inciting factors. A systematic review analyzed 126 cases of diabetic myonecrosis in July 2014 from database inception, which revealed that thigh swelling was the most commonly reported affected site [ 7 ]. Diabetic myonecrosis usually has a mean duration of symptoms ranging from one day to 14 weeks [ 5 ]. The frequency of reoccurrence is still undetermined, although case reports reveal that the symptoms tend to recur in a different location. About 93% of patients that develop diabetic myonecrosis frequently have other concomitant diabetic complications, commonly diabetic nephropathy.

Complications of diabetic myonecrosis are uncommon but are usually spontaneous compartment syndrome and superimposed infection. The laboratory findings of diabetic myonecrosis stem from the disease's inflammatory process, which is indicated by elevated creatine kinase and erythrocyte sedimentation rate. Elevated white blood cells (WBCs) have also been commonly seen in multiple cases. An MRI scan is usually recommended for further evaluation [ 8 ]. It typically reveals signal intensity in the affected intramuscular and subcutaneous tissues, a hyperintense signal on T2-weighted imaging, and an isointense to hypointense signal on T1-weighted images associated with inflammatory changes and edema. The clinical manifestations and diagnostic findings of diabetic myonecrosis overlap with other etiologies; therefore, a diagnosis can only be established by excluding other etiologies such as pyomyositis, spontaneous gangrenous myositis, nontraumatic clostridial myonecrosis, and necrotizing fasciitis. A tissue biopsy is the definitive diagnostic test, but it is not often recommended for diagnosis, particularly in patients with concomitant diabetes complications, long-standing diabetes, and the absence of other probable etiologies [ 8 ]. Other tests, such as Doppler ultrasound, can rule out differential diagnosis of deep venous thrombosis or bacterial infection of the affected muscle.

The recorded incidence of diabetic myonecrosis has been limited since its discovery. Hence, standardized treatment management has yet to be established. It has been noted that there is a spontaneous resolution within 8-13 weeks in patients after bed rest and analgesic use [ 1 , 9 ]. Treatment for diabetic myonecrosis targets symptomatic management with rest, optimal glycemic control, nonsteroidal anti-inflammatory drug (NSAID) therapy, and low-dose aspirin.

NSAID can be used for short-term analgesia; however, risk has to be weighted with benefits since diabetes muscle infarction is associated with poorly controlled DM and is likely associated with conditions such as renal impairment and cardiovascular disease. Low-dose aspirin is initiated if there is no contraindication. Aspirin is used to prevent infarct recurrence, probably due to improvement in the dysfunctional state of the epithelium, although evidence is lacking. Other antiplatelet agents, such as clopidogrel, can be used for patients with aspirin allergies. The combination of NSAID and antiplatelet increases gastrointestinal bleeding risk, and one must be mindful of its usage. Physiotherapy usage is debatable; physical therapy (PT) is normally avoided in the acute stage of diabetic myonecrosis because it could prolong the recovery phase, but you also do not want the patient to be deconditioned; hence, PT Is mostly advised after discharge and has been proven beneficial in post-discharge care [ 10 ].

The long-term outlook of patients diagnosed with diabetic myonecrosis is poor as the disease indicates severe end-organ damage from the progression of the underlying diabetes mellitus [ 10 ]. Diabetes myonecrosis resolves over 5.5 weeks to 13 weeks, depending on the level of therapy initiated; with antiplatelet agents and anti-inflammatory drugs, the time frame for recovery is 5.5 weeks versus rest and analgesia at eight weeks and surgical excision at 13 weeks of recovery period. With resolution, the recurrence rate is approximately 40%. The long-term outcome tends to be poor due to five-year mortality from superimposed diabetic complications [ 11 ].

Conclusions

Diabetic myonecrosis is a rare condition and hence is underdiagnosed. In patients with uncontrolled diabetes, especially with diabetic complications, physicians should have high clinical suspicion to diagnose diabetic myonecrosis when patients present with an acute unilateral painful swollen limb. However, other more common etiologies for acute unilateral painful swollen limbs such as deep vein thrombosis and cellulitis or different infectious etiologies will need to be ruled out using imaging techniques. Early noninvasive diagnosis is possible with MRI. Treatment involves symptomatic management and prevention of recurrence with low-dose aspirin and optimal glycemic control. The diagnosis, however, remains a marker of severe uncontrolled diabetes with a poor prognosis.

Acknowledgments

Adejoke Johnson is the corresponding author who worked on data acquisition, main discussion, and case presentation of the case report and drafted and revised the final version to be published. Zin Thawdar Oo and Thar Sann Oo contributed to the abstract and case presentation write-up. Damion Hunter and Zin Min Htet contributed to the discussion of the report. Vishal Reddy Bejugam contributed to gathering images and laboratory data for the report. Gabriel Purice contributed to the overall conclusion of the report.

The authors have declared that no competing interests exist.

Human Ethics

Consent was obtained or waived by all participants in this study

• Open access
• Published: 11 September 2024

The relation of mTOR with diabetic complications and insulin resistance in patients with type 2 diabetes mellitus

• Noha G. Amin   ORCID: orcid.org/0000-0002-8225-5052 1 ,
• A. Abdel Rahim 1 ,
• Kamel Rohoma 1 ,
• Reham A.Abo Elwafa 2 ,
• Hossam M. F. Dabees 1 &
• Shimaa Elrahmany 1  

Diabetology & Metabolic Syndrome volume  16 , Article number:  222 ( 2024 ) Cite this article

Metrics details

Dysregulation of the mechanistic target of rapamycin (mTOR) has been related to several metabolic conditions, notably obesity and type 2 diabetes (T2DM). This study aimed to evaluate the role of mTOR in patients with T2DM, and its relationship with insulin resistance and microvascular complications.

This case-control study was conducted on 90 subjects attending the Outpatient Internal Medicine Clinic in Damanhur Teaching Hospital. Subjects were divided into 3 groups, Group I: 20 healthy controls, Group II: 20 subjects with T2DM without complications, and Group III: 50 subjects with T2DM with microvascular complications. An Enzyme-linked immunosorbent assay was used to measure serum mTOR levels. T2DM and diabetic complications were defined according to the diagnostic criteria of the American Diabetes Association.

The results revealed significant positive correlations to HbA1c ( r  = 0.530, P  < 0.001), fasting glucose ( r  = 0.508, P  < 0.001), and HOMA- IR ( r  = 0.559, P  < 0.001), and a significant negative correlation to eGFR ( r =-0.370, P  = 0.002). Multivariate analysis revealed an independent association of mTOR and HbA1c values with the presence of microvascular complications. The prediction of microvascular complications was present at a cutoff value of 8 ng/ml mTOR with a sensitivity of 100% and specificity of 95% with an AUC of 0.983 and a p -value < 0.001.

mTOR is a prognostic marker of diabetic microvascular and is associated with insulin resistance in patients with T2DM.

Trial Registration

The study was conducted following the Declaration of Helsinki, and approved by the Ethics Committee of Alexandria University (0201127, 19/7/2018).

Introduction

Diabetes mellitus (DM) is counted among the oldest diseases recognized by humans; it was first described by ancient Egyptian physicians 3500 years ago [ 1 ]. Currently, DM is deemed one of the most common chronic diseases worldwide, and its prevalence is increasing. Moreover, in addition to being a major consumer of global health expenditure, DM is a main driver of morbidity and mortality [ 2 , 3 ].

Hyperglycemia, the hallmark of DM, induces microvascular damage through several mechanisms, such as polyol pathway flux, increased advanced glycation end products (AGEs) synthesis, persistent protein kinase C activation and an enhanced hexosamine pathway [ 4 ]. Diabetic microvascular complications are the primary cause of acquired blindness, nontraumatic lower limb amputation and end-stage renal disease [ 5 ]. Timely recognition and management of these complications is mandatory for preventing such damage.

In 1994, the mechanistic (formerly known as mammalian) target of rapamycin (mTOR) was identified as the direct target of rapamycin responsible for its antifungal, immunosuppressive and antitumor effects [ 6 , 7 ]. Since then, the role of mTOR in cell growth and organismal physiology has been highlighted.

mTOR is a ubiquitous highly conserved serine/threonine protein kinase, that represents the catalytic subunit of protein complexes, mTOR complex 1 (mTORC1) and 2 (mTORC2). mTORC1 plays a fundamental role in maintaining the balance between anabolism and catabolism response to intracellular and environmental stresses via the regulation of diverse processes such as promoting protein, lipid and nucleotide synthesis, and suppressing autophagy [ 8 ]. On the other hand, mTORC2 promotes cellular proliferation and survival through several mechanisms, most notably, through the activation of Akt, which is the main effector of insulin/ phosphoinositide 3-kinase (PI3K) signaling [ 9 ].

Recently, the role of mTOR in the development of DM and its vascular complications has drawn increased amount of attention. However, its ability to identify diabetic microvascular complications has not been widely studied. The urgent need for a proper marker for microvascular complications targeting early diagnosis and effective management, together with the promising role of mTOR in this field motivated us to investigate the role of mTOR in the detection of diabetic microvascular complications.

Materials and methods

Study design and subjects.

This case-control study recruited 90 subjects attending the Outpatient Internal Medicine Clinic in Damanhur Teaching Hospital. The study design was approved by the ethics committee of Alexandria University. The participants signed an informed consent form before any study-related procedures took place. The study followed the criteria established by the Declaration of Helsinki.

The study participants were divided into 3 groups.

Group I: Twenty healthy subjects as the control group,

Group II: included 20 subjects with T2DM without complications.

Group III: included 50 subjects with T2DM with microvascular complications.

The following patients were excluded from the study: Patients with type 1 diabetes, recent acute infection within 2 months, severe hepatic impairment, endocrine and metabolic diseases other than T2DM, or a history of malignant disease, pregnant and lactating females.

Study methods

The following procedures were performed for all the subjects:

Clinical assessment

A thorough history was obtained focusing on the medical history, duration of diabetes and associated comorbidities. BMI was calculated (weight in kg divided by height in m2). Waist circumference (WC) and hip circumference were assessed, and the waist to hip ratio (W/H) was calculated as the ratio between the waist measurement and the hip measurement.

Neurological examination was performed including assessment of ankle reflexes and knee reflexes, monofilament assessment, and a test for vibration perception threshold (VPT). Neuropathy was defined if there was a positive monofilament test plus either an absent ankle reflex or a VPT > 25 V.

Assessment of the ankle-brachial index (ABI)

A handheld Doppler was applied to assess both the dorsalis pedis and posterior tibial arteries. The systolic pressure of the PT and DP arteries of each leg was measured using a 5 MHz Doppler probe (Nicolet Elite 200 R, VIASYS Healthcare Inc., Madison, WI, USA). A lower value of the two calculated ABI in both limbs was used for statistical analysis [ 10 ].

Biochemical analysis

Venous blood samples (10 ml from each patient) were collected from the antecubital vein into vacuum tubes with the appropriate additives. Subjects were advised to fast overnight for 12 h and were free of smoking or strenuous exercise.

The withdrawn venous samples were split into 2 parts. The first part was further subdivided into 2 vacuum tubes, a plain tube left to clot at 37℃ to allow subsequent serum separation by centrifugation for immediate assessment of fasting plasma glucose (FPG), serum creatinine and insulin levels, and a dipotassium ethelene diamine tetra-acetic acid (EDTA)-containing vacutainer tube for measuring glycated hemoglobin (HbA1c). The second part of the sample was preserved at -70℃ for the mTOR assay. An enzyme linked immunosorbent assay (ELISA) was used to measure the serum mTOR concentration [ 11 ].

Insulin resistance was estimated by the Homeostasis Model Assessment 2 (HOMA2) calculator (HOMA2-IR) using the Oxford online HOMA IR calculator 2008 [ 12 ].

A morning urine sample was used to assess the urine albumin/creatinine ratio (ACR), which was repeated twice [ 13 ]. In addition, the estimated glomerular filtration rate (eGFR) was calculated using the CKD Epidemiology Collaboration (CKD-EPI) formula [ 14 ]. Diabetic kidney disease (DKD) was defined as albuminuria (UACR > 30 mg/g) and/or decreased eGFR < 60 mL/min/1.73 m2.

Fundus examination

Fundus examination was performed by an experienced ophthalmologist for the detection of diabetic retinopathy (DR). Fluorescein angiography was ordered once indicated [ 15 ].

Statistical analysis

All the statistical analyses were performed using SPSS software (version 20.0; IBM Corporation, Armonk, NY, USA). The data are presented as the mean ± SD.

For comparing parameters between the three groups, chi square tests and ANOVA were utilized. The Kruskal- Wallis test was applied for non-normally distributed quantitative variables. A P  value ≤ 0.05 was considered to indicate statistical significance.

To test the relationships between mTOR and different parameters, linear regression analyses were implemented. The independent correlations related to microvascular complications were assessed by multivariate analysis. The utility of the mTOR concentration as a predictor of microvascular complications in patients with T2DM was further evaluated using a receiver operating characteristic (ROC) curve.

The baseline demographic data are shown in Table  1 , where no significant differences were found between the active and control groups regarding sex, age, body mass index, waist circumference or waist-to- hip ratio.

Assessment of the mTOR level revealed a significantly greater level in patients with diabetes who have microvascular complications than in those without microvascular complications and in the control group. These findings, together with other biochemical and clinical parameters, are shown in Tables  2 and 3 .

Correlation between mTOR and different parameters in the whole population showed positive significant correlation between mTOR and FPG ( r  = 0.508, P  < 0.001), HbA1C ( r  = 0.530, P  < 0.001) and HOMA IR2 ( r  = 0.559, P  < 0.001). On the other hand, there was negative significant correlation between mTOR and eGFR ( r =-0.370, P  = 0.002). The details are shown in Table  4 .

Multivariate analysis of the parameters associated with the occurrence of microvascular complications in subjects with diabetes showed that the mTOR and HbA1c values were independently associated factors (Table  5 ). The ROC curve showed an mTOR cutoff value of 8 ng/ml to predicting patients with microvascular complications with a sensitivity of 100% and specificity of 95% with an AUC of 0.983 and a p -value < 0.001. Figure  1 .

ROC curve for the ability of the mTOR to predict microvascular complications in patients with diabetes

mTOR is considered a prime regulator of cellular growth and metabolism in reaction to several factors such as growth factors, nutrients, and several extracellular signals. mTOR has been the focus of previous research in the field of neoplastic disorders in several studies. However, recently the dysregulation of mTOR has been related to several metabolic conditions, notably obesity and T2DM [ 16 ].

Several in vivo physiological studies have shown that the mTORC1 pathway is essential for glucose homeostasis at the organismal level and have confirmed its important function in maintaining the balance of cellular metabolism, as revealed by Kennedy & Lamming. Nevertheless, exaggerated activation of mTORC1 has also been linked to metabolic derangements; thus tight balancing of mTORC1 in response to different metabolic stimuli is critical in metabolically active tissues exposed to variable modifications [ 17 ].

In this study, mTOR was significantly positively correlated with various parameters of the glycemic profile including FPG, and HbA1c. Inconsistent with our work, this was explained previously by Eisenreich et al., who reported that hyperglycemia and related activated growth factors, result in the activation of mTOR predominantly through the phosphatidylinositol 3-kinase/Akt signaling pathway. The activated growth factors included insulin-like growth factor, platelet-derived growth factor, and epidermal growth factor [ 18 ].

The role of mTOR in glucose homeostasis seems to be intricate, with some opposing effects depending on the duration and level of mTOR activation. This relationship presumably follows a U-shaped curve, such that both increased and decreased mTOR activity have unfavorable impacts on metabolism [ 19 ]. Fang et al. [ 20 ] demonstrated that short-term rapamycin treatment had detrimental metabolic effects on mice. However, prolonged treatment with rapamycin was associated with improved metabolic status and enhanced insulin sensitivity. This could partially explain the ‘‘Janus effect’’ of mTOR inhibitors on glucose homeostasis [ 21 ].

Insulin resistance is a cornerstone of the pathogenesis of T2DM. The association between insulin resistance and cardio-metabolic risk is well established. Despite the great variability in the threshold values, HOMA-IR has been used to define insulin resistance. In the present study, mTOR was significantly positively correlated with HOMA IR2 [ 22 ].

mTORC1 activation enhances insulin resistance in the main insulin-target organs. In adipose tissue, mTORC1 inhibits insulin signaling via ribosomal S6 kinase 1 (S6K1), which occurs due to the serine-phosphorylation of insulin receptor substrate-1 (IRS-1) [ 23 ]. This phenomenon was also reported in the liver and skeletal muscles of obese rats [ 24 ]. In hepatocytes, the mTOR/S6K1-mediated serine phosphorylation of IRS-1 promotes gluconeogenesis through impairment of the PI3K-Akt metabolic pathway. Additionally, proteasomal degradation of insulin receptor substrate- 2 (IRS-2) is enhanced through a mechanism similar to that of mTOR/S6K1-mediated serine phosphorylation [ 25 ]. In muscles, in addition to IRS-1 phosphorylation, mTORC1 reduces muscle mass and oxidative function [ 26 ].

On the other hand, mTORC1 is considered a positive regulator of β-cell mass and function; thus, mTOR activation leads initially to improved insulin secretion. Nevertheless, sustained mTOR activation leads to β-cell exhaustion, reduced cell survival and enhanced apoptosis, and eventually deterioration of insulin secretion capacity [ 27 ].

The results of this study showed a significantly higher level of mTOR in diabetic subjects with microvascular complications than in diabetic subjects without complications, and in the control group.

Our results showed a significant negative correlation between mTOR levels and the eGFR. Moreover, when subjects with complications were further classified based on their eGFR and/ or the presence of albuminuria, the mTOR level was significantly greater in those with DKD.

The classic presentation of kidney disease in patients with diabetes, known as diabetic kidney disease, is characterized by the detachment of podocytes from the epithelial basement membrane in the glomerulus. The detachment of glomerular podocytes is followed by their loss and subsequent cellular loss of proximal tubules, and consequently albuminuria develops. The critical role of insulin-activated mTORC1 in the development and progression of DKD has been previously studied. In agreement with our results, mTOR has been demonstrated previously to be involved in hyperglycemia-induced renal diseases [ 28 ].

Additionally, several pathways have been suggested previously for the early prevention of DKD focusing on the pivotal role of mTOR through rapamycin treatment [ 28 ] or reducing the number of mTORC1 copies in podocytes [ 29 , 30 ].

In vitro, Lu et al. reported that pretreatment of glomerular mesangial cells with rapamycin mitigated oxidative stress and decreased the number of apoptotic cells, which were induced by high glucose concentrations and resulted in the downstream effects of mTOR activation. Furthermore, in vivo, rapamycin treatment in diabetic rats attenuated albuminuria and improved renal function in diabetic rats [ 31 ]. Similarly, Wu et al. [ 32 ] reported that early glomerular pathological changes (mesangial expansion, glomerular hypertrophy and basement membrane thickening) were attenuated, both in vivo and in vitro, by inhibiting Akt/mTOR/p70S6K signaling activity.

In addition to the aforementioned effects of mTOR inhibition, Yasuda et al. [ 33 ] showed that mTOR inhibition ameliorated podocyte apoptosis. The inhibition of podocyte apoptosis in DKD is considered a fundamental therapeutic target; owing to the importance of podocytes in maintaining the integrity of the glomerular filtration barrier and because podocytes are terminally differentiated cells that are unable to proliferate.

Earlier this year, Dong and colleagues demonstrated that the application of rapamycin, in high glucose-induced human renal glomerular endothelial cells could significantly increase platelet and endothelial cell adhesion molecule-1 (CD31) and vascular endothelial-cadherin expression, while reversing the over-expression of Collagen 1 and α-smooth muscle actin and alleviating endothelial-to-mesenchymal transition (EndMT), which plays a key role in the development of DKD [ 34 ].

Consistent with our findings, mTORC1 has been implicated in the development of diabetic retinopathy. Diabetic retinopathy is a complex and multifactorial process. Exposure to sustained hyperglycemia leads to the activation of oxidative stress and the overproduction of reactive oxygen species (ROS) [ 35 ]. This is followed by a significant increase in inflammatory cytokines and hypoxia-stimulated vascular endothelial growth factor (VEGF) production. VEGF stimulates retinal angiogenesis or neovascularization, promoting further development of diabetic retinopathy.

Previous studies have shown that the insulin/mTOR pathway stimulates the production of VEGF in the retinal pigment epithelial cell (RPE). Insulin and insulin-like growth factor-1 (IGF-1) are involved in angiogenesis and DR. These findings explain the observations relating intensified insulin treatment to the worsening of diabetic retinopathy [ 36 ]. Moreover, suppression of DR progression in insulin-treated mice was observed following berberine treatment, chiefly through attenuation of AKT/mTOR-mediated retinal expression of hypoxia-inducible factor-1α (HIF-1α) and VEGF [ 37 ].

Furthermore, PI3K/AKT/mTOR activation promotes angiogenesis through the interaction between Akt and Ras homolog gene family member B (RhoB). This interaction enhances the development and survival of retinal endothelial cells during the process of vascular genesis [ 38 , 39 ].

Additionally, He et al. [ 40 ] revealed that PI3K/AKT/mTOR activation was associated with endothelial-mesenchymal transition in streptozotocin rats with DR. In addition, maternally expressed gene 3 (MEG3) overexpression led to EndMT suppression through inhibition of the PI3K/AKT/mTOR pathway.

Diabetic peripheral neuropathy is the most common chronic complication among patients with T2DM. Hyperactive mTORC1 is reported to induce chronic neuropathic changes by interfering with synaptic integrity. Moreover, the suppression of mTORC1 activity may result in antinociceptive effects in experimental models of inflammatory and neuropathic pain [ 41 , 42 ]. mTOR is present in the sensory nervous system and its downstream signals contribute to transmission, modulation, and development of peripheral pain sensitization [ 42 , 43 ].

Liu and colleagues demonstrated that impaired autophagy due to enhanced activity of the PI3K/AKT/mTOR pathway was associated with significantly diminished paw mechanical withdrawal thresholds (MWTs) in T2DM rat models. Moreover, following PI3K inhibitor administration, the MWT was significantly improved, and this change was accompanied by suppression of the PI3K/AKT/mTOR pathway. Thus, hyperalgesia in diabetic rats was alleviated by inhibition of the PI3K/AKT/mTOR signaling pathway [ 44 ].

In contrast, Dong et al. reported that high glucose (HG) treatment of neuronal Schwann cells leads to enhanced apoptosis and reduced cell proliferation as a result of downregulated Akt/mTOR pathway. These effects were reversed by Muscone through the activation of the Akt/mTOR signaling pathway [ 45 ].

Similarly, Zhang et al. recently illustrated that artesunate alleviated nerve injury induced by hyperglycemia, both in vivo and in vitro, by inhibiting apoptosis and enhancing Schwann cell viability via activation of the PI3K/AKT/mTOR signaling pathway [ 46 ].

These contradictory results emphasize the fine balance required for mTOR and related pathway activation to maintain neuronal cell integrity and function by preserving the delicate interaction between cell survival and cell death as modulated by apoptotic and autophagic pathways [ 47 ].

The results of this study point toward the role of mTOR as a predictor of the occurrence of diabetes-related microvascular complications in the future. The ROC curve showed an mTOR cutoff value of 8 ng/ml for predicting patients with microvascular complications with a sensitivity of 100% and specificity 95% with an AUC of 0.983 and a p -value < 0.001.

This study had some limitations; including that it was a single-center study that included only Egyptian subjects. However, further investigations are needed to confirm the application of these findings to other populations. Future research is needed to confirm whether mTOR levels are independently associated with the development of microvascular complications. In addition, the size of the studied sample was small.

In this case- control study, mTOR was able to identify microvascular complications in T2DM patients with excellent diagnostic performance, suggesting that mTOR is a promising predictor of diabetes-related microvascular complications in patients with T2DM.

Data availability

No datasets were generated or analysed during the current study.

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Noha G. Amin, A. Abdel Rahim, Kamel Rohoma, Hossam M. F. Dabees & Shimaa Elrahmany

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A.A & K.R Conceptualization and methodology, N.A and K.R performed formal analysis, H.D and R.A data curation and figures, N.A and S.R wrote the main manuscript and revised it. All authors have read and agreed to the published version of the manuscript.

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Amin, N.G., Rahim, A.A., Rohoma, K. et al. The relation of mTOR with diabetic complications and insulin resistance in patients with type 2 diabetes mellitus. Diabetol Metab Syndr 16 , 222 (2024). https://doi.org/10.1186/s13098-024-01450-5

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DOI : https://doi.org/10.1186/s13098-024-01450-5

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Adjunctive therapy with chinese herbal medicine lowers risk of hearing loss in type 2 diabetes patients: results from a cohort-based case-control study.

1. Introduction

3. discussion, 4. materials and methods, 4.1. data source, 4.2. underlying cohort establishment, 4.3. ascertainment of case and control groups, 4.4. identification of chm exposure, 4.5. measurement of covariates, 4.6. evaluation of data, 5. conclusions, author contributions, institutional review board statement, informed consent statement, data availability statement, conflicts of interest.

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Huang, H.-J.; Livneh, H.; Yen, C.-T.; Lu, M.-C.; Chen, W.-J.; Tsai, T.-Y. Adjunctive Therapy with Chinese Herbal Medicine Lowers Risk of Hearing Loss in Type 2 Diabetes Patients: Results from a Cohort-Based Case-Control Study. Pharmaceuticals 2024 , 17 , 1191. https://doi.org/10.3390/ph17091191

Huang H-J, Livneh H, Yen C-T, Lu M-C, Chen W-J, Tsai T-Y. Adjunctive Therapy with Chinese Herbal Medicine Lowers Risk of Hearing Loss in Type 2 Diabetes Patients: Results from a Cohort-Based Case-Control Study. Pharmaceuticals . 2024; 17(9):1191. https://doi.org/10.3390/ph17091191

Huang, Hui-Ju, Hanoch Livneh, Chieh-Tsung Yen, Ming-Chi Lu, Wei-Jen Chen, and Tzung-Yi Tsai. 2024. "Adjunctive Therapy with Chinese Herbal Medicine Lowers Risk of Hearing Loss in Type 2 Diabetes Patients: Results from a Cohort-Based Case-Control Study" Pharmaceuticals 17, no. 9: 1191. https://doi.org/10.3390/ph17091191

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Weekly Insulin Injections As Effective for Diabetes as Daily Shots, Studies Show

Key Takeaways

A new form of weekly insulin can control type 1 and type 2 diabetes as well as daily injections

The weekly shot involves a new class of insulin called efsitora

Such shots would allow for easier control of blood sugar than daily jabs, researchers say

WEDNESDAY, Sept. 11, 2024 (HealthDay News) -- Weekly insulin shots can help control both type 1 and type 2 diabetes as well as daily injections do, a pair of clinical trials have found.

A new class of insulin called efsitora alfa has been designed to require injections only once a week, researchers said.

Two phase 3 trials presented Tuesday at the European Association for the Study of Diabetes annual meeting in Madrid show that efsitora is as safe and effective as standard daily insulin shots:

One trial in 928 people with type 2 diabetes found that weekly efsitora controlled blood sugar levels as well as a long-acting form of insulin called degludec.

The other trial found that once-weekly efsitora also performed as well as daily degludec in 623 people with type 1 diabetes.

“A once-weekly insulin has the potential to simplify dose administration and diminish barriers to starting insulin therapy by means of a reduction in injection burden as compared with a once-daily insulin,” wrote the team behind the type 2 diabetes trial, which was led by Dr. Carol Wysham , an endocrinologist with the MultiCare Rockwood Center for Diabetes and Endocrinology in Spokane, Wash.

"Traditionally, basal insulins are dosed once a day -- a treatment schedule that can make compliance difficult for a significant portion of people living with type 2 diabetes," said Wysham said in a news release from drug maker Eli Lily. "Efsitora has the potential to address treatment burden and improve adherence -- all while lowering A1C. These results can make a significant impact for people living with type 2 diabetes looking for a once-weekly option that provides similar outcomes as daily insulins."

In both clinical trials, which lasted 52 weeks, researchers randomly assigned participants to taking either efsitora or degludec insulin.

The major difference in the results between the two trials involved hypoglycemic (low blood sugar) events.

The type 2 diabetes trial found no statistically significant difference between efsitora and degludec when it came to hypoglycemia.

But hypoglycemia occurred more often for type 1 diabetics taking efsitora (10%) compared with degludec (3%), results show.

More work is needed to figure out the best dose “to maintain efficacy while mitigating the risk of hypoglycemia with weekly efsitora treatment in people with type 1 diabetes,” concluded the type 1 diabetes trial team led by Dr. Richard Bergenstal , executive director of the HealthPartners Institute's International Diabetes Center in Minneapolis.

"People with type 1 diabetes need insulin every day. Currently, they can deliver the insulin using an automated insulin delivery system or by taking a daily basal insulin injection and multiple mealtime insulin injections each day," Bergenstal explained in an Eli Lilly news release .  "This new data shows that with one dose a week of basal insulin, efsitora was able to achieve a similar A1C reduction as taking an injection of one of the most used background insulins every day. I look forward to further evaluation of these data, including ways to minimize hypoglycemia, so once-weekly insulin can be one option for personalizing the management of type 1 diabetes."

The type 2 diabetes trial also found that efsitora worked well in diabetics even if they were taking a GLP-1 drug like Ozempic.

“Given treatment guidelines and recommendations to incorporate GLP-1 receptor agonists earlier in treatment, along with their growing use worldwide, it is relevant to show that efsitora can be effectively and safely added to such therapy,” Wysham’s team concluded in a meeting news release.

Type 1 diabetes is an inherited condition in which the immune system destroys or damages the body’s ability to make insulin. People with type 2 diabetes develop resistance to insulin, which also can destroy or damage the ability to make insulin.

Results from the type 2 diabetes trial were published Sept. 10 in the New England Journal of Medicine , while results from the type 1 trial were published Sept. 10 in The Lancet .

More information

The Cleveland Clinic has more on type 1 and type 2 diabetes .

SOURCE: European Association for the Study of Diabetes, news release, Sept. 10, 2024; Eli Lilly, news releases, Sept. 10, 2024

What This Means For You

Once approved, a new form of insulin could allow people to receive shots once a week rather than once a day.

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Clinical pearls, suggested readings, case study: hemachromatosis in type 2 diabetes.

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Peter Capell; Case Study: Hemachromatosis in Type 2 Diabetes. Clin Diabetes 1 April 2004; 22 (2): 101–102. https://doi.org/10.2337/diaclin.22.2.101

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G.O. is a 50-year-old white man referred for help in managing his diabetes. Two years before his visit, diabetes was diagnosed during a routine exam. He was started on oral hypoglycemic agents. He initially responded to this treatment, but over the ensuing 2 years, his medication doses were slowly raised until he was on 15 mg glyburide and 2,000 mg metformin. At the time of referral, his fasting blood glucose levels were in the range of 150 mg/dl and his hemoglobin A 1c (A1C) was 8%. He requested a consultation when he was advised to start on insulin therapy.

His medical history was significant for heavy alcohol intake and hepatitis B with full recovery. Family history was negative for diabetes and hemochromatosis. His review of systems was positive for joint discomfort in his hands and erectile dysfunction.

Physical exam revealed normal vital signs and no retinopathy or other signs of diabetic complications. His hand joints showed mild swelling and tenderness over the proximal interphalangeal joints, and his skin was slightly, diffusely hyperpigmented.

Lab data included a random glucose of 253 mg/dl, A1C of 7.9%, normal creatinine and electrolytes, aspartate aminotransferase (GOT) of 66 units/l (normal < 44), alanine aminotransferase (ALT) of 133 units/l (normal < 31 units/l), normal bilirubin and alkaline phosphatase levels, normal testosterone level, and negative hepatitis antigen screen. His iron level was 306 μg/dl (normal < 155) with an iron-binding capacity of 315 μg/dl (normal < 400) and percent saturation of 97% (normal < 50%). Serum ferritin was 2,920 μg/l (normal < 160). The polymerase chain restriction assay demonstrated homozygosity for the C282Y chromosome. Referral to the hepatology clinic resulted in a liver biopsy, which identified increased iron stores and early periportal fibrosis.

Following confirmation of a diagnosis of hemochromatosis, he was started on phlebotomy therapy. Family screening was encouraged and resulted in the finding of asymptomatic diabetes associated with hemochromatosis in his brother. His medication doses have not changed, nor have his fasting glucose level or A1C results after 4 months of phlebotomies.

What is the prevalence of hemochromatosis in the general and diabetic population?

What is the effect of treatment on diabetic control in patients with hemochromatosis?

Should all people with diabetes over age 30 be screened for hemochromatosis?

Hereditary hemochromatosis is an autosomal recessive genetic disorder caused by a mutation in the HFE gene located on the short arm of chromosome 6. This mutation results in increased intestinal absorption of iron and eventually to iron overload. About 10% of the white population in the United States is heterozygote, with the frequency for homozygosity at 0.2–0.5%. Heterozygote individuals are gene carriers but are not medically affected.

Onset of symptoms is seldom apparent before age 40 because it takes years to build up enough iron to cause tissue damage. Liver function abnormalities are the most frequent finding leading to a diagnosis. Other important organ systems usually involved include the pancreas (diabetes), skin (hyper-pigmentation), joints (arthralgias and arthritis), heart (arrhythmias), and gonads (hypogonadism).

Approximately 50% of patients diagnosed with hemochromatosis will have either type 1 or type 2 diabetes. The likelihood of finding hemochromatosis in the adult population of diabetic patients is reportedly between 1–2%. Diabetes is not uncommonly the only apparent manifestation of hemochromatosis in unrecognized cases.

Early recognition of the presence of hemochromatosis is extremely important. Prompt therapy can prevent cirrhosis of the liver, development of a hepatoma, joint and gonadal damage, and the development of diabetes. In addition, as in this case, it can lead to early recognition of the disease in family members. Unrecognized, advanced hemochromatosis carries a high risk for premature death.

Development of diabetes in hemochromatosis is likely multifactorial. Selective β-cell damage, due to uptake of iron, leads to impaired insulin synthesis and release. α-Cell function is not impaired. In addition, liver fibrosis leads to insulin resistance and contributes to some patients requiring large amounts of insulin to obtain optimal blood glucose control. A family history of diabetes is observed in 25% of patients with hemochromatosis who develop diabetes. In contrast, only 4% of those with hemochromatosis who fail to develop diabetes have a positive family history. Therefore, it is likely that all three factors—β-cell damage, insulin resistance, and underlying genetic tendencies—play a causal role in patients with hemochromatosis developing diabetes.

Phlebotomy therapy has a variable impact on diabetes control. In a large study exploring the effect of therapy on diabetes control, 40% of 72 patients on insulin or oral agents showed improved glucose control following phlebotomy therapy. This same study reported that 6% of patients were able to stop insulin therapy during phlebotomy therapy, but 12% of the study group required increased medication to achieve good glycemic control. The majority of diabetic patients will experience no change or a progressive worsening in their diabetes management despite phlebotomy treatment.

The issue of screening all diabetic patients for hemochromatosis is currently debated. Screening by transferrin saturation using a level of > 50% is reasonably inexpensive. The dilemma is that some reports indicate no increased risk of hemochromatosis in an adult diabetic population. Furthermore, an elevated transferrin level is nonspecific, and a positive result will lead to many unnecessary evaluations being performed. Certainly type 2 diabetes and abnormal liver tests (as in this case), arthritis, or a family history of iron overload disease (as seen with this patient’s brother) should trigger an order for a transferrin level.

Hemochromatosis is present in 1–2% of all diabetic patients, and diabetes is often the first clinical manifestation of the disease.

Early recognition and treatment is imperative to prevent fatal liver or heart abnormalities and can prevent the onset of diabetes or improve diabetes control.

Screening all diabetic patients for hemochromatosis may not be cost-effective. However, screening patients with a family history of iron overload disease, abnormal liver enzymes, or arthritis seems prudent.

Peter Capell, MD, is a clinical professor of medicine in the Division of Endocrinology and Metabolism at the University of Washington School of Medicine in Seattle, Wash.

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