hypothesis of diabetes

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Published: 04 November 2019

Double or hybrid diabetes: A systematic review on disease prevalence, characteristics and risk factors

Jomana Khawandanah 1 , 2

Nutrition & Diabetes volume 9 , Article number: 33 ( 2019 ) Cite this article

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Diabetes mellitus is a worldwide epidemic affecting the health of millions of people. While type 1 diabetes (T1D) is caused by autoimmune destruction of the insulin-producing beta cells of the pancreas, type 2 diabetes (T2D) results from a combination of insulin resistance and beta cell insulin secretory defect. Clear definition and diagnosis of these two types of diabetes has been increasing more and more difficult, leading to the inclusion of a new category, namely double or hybrid diabetes (DD) that demonstrates symptoms of both T1D and T2D via the accelerator hypothesis. In this review, we discuss the worldwide prevalence of DD, its main physiological characteristics, including beta-cell autoimmunity, insulin resistance, and cardiovascular disease, the main risk factors of developing DD, mainly genetics, obesity and lifestyle choices, as well as potential treatments, such as insulin titration, metformin and behavioural modifications. Increasing awareness of DD among the general population and primary care practitioners is necessary for successfully treating this complex, hybrid disease in the future.

Pathophysiology, phenotypes and management of type 2 diabetes mellitus in Indian and Chinese populations

Heterogeneity and endotypes in type 1 diabetes mellitus

Disease-modifying therapies and features linked to treatment response in type 1 diabetes prevention: a systematic review

Introduction.

Diabetes mellitus is a chronic metabolic disease that is defined by persistent increased blood glucose levels (fasting blood glucose ≥ 126 mg/dl, random plasma glucose ≥ 200mg/dl, HbA1c ≥ 6.5%) 1 leading at higher risk to serious and chronic microvascular and metabolic complications of type 1 diabetes (T1D) and the macrovascular complications of type 2 diabetes (T2D) 2 , 3 , 4 , 5 , 6 , 7 . The world prevalence of diabetes in adults was 6.4% (285 million people) in 2010, and are expected to raise to 7.7% by 2030 8 . Of course, ethnicity-dependent differences are expected 9 , 10 .

T1D (insulin-dependent) results in the destruction of the insulin-producing beta cells of the pancreas 7 . The cause of T1D is not clearly defined yet, but there is evidence for not only strong genetic predisposition, but also for environmental triggering, leading to complete dependence on daily insulin injections or pump and specialised medical care 11 . T1D results in the presence of autoantibodies against glutamic acid decarboxylase (GAD/GAD65), islet cells, insulin (IAA), protein tyrosine phosphatase-related islet antigen 2 (IA2/IA2β) as well as zinc transporter protein (ZnT8A) in the blood of these patients 12 . T1D is one of the most common metabolic/endocrine diseases diagnosed in children (80–90% of diabetic children) 13 ; as an example, more than 3 million patients suffered from T1D in US in 2010, corresponding to 1 in 300 by 18 years old 14 . Global epidemiological studies have demonstrated that the incidence of T1D has been increasing to 2–5% annually 12 . On the other hand, the most common type in adults is T2D (non-insulin-dependent) that appears when the body develops resistance to insulin 7 , however there is also an recently increasing presence of young-onset T2D in children and adolescents 15 . T2D is a major metabolic disorder, which is characterised by increased blood sugar as a result of insulin resistance and due to reduced insulin secretion from pancreatic beta cells. Unhealthy dietary habits, obesity, genetic factors and a sedentary lifestyle are known to be the key risk factors for T2D development. Globally, around 5.1 million people between the ages of 20 to 79 died of T2D in the year 2015, which accounts for nearly 9% of overall mortality for this age group 16 . The increased consumption of dietary energy in comparison with low energy expenditure, resulting in obesity and weight gain is the major risk factor.

According to the first World Health Organization (WHO) global report on diabetes an outstanding number of 422 million adults live with this Non-Communicable Diseases (NCD) worldwide 17 . This number has almost made fourfold since 1980, which is largely because of the rise in T2D and other associated conditions including obesity, causing 1.5 million deaths due to heart attack, stroke, kidney failure or blindness in 2012 alone 17 . Specifically, the Kingdom of Saudi Arabia (KSA) was at the top 3 countries for diabetes prevalence in 2010, with an increased 18.9% prevalence projected for 2030 8 . Similarly, in children and adolescents of various ethnic groups worldwide, the prevalence of diabetes can range between 0.2–1.2%, with T1D being the most common type 18 . This increase is observed in the general Middle-East population and is mainly due to the nutrition transition associated to fast economic development, lifestyle changes reduced physical activity and escalated obesity 19 , 20 . In the Saudi National Diabetes Registry, all-cause mortality rate was ~17 per 1000 person-years, greater in men and older individuals, and associated with longer duration of diabetes, macrovascular complications, retinopathy, neuropathy, hypertension etc. 21 .

T1D or T2D?

Initial clinical observations in the ‘70s resulted in separating diabetes mellitus in two distinct forms—T1D defined by a defective immune system ( autoimmunity) , and T2D defined by loss of insulin responsiveness ( metabolic syndrome) 22 . Losing the control of blood glucose can result in beta cells being unable to secrete insulin, in tissues resisting to its action, or both. Classifying a clinical condition is very important in disease diagnosis and treatment as it can guide clinicians to translate scientific understanding to clinical practice 23 . Each classification can be further sub-divided depending on severity, and can be differently treated, ranging from insulin injections to lifestyle interventions 23 . However, distinguishing between T1D and T2D has increasingly become more difficult in terms of clinical characteristics and aetiology, as they both share beta-cell inefficiency. There is evidence that supports the hypothesis that T1D ( fast diabetes ), similarly to T2D ( slow diabetes ), will eventually cause insulin resistance, with body mass playing an important role 24 . Therefore, rather than expressing diabetic patients’ clinical variation into distinct categories, one could consider the diabetic spectrum/continuum as a dimensional factor 23 (Fig. 1 ). Clinicians have already raised doubts regarding the classification of young patients with classical features of T1D (antibodies and ketoacidosis), but with obesity and a history of T2D in the family 25 . In an early case report of a 5-year-old boy, the co-existence of both types of diabetes was evident, with a single classification not possible; a condition that was taken into account during diagnosis and treatment 26 . Other examples include a case of a 13-year-old obese girl with elevated levels of blood glucose and beta-cell antibodies that was treated with insulin injections instead of blood glucose-reducing drugs, and another 13-year-old girl with T1D, but with excess weight resulting in insulin insensitivity, treated with metformin additionally to her very high insulin dosages 27 .

Qualitatively comparing the most prominent clinical features of T1D and T2D

The ‘accelerator hypothesis’

The ‘accelerator hypothesis’ was first described in 2001 and argues that T1D and T2D are one and the same disorder, but distinguishable by the measure and tempo of three accelerators, one being intrinsic and two being acquired 28 . The accelerators include firstly beta cell death, important for diabetes development, secondly insulin resistance, caused by weight gain, visceral fat and sedentary lifestyle, and thirdly, beta cell autoimmunity (immune damage), driven by genetic factors 29 (Fig. 2 ). Testing the accelerator hypothesis in children in the United Kingdom showed that the age of diagnosis of T1D is correlated with adiposity and higher body mass index (BMI), with strong gender-specific effects, as boys presented with T1D at a significantly earlier age 30 . Epidemiological data in many European countries proposed that children with T1D are increasingly becoming heavier, and with higher waist circumference, at age of disease onset, suggesting the importance of environmental accelerators in T1D development 31 . However, this observation was not confirmed in children of other ethnic groups (South Asian and Australian), suggesting that body fat composition, rather than BMI, might be a better measure of insulin resistance 32 . While several studies implicate the role of obesity during childhood as a risk factor for developing T1D, the association remains weak with undetermined causality 33 ; therefore, more studies are necessary prior to testing this hypothesis in practice for T1D prevention 34 .

The role of insulin resistance in the development of diabetes phenotype (adapted from Stene, 2016)

The phenomenon of double diabetes

The term ’double diabetes’ (DD) refers to the cases where the patient demonstrates characteristics as a result of a mixture of T1D and T2D (Fig. 3 ) 35 . Merger et al. found that in a large epidemiological study showed that a total of 25.5% of patients suffering from T1D additionally presented the metabolic syndrome 36 . Similarly, in a study including youth onset diabetes patients from east Delhi and the neighbouring Indian region researchers classified 7% of their subjects as DD patients 37 . In KSA it has also recently been estimated that around one-third of young diabetic patients suffer from atypical forms of diabetes 38 . Common symptoms of DD include obesity, insulin resistance, type of latent autoimmune diabetes in youth (LADY) 39 , autoantibodies, namely GAD56, IA2 and insulin antibodies, in T1D 40 . DD can be a major event during the young onset (11–19 years old) of diabetic patient, as a result of weight gain and insulin resistance caused as side effects of insulin treatment 41 . A potentially positive family history and increased BMI (>85 th percentile) could be considered as clinical measures to recognise such DD cases from those with visible T1D 37 . It is necessary that DD phenotype is appropriately managed in terms of both the diagnosis and therapeutic approach as it is extremely hard for these patients, who are usually mainly identified during paediatric ages 42 . DD appears to be an independent and potential risk factor for patients with T1D in gaining macro- and micro-vascular diseases 36 . Microvascular diseases in DD demonstrate an elevated risk for nephropathy and retinopathy, while macrovascular comorbidities include the metabolic syndrome 36 . There is still a lack of awareness for metabolic comorbidities and essential efforts are needed in order to recognise these patients and find strategies to decrease the rate of metabolic Syndrome in T1D 36 . An accurate treatment including a mixture of lifestyle indicators and sufficient insulin is required for these patients in order to boost their glycemic control and inhibit diabetes-associated complications 37 . Lifestyle behavioural modification changes, such as dietary and physical activity plans, may be suitable towards the prevention/management of both T1D and T2D 39 .

How to diagnose DD

Understanding double diabetes

Worldwide prevalence.

Since 1991, there was evidence of a ‘third’ type of diabetes—i.e. DD—which was originated by the observation that insulin deficiency and insulin resistance co-exist, but its classification was problematic by the lack of accurate measurement of the latter 43 . However, the first epidemiological data together with heredity observations made clinicians believe that around 4% of all T1D patients have the potential to also have T2D 43 . With the increase of obesity worldwide that has been observed over the last two decades 44 , among children with T1D ~25% suffered from excess body weight, which could be correlated with poor diabetic control, instable levels of blood glucose and elevated insulin dosage 45 . More recently, Merger et al. (2016) also confirmed the same percentage (25.5%) among T1D patients, which exhibited even higher macrovascular-associated comorbidities, such as coronary heart disease and stroke, increased microvascular conditions, both independently of glucose control. In another study including 200 patients with youth onset diabetes, 7% (mean age of 22.2 years and mean BMI of 29.8) were categorised in DD, with 29% still under the unknown category 37 .

The example of Middle East

In KSA, the rapid economic growth in the last 40 years and the heightened adoption of the westernised lifestyle has led to unhealthy dietary patterns and reduced physical activity 46 . Global estimates have shown that KSA belongs to the top ten countries with the highest current and projected diabetes prevalence worldwide (second highest in the Middle-East 47 . Specifically, it is the fourth country worldwide in terms of the incident rate of T1D (33.5 per 100 000 people) 48 . The diabetes burden in the Saudi society is still on the rise, suggesting that the more people being diagnosed with diabetes, the more will be at risk of developing hypertension, heart disease, stroke, kidney disease, blindness, amputations, dental disease and nervous system disease 49 . Additionally, it has been shown that almost one third of the young (12–20 years old) diabetic patients in KSA demonstrate both T1D and T2D clinical characteristics, therefore revealing atypical forms of DD 38 . A recent study was published determining the clinical and biological characteristics of DD among the Saudi youth, at a small scale including one clinic (n=312) and investigated a number of demographic, social, family and risk factors 38 . Furthermore, while diabetes risk factors in children and adolescents have been investigated for T1D and T2D in KSA 21 , additional studies are still needed for DD in the young population (11–19 years old).

Pathophysiology

Diabetes, including DD, is not a simple, single clinical entity, but comprises a rather broad, mixed range of complex pathophysiological disease features.

Impaired immunity

Immunoglobulins can indicate the status of humoral immunity and are produced by B cells as a response to inflammatory diseases, such as diabetes 50 . Early on it was shown that T1D patients have a significantly lower serum concentration of immunoglobulin G (IgG), but comparable serum concentration of immunoglobulin A and M (IgA and IgM) with control non-diabetic subjects 51 . Nevertheless, a few T1D patients with onset in adolescence (<15 years old) were found completely deficient for IgA and IgG, indicating a more complicated mechanism 51 . On the other hand, population-based studies in T2D adult patients also show reduced IgG and IgM, but elevated IgA and immunoglobulin E (IgE) concentration, proposing immunoglobulins as valuable predictive indicators for T2D 50 , 52 . This immunoglobulin deficiency make T2D patients more prone to specific infections 53 , and quantification of this impaired immune response in DD will shed light to the exact mechanisms involved, as such studies in DD do not yet exist.

Autoimmunity

In T1D pathogenesis cellular autoimmune pathways cause destruction of insulin-secreting β-cells in the pancreas, resulting in inflammation 54 . Autoantibody positivity has been proposed as a predictive marker for estimating diabetes progression 55 . However, as mentioned above, distinct classification of diabetic patients is not always possible. In as early as 1993, it was recognised that there was a subset of non-insulin dependent patients with a later adult-onset of diabetes that also slowly developed latent autoimmune insulitis over the years, as revealed by analysing GAD autoantibodies 56 . In another study characterising autoimmunity in a young T2D population, it was found that, while the frequency of autoimmunity was significantly lower in T2D compared to T1D, there were still 8.1%, 30.3% and 34.8% of T2D children and adolescents testing positive for ICAs, GADs and IAAs, respectively, even without ever being managed with an insulin treatment 57 . Similarly, β-cell autoantibodies were detected in a subcategory of T2D children and adolescents, demonstrating LADY 58 . In addition, the detection of such autoantibodies, against not only β-cells but also self-reactive T-cells, in older patients brought about the clinical condition of latent autoimmune diabetes of the adult 59 . This is not be completely unexpected as the two main environmental determinants in T2D, namely diet and physical activity, can directly influence the expression of immune genes and the levels of systemic immune/inflammatory factors, such as interleukin 1β (IL-1β) and tumour necrosis factor α (TNFα) involved in the development of obesity 60 . It has been suggested that islet autoantibody assessment should be part of the T2D diagnostic evaluation, not only for predicting disease progression but also for distinguishing this pathogenically different T2D phenotype 61 . Additionally, black and white children with insulin-treated diabetes showed T2D-related symptoms in terms of obesity, irrespectively of their autoimmunity, further highlighting the ethnicity-dependent, heterogeneous pathogenesis mechanisms 26 . Almost 25% of young (<21 years old) T1D patients show a minimum of one organ-specific autoantibody, with females being at elevated risk of multiple autoimmunity and with some autoantibodies like against transgluminase are associated with younger age 62 .

Insulin resistance

Obesity-associated insulin resistance is considered as a chronic inflammatory condition originated in fat tissue 63 ; in fact, based on key criteria used to define autoimmune diseases, obesity-associated insulin resistance, and T2D itself, have been recently proposed to this category 64 . However, as early as in 1986, researchers studied the natural progression of insulin resistance also in T1D patients, and demonstrated that most T1D patients with long disease duration showed various degrees of insulin resistance 65 . Especially in T1D patients with microalbuminuria, the insulin sensitivity was found particularly high, and one of the causes for increased health risks of these patients, such as for the development of renal and cardiovascular diseases 66 . A similar outcome was observed in young T1D patients with a unique insulin resistance phenotype, impaired cardiopulmonary fitness and exercise capacity, potentially implying a different pathophysiology from T2D 67 . The importance of insulin sensitivity start to be highly recognised as a missing link in the treatment and prevention of T1D, together with regulation of autoimmunity 68 . To appropriately assess insulin resistance in T1D patients, an insulin-resistance-syndrome (IRS) score was created based on varying clinical factors, such as waist-to-hip ratio, hypertension, high-density lipoprotein cholesterol/triglyceride plasma levels and presence of T2D in the family 69 . However, insulin dose and the metabolic syndrome were not good predictors in a study with DD patients 70 . All this evidence led once again to the complex concept of DD and the involvement of elevated insulin resistance in T1D, implication of liver fat and lipid profile, and subsequent increase of cardiovascular disease risk 71 .

Cardiovascular disease

Cardiovascular disease is the most common death cause in diabetic patients, nevertheless little is known about T1D effects on cardiovascular risks in younger populations 67 . Following up the link between insulin resistance and cardiovascular disease risk, a study in 1998 concluded that family history of T2D mediates this risk in T1D patients, further highlighting the complex association involved 72 . More specifically, both female and male T1D patients, especially the ones with T2D family history, were found to have increased intima-media thickness of the carotid artery, a common factor of atherosclerosis; future studies will show the causality and predictive values of this marker 73 . In the case of DD patients, meaning obese T1D patients, long-term hyperglycaemia together with abnormal partitioning of lipids can possibly lead to the boost of atherothrombotic pathophysiological characteristics 74 .

Risk factors

The development of a complex disease like DD can be caused by a variety of risk factors, including genetic, pathophysiological, environmental and lifestyle.

Genetic predisposition

It is well known that T1D has sound genetic elements, with the main genetic susceptibility region belonging to the human leukocyte antigen (HLA) class II genes in chromosome 6, and more than 40 other non-HLA genetic markers being confirmed 75 . Furthermore, family history of T1D can significantly increase the risk of developing autoantibodies in childhood 76 . However, early investigations pointed towards the involvement of certain HLA haplotypes also in non-insulin dependent diabetes, proposing HLA as the main genetic cause of glucose intolerance in both T1D and T2D 77 . The influence of genetics is also evident in the reported higher chances of developing diabetes amongst first-degree consanguinity, where the genetic sharing is higher 78 . Apart from T1D, T2D is considered a complex genetic disease, with strong environmental triggers, consisting of various metabolic conditions, all linked with glucose intolerance and damage to insulin secretion 79 . Following genome-wide association studies that are considered the most promising in discovering novel disease markers 80 , the genetic architecture of T2D has been well-characterised 81 . A polymorphism in the potassium voltage-gated channel subfamily J member 11 (KCNJ11) gene in a case-control study in KSA 82 , and polymorphisms in the adenosine binding cassette transporter 1 (ABCA1) gene in a meta-analysis 83 , were significantly associated with T2D as they were observed more frequently in T2D patients. Additionally, polymorphisms in the fat mass and obesity-associated (FTO) gene, the so-called ‘obesity gene’, has been recognised to be involved in the progression of insulin resistance and presence of T2D in obese patients 84 , as well as responsiveness to dietary, exercise and drug-based weight loss interventions 85 . Finally, to the best of our knowledge no genetic study exists thus far regarding DD, however it would be very interesting to investigate the specific combination of polymorphisms that DD patients carry.

The role of obesity in T2D is well-known and considered the single best predictor, with the vast majority of T2D patients (>85%) being overweight or obese leading to higher cardiovascular risks due to this uncontrolled weight gain 86 . These patients have increased pressure on the ability of their body to use insulin effectively to control blood sugar levels, therefore they are at increased risk of developing diabetes 87 . While in the Epidemiology of Diabetes Complications Study the prevalence of being overweight in T1D was found lower compared to the general population 88 , more recently in a sample of >2,700 T1D patients, depending on the diabetes duration, 20–25% were overweight and 6–10% were obese, with BMI status not being significantly associated with insulin dose and intensity of insulin treatment 89 . In children it was soon evident that both girls and boys developing T1D were taller and heavier during childhood than healthy children—mainly more overweight, but not more obese 90 with every 10% weight increase resulting in 50–60% T1D risk increase before the age of three years 91 . Similarly, in another study with almost 12,000 children and adolescents (3–19 years old), the prevalence of overweight (but again not obese) in young T1D patients was higher compared to the non-diseased group 92 . These results were also confirmed in population-based studies in Norway and other European countries, where there was a weak, but significant, almost linear association between weight at birth and elevated risk of developing T1D in early childhood 93 , with the role of infant feeding still unknown 94 . Meta-analysis of four studies also showed that observed childhood obesity, assessed at different ages ranging from 1 to 12 years old, led to double chances of subsequent T1D development 95 . This effect is likely to be mediated via elevated beta-cell stress caused by hyperinsulinemia and lower insulin sensitivity linked with quick linear growth and obesity 96 . Weight gain early in childhood was also suggested to predict the risk of islet autoimmunity in children having a T1D first-degree relative 97 . Overall, obesity is an associated and precipitating factor for the development of both T1D and T2D in children, meaning that it plays a critical role also in the progression of DD 42 .

The diet of an individual influences the quantity of insulin produced in order to meet the body’s blood glucose targets and to maintain optimal levels of blood glucose. Dietary patterns have been well linked with diabetes pathology and metabolic syndrome, more specifically with T2D development and treatment, with such effects varying according to sex and ethnicity 98 . Together with other risk factors like sedentary lifestyle, increased intake of high-carbohydrate, low-macronutrient and energy-dense fast foods is considered amongst the most prominent T2D risk factors 99 . For example, very recently in the Whitehall II Study, scientists identified a specific dietary pattern, including high consumption of diet soft drinks, sugar-sweetened beverages, burgers, crisps, white bread and other snacks that was associated with insulin resistance and increased T2D risk after adjusting for a range of cofounders 100 . On the other hand, fibre-rich foods have unequivocally been associated with reduced obesity and T2D risk according to several observational studies 101 . Research has also suggested that a low-carbohydrate ketogenic diet 102 , increased whole-grain intake 103 , consumption of certain whole fruits like grapes, apples and blueberries 104 and high consumption of green leafy vegetables in fact resulted in lowered T2D risk 105 are effective in reducing the risk and disease effects of T2D. Lastly, while the role of diet is evident in T2D, in T1D the effects are smaller, however there has been evidence that short duration of breast feeding, early introduction of cow’s milk formula, a late start of gluten consumption as well as high milk consumption at one year of age are considered dietary risk factors for the initiation of beta-cell antibodies 106 . Overall, given the important role of increased BMI in the development of DD, dietary patterns is also a critical factor in DD, however more targeted investigations are still needed.

Physical activity

Active lifestyle has proven to be associated with several benefits to human health and wellbeing. Key among these benefits is its positive effects on muscle growth, muscle glucose utilisation, insulin liver sensitivity and overall glycemic control 107 . In other words, an active lifestyle can contribute to improvement in glycemic control and insulin action, even in cases with a family history of diabetes 46 . Looking more closely into specific physical activity patterns of diabetic patients, it seems that the latter have significantly lower total activity counts compared to healthy individuals with normal glucose levels, and also seemed to be more sedentary during the afternoon hours 108 . A meta-analysis suggests that individuals living a sedentary lifestyle have a significantly higher T2D and metabolic syndrome risk, while physical activity contributes positively to preventing or delaying T2D progression either by affecting BMI or improving insulin sensitivity 109 . Research suggests that adequate physical activity can lead to delaying the development of long-term complications of diabetes like retinopathy, neuropathy, nephropathy as well as reduce the rate of progression of existing complications 109 . The joint position statement of the American Diabetes Association and the American College of Sports Medicine 110 as well as the exercise guidelines of the American Heart Association 111 recommend that T2D patients require to exercise no less than once every 48 h (three times a week) in order to manage insulin resistance and blood glucose levels. Furthermore, the positive effects of exercise on insulin resistance is likely to be lost 48–72 h of exercise 112 , and short, vigorous exercise bouts have shown to enhance insulin resistance in T2D patients 113 .

Potential management & treatment

Thus far, the best approach for treating DD has not been agreed, however since insulin resistance and weight gain are the main clinical, pathophysiological features of this ‘mixed’ disease, successful treatment regimens should include optimal measures to tackle these 35 . For example, developing insulin titration approaches is necessary to ensure patients receive adequate doses of insulin to maintain glycemic control 114 . Also, introducing strategies for lifestyle changes is required to avoid weight gain, obesity and to maintain low insulin resistance. Enhancing high-quality research and education on diabetes mellitus in relation to dietary practice and physical exercise has the potential to significantly reduce its prevalence and adverse health effects in target populations 46 .

Insulin dosage and titration

The current advanced strategies in tackling diabetes, such as motoring devices and insulin analogs have significantly upgraded the quality of life of T1D patients. However, especially in the young populations, poor glycemic control is still evident causing not only to short-term, but also chronic disease complications 115 . Physiological factors contributing to this ineffective glycemic control are partially associated with the expected hormonal changes occurring during puberty. For instance, there is a significant increase in insulin response to intravenous or oral glucose 116 and a significant decrease in glucose disposal 117 in children and adolescents. Therefore, to ensure adequate glycemic control, insulin dosages are often elevated, and need to be constantly adjusted to avoid poor control during later stages of puberty. Additionally, overweight DD patients with insulin resistance do not often have insulin doses that have been titrated to reach target levels resulting in suboptimal treatment. The safety and efficiency of a daily insulin titration regime in regulating HbA1c levels was recently demonstrated in T2D patients 114 .

Metformin (Glucophage) is an oral antihyperglycemic drug, which is used as the first line treatment for the prevention and management of T2D, both in adults and children, and particularly for obese patients showing hyperinsulinemia 118 . The drug helps T2D patients respond better to their own insulin; decreases the quantities of glucose absorbed by intestines; and reduces the amount of glucose produced by the liver (Gong et al., 2012). In most clinical settings around the world, when metformin in combination with diet and exercise fails to keep blood sugar on normal levels, other therapeutic interventions are adopted, such as bariatric surgery 119 . Interestingly, metformin was successfully tested for its improved efficacy in treating T1D adult and adolescent patients, for a joint treatment together with insulin injections 120 . Furthermore, adding metformin to insulin therapy significantly improved insulin resistance in patients with DD-similar profiles 121 .

Behavioural modification and lifestyle intervention

It was soon evident that lifestyle changes are the key to the prevention and treatment of environmentally-induced T2D, mainly caused by the sedentary lifestyle and obesity, and were more effective than metformin alone 122 . Successful interventions to tackle increased BMI, increased (saturated) fat consumption and reduced physical activity have been reported, resulting in significant weight loss and 58% diabetes risk reduction 123 . Lifestyle interventions in individuals with elevated risk of T2D can introduce sustaining lifestyle changes that result in long-term prevention of T2D 124 . For example, in the Diabetes in Europe—Prevention using Lifestyle, Physical Activity and Nutritional Intervention (DE-PLAN) project it was shown that T2D prevention via lifestyle intervention at a real-life primary health care setting provided by well-trained nurses led to beneficial long-term (3-year follow-up) outcomes, including modest reduction of weight, cardiovascular risk factors and overall diabetes risk 125 .

Conclusions and future directions

As shown above, ‘hybrid’ DD is a complex phenomenon, demonstrating characteristics of both T1D and T2D, which is often misdiagnosed or ignored. There has been a rise in its prevalence, which is associated with the co-current increase of T2D due to the adoption of a ‘westernised’ lifestyle with sedentary behaviour and increased consumption of fat-based diets. Appropriate assessment of diabetes is necessary for early and correct diagnosis, which can be only achieved by increasing awareness of DD among general populations and primary care physicians. Additional research in DD patients in high-risk populations, such as in Middle East, is necessary to further document the health risks and symptoms of these patients, in order to develop appropriate, successful, long-term therapy regimens to treat them.

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Jomana Khawandanah

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Khawandanah, J. Double or hybrid diabetes: A systematic review on disease prevalence, characteristics and risk factors. Nutr. Diabetes 9 , 33 (2019). https://doi.org/10.1038/s41387-019-0101-1

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Scientists Think They've Found a New Cause of Type 2 Diabetes

More than half a billion people worldwide are affected by type 2 diabetes , and yet researchers still don't know what's behind the condition's breakdown in insulin functionality.

Researchers from Case Western Reserve University in the US have now pulled back the molecular curtain and figured out why insulin, the hormone that maintains stable blood sugar, often stops working at its full effect.

The principal investigator, Jonathan Stamler , is widely acclaimed for the discovery of S-nitrosylation , which is the process that turns nitric oxide (NO) into a ubiquitous messenger molecule capable of sharing information between cells. It's kind of like putting a stamp on a letter.

Nitric oxide is produced in almost all cell types and tissues , and it plays a crucial role in the functioning of the nervous system, the immune system, and in blood vessel dilation. What's more, dysregulation of S-nitrosylation is increasingly found to be associated with a number of health conditions, such as multiple sclerosis, Parkinson's disease, sickle cell disease, and asthma.

Only recently, however, has NO been linked to aspects of the body's metabolism.

Stamler and his colleagues previously suspected that the role of NO is overlooked in some types of diabetes, and now, they have the evidence to support their hypothesis.

The team at Case Western Reserve has discovered a novel enzyme, called SCAN (SNO-CoA-assisted nitrosylase), that plays a role in S-nitrosylation . It helps attach NO to its target proteins, such as the receptors on insulin.

In humans and mice with resistance to insulin, SCAN activity appears to be heightened.

In mouse models of diabetes, Stamler and his colleagues found that when SCAN was inhibited, the animals did not show the classic symptoms.

Together, the findings suggest that type II diabetes may be driven by an overabundance of NO attaching to proteins like insulin. Any enzymes, like SCAN, that work to attach NO to its receptors could, therefore, be useful targets in future research.

Stamler hopes that by blocking the SCAN enzyme, scientists may find new treatments for at least some types of diabetes.

Type I diabetes, however, is caused by a sheer lack of insulin production, and this would probably require a different avenue of treatment.

"This paper shows that dedicated enzymes mediate the many effects of nitric oxide," explains Stamler.

"Here, we discover an enzyme that puts nitric oxide on the insulin receptor to control insulin. Too much enzyme activity causes diabetes. But a case is made for many enzymes putting nitric oxide on many proteins, and, thus, new treatments for many diseases."

The study was published in Cell .

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Pathogenesis and remission of type 2 diabetes: what has the twin cycle hypothesis taught us?

Affiliation.

1 Magnetic Resonance Centre, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.
PMID: 33225228
PMCID: PMC7673778
DOI: 10.1097/XCE.0000000000000201

Type 2 diabetes has been regarded a complex multifactorial disease that lead to serious health complications including high cardiovascular risks. The twin cycle hypothesis postulated that both hepatic insulin resistance and dysfunction rather than death of beta (β) cell determine diabetes onset. Several studies were carried out to test this hypothesis, and all demonstrated that chronic excess calorie intake and ectopic fat accumulation within the liver and pancreas are fundamental to the development of this disease. However, these recent research advances cannot determine the exact cause of this disease. In this review, the major factors that contribute to the pathogenesis and remission of type 2 diabetes will be outlined. Importantly, the effect of disordered lipid metabolism, characterized by altered hepatic triglyceride export will be discussed. Additionally, the observed changes in pancreas morphology in type 2 diabetes will be highlighted and discussed in relation to β cell function.

Keywords: hepatic very low density lipoprotein triglyceride export; pancreas morphology; pathogenesis; remission; twin cycle hypothesis; type 2 diabetes; β-cell dysfunction.

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The twin cycle hypothesis of…

The twin cycle hypothesis of the aetiology of T2DM. Liver cycle: Prolonged exposure…

Change in liver fat, hepatic…

Change in liver fat, hepatic insulin resistance, and VLDL-TG production within the Counterbalance…

Change in lipid parameters after…

Change in lipid parameters after remission of T2DM within the DiRECT study. Liver…

β-cell failure in response to…

β-cell failure in response to change in lipid parameters during re-emergence of T2DM…

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Type 2 (Non-Insulin-Dependent) Diabetes Mellitus

The thrifty phenotype hypothesis.

CN Hales; DJP Barker

Int J Epidemiol. 2013;42(5):1215-1222.

Introduction
Insulin Deficiency in Type 2 Diabetes
Foetal and Infant Growth and Type 2 Diabetes
Brief Review of Evidence
Conclusions

In this contribution we put forward a novel hypothesis concerning the aetiology of Type 2 (non-insulin dependent) diabetes mellitus. The concept underlying our hypothesis is that poor foetal and early post-natal nutrition imposes mechanisms of nutritional thrift upon the growing individual. We propose that one of the major long-term consequences of inadequate early nutrition is impaired development of the endocrine pancreas and a greatly increased susceptibility to the development of Type 2 diabetes. In the first section we outline our research which has led to this hypothesis. We will then review the relevant literature. Finally we show that the hypothesis suggests a reinterpretation of some findings and an explanation of others which are at present not easy to understand.

Table 1. Relationship of 32–33 split proinsulin to systolic blood pressure in men aged 59–70 years. 32–33 split proinsulin was measured in plasma from a sample taken after an overnight fast
32–33 split proinsulin (pmol/l)	Mean systolic pressure (mm Hg)	Number of men
−1.5	161	96
−2.5	164	90
−3.6	163	93
−5.8	165	96
>5.8	170	93
Total	164 (SD 23)	468

p -value for trend = 0.003 a (adjusted for BMI, age, room temperature)

Authors and Disclosures

CN Hales 1 and DJP Barker 2

1 Department of Clinical Biochemistry, Addenbrooke's Hospital, Cambridge, UK and 2 MRC Environmental Epidemiology Unit, University of Southampton, Southampton General Hospital, UK

* Based upon the Banting Lecture given by CN Hales at the 27 th Annual Meeting of the European Association for the study of Diabetes in Dublin on 11 September 1991.

† Hales CN, Barker DJP. Type 2 (non-insulin-dependent) diabetes mellitus: the thrifty phenotype hypothesis. Diabetalogia 1992;35:595–601. Reprinted with permission.

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Diabetes mellitus refers to a group of diseases that affect how the body uses blood sugar (glucose). Glucose is an important source of energy for the cells that make up the muscles and tissues. It's also the brain's main source of fuel.

The main cause of diabetes varies by type. But no matter what type of diabetes you have, it can lead to excess sugar in the blood. Too much sugar in the blood can lead to serious health problems.

Chronic diabetes conditions include type 1 diabetes and type 2 diabetes. Potentially reversible diabetes conditions include prediabetes and gestational diabetes. Prediabetes happens when blood sugar levels are higher than normal. But the blood sugar levels aren't high enough to be called diabetes. And prediabetes can lead to diabetes unless steps are taken to prevent it. Gestational diabetes happens during pregnancy. But it may go away after the baby is born.

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Diabetes symptoms depend on how high your blood sugar is. Some people, especially if they have prediabetes , gestational diabetes or type 2 diabetes , may not have symptoms. In type 1 diabetes , symptoms tend to come on quickly and be more severe.

Some of the symptoms of type 1 diabetes and type 2 diabetes are:

Feeling more thirsty than usual.
Urinating often.
Losing weight without trying.
Presence of ketones in the urine. Ketones are a byproduct of the breakdown of muscle and fat that happens when there's not enough available insulin.
Feeling tired and weak.
Feeling irritable or having other mood changes.
Having blurry vision.
Having slow-healing sores.
Getting a lot of infections, such as gum, skin and vaginal infections.

Type 1 diabetes can start at any age. But it often starts during childhood or teen years. Type 2 diabetes, the more common type, can develop at any age. Type 2 diabetes is more common in people older than 40. But type 2 diabetes in children is increasing.

When to see a doctor

If you think you or your child may have diabetes. If you notice any possible diabetes symptoms, contact your health care provider. The earlier the condition is diagnosed, the sooner treatment can begin.
If you've already been diagnosed with diabetes. After you receive your diagnosis, you'll need close medical follow-up until your blood sugar levels stabilize.

There is a problem with information submitted for this request. Review/update the information highlighted below and resubmit the form.

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To understand diabetes, it's important to understand how the body normally uses glucose.

How insulin works

Insulin is a hormone that comes from a gland behind and below the stomach (pancreas).

The pancreas releases insulin into the bloodstream.
The insulin circulates, letting sugar enter the cells.
Insulin lowers the amount of sugar in the bloodstream.
As the blood sugar level drops, so does the secretion of insulin from the pancreas.

The role of glucose

Glucose — a sugar — is a source of energy for the cells that make up muscles and other tissues.

Glucose comes from two major sources: food and the liver.
Sugar is absorbed into the bloodstream, where it enters cells with the help of insulin.
The liver stores and makes glucose.
When glucose levels are low, such as when you haven't eaten in a while, the liver breaks down stored glycogen into glucose. This keeps your glucose level within a typical range.

The exact cause of most types of diabetes is unknown. In all cases, sugar builds up in the bloodstream. This is because the pancreas doesn't produce enough insulin. Both type 1 and type 2 diabetes may be caused by a combination of genetic or environmental factors. It is unclear what those factors may be.

Risk factors

Risk factors for diabetes depend on the type of diabetes. Family history may play a part in all types. Environmental factors and geography can add to the risk of type 1 diabetes.

Sometimes family members of people with type 1 diabetes are tested for the presence of diabetes immune system cells (autoantibodies). If you have these autoantibodies, you have an increased risk of developing type 1 diabetes. But not everyone who has these autoantibodies develops diabetes.

Race or ethnicity also may raise your risk of developing type 2 diabetes. Although it's unclear why, certain people — including Black, Hispanic, American Indian and Asian American people — are at higher risk.

Prediabetes, type 2 diabetes and gestational diabetes are more common in people who are overweight or obese.

Complications

Long-term complications of diabetes develop gradually. The longer you have diabetes — and the less controlled your blood sugar — the higher the risk of complications. Eventually, diabetes complications may be disabling or even life-threatening. In fact, prediabetes can lead to type 2 diabetes. Possible complications include:

Heart and blood vessel (cardiovascular) disease. Diabetes majorly increases the risk of many heart problems. These can include coronary artery disease with chest pain (angina), heart attack, stroke and narrowing of arteries (atherosclerosis). If you have diabetes, you're more likely to have heart disease or stroke.

Nerve damage from diabetes ( diabetic neuropathy ). Too much sugar can injure the walls of the tiny blood vessels (capillaries) that nourish the nerves, especially in the legs. This can cause tingling, numbness, burning or pain that usually begins at the tips of the toes or fingers and gradually spreads upward.

Damage to the nerves related to digestion can cause problems with nausea, vomiting, diarrhea or constipation. For men, it may lead to erectile dysfunction.

Kidney damage from diabetes ( diabetic nephropathy ). The kidneys hold millions of tiny blood vessel clusters (glomeruli) that filter waste from the blood. Diabetes can damage this delicate filtering system.
Eye damage from diabetes ( diabetic retinopathy ). Diabetes can damage the blood vessels of the eye. This could lead to blindness.
Foot damage. Nerve damage in the feet or poor blood flow to the feet increases the risk of many foot complications.
Skin and mouth conditions. Diabetes may leave you more prone to skin problems, including bacterial and fungal infections.
Hearing impairment. Hearing problems are more common in people with diabetes.
Alzheimer's disease . Type 2 diabetes may increase the risk of dementia, such as Alzheimer's disease.
Depression related to diabetes . Depression symptoms are common in people with type 1 and type 2 diabetes.

Complications of gestational diabetes

Most women who have gestational diabetes deliver healthy babies. However, untreated or uncontrolled blood sugar levels can cause problems for you and your baby.

Complications in your baby can be caused by gestational diabetes, including:

Excess growth. Extra glucose can cross the placenta. Extra glucose triggers the baby's pancreas to make extra insulin. This can cause your baby to grow too large. It can lead to a difficult birth and sometimes the need for a C-section.
Low blood sugar. Sometimes babies of mothers with gestational diabetes develop low blood sugar (hypoglycemia) shortly after birth. This is because their own insulin production is high.
Type 2 diabetes later in life. Babies of mothers who have gestational diabetes have a higher risk of developing obesity and type 2 diabetes later in life.
Death. Untreated gestational diabetes can lead to a baby's death either before or shortly after birth.

Complications in the mother also can be caused by gestational diabetes, including:

Preeclampsia . Symptoms of this condition include high blood pressure, too much protein in the urine, and swelling in the legs and feet.
Gestational diabetes. If you had gestational diabetes in one pregnancy, you're more likely to have it again with the next pregnancy.

Type 1 diabetes can't be prevented. But the healthy lifestyle choices that help treat prediabetes, type 2 diabetes and gestational diabetes can also help prevent them:

Eat healthy foods. Choose foods lower in fat and calories and higher in fiber. Focus on fruits, vegetables and whole grains. Eat a variety to keep from feeling bored.
Get more physical activity. Try to get about 30 minutes of moderate aerobic activity on most days of the week. Or aim to get at least 150 minutes of moderate aerobic activity a week. For example, take a brisk daily walk. If you can't fit in a long workout, break it up into smaller sessions throughout the day.

Lose excess pounds. If you're overweight, losing even 7% of your body weight can lower the risk of diabetes. For example, if you weigh 200 pounds (90.7 kilograms), losing 14 pounds (6.4 kilograms) can lower the risk of diabetes.

But don't try to lose weight during pregnancy. Talk to your provider about how much weight is healthy for you to gain during pregnancy.

To keep your weight in a healthy range, work on long-term changes to your eating and exercise habits. Remember the benefits of losing weight, such as a healthier heart, more energy and higher self-esteem.

Sometimes drugs are an option. Oral diabetes drugs such as metformin (Glumetza, Fortamet, others) may lower the risk of type 2 diabetes. But healthy lifestyle choices are important. If you have prediabetes, have your blood sugar checked at least once a year to make sure you haven't developed type 2 diabetes.

Diabetes care at Mayo Clinic

Ferri FF. Diabetes mellitus. In: Ferri's Clinical Advisor 2022. Elsevier; 2022. https://www.clinicalkey.com. Accessed May 7, 2022.
Classification and diagnosis of diabetes: Standards of medical care in diabetes — 2022. Diabetes Care. 2022; doi:10.2337/dc22-S002.
Papadakis MA, et al., eds. Diabetes mellitus. In: Current Medical Diagnosis & Treatment 2022. 61st ed. McGraw Hill; 2022. https://accessmedicine.mhmedical.com. Accessed May 4, 2022.
Diabetes risk factors. Centers for Disease Control and Prevention. https://www.cdc.gov/diabetes/basics/risk-factors.html. Accessed June 2, 2022.
Cunningham FG, et al. Diabetes mellitus. In: Williams Obstetrics. 25th ed. McGraw-Hill Education; 2018. https://accessmedicine.mhmedical.com. Accessed June 2, 2022.
Diabetes and DKA (ketoacidosis). American Diabetes Association. https://www.diabetes.org/diabetes/dka-ketoacidosis-ketones. Accessed May 4, 2022.
Diabetes Canada Clinical Practice Guidelines Expert Committee. Complementary and alternative medicine for diabetes. Canadian Journal of Diabetes. 2018; doi:10.1016/j.jcjd.2017.10.023.
Nimmagadda R. Allscripts EPSi. Mayo Clinic. June 16, 2022.
Jameson JL, et al., eds. Diabetes mellitus: Diagnosis, classification and pathophysiology. In: Harrison's Principles of Internal Medicine. 20th ed. McGraw-Hill Education; 2018. https://accessmedicine.mhmedical.com. Accessed June 2, 2022.
Pharmacologic approaches to glycemic treatment: Standards of medical care in diabetes — 2022. Diabetes Care. 2022; doi:10.2337/dc22-S009.
Facilitating behavior change and well-being to improve health outcomes: Standards of medical care in diabetes — 2022. Diabetes Care. 2022; doi:10.2337/dc22-S005.
AskMayoExpert. Type 1 diabetes mellitus. Mayo Clinic; 2021.
Glycemic targets: Standards of Medical Care in diabetes — 2022. Diabetes Care. 2022; doi:10.2337/dc22-S012.
Comprehensive medical evaluation and assessment of comorbidities: Standards of Medical Care in Diabetes — 2022. Diabetes Care. 2022; doi:10.2337/dc22-S004.
Prevention or delay of type 2 diabetes and associated comorbidities: Standards of Medical Care in diabetes — 2022. Diabetes Care. 2022; doi:10.2337/dc22-S003.
Obesity and weight management for the prevention and treatment of type 2 diabetes: Standards of Medical Care in Diabetes — 2022. Diabetes Care. 2022; doi:10.2337/dc22-S008.
Diabetes technology. Standards of Medical Care in Diabetes — 2022. 2022; doi:10.2337/dc22-S007.

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Four Theories

The workshops, conclusions, four theories and a philosophy: self-management education for individuals newly diagnosed with type 2 diabetes.

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T. Chas Skinner , Sue Cradock , Francesca Arundel , William Graham; Four Theories and a Philosophy: Self-Management Education for Individuals Newly Diagnosed With Type 2 Diabetes. Diabetes Spectr 1 April 2003; 16 (2): 75–80. https://doi.org/10.2337/diaspect.16.2.75

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Many reviews of educational interventions for people with diabetes have criticized the lack of reported theory in the development or descriptions of these programs. 1 , 2 Yet these reviews seem to ignore a fundamentally more important omission in the self-management education and behavior change literature—a lack of reporting of the projects’ philosophies of care. A program that is designed to persuade or motivate individuals with diabetes to do what health care professionals think they should do, for example, is substantially different from a program built on the philosophy of supporting individuals to achieve their own goals for diabetes management. This issue of philosophy is of fundamental importance because it influences the theories that may be used, the educators’ attitudes (cognitive, affective, and behavioral), and the content and style of any educational material and interaction.

This article reports on the development of a series of self-management education workshops for individuals newly diagnosed with type 2 diabetes. It focuses on how different theories from health psychology have been used to guide the development of the workshops and how these theories have been implemented in delivering the workshops.

The Health District of Portsmouth, U.K., has a population of 560,000, an estimated 17,000–18,000 of whom have diabetes (3% prevalence). To develop diabetes services for this population, the Diabetes Service Advisory Group, which represents all of the primary and secondary care organizations involved in delivering diabetes services locally, held a workshop facilitated by the local Health Authority (governing body for the Health District). Workshop participants, including health care professionals, commissioners of health services, and people with diabetes, were asked to set priorities for the delivery of better health care for people with diabetes in the locality. “Patient education at diagnosis” topped the resulting list of priorities.

One of the primary care groups, which served a population of 190,000, then highlighted diabetes as one of a set of priorities within its own Health Improvement Plan for the locality and funded an education initiative to provide workshops aimed at individuals newly diagnosed with type 2 diabetes. The goals of this initiative were:

to provide individuals with information regarding the causes, effects, and management of type 2 diabetes;

to enable newly diagnosed individuals to discuss and explore their experiences, frustrations, and successes in living with diabetes;

to ensure that those living with type 2 diabetes are aware of their specific health risks for developing the complications of diabetes;

to provide an expert forum for participants to discuss methods of reducing their identified risk factors; and

to support individuals in developing their own diabetes management plan.

As part of the initial workshop development process, project team members agreed on a core set of philosophical principles against which they could judge all of their work on the initiative. This was done through the team members describing their core principles of care and what they felt the workshops should provide for participants. Through discussing and clarifying these initial aspirations, team members reached the following consensus on their underlying philosophy for the workshops:

All workshop facilitators acknowledge and accept that people with diabetes are completely responsible for their condition and that this responsibility is nonnegotiable, indivisible, and inescapable.

All participants will make decisions that move them toward a direction of best possible physical and emotional health, as they understand it.

Individuals with diabetes will be given an open, honest, and complete picture of diabetes.

Individuals will be supported in processing and understanding this information.

Health care professionals will view all individuals with the utmost respect and unconditional positive regard. Empathy, warmth, and enacted equality of all individuals present are essential for the success of any educational interaction.

In essence, team members summarized their philosophy as that of “informed choice,” which they felt is the key to empowerment, 3 , 4 based on a humanistic view of the individual.

A review of the literature failed to identify any programs for those newly diagnosed with type 2 diabetes that espoused or fit with such a philosophy. Therefore, the workshops were developed from scratch.

Given the principles listed above, the project team—a health psychologist, two diabetes nurse specialists, and an individual with type 2 diabetes who had recently started using insulin—set out to develop daylong workshops using an iterative process. The team developed an initial outline and workshop booklet, which was then implemented in two pilot workshops. Different team members facilitated different sections of the workshops, trying out their own ideas for engaging the group while adhering to the underlying philosophical principles. The team then reviewed the pilot efforts, focusing on those elements that seemed to work well and developing these further. This process was repeated in another series of workshops until all group members were happy with the format, which was then followed as the standard for all subsequent workshops.

After reviewing the pilot workshops, team members agreed that it was of fundamental importance for the workshops not to be guided by an overarching philosophy, but also to encompass sound theoretical principles for effective self-management education and the development of individuals’ motivation and sense of control over their diabetes. Toward this end, four key theories were used to guide the delivery of the workshops.

Self-Regulation Theory 5 focuses on individuals’ illness representation or personal model of diabetes as a key determinant of their behavioral and emotional responses to illness. Research in this field has identified five core elements, across cultures, that form our illness representations:

Identity (What is diabetes? What symptoms are experienced? What is actually wrong?)

Cause (What caused my diabetes?)

Timeline (How long will this last?)

Consequences (How will diabetes affect me now and in the future?)

Treatment effectiveness (How good is my treatment at controlling or curing my diabetes?)

Research in adults and adolescents with diabetes has consistently demonstrated that individuals hold a diverse set of illness beliefs that do not fit the medical view of diabetes and that these beliefs are robust and proximal determinants of patients’ emotional well-being and self-care behavior. 6 , 7 Individuals often have relatives or know people who have diabetes, have seen media portrayals of people with diabetes, and have heard about some of the complications of diabetes. Therefore, individuals come to the workshops already having a personal model of diabetes. However, these beliefs are not necessarily accurate, up-to-date, or complete.

The Portsmouth workshops seek to elicit individuals’ beliefs and knowledge about diabetes so that misunderstandings and misconceptions can be addressed and revised. One of the benefits team members have noticed from this exercise is that individuals who have not been aware of any symptoms of diabetes recognize retrospectively that they have been experiencing these symptoms without attributing them to their diagnosis of diabetes. The exercise has also revealed that some participants hold very interesting beliefs about their illness, such as the woman who said, “I don’t think it is diabetes. I just think the walls of my womb are falling in because I am peeing so much of the time.”

Dual Process Theory 8 was used to guide the process of education and addressing individuals’ current understanding of diabetes. Dual process theory makes a distinction between heuristic and systematic processing.

Much patient education relies predominantly on heuristic processing, through which patients have a rather passive role, mostly listening to health care professionals telling them about their illness. In such instances, health care professionals are seen as experts who should be listened to and whose advice should be followed. However, the information provided is usually generic and usually easily rationalized as not relevant to the individual. Where attitudes do change, they tend to be surface changes and susceptible to further change in light of other, contradictory information from other “experts,” be they health care professionals, relatives, friends with diabetes, or the media.

To overcome these issues, dual process theory emphasizes the need to actively involve individuals in the learning process. This means providing individuals with the least possible information from which to learn. The workshops note, for example, that the problem in type 2 diabetes is insulin resistance. Then, through good questioning and analogies (the workshops use the analogy that having insulin resistance is a bit like having a rusty lock on your front door), facilitators support individuals in working out how this information relates to what is happening in their bodies now and in the future (e.g., that because they are resistant to insulin, their pancreas needs to work harder and may then get tired out and start being inefficient). Figure 1 provides an example of a picture that the group generates at the workshops, with only the two highlighted pieces of information provided to them. This more active learning leads to changes in beliefs that are more resistant to the influences of contradictory information. It equips individuals with principles by which new information can be explored and tested. And, because it helps individuals understand how the information relates to what is happening in their own bodies, it makes this information more difficult to rationalize away.

As a result of this approach, individuals who have participated in a program evaluation up to a year after attending a workshop have been able to give amazingly detailed descriptions of the workshop. This is in stark contrast to individuals’ recall of one-on-one consultations. 9

Self-Determination Theory 10 focuses on the difference between controlled and autonomous motivation. Controlled motivation means doing things for extrinsic reasons, such as to make others happy or to receive a contingent reward. Autonomous motivation, in contrast, means doing things for intrinsic reasons or for oneself. This type of motivation is predictive of successful self-care, weight loss, and glycemic control. 11 , 12

To support the development of autonomous motivation for diabetes self-care, the individuals in these workshops conduct their own health assessments and record the results on their own health profiles ( Figure 2 ). This serves to further the processing of the information they have received, but also helps them make informed choices about their diabetes and what they wish to do for the future. At the end of the daylong workshops, individuals set their own goals based on their health assessments and management plans. This emphasizes participants’ autonomy and encourages them to make their own decisions about their diabetes management.

To facilitate a better understanding of their individual health risks, workshop participants take part in measuring many of the tests and assessments that are usually performed on them. This not only helps to identify their individual health risks, but also helps them to see the relevance of the tests they will have as a regular part of their future health assessments and understand how these measurements affect their risk of developing complications. Project team members continue to be amazed at how many people being treated for hypertension do not know what blood pressure is, let alone what their own blood pressure levels are or what they should be. Although this process of gaining an insight into potential risks could lead to anxiety, it is a necessary part of understanding the nature of diabetes, and it acts as a motivator for behavior change. Understanding what their individual health risks are naturally leads participants to the question, “What can I do about it?”

Social Learning Theory 13 focuses on individuals’ perceptions of their ability to enact behaviors and follow through on action plans. In psychological terms, this is referred to as self-efficacy, but it is very similar to the concept of self-confidence. Self-efficacy has been shown to be one of the most consistent predictors of successful self-care behavior and has been incorporated into most health psychology models. 14

The Portsmouth workshops support the development of participants’ sense of self-efficacy throughout their daylong agenda. This is done by reinforcing the message that any changes, no matter how small, have benefits for improving health. At the end of the workshops, facilitators support participants in setting “SMART goals”: s pecific, m easurable, a ction goals that are r ealistic and t ime-limited. The range of goals and strategies set by participants has been stunning, from talking to a doctor about depression to exploring low-fat cooking options, to moving salt from the table to the refrigerator to discourage overuse when it is close at hand. This structured session at the end of the workshops also encourages individuals to anticipate barriers to achieving their goals and uses structured problem solving to help them overcome these potential barriers.

As part of their health assessments, workshop participants complete a depression screening questionnaire. Depression is more prevalent among people with diabetes, decreases self-efficacy, and is a major barrier to behavior change and successful glycemic control. More than one-third of the workshop participants score at about the clinical cutoff point on the depression screening questionnaire.

All individuals within the Portsmouth City Primary Care Trust who have newly diagnosed type 2 diabetes are booked into a workshop on confirmation of diagnosis. A sufficient number of workshops is offered to ensure that individuals can attend within 1 month of diagnosis. Because each daylong workshop is structured with the “bad news” about diabetes coming in the morning before the “good news” about self-management in the afternoon, availability for the whole day is confirmed, and participants are rescheduled if they cannot attend the entire workshop. Each workshop is limited to 10 participants, plus their partners, to provide sufficient time to address collective and individual needs.

Table 1 provides an outline of the entire workshop. After the introductions, participants are invited to tell their stories of how they were diagnosed with diabetes and what they already know about diabetes. Participants’ responses are noted on flip charts at the front of the room, so that this information can be reviewed later. Both individuals with diabetes and their partners are also asked to identify one thing they would like to get from the workshop. The facilitator then works through the symptoms and causes of diabetes. This supports participants in understanding what insulin resistance is and what insulin does so that they can then work through how this relates to their own symptoms and causal beliefs.

After coffee, the next section focuses on the complications of diabetes and the health assessments that participants’ diabetes care team will be doing on a regular basis. Again using dual process theory, participants are supported in working out what blood pressure, total cholesterol, HDL cholesterol, and blood glucose are and how these relate to the different complications of diabetes that were identified in the first session.

The group then dissipates to rotate through various workstations around the room, where they can take their blood pressure; get their total and HDL cholesterol checked; learn how to use a blood glucose meter and perform a blood glucose check; complete the depression screening questionnaire; self-assess their current diet against nutritional guidelines; and self-assess their risks of developing complications of the feet and eyes. This process is supported by two health care professionals and a layperson with diabetes, who shows participants how to check their blood glucose levels. Participants use the information they gather to complete a health profile ( Figure 1 ), which they will use later in the day to facilitate goal setting.

The lay facilitator then tells the group his personal story of living with type 2 diabetes for more than 20 years and gives himself his lunchtime insulin injection to help people understand that insulin therapy can be a positive and near-painless experience. This can help dispel participants’ fears about insulin.

After lunch, the sessions focus on the various dietary recommendations, breaking them down into key messages and exploring how each recommendation or change would affect the different measures that were discussed and assessed in the morning. The workshops take a similar approach with regard to current recommendations for physical activity and how this influences patients’ health. The group also discusses issues related to medication taking, blood glucose monitoring, and, where appropriate, smoking.

The final session supports participants as they review the day, first by encouraging them to generate a list of all the things they can do to influence their diabetes, such as change the amount of food they eat, the types of fat they include in their diets, and so forth. The group then links each of these behaviors to the various elements of their health profile, which are, in turn, linked to the complications of diabetes.

Participants then use their health profile and the day’s learning to identify something they want to change and develop a behavioral goal and action plan. This plan identifies which risk factor they want to change, which behavior they must change to do this, what their exact goal is, and how they plan to achieve this goal. These plans are written down in patients’ workshop handbooks, and copies are sent to their primary care provider for follow-up.

Finally, the group works through the list of questions participants wanted to address, and any outstanding questions are answered. This question/answer period concludes the group portion of the workshop. Participants are then given an opportunity to have a brief, private one-on-one chat with one of the facilitators.

These workshops are a relatively new initiative in the United Kingdom. The only other model currently in use (in Bournemouth, U.K.) provides patient education at diagnosis in a specialist diabetes center.

The Portsmouth workshops were designed to provide self-management education for people with newly diagnosed type 2 diabetes, and this goal has been achieved with a substantial degree of success. The general practitioners who refer their patients to these workshops have reported that the programs make their jobs of providing care for these patients easier and allow them to have conversations with patients that they have never had before.

These workshops are now embedded into routine care provided by the Portsmouth Trust and, being run in a local community center, are accessible to all individuals. They are cost-effective and financially sustainable, costing about $80 U.S. per person, including all assays, refreshments and lunch, staffing, room rental fees, and stationery. Initial evaluation indicates these workshops result in significant changes in self-management behavior and are accompanied by significant reductions in hemoglobin A 1c , total cholesterol, and body mass index. 15

This workshop model is now also being used to provide self-management education for newly diagnosed patients in two neighboring primary health care organizations and for screen-detected patients in another city in England that has a substantial (24%) South Asian ethnic population. It is also being reviewed by several other health care providers around England. Experience to date has indicated that the workshops can address multicultural patient education, but that, for some ethnic or religious groups, single-sex workshops or workshops conducted in participants’ native languages are needed. These workshops are also now used by the local primary care trust as part of community nurses’ continuing professional development.

Workshop organizers are convinced that group self-management education that is grounded in an empowerment philosophy and psychological theory and attended by individuals when told it is part of their diabetes care is enjoyed by patients and professionals, is effective in changing beliefs about diabetes and initiating lifestyle change, is easily integrated into diabetes care pathways, and is sustainable and affordable.

The model of type 2 diabetes created by the individuals participating in the workshop.

Health profile used in workshops to help people make diabetes management decisions. The shading is designed to give a visual representation of the increase in risk for coronary heart disease and the treatment targets (to try to get everything into the white and keep it there). The “go to page” column gives the page numbers in the patient handbook that provide more information about each risk factor and what self-management tasks will influence the risk factor.

Workshop Outline

T. Chas Skinner, PhD, is a health psychologist in the Department of Diabetes and Endocrinology at Leicester Royal Infirmary in Leicester, U.K. Sue Cradock, RGN, DipN, MSc, is a consultant nurse in diabetes, and Francesca Arundel, RGN, BSc, is a diabetes nurse specialist at the Portsmouth Diabetes Centre & Portsmouth City Primary Care Trust in Portsmouth, U.K. William Graham is the lay facilitator for the Portsmouth, U.K., diabetes workshops.

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Two decades since the fetal insulin hypothesis: what have we learned from genetics?

Alice e. hughes.

Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK

Andrew T. Hattersley

Sarah e. flanagan, rachel m. freathy, associated data.

This review did not generate any new data.

Graphical abstract

In 1998 the fetal insulin hypothesis proposed that lower birthweight and adult-onset type 2 diabetes are two phenotypes of the same genotype. Since then, advances in research investigating the role of genetics affecting insulin secretion and action have furthered knowledge of fetal insulin-mediated growth and the biology of type 2 diabetes. In this review, we discuss the historical research context from which the fetal insulin hypothesis originated and consider the position of the hypothesis in light of recent evidence. In summary, there is now ample evidence to support the idea that variants of certain genes which result in impaired pancreatic beta cell function and reduced insulin secretion contribute to both lower birthweight and higher type 2 diabetes risk in later life when inherited by the fetus. There is also evidence to support genetic links between type 2 diabetes secondary to reduced insulin action and lower birthweight but this applies only to loci implicated in body fat distribution and not those influencing insulin resistance via obesity or lipid metabolism by the liver. Finally, we also consider how advances in genetics are being used to explore alternative hypotheses, namely the role of the maternal intrauterine environment, in the relationship between lower birthweight and adult cardiometabolic disease.

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Supplementary Information

The online version of this article (10.1007/s00125-021-05386-7) contains a slideset of the figures for download, which is available to authorised users.

Introduction

Lower birthweight is associated with a higher risk of adult cardiometabolic disease, including type 2 diabetes [ 1 ]. This relationship was first observed in a study from 1991 linking birthweight records to results of glucose tolerance tests performed in adult men [ 2 ], and multiple epidemiological studies have since confirmed this association [ 3 ]. The ‘thrifty phenotype’ hypothesis was put forward as an explanation in 1992, suggesting that maternal malnutrition led to poor fetal growth, with adaptation to a nutritionally depleted intrauterine environment resulting in abnormal pancreatic beta cell function and reduced capacity to secrete insulin extending into adult life [ 4 ]. The thrifty phenotype hypothesis has since expanded to include preconceptual, periconceptual and other intrauterine exposures and postnatal outcomes, and is now known as the Developmental Origins of Health and Disease (DOHaD) hypothesis [ 5 ].

An alternative explanation (the fetal insulin hypothesis) was put forward in 1998, proposing that lower birthweight and adult-onset type 2 diabetes are two phenotypes of the same genotype (Fig. (Fig.1) 1 ) [ 6 , 7 ]. Jørgen Pedersen identified fetal insulin as a key intrauterine growth factor in 1952 [ 8 ] and this, together with the observation that monogenic diseases affecting insulin secretion and action were accompanied by lower birthweight, formed the premise of the fetal insulin hypothesis. It proposed that insulin secretion and resistance, genetically determined and present from conception, also affect intrauterine growth and explain the relationship between lower birthweight and adult-onset type 2 diabetes observed in epidemiological studies [ 1 – 3 ].

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Principles of the fetal insulin hypothesis compared with the thrifty phenotype hypothesis. This figure is available as part of a downloadable slideset

In the two decades since the fetal insulin hypothesis was founded, advances in research encompassing the genetics of type 2 diabetes and birthweight have made it possible to test the hypothesis and answer important questions about the relationship between fetal growth and development of type 2 diabetes in later life. In this review, we evaluate the evidence for and against the fetal insulin hypothesis, considering recent evidence from genetic and epidemiological studies. We also consider how genetics could be utilised to explore the complex relationships between the intrauterine environment, fetal genotype and adult-onset type 2 diabetes. The scope of the review does not encompass evaluation of the position of the DOHaD hypothesis in relation to type 2 diabetes risk, as this has been considered in detail in another recent review [ 9 ].

The fetal insulin hypothesis from the perspective of monogenic research

The role of fetal genotype in determining insulin-mediated growth in utero: studies in families affected by gck -mody.

A study of birthweights from pregnancies affected by MODY due to a heterozygous mutation in the glucokinase gene ( GCK ) [ 6 ] provided important insights into how the fetal genotype determines insulin-mediated growth in utero. These mutations result in reduced sensing of glucose by the pancreatic beta cell, so individuals with GCK -MODY regulate glucose at a higher set-point (fasting plasma glucose 5.5–8 mmol/l [ 10 ]) and have stable, mild hyperglycaemia throughout life [ 11 ]. An analysis of birthweights in 23 families with GCK -MODY found that where the mother had GCK -MODY and her fetus did not, birthweight was approximately 600 g higher than average due to higher fetal insulin secretion in response to maternal hyperglycaemia. However, when the fetus had inherited the GCK mutation from their mother, birthweight was no different from average because in such pregnancies glucose is sensed by both mother and fetus at the same level and a normal amount of insulin is secreted. In contrast, where the mother did not have GCK -MODY and the fetus had inherited a mutation in GCK from the father, birthweight was reduced by approximately 500 g (Table (Table1). 1 ). In this case, maternal glucose crossing the placenta is sensed at a higher threshold by the fetus, resulting in less insulin secretion. This work contributed important knowledge to the relationship between maternal blood glucose levels and fetal genotype in regulating intrauterine growth, prompting the proposal of the fetal insulin hypothesis [ 7 ].

Birthweight in monogenic diseases associated with reduced insulin secretion and action

Gene	Disease	Effect on birthweight at term gestation	In support of fetal insulin hypothesis?	References
Reduced insulin secretion
	MODY	↓~500 g	✓	[ ]
	MODY	↔Normal		[ ]
	MODY	↑~800 g		[ ]
	MODY	↓~800 g	✓	[ ]
,	Neonatal diabetes	↓~800 g	✓	[ – ]
Absent insulin secretion
	Neonatal diabetes	↓~1500 g	✓	[ ]
, , , ,	Pancreatic agenesis	↓~1500 g	✓	[ – ]
Insulin resistance
	Congenital insulin resistance	↓~1500 g	✓	[ – ]
, ,	Congenital generalised lipodystrophy	↔Normal		[ , – ]
, ,	Familial partial lipodystrophy	↔Normal		[ – ]

Studying the genetics of GCK -MODY pregnancies to gain knowledge of birthweight has been clinically important as it has informed obstetric care. Historically, these at-risk pregnancies were monitored with serial ultrasound scans and the fetus was assumed not to have inherited the maternal mutation if there was evidence of fetal overgrowth (abdominal circumference >75th percentile for gestational age). In this case, treatment of maternal hyperglycaemia was trialled, followed by planned delivery at 38 weeks gestation to mitigate the intra- and postpartum risks of having a large-for-gestational-age (LGA) baby. More recently, non-invasive prenatal diagnostic testing of cell-free fetal DNA in maternal blood has become available [ 12 ] and has the potential to prevent unnecessary treatment of maternal hyperglycaemia in fetuses who have inherited a GCK mutation.

Single-gene mutations that result in reduced insulin secretion typically reduce birthweight

The discovery that neonatal diabetes is commonly caused by mutations in single genes affecting insulin secretion has lent further support to the fetal insulin hypothesis (Table (Table1) 1 ) [ 6 , 13 – 23 ]. These cases are rare and represent a severe phenotype but the principle that genetics determines both fetal growth and postnatal insulin secretion is supported by the observation that infants with neonatal diabetes have very low birthweights (median SD score (SDS) for sex and gestational age −1.7 [ 24 ]). Furthermore, the severity of fetal growth restriction depends on the amount of fetal insulin secretion, as infants with complete absence of fetal insulin secretion due to loss-of-function mutations in the insulin gene or pancreatic agenesis are half of normal birthweight by term gestation (median SDS for sex and gestational age <−3.0, unpublished data from A. Hughes et al). This is in contrast to other animal species, where absent fetal insulin secretion reduces birthweight to a much lesser extent than in humans [ 25 ]. Therefore, human birthweight is a bioassay of inherent insulin secretory capacity, and monogenic disorders of insulin secretion provide unique insights into the genetic link between lower birthweight and diabetes resulting from reduced insulin secretion.

Birthweights in HNF4A -MODY and HNF1A -MODY are not consistent with the fetal insulin hypothesis

Not all instances of monogenic diabetes secondary to reduced insulin secretion are associated with lower birthweight. Heterozygous mutations in the genes encoding the transcription factors hepatic nuclear factor-4α and -1α ( HNF4A and HNF1A , respectively) result in reduced insulin secretion [ 26 , 27 ] and mutation carriers develop diabetes in childhood or early adulthood [ 28 ]. The fetal insulin hypothesis would predict that affected individuals have a low birthweight, yet individuals with HNF1A -MODY have normal birthweights and inheritance of HNF4A -MODY is associated with fetal and neonatal hyperinsulinism and macrosomia (Table (Table1) 1 ) [ 29 ]. It has been proposed that fetal hyperinsulinism causes accelerated postnatal pancreatic beta cell apoptosis, which subsequently predisposes to early-onset diabetes [ 30 ]. However, it has recently been found that higher birthweight is associated with reduced penetrance of HNF4A -MODY (unpublished data from J. Locke and K. Patel). Therefore, higher birthweight in HNF4A -MODY is likely to represent a greater inherent capacity to secrete insulin, and differential expression of HNF4A isoforms in the fetus and in later life [ 31 , 32 ] may provide an alternative explanation for these contrasting effects of HNF4A mutations.

Monogenic diseases resulting in severe insulin resistance have heterogeneous effects on birthweight

The relationship between birthweight and monogenic diabetes secondary to impaired insulin action is unclear (Table (Table1). 1 ). Consistent with the fetal insulin hypothesis, infants with severe congenital insulin resistance secondary to loss-of-function mutations in the insulin receptor gene, INSR , have very low birthweights [ 33 – 35 ]. Single-gene mutations resulting in either congenital generalised or familial partial lipodystrophy are characterised by peripheral insulin resistance due to an absence of subcutaneous adipose tissue, and affected individuals typically develop diabetes in adolescence [ 36 ]. However, birthweights of infants with congenital generalised lipodystrophy have been reported to be normal [ 37 ] and though there are reports of low birthweight in familial partial lipodystrophy [ 38 , 39 ], this has not been widely reported as a typical clinical feature in the literature [ 40 – 42 ].

The fetal insulin hypothesis from the perspective of epidemiological research

Paternal type 2 diabetes is associated with lower offspring birthweight but is not clearly related to heritable insulin resistance.

Observational studies of paternal diabetes status and offspring birthweight have provided evidence for a shared genetic predisposition to lower birthweight and type 2 diabetes [ 43 , 44 ]. The study of paternal diabetes is important, since maternal diabetes leads to higher birthweight [ 45 ] and masks the effect of fetal genes predisposing to diabetes inherited from the father. This was clearly shown by a study of 236,030 participants (UK Biobank study) wherein paternal diabetes was associated with a 45 g lower birthweight compared with birthweights of infants who had no parent with diabetes. In contrast, birthweight in offspring of parents who both had diabetes was not different from birthweight of infants for whom neither parent had diabetes(Fig. diabetes(Fig.2) 2 ) [ 43 ].

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Birthweight according to parental diabetes status in the UK Biobank study [ 43 ]. ** p <0.001 vs birthweight where neither parent was reported to have diabetes. Figure adapted from Tyrell et al [ 43 ] under the terms of the Creative Commons Attribution 3.0 Unported License. This figure is available as part of a downloadable slideset

The fetal insulin hypothesis proposed a possible role for heritable insulin resistance, and there has been evidence for a relationship between low birthweight and higher levels of paternal insulin resistance in case–control ( n =119) [ 46 ] and cross-sectional ( n =2788) [ 47 ] studies. However, paternal insulin resistance was not independently associated with offspring birthweight in a birth-cohort study of 986 UK parent–offspring trios [ 48 ], and there was a positive correlation between paternal HOMA-IR and umbilical cord insulin levels in 644 fathers and babies [ 49 ]. Together, this suggests that in utero there may in fact be a compensatory rise in insulin levels in the face of insulin resistance to maintain fetal growth.

The fetal insulin hypothesis from the perspective of polygenic research

Type 2 diabetes risk loci are associated with lower birthweight.

The first genome-wide association studies (GWAS) transformed the landscape of research into the genetics of type 2 diabetes [ 50 – 52 ] and allowed us to test the fetal insulin hypothesis. Initially, variants at type 2 diabetes risk loci affecting insulin secretion were tested for their association with birthweight and it was found that fetal risk alleles at the CDKAL1 and HHEX-IDE loci were associated with a lower birthweight [ 53 , 54 ]. The effect was also important; the reduction in birthweight in a fetus carrying four risk alleles was equivalent to that seen in a fetus whose mother smoked three cigarettes per day in the third trimester of pregnancy.

The first GWAS for birthweight shortly followed [ 55 ] and one of the first variants identified was at the known type 2 diabetes risk locus in ADCY5 , which plays a key role in coupling glucose to insulin secretion from the pancreatic beta cell [ 56 ]. Since then, successively larger GWAS of birthweight, with the latest including data on >400,000 individuals, have identified a total of 190 loci associated with birthweight [ 57 – 59 ]. Using a recently developed method [ 59 , 60 ], the statistical power from these large samples could then be harnessed to estimate the independent maternal and fetal effects at each locus. To date, 11 variants with fetal effects both on birthweight and on type 2 diabetes risk have been identified (Table (Table2 2 ).

Fetal risk loci associated with birthweight and type 2 diabetes

Birthweight and type 2 diabetes risk locus	Effect of fetal type 2 diabetes risk-raising allele on birthweight ( score)	Likely biology underlying type 2 diabetes risk
	−0.02	Higher insulin resistance [ , ]
	−0.06	Reduced insulin secretion [ , ]
	−0.05	Reduced insulin secretion [ , ]
	+0.03	Reduced insulin secretion [ , ]
	−0.02	Not known
	−0.04	Reduced insulin secretion [ , ]
	−0.02	Not known
	−0.03	Not known
	−0.02	Reduced insulin secretion [ , ]
	−0.01	Reduced insulin secretion [ , ]
	−0.04	Reduced insulin secretion [ ]

Birthweight SNPs [ 59 ] at these loci are in linkage disequilibrium ( R 2 >0.3) with a primary or secondary signal type 2 diabetes SNP [ 61 ]. A 1 SD change in birthweight is equivalent to ~450 g

There is heterogeneity in the relationship between birthweight and type 2 diabetes risk loci

Type 2 diabetes risk alleles associated with pancreatic beta cell function.

The strongest associations between type 2 diabetes risk alleles and lower birthweight are at loci that primarily affect pancreatic beta cell function (e.g. ADCY5 and CDKAL1 ; Fig. Fig.3). 3 ). However, not all risk alleles at beta cell loci are associated with lower birthweight. For example, the fetal risk allele at TCF7L2, which has a relatively large effect on type 2 diabetes risk, has no effect on birthweight, and the fetal risk allele at the ANK1 locus is associated with a higher birthweight [ 59 ] despite its role in regulating NKX6-3 [ 61 ], a vital transcription factor involved in pancreatic beta cell development [ 62 ]. These emerging patterns of association are consistent with the heterogeneous birthweight effects of monogenic causes of diabetes secondary to reduced insulin secretion and suggest that different susceptibility loci exert their effects on beta cell function at different stages in the life course.

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Object name is 125_2021_5386_Fig3_HTML.jpg

The effect of fetal type 2 diabetes (T2D) risk alleles on birthweight (BW) clustered by their likely underlying biology (beta cell function, proinsulin secretion and insulin resistance secondary to obesity, lipodystrophy-like fat distribution or disrupted liver lipid metabolism) [ 81 ]. SNPs within each cluster are ordered from top to bottom by highest to lowest T2D risk (established from a genome-wide association study of participants of European ancestry [ 61 ]). SNPs that appear in more than one cluster ( ADCY5 , CCND2 , CDC123/CAMK1D , HSD17B12 , HNF4A ) are shown by an accompanying number in parentheses. There are two distinct signals at ANKRD55 (shown as ANKRD55_1 and ANKRD55_2 ). The error bars show the 95% CIs for the estimated fetal effect on birthweight in Europeans (independent of any maternal effect [ 59 ]), with 1 SD change in birthweight being equivalent to ~450 g. This figure is available as part of a downloadable slideset

Type 2 diabetes risk alleles associated with insulin resistance, obesity or liver lipid metabolism

Certain type 2 diabetes risk alleles associated with insulin resistance secondary to a metabolically unfavourable lipodystrophy-like fat distribution (e.g. IRS1 ) are associated with lower birthweight but those implicated in obesity or liver lipid metabolism are not. Consistent with this, recent evidence shows that fetal carriage of variants associated with adult adiposity and a favourable metabolic profile (including higher insulin sensitivity) [ 63 ] is associated with higher birthweight [ 64 ]. This could mean that a genetic predisposition to lower insulin sensitivity results in a lower birthweight but, in keeping with the monogenic and epidemiological data, the different pathways affecting insulin action are not consistently shared between birthweight and type 2 diabetes risk (Fig. (Fig.3 3 ).

Quantifying the relationship between lower birthweight and type 2 diabetes that can be attributed to genetic risk

While there is now clear support for the fetal insulin hypothesis, the question remains as to how much of the association between lower birthweight and type 2 diabetes is explained by the genetic associations. Most variants in the type 2 diabetes risk loci do not appear to be associated with birthweight and the finding that a fetal genetic score for birthweight predominantly influences pathways independent of fetal insulin secretion [ 65 ] suggests that a substantial proportion of the fetal genetic variability underlying birthweight does not overlap with underlying susceptibility to type 2 diabetes. However, it remains uncertain how much of the relationship (the covariance) between lower birthweight and type 2 diabetes could be explained by the genetic factors that do overlap. To date, using genome-wide data, shared genetic effects of common variants have been estimated to explain 36% (15–57%) of the negative covariance between birthweight and type 2 diabetes risk [ 59 ], although this comes with the important caveat of uncertainty introduced by the likely non-linear relationship between the two phenotypes [ 57 ].

Mendelian randomisation studies exploring the role of the intrauterine environment in determining relationships between lower birthweight and adult cardiometabolic disease

While there is accumulating evidence for the relationship between lower birthweight and type 2 diabetes having a shared genetic aetiology, long-lasting effects of the intrauterine environment on early development are thought to play an important role. Many studies of animal models have shown this to be the case [ 66 ] and the most convincing evidence in humans has come from studies of offspring born during periods of famine, showing that they are at a higher risk of disorders of glucose metabolism and type 2 diabetes in adulthood (reviewed in detail in [ 67 ]). In addition, monozygotic twins discordant for type 2 diabetes have a lower birthweight [ 68 ], a finding which supports an effect of the intrauterine environment on both restricted fetal growth and developmental programming of metabolism.

Genetics can be used to test whether there is a causal relationship between an intrauterine exposure and adult type 2 diabetes by analysing genetic variants specifically associated with the exposure in a technique called Mendelian randomisation [ 69 ]. It is akin to a randomised control trial, since genetic variants are randomly assigned at birth and as the genes are specific to the exposure it is not generally subject to confounding from other factors that may mediate the relationship between the exposure and outcome.

There have been attempts to use Mendelian randomisation to show that lower birthweight is causally related to type 2 diabetes [ 70 – 72 ] but the results were difficult to interpret as they did not appropriately differentiate between maternal and fetal effects [ 73 – 75 ]. Methods have been established to account for maternal and fetal effects and test for causal associations between pregnancy exposures and offspring traits [ 59 , 60 , 76 ]. A recent, large study of genotyped parent–offspring pairs ( n =45,849) showed no evidence for a causal relationship between maternal intrauterine exposures that influence birthweight and offspring quantitative cardiometabolic traits (glucose, lipids, BP, BMI) [ 76 ]. A specific example tested by Mendelian randomisation and relevant to the fetal insulin hypothesis is the relationship between maternal systolic BP (SBP) and offspring birthweight and SBP. This showed that while high maternal SBP results in reduced fetal growth, it is not causal for high offspring SBP but instead reflects a shared genetic predisposition to higher SBP (Fig. (Fig.4) 4 ) [ 59 , 76 ]. This example demonstrates a key underlying premise of the fetal insulin hypothesis: that the fetal genotype can explain observational relationships between lower birthweight and adult traits. However, unlike the fetal insulin hypothesis, the relationship between lower birthweight and higher adult SBP may be explained by a combination of maternal intrauterine effects on birthweight and fetal genetic susceptibility to higher adult SBP.

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Object name is 125_2021_5386_Fig4_HTML.jpg

Principles of using Mendelian randomisation to explore the roles of pregnancy exposures and fetal genetics in the relationship between birthweight and risk of adult cardiometabolic disease. The example in this figure shows that the relationship between lower birthweight and higher offspring SBP is mediated by a combination of intrauterine effects on birthweight and fetal genetic susceptibility to higher adult SBP. Figure adapted from Lawlor et al [ 75 ] under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/ ), which permits unrestricted use, distribution, and reproduction in any medium. This figure is available as part of a downloadable slideset

In the two decades since the fetal insulin hypothesis was first proposed, advances in genetic research have shed light on what contributes to fetal insulin-mediated growth and its implications for long-term risk of type 2 diabetes. Strong evidence from monogenic studies has been supported by epidemiological observations and discoveries arising from large-scale GWAS of type 2 diabetes and birthweight. Taken as a whole, it is clear that both lower birthweight and type 2 diabetes reflect, in part, a shared genetic predisposition to reduced insulin secretion. However, while impaired insulin action was considered a key part of the original fetal insulin hypothesis, studies of birthweight relating to monogenic lipodystrophies, paternal insulin resistance and the biology underlying shared birthweight and type 2 diabetes risk loci suggest this may be a less important factor in mediating the relationship between lower birthweight and type 2 diabetes risk.

Research investigating the premise of the fetal insulin hypothesis will continue to be important as type 2 diabetes becomes more prevalent globally. As this is predominantly associated with rising levels of obesity, it is possible that the variance in adult type 2 diabetes risk that can be explained by genes which also reduce insulin-mediated fetal growth becomes less important. This is because risk variants associated with high BMI are not strongly represented in birthweight GWAS and mothers with higher BMIs are at risk for diabetes in pregnancy, which leads to higher birthweights. Addressing this and other important challenges, including diversifying research to include non-European populations and exploring non-linear relationships and gene–environment interactions, will provide further insights into the genetics of insulin-mediated fetal growth and its implications for health and disease across the life course.

(PPTX 476 kb)

Acknowledgements

We thank J. Locke and K. Patel (both Institute of Biomedical and Clinical Science, University of Exeter Medical School, UK) for their permission to cite their unpublished data in this review.

Authors’ relationships and activities

The authors declare that there are no relationships or activities that might bias, or be perceived to bias, their work.

Contribution statement

All authors were responsible for drafting the review and revising it critically for important intellectual content. All authors approved submission. RMF is the guarantor of this work and accepts full responsibility for its content and controlled decision to publish.

Abbreviations

DOHaD	Developmental Origins of Health and Disease
GWAS	Genome-wide association studies
SBP	Systolic BP
SDS	SD score

AEH is supported by the Wellcome Trust and University of Exeter through a GW4 Clinical Academic Training PhD Fellowship. ATH is supported by the Wellcome Trust through a Senior Investigator Award (Grant Number WT098395/Z/12/Z) and is a National Institute of Health Research (NIHR) Senior Investigator. SEF and RMF have Sir Henry Dale Fellowships jointly funded by the Wellcome Trust and the Royal Society (Grant Numbers 104150/Z/14/Z and 105636/Z/14/Z).

Data availability

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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Two decades since the fetal insulin hypothesis: what have we learned from genetics?

Andrew T. Hattersley

Graphical abstract

Supplementary Information

Introduction

The fetal insulin hypothesis from the perspective of monogenic research

Single-gene mutations that result in reduced insulin secretion typically reduce birthweight

Birthweights in HNF4A -MODY and HNF1A -MODY are not consistent with the fetal insulin hypothesis

Monogenic diseases resulting in severe insulin resistance have heterogeneous effects on birthweight

The fetal insulin hypothesis from the perspective of epidemiological research

The fetal insulin hypothesis from the perspective of polygenic research

There is heterogeneity in the relationship between birthweight and type 2 diabetes risk loci

Type 2 diabetes risk alleles associated with insulin resistance, obesity or liver lipid metabolism

Quantifying the relationship between lower birthweight and type 2 diabetes that can be attributed to genetic risk

Mendelian randomisation studies exploring the role of the intrauterine environment in determining relationships between lower birthweight and adult cardiometabolic disease

Acknowledgements

Authors’ relationships and activities

Contribution statement