Overweight and obesity in children and adolescent with Type 1 Diabetes: A challenging combination 

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Author(s):

	Ioanna Kosteria
	Pediatric Endocrinology Dept. of Endocrinology-Growth and Development, Children’s Hospital “P. & A. Kyriakou”, Athens, Greece
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	Elpis Vlachopapadopoulou
	Dr Vlachopapadopoulou is a member of the Endocrine Society since 1994, of the European Society of Pediatric Endocrinology since 1997 and of the European Society of Endocrinology since 2006.
	View Author’s Full Biography

Introduction  

Type 1 Diabetes Mellitus (T1D) is the most prevalent form of Diabetes during childhood and adolescence. A trend of increasing prevalence has been documented. The pathophysiology of the disease consists of the body’s inability to produce insulin due to the autoimmune destruction of the beta cells in the pancreas. Regarding body weight homeostasis, although T1D has been historically associated with weight loss and the catabolic effects of insulinopenia, access to insulin and intensified insulin regimens have allowed children with T1D to have normal growth and to follow a lifestyle similar to their peers. It is, therefore, not surprising, that the global epidemic of obesity had an impact on the prevalence of overweight or obesity in children with T1D. The impact of increased body weight on glycemic control as well as the contribution of the vicious cycle of increasing requirements of insulin in order to consume larger amounts of food and vice-versa is important to be studied and analyzed in detail, aiming to clarify the pathophysiology. 

Epidemiology 

The SEARCH for Diabetes in Youth Study reported that the weight of 22.1 % and 12.6% of children with T1D aged 3-19 years, was in the overweight or obesity range, respectively, compared to 16.1% and 16.9% of their peers from the National Health and Nutrition Examination Survey (NHANES) ​(1)​. Similar were the percentages reported by the T1D exchange, with age, female sex, lower educational and socioeconomic status being associated with higher BMI  ​(2)​. In the international (but mostly European) SWEET registry the prevalence of overweight and obesity were 22.3%, and 7.3% in males and 27.2%, and 6.8% in females, respectively ​(3)​, whereas the German-Austrian registry estimated a prevalence of 15.3% of overweight and obese children (10) (Fig 1). Longitudinal data showed an increase in the prevalence of obesity in adults with T1D from 3.4% (1986 to 1988) to 22.7% (2004 to 2007), with the rate of increase being faster than the respective one in the general population ​(4).​ Encouragingly, cross-sectional data from four cohorts of children aged 8-16 years with T1D from Joslin Diabetes Center in different timepoints (1999, 2002, 2006, 2009) showed that the prevalence of overweight/obesity did not significantly change 27% (1999), 36% (2002), 33% (2006), and 31% (2009) (p = 0.54) ​(5)​, possibly also reflecting the stabilization of the percentages of overweight and obesity in wealthier countries ​(6).​  

Fig 1. Prevalence of overweight and obesity across 4 major databases of children with T1D.   

Risk factors for weight gain in T1D 

The DCCT trial showed that intensive insulin treatment and tight glycemic control were associated with increasing weight, since the intensive treatment arm achieved better ΗbA1c but gained substantially more weight compared to the conventional treatment arm (5.1 vs 2.4 kg, p<0.0001) ​(8)​. A recent analysis following the weight trajectories of the participants of the DCCT trial further demonstrated that factors associated with weight gain were higher HbA1c at baseline, greater improvement, higher insulin doses and a family history of T2D. Weight gain in participants on conventional treatment was similar to that of control subjects without diabetes. Peripheral hyperinsulinism caused by higher insulin doses and increased carbohydrate intake to manage or prevent episodes of hypoglycemia were considered as probable drivers of weight gain ​(9)​. 

Longitudinal data from the German-Austrian registry (DPV) demonstrated that the increase in BMI was higher in females, in children with lower BMI at diabetes onset, children diagnosed during puberty, receiving intensified insulin regimen and higher daily insulin dose, with longer diabetes duration and diagnosed earlier in life, highlighting the importance of biological and temporal factors ​(10)​. Diabetes duration and age were also important predictors of weight gain especially in girls, in retrospective analysis of children diagnosed with T1D from 1991 to 2015, in Belgium ​(11)​. The SEARCH study also confirmed the preponderance of mainly female adolescents regarding excess weight and body fat and highlighted the importance of lower socioeconomic status and/or minority status ​(12)​. Regarding insulin regimen, the study from Joslin Diabetes Center that compared the cohorts from 1999, 2002 and 2006 reported that the prevalence of overweight and obesity remained stable despite the increase in intensified insulin regimens from 52 to 97%. In fact, BMI z-score did not correlate with ΗbA1c or intensive insulin treatment but was related to insulin dose​ (5)​. In contrast, low HbA1c and pump treatment correlated with higher BMI in the Scandinavian registry. Diabetes duration, higher insulin doses and a history of severe hypoglycemia were also important predictors  ​(13)​.   

Lifestyle/nutritional factors may also contribute to excess weight in T1D. Although exercise is a main pillar of T1D management, people with T1D are reported to exercise less compared to healthy controls ​(14)​. Fear of hypoglycemia and lack of exercise-specific guidance, among others, are commonly reported barriers, preventing children to practice ​(15)​. Excess snacking as a means to avoid or treat exercise-induced hypoglycemia may also contribute to weight gain, apart from lack of activity per se. Fear of hypoglycemia (not related to exercise), disordered eating behaviors ​(16)​, as well as higher intake of saturated fats, highly processed foods and lower intake of fibers ​(17)​ are contributing factors to excess weight and poor glycemic control in children with type 1 diabetes ​(18–20)​.  

Genetic predisposition may also have a role in increased body weight in patients with T1D. A Mendelian randomization analysis using 23 single nucleotide polymorphisms associated with childhood obesity and the results of genome-wide association studies of T1D identified an increased odds ratio (OR) for childhood adiposity on T1D (OR 2.76, 95% CI 1.40–5.44, after correction for possible biases) ​(21)​.  

Consequences of overweight/obesity in T1D 

The deleterious effects of body weight gain were obvious from the DCCT/EDIC trial. Central obesity, insulin resistance (IR), dyslipidemia and atherosclerosis were significantly correlated with body weight. In fact, those from the intensive treatment arm of the study that were on the highest quartile of weight gain, despite better glycemic control, longitudinally presented similar rate of cardiovascular events compared to the conventional treatment arm, indicating that weight gain outweighed the beneficial effect of improved glycemic control (22). Similarly, the analysis of 26 125 people with T1D from the National Diabetes Registry from 1998 to 2012 revealed that a BMI above 25 kg/m2 was significantly correlated with an increased risk of mortality, major cardiovascular events and heart failure ​(23)​.    

Results from studies focused on youth with T1D are equally alarming. The study of 11 348 children 2 -18 years enrolled in T1D Exchange between 2010 and 2012 revealed that the odds of either hypertension or dyslipidemia were higher in obese than healthy weight participants (OR 3.5, 99% CI 2.0-6.1 and 2.2, 99% CI 1.6-3.1, respectively). Interestingly, participants with obesity tended to be diagnosed with micro-/macroalbuminuria less often than healthy weight participants (OR 0.6, 95% CI 0.4-1.0) ​(24)​. Studies comparing youth with T1D and T2D also yielded interesting findings. A cross-sectional, retrospective study of 669 patients with T1D or T2D aged 2–19 years found that the T1D children with overweight and obesity had significantly higher triglycerides compared to normal weight T1D children and comparable to those of children with T2D. Increasing weight was associated with lower HDL levels in both T1D and T2D children ​(25)​. Multiple markers of cardiovascular and renal function, including heart rate, blood pressure, leptin, hs-CRP, adiponectin, urine albumin to creatinine ratio, estimated glomerular filtration rate, as well as VO2 max, arterial stiffness, distensibility of brachial artery and endothelial hyperemic index, were examined and compared in a multicenter study among 284 obese T1D, non-obese T1D and T2D adolescents, aged 12–21 years. The study revealed that adolescents with obesity and T1D had a worse cardiometabolic profile compared to non-obese and similar to that of T2D adolescents. In fact, hypertension and increased resting heart rate were most prominent in obese T1D ​(26)​. Finally, the Swedish National Diabetes Registry analyzed the data from 3 473 females 16-35 years old with regards to any type of diabetic angiopathy (retinopathy, microalbuminuria, macroalbuminuria and/or hypertension) in relation to BMI and found a gradually increased odds ratio for all types of angiopathy for overweight and obesity (OR 1.15, 95% CI 1.14-1.64 and OR 1.30, 95% CI 1.08-1.56, respectively) ​(27)​. 

Insulin resistance in Type 1 Diabetes 

IR is a common, if not universal, finding in people with T1D, that has been proved by numerous clamp studies that have consistently shown that glucose disposal rate is significantly decreased. IR in T1D exhibits some distinct characteristics compared to T2D, specifically that it occurs in the absence of increased BMI, visceral obesity, increased fat mass, hypertriglyceridemia or increased blood pressure. In fact, for the same BMI, people with T1D are more insulin resistant. Interestingly, it has been proven that IR is not associated with HbA1c or other CGM metrics ​(28)​. It has been shown that IR is mainly driven by the peripheral hyperinsulinemia caused by exogenous insulin administration and the subsequent exposure of the liver in supraphysiological doses of insulin that are needed to ensure adequate insulin quantity in blood circulation and euglycemia ​(29)​. Clamp studies have proven that basal insulin levels are more important than glycemic levels (as expressed by HbA1c) in inducing IR. Addressing increased IR in T1D is important as it is an independent factor for cardiovascular disease. The Coronary Artery Calcification in Type 1 Diabetes Cohort (CACTI study) clearly showed that decreased peripheral glucose utilization in T1D individuals compared to controls led to higher Non-Esterified Fatty Acid (NEFA) levels and was predictive of coronary artery calcification​ (28)​. The presence of excess weight further enhances IR through well-established pathways. 

The bidirectional relation between obesity and T1D  

The parallel increase in the prevalence of T1D with the prevalence of childhood obesity has given rise to the hypothesis that increased body weight may have a causal or a triggering effect. A Mendelian randomization study based on 15 573 cases and 158 408 controls showed that childhood body size at the age of 10 years is a predisposing factor for T1D​ (30)​. A recent systematic review and meta-analysis of seven cohort studies concluded that people with overweight or obesity had an almost 2-fold risk for developing T1D ​(31)​. Similarly, the TRIGR study showed that genetically at-risk children for T1D that were overweight at the age of 2-10 years, had a twofold higher risk for progressing from stage 2 (≥2 positive autoantibodies) to clinically overt diabetes ​(32)​. The analysis of all children younger than 15 years old, diagnosed from September 1986 to April 1989, from the Finnish Registry confirmed the increased risk for developing T1D in case of obesity after the age of 3 years, but further showed that a 10% unit increment in relative weight before 3 years of age resulted in 50-60% increase in the risk of T1D and a 20-40% increase from 3 to 10 years of age.  Similar were the results from the TEDDY study for the prevention of T1D, which showed that a higher rate of weight gain in early childhood was associated with an increased risk of progression from positive autoantibodies to clinical T1D (HR 2.57, 95% CI 1.34-4.91 per 1 kg/year) ​(33)​. Zucker et al., examined the effect of the increase of body weight later in life and reported that an increase of BMI SD by one at the age of 16-19 years was associated with a 25% greater risk for developing T1D in early adulthood ​(34)​. 

Several mechanisms have been suggested as a possible explanation for the effect of obesity in the development of T1D. Chronic inflammation present in obesity mediates several immunologic deviations, including disturbed Th/Treg balance or fewer B regulatory cells both systemically and locally. The inflammation of the adipose tissue results in secretion of inflammatory cytokines that induce IR and may even promote the production of autoantibodies due to increased apoptosis of adipocytes. The measurement of circulating adipokines and cytokines in the serum of newly diagnosed children revealed higher levels of leptin, visfatin, chemerin, TNF-alpha and CRP, and lower total adiponectin and omentin, in obese vs lean children, indicative of a proinflammatory profile ​(35)​. Other possible mechanisms include the direct effect of unhealthy diet on the fragility and susceptibility of β-cell ​(36)​, as well the indirect effect of diet and obesity induced inflammation on the gut microbiome, that are common for both T1D and T2D ​(37)​. The “Accelerator Hypothesis” published by Wilkin in 2001, supported the idea that insulin resistance accelerates β-cell loss through various mechanisms, including ER stress, oxidative stress and inability to remove ROS, accumulation of misfolded proteins, secretion of dysfunctional insulin and stimulation of autoantibody production to newly presented neoantigens, leading thus to faster development of insulinopenia and insulin dependency ​(38)​. The SEARCH study group studied this hypothesis but found an association between BMI SDS and age at diagnosis only among children with low fasting c-peptide levels, suggesting that b-cell function was already compromised and was subsequently unable to compensate for the additional insulin needs dictated by the increase in body weight​ (39)​.  

Double or hybrid or 1.5 diabetes 

As already mentioned, the presence of obesity-induced IR sometimes perplexes the differential diagnosis between T1D and T2D (see table1). It is not rare that a child with T2D presents with DKA and low c-peptide at diagnosis because of glucotoxicity and lipotoxicity that may impair insulin secretion. On the other hand, the IR of obesity may raise residual C-peptide levels in an obese child with T1D. In fact, among participants of the SEARCH study, 54.5% were typical T1D cases, characterized by autoimmunity and insulin sensitivity, 15.9% were typical T2D cases (no autoimmunity, IR) and 19.5% were children sharing characteristics of T1D and T2D (autoimmunity and obesity-induced IR) ​(40)​. Although there is still no universally accepted definition of double diabetes, it is important to consider the deleterious consequences of the unfavorable metabolic profile of children with T1D and obesity, especially in the era of the new treatments that are emerging ​(41)​. 

Table 1: Main features of the different types of diabetes of the young 

Prevention & Treatment of obesity in T1D 

Lifestyle 

Educational and behavioral strategies aiming to promote healthy eating habits and increased physical activity are the main pillars of managing obesity. They are especially important for children with T1D aiming to maintain BMI within the normal range, improve their glycemic control and prevent long-term cardiovascular complications. According to ISPAD guidelines published in 2022, the recommended carbohydrate intake for adolescents with overweight/obesity should constitute 40% of the total energy intake, slightly lower than the 45% recommended for healthy weight adolescents, while the recommended protein intake should constitute around 25%, slightly higher than the 15-25% recommended for healthy weight adolescents ​(42)​. Adequate fiber intake (14g/1 000 kcal) should also be encouraged. It has been suggested that carbohydrate-centered education in T1D may lead to overconsumption of carbs at the expense of other macronutrients ​(43)​. Regular weight and height measurements, plotting on the growth chart and evaluation of the growth curve, as well as calculation of BMI, and plotting on the WHO BMI curves, are of utmost importance to ensure appropriate growth rate for age, sex and pubertal status, and timely diagnosis of excess weight gain that is more frequently encountered but also weight loss. Moreover, screening for disordered eating and early recognition of signs of bulimia should be integrated in the ambulatory care of children with T1D ​(44)​.  

Exercise recommendations for children with T1D include at least 60 min per day of moderate to vigorous-intensity, primarily aerobic, physical activity and vigorous intensity aerobic activities, as well as muscle- and bone-strengthening activities, at least 3 days a week​ (45)​. Barriers to exercise should be recognized and addressed. Individualized exercise plans with suggested snacks, before, during and after exercise should be offered along with instructions on insulin management. The 2022 ISPAD guidelines provide detailed advice on how to manage exercise, including the need to calculate ideal BMI for individuals with a body mass index centile ≥91st and the need to diminish suggested carb quantities for individuals with increased sedentary time ​(45)​. Fear of hypoglycemia should be specifically addressed aiming to prevent excessive consumption of carbohydrates ​(46)​. 

The use of technology and new insulin analogues is extremely useful in ensuring a more physiological exposure to insulin, as well as in preventing hypoglycaemia and subsequent defensive snacking ​(47,48)​. However, people shifting from multiple daily injections (MDI) to continuous subcutaneous insulin infusion through a pump (CSII), often feel freer to snack whenever they desire and not following a specific timetable, as they can bolus frequently without the additional burden of an injection. In this case, the possible risk of excessive calorie intake leading to excessive weight gain must be emphasized ​(49,50)​. The timing of insulin administration and matching with carb intake should also be highlighted to avoid both under- and over-insulinization. Moreover, pump and closed loop features including temporary basal rates, temporary exercise targets, automated insulin suspension, suspension on prediction of hypoglycemia and autocorrections, may help prevent exercise-induced glucose fluctuations, thus facilitating children’s engagement in sport activities ​(51,52)​.  

Pharmacotherapy of obesity in children and adolescents with Type 1 diabetes 

Current literature provides scarce data on the pharmacological treatment of obesity in T1D and even more limited data are available for children.  

Orlistat, a reversible inhibitor of gastric and pancreatic lipases, approved by the FDA for the treatment of obesity in adolescents over 12 years old, is not contraindicated, but has not been studied in people with T1D ​(53).​ 

Similarly, there are no clinical studies in adolescents with T1D on the use of phentermine, or of the phentermine/topiramate combination, also approved by FDA for adolescent obesity. People with T1D should be advised to use these medications as an adjunct treatment and not to discontinue insulin treatment due to DKA risk. They should also be informed on the increased risk of hypoglycemia (both due to nausea/vomiting and weight loss) and be assessed for depressive symptoms and suicidal ideation that are more common in people with T1D and may be aggravated by the medications. Other side effects, including tachycardia or paresthesias, should also be explained, as they are also common symptoms in T1D ​(54,55).​  

Pramlintide, a synthetic analog of islet amyloid polypeptide (IAPP) is FDA approved in the USA, as an adjunct treatment to insulin for adults with T1D, that has resulted in HbA1c reduction and weight loss. However, it is only scarcely used in everyday practice due to hypoglycemia and gastrointestinal side effects, especially nausea. Pramlintide is initiated at a dose of 15 μg as a subcutaneous injection before each meal and titrated by 15 μg to a maintenance dose of 30-60 μg before meals. It is important to lower insulin doses when the drug is initiated ​(56).​ 

Although metformin is widely used in children with T2D older than 10 years of age, its use has not been approved for people with T1D, despite some promising results ​(57)​. However, both ADA guidelines and NICE guidance do not discourage the addition of metformin as an adjunct treatment to adults with T1D and excess weight ​(57,58)​. Randomized trials in adolescents have shown that it did not lead to substantial weight loss or improvement of glycemic control, but it did lead to reduction of insulin requirements ​(59,60)​.  

GLP-1 analogs have also been recently approved for children with T2D and/or severe obesity ​(61)​. Their use in T1D, as an adjunct treatment to insulin, has been studied in randomized controlled trials (RCT) in adults receiving both MDI and pump treatment, leading to weight reduction and an improvement of glycemic control with larger doses leading to better results, irrespective of baseline HbA1c or BMI. However, treatment was discontinued in 14.7% of participants due to severe gastrointestinal side effects. It also led to increased frequency of episodes of symptomatic hypoglycemia, as well as more episodes of hyperglycemia and ketosis ​(62,63)​. Although not statistically significant, more cases of DKA were also reported in pump users ​(64)​.   

Long-acting glucagon-like peptide-1 (GLP-1) analogs, namely semaglutide, have not yet been studied in RCTs for adolescents with T1D. However, the only two published studies for adults have demonstrated that semaglutide resulted in both weight loss and improved glycemic control in adults with T1D and excess weight ​(65,66)​. Similarly, tirzepatide, a glucose-dependent insulinotropic polypeptide (GIP) receptor and GLP-1 receptor agonist has only been recently shown to have promising results in adults with T1D ​(67)​.  

Sodium-glucose cotransporter 2 (SGLT2) and dual SGLT1 and SGLT2 inhibitors have been widely studied in randomized trials in adults with T1D with beneficial effects on weight loss, decrease of insulin requirements and HbA1c ​(68,69)​. However, these medications were not approved by authorities for use in T1D due to the estimated 8-fold increase in cases of euglycemic ketoacidosis ​(70)​. Nonetheless, given the beneficial effects of SGLT2 inhibitors not only on body weight and glycemic control, but also on cardiovascular and renal function, an international consensus has been published to mitigate the risk of DKA in people with T1D.   

Finally, Dipeptidyl Peptidase 4 (DPP-4) inhibitors have been studied in small, randomized trials in adults with T1D, without achieving substantial weight loss or reduction in HbA1c ​(71,72)​.  

Bariatric surgery 

Successful management of obesity with dietary intervention, increased physical activity or even pharmacotherapy may not be accomplished. In such cases metabolic and bariatric surgery may lead to substantial weight loss ​(73)​. Currently there are no clinical studies on bariatric surgery in children with T1D. A recent systematic review and meta-analysis of published case reports, case series, retrospective studies and 2 cohorts, including 648 adult patients with T1D who underwent bariatric surgery, reported a significant decrease in body weight (BMI: 42.6 ± 4.7 kg/m2 and 29.4 ± 4.7 kg/m2, pre and postoperatively, respectively) for a mean follow-up period of 32 ± 23.2 months. Mean insulin doses were impressively decreased by almost 10 IU/day (0.2 U/kg/day) and HbA1c was reduced by a weighted mean difference of 0.71 (around 6.6%) ​(74)​. Another systematic review, performed using the PRISMA guidelines and based on 30 studies and 706 people with T1D and obesity, confirmed the decrease in insulin doses from a mean of 92.3 IU/day to a mean of 35.8 IU/day postoperatively, but the effect on HbA1c differed among studies. No deaths were reported, and main postoperative complications were gastric ulcer, one marginal ulcer, incisional hernia, ulcer at the gastro-jejunal anastomosis, esophageal dysmotility, persistent nausea and nutritional deficiencies. Main side-effects included episodes of DKA and episodes of mild and severe hypoglycemia ​(75)​. Regarding common comorbidities of T1D and obesity, a decrease in the number of patients with hypertension, dyslipidemia, and obstructive sleep apnea by 42.8, 25, and 66 %, respectively, was reported after a mean follow-up time of 4.6 years. Regarding diabetic angiopathy, there was no improvement in retinopathy while there was a beneficial effect on albuminuria, as 25 % of patients with microalbuminuria regressed to normo-albuminuria. Almost 10% of a total of 32 patients, had an incident of severe hypoglycemia postoperatively and 2 had a DKA episode reportedly due to insulin omission ​(76)​. The predisposing factors for DKA have been reported to be surgical stress, suboptimal care, discontinuation or non-compliance with insulin therapy, infection, and electrolyte imbalance ​(77)​. Finally, a case-control study that compared 387 people with T1D, who underwent Roux-en-Y gastric bypass with 387 matched for sex, age, BMI and calendar year of surgery T1D patients, reported a lower risk for cardiovascular mortality and disease, heart failure and stroke and a 2-fold higher risk for severe hypoglycemia ​(78)​. Overall, bariatric surgery in people with T1D appears to be equally effective regarding weight loss as in people without T1D. The effect on glycemic control, however, is ambiguous, while there are still concerns on hypoglycemic and hyperglycemic episodes post-operatively. Longitudinal studies on complications are scarce but results so far are promising.  

Conclusion  

The global prevalence of overweight and obesity in children with T1D calls for the intensification and prioritization of the efforts for weight management in this population. It is especially important given the detrimental metabolic consequences of excess weight and increasing insulin resistance. Nutritional intervention, exercise, adjunct pharmacotherapy and bariatric surgery are the main pillars of weight management strategies. However, special consideration should be given to the specific barriers that limit the success of these approaches, such as fear of exercise and fear of hypoglycemia, treatment-related adverse events, including both acute hypo- and hyperglycemias, as well as the increased prevalence of disordered eating behaviors and the overall psychological burden of children with T1D. Structured, personalized education and counselling combined with insulin dosing adjustments constitutes the cornerstone for safely sustaining weight loss and achieving good glycemic control. The need for multi-centered randomized trials of emerging treatments in youth with T1D and excess weight is undisputable, as well as the need to improve access to trials/medication, reimbursement of these treatments and provision of multi-disciplinary care. Finally, the implementation of policies that enhance healthy eating and living behaviors in youth (with or without T1D) are of utmost importance for curbing and preventing the “obesity epidemic”.  

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