Drawing lines in the sand: The growing threat of obesity in type 1 diabetes

Abstract

In this editorial, we comment on the article by Zeng et al published in the recent issue of the World Journal of Diabetes in 2024. We focus on the epidemiological, pathophysiological, and clinical interplay between obesity and type 1 diabetes mellitus (T1DM). Overweight and obesity represent a growing threat for modern societies and people with T1DM could not be an exception to this rule. Chronic exogenous insulin administration, genetic and epigenetic factors, and psy-chosocial and behavioral parameters, along with the modern way of life that incorporates unhealthy eating patterns and physical inactivity, set the stage for the increasing obesity rates in T1DM. As our knowledge of the underlying mechanisms that lead to the development of obesity and hyperglycemia expands, it becomes clear that there are overlap zones in the pathophysiology of the two main types of diabetes. Stereotypes regarding strict dividing lines between “autoimmune” and “metabolic” phenotypes increase the risk of trapping physicians into ineffective therapeutic approaches, instead of individualized diabetes care. In this context, the use of adjuncts to insulin therapy that have the potential to alleviate cardiorenal risk and decrease body weight can reduce the burden of obesity in patients with T1DM.

Key Words: Obesity, Overweight, Type 1 diabetes, Metabolic syndrome

Core Tip: Overweight and obesity rates increase in people with type 1 diabetes mellitus as a result of social, environmental, genetic, and epigenetic factors. Increased awareness from healthcare teams and a personalized approach that incorporates behavioral, lifestyle, and pharmacological interventions are needed to prevent aggravation of glycemic control and obesity-related complications in this group of patients with diabetes.

INTRODUCTION

According to a famous historical myth, William Barrett Travis (1809-1836) scratched a line in the courtyard grounds of the Alamo fortress and invited his soldiers to join him on one side to commit their lives to the fight against Santa Anna’s army or to stay on the other and attempt escape. Eventually, Travis and his men died while defending the Alamo. In medicine in general, but in diabetes more specifically, physicians often have to draw dividing lines and classify patients into different types of the disease. However, the more we delve into the pathophysiology of hyperglycemia, the more it becomes evident that at least in some cases these lines are not so clear.

In a recently published observational study in the World Journal of Diabetes, Zeng et al[1] found that one in five (19.8%) Chinese patients with type 1 diabetes mellitus (T1DM) lived with overweight or obesity, while a relatively high prevalence of hypertension and dyslipidemia was reported in the study cohort (33.66% and 15.84%, respectively). The authors also demonstrated that visceral fat was a better predictor of metabolic syndrome in this population compared to conventional markers, such as body mass index (BMI) and waist-hip ratio. Despite the observational nature of the investigation and the fact that body composition was evaluated by bioelectrical impedance analysis instead of the gold standard method of dual energy X-ray absorptiometry, the study provides useful insights into the growing worldwide challenge of obesity in people with T1DM.

Traditionally, the main pathophysiological driver of metabolic disturbance in people with T1DM has been considered autoimmunity. On the contrary, type 2 diabetes mellitus (T2DM) is predominantly characterized by insulin resistance (IR). Although this distinction is definitely true, emerging evidence highlights that there are overlapping mechanisms in the pathogenesis of the two main types of diabetes. For example, genuine autoimmune pathways contribute to the development of hyperglycemia in T2DM[2], while IR is present in a significant proportion of people with T1DM and its prevalence increases parallel to the duration of the disease[3]. Beta-cell apoptosis is another common feature of T1DM and T2DM. Older studies suggest that in both types of diabetes there is abundant intra-islet expression of inflammatory mediators (predominantly interleukin-1β) which activate apoptosis pathways, ultimately leading to beta-cell failure[4]. However, what differs between T1DM and T2DM is the rate of loss of beta cell mass, which is progressive in the latter and abrupt in the former.

Furthermore, the increasing number of new cases of T1DM in recent decades raises the question to what extent the obesogenic environment contributes to this phenomenon[5,6]. Another interesting point to consider is whether the strictly “autoimmune” perspective on approaching T1DM treatment should be redefined in an era when new drug categories can offer cardiorenal protection along with weight-lowering effects.

EPIDEMIOLOGICAL, PATHOPHYSIOLOGICAL, AND CLINICAL CONSIDERATIONS ON INTERPLAY BETWEEN TYPE 1 DIABETES AND OBESITY

Several studies have reported an increase in the incidence and prevalence of overweight and obesity in people with T1DM in recent decades. Data from the Pittsburgh cohort show that the prevalence of obesity among adults with T1DM increased over time, reaching 22.7% at the end of the observational period (2004-2007) compared to only 3.4% at baseline (1986-1988)[7]. But how can this impressive increase in obesity rates among people with T1DM be explained? Although the problem is multifactorial and there is no simple answer to the question, it can be hypothesized that patients with T1DM follow the trend seen in the general population of unhealthy eating behaviors and limited physical activity, while the identification of insulin therapy in recent decades should also have played a role[8].

An argument supporting the notion that the pathophysiology of the two major types of diabetes shares common pathways is that some genes involved in the development of obesity have also been linked to T1DM. Polymorphisms in the FTO gene, which is involved in appetite control and eating behaviors, have been shown to be associated with the risk of overweight and obesity and poor metabolic control in children with T1DM[9]. In a large cohort of people with T1DM, genetic variants in the TCF7L2 gene (which has traditionally been associated with the risk of T2DM) were found to correlate with a milder immunologic phenotype and increased endogenous insulin production[10]. These data suggest the existence of a subtype of T1DM driven by pathogenic mechanisms similar to those of T2DM that are genetically regulated. Furthermore, due to defects in the production and action of insulin, glucagon, amylin, leptin, and other enteroendocrine hormones observed in T1DM, the homeostatic balance of food intake is impaired[11]. Other factors, including altered sympathetic nervous system activity and intestinal dysbiosis, have been proposed to contribute to the disruption of weight regulation mechanisms in patients with autoimmune diabetes[12]. A systematic review and meta-analysis that included 2658 subjects demonstrated a continuous association between BMI and the subsequent risk of T1DM development (pooled odds ratio 1.25 per 1 standard deviation higher BMI)[13], suggesting that increased body weight and IR can interact with autoimmunity in the presentation of the disease. It is well established that conditions that increase beta-cell secretory demand, such as IR or excessive hyperglycemia, can accelerate beta-cell death and apoptosis through amplification of oxidative stress and chronic systemic inflammation[14]. This theory is supported by epidemiological evidence showing that people with obesity are diagnosed with T1DM at a significantly younger age than peers of normal weight[15].

There is evidence that obesity can increase the risk of complications in patients with T1DM. Rodrigues et al[16] have shown that among individuals with T1DM, overweight and obesity are associated with the presence and progression of coronary artery calcium, independently of other cardiovascular risk factors. A different study from Australia showed that people of both sexes with T1DM and a BMI greater than 30 kg/m² had a higher risk of retinopathy and cardiovascular disease (CVD) compared to peers with a BMI less than 30 kg/m², despite similar levels of glycated hemoglobin (HbA1c)[17]. Similarly to what is observed in T2DM, the coexistence of T1DM and nonalcoholic fatty liver disease is associated with an increased prevalence of asymptomatic and symptomatic CVD[18]. De Block et al[19] reported that among individuals with T1DM, microvascular complications such as retinopathy and neuropathy were more common in those with overweight compared to subjects of normal weight (odds ratio 2.1 and 1.6, respectively). Obesity in T1DM has been associated with a 52% increase in the odds of kidney disease[20]. Finally, CVD-related deaths in people with T1DM were found to increase with increasing BMI, with the association more evident in men than in women[21].

WEIGHT-LOWERING DRUGS IN TYPE 1 DIABETES

Glucagon-like peptide 1 receptor agonists (GLP-1 RA) have completely transformed the landscape of T2DM management, not only because they can provide robust reductions in HbA1c with a minimal risk of hypoglycemia, but also due to their potential to alleviate cardiorenal risk. GLP-1 RA have been also approved for the treatment of overweight and obesity regardless of diabetes status. Trials that tested the administration of GLP-1 RA in people with T1DM as an adjunct to insulin therapy, showed that these drugs can significantly reduce body weight, HbA1c, and the total daily insulin dose[22]. However, these benefits were not without cost, since liraglutide treatment increased the risk of hyperglycemia with ketosis, probably as a result of gastrointestinal side effects and a decrease in insulin dose[23]. The GLP-1/glucose-dependent insulinotropic polypeptide dual agonist tirzepatide has a potent glucose-lowering action[24]. Data in people with T1DM are currently lacking; however, Mendoza and Parsiani[25] recently reported a case of a patient with T1DM and obesity who received tirzepatide and experienced a substantial improvement in body weight and glycemic control, underlining the need for additional studies in the field.

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are oral hypoglycemic agents that are licensed for the treatment of T2DM, chronic kidney disease, and heart failure. Although their weight-lowering effects are less impressive than those of incretin mimetics, their cardiorenal benefits appear to be present in people with T1DM, making them an attractive therapeutic choice for patients at high CV risk[26,27]. Relevant studies have shown that SGLT2i can decrease HbA1c, glycemic variability, insulin dose, and body weight in individuals with T1DM; however, at the cost of increased rates of diabetic ketoacidosis[28].

Interestingly, there are several therapies in the drug development pipeline that promise that in the future the treatment of T1DM will not be based exclusively on insulin. Leptin, stem cell therapies, immune ablation, and standard immunosuppressants have been tested in animal and human studies; however, there is no solid evidence to support the universal implementation of these therapeutic approaches in daily clinical practice, at least for the moment[23].

Table 1 presents the advantages and disadvantages of the use of the new glucose-lowering agents in individuals with T1DM.

Table 1 Advantages and disadvantages of use of new glucose-lowering agents in individuals with type 1 diabetes mellitus.

Drug class	Advantages	Disadvantages
GLP-1 RA	Reduction in HbA1c, insulin dose, and body weight/cardioprotective effects/improvement in liver steatosis	GI side effects/increase in ketosis rates/increased cost for health care systems
SGLT2i	Reduction in HbA1c, insulin dose, body weight, and glycemic variability/cardio-renal protective effects	Increased risk of DKA/minimal weight-lowering effects/increased cost for health care systems
Tirzepatide	Reduction in HbA1c, insulin dose, and body weight/improvement in liver steatosis	Very limited data in T1DM/increased cost for health care systems

T1DM: Type 1 diabetes mellitus; HbA1c: Glycated hemoglobin; DKA: Diabetic ketoacidosis; GI: Gastrointestinal; GLP-1: Glucagon-like peptide 1 receptor agonists; SGLT2i: Sodium-glucose cotransporter 2 inhibitors.

CONCLUSION

Overweight and obesity represent a growing threat for modern societies and people with T1DM could not be an exception to this rule. Chronic exogenous insulin administration, genetic and epigenetic factors, and psychosocial and behavioral parameters, along with the modern way of life that incorporates unhealthy eating patterns and physical inactivity, set the stage for increasing obesity rates in T1DM[29,30]. More specifically, it has been suggested that non-physiological insulin replacement therapy resulting in peripheral hyperinsulinemia, insulin profiles that do not match basal and mealtime insulin needs, reduced physical activity as a consequence of diabetes complications (e.g., neuropathy and retinopathy) and fear of hypoglycemia, defensive eating to avoid hypoglycemia, and emotional eating related to depression and diabetes burden are important contributing factors[31,32].

As our knowledge of the underlying mechanisms that lead to the development of obesity and hyperglycemia expands, it becomes clear that there are overlap zones in the pathophysiology of the two main types of diabetes. Stereotypes regarding strict dividing lines between “autoimmune” and “metabolic” phenotypes increase the risk of trapping physicians into ineffective therapeutic approaches, instead of individualized diabetes care. In this context, the use of adjuncts to insulin therapy that have the potential to alleviate cardiorenal risk and decrease body weight can reduce the burden of obesity in patients with T1DM.