Obesity in type 1 diabetes: an overlooked immune-metabolic issue

KEYWORDS:

• Type 1 diabetes
• obesity
• autoimmunity
• Adiposity
• Diabetic complications
• Autoimmune diabetes

Overweight/obesity (ow/ob) and type 1 diabetes (T1D) are harmful metabolic disorders whose incidence has been on the rise for years [1,2]. Ow/ob is becoming increasingly common in individuals with T1D [3]. Data from the major clinical studies in T1D (such as the T1D Exchange Registry, the Prospective Diabetes Follow-up Registry or the SEARCH for Diabetes in Youth Study study) suggest that the rates of ow/ob in T1D may vary depending on age, ethnicity and country of residence. In countries with a high prevalence of ow/ob, such as Mexico or the U.S.A., about 1 out of 3 people living with T1D are overweight, while obesity affects up to 20% of the T1D population [4,5]. In some European countries, a higher prevalence of ow/ob has been reported among people with T1D than in the general population [6–8]. Overall, there is clear evidence that the obesity pandemic does not spare individuals with T1D, with an increasing prevalence observed over time, as suggested by data from both the Pittsburgh Epidemiology of Diabetes Complications Study and the Diabetes Control and Complications – Epidemiology of Diabetes Interventions and Complications (DCCT-EDIC) trial [9,10]. Importantly, such observation is also accurate for children and adolescents, as highlighted by several pediatric studies reporting a prevalence of obesity ranging from 5 to 20% [11–13]. The epidemic of ow/ob in a high-risk population such as the one with T1D might have devastating consequences, especially if the deleterious effect of adiposity starts at a very young age. Nonetheless, since T1D is traditionally considered a disease of lean people, the issue of ow/ob has often been overlooked and barely investigated among people with T1D. The lack of robust evidence in anti-obesity treatment for individuals with T1D is a significant concern, whether it be through pharmacological, nutritional, exercise therapy or surgical interventions [14].

This highlights the need for further research addressing the issue of ow/ob in T1D because of the several factors possibly differentiating adipose tissue accumulation between people with and without T1D regarding drivers, features and consequences, as discussed in the following sections.

1. Fat accumulation in autoimmune diabetes: different drivers, different clinical and metabolic features

Although body mass index (BMI) is used in clinical practice to identify ow/ob, it does not provide a precise evaluation of adiposity localization and quality, which may differ between people with and without T1D. Indeed, the several drivers hypothesized to explain the increasing prevalence of ow/ob among people with T1D, such as intensification of exogenous insulin therapy, reduced physical activity or defensive carbohydrate intake, which is the consumption of carbohydrates to prevent or treat hypoglycemic events [3,15], may all facilitate unhealthy weight gain. These drivers work on top of the obesogenic landscape, characterized by overeating, increased availability of junk food, and an inclination toward a sedentary lifestyle, to which people with T1D are exposed, as well as the general population [14]. Although the absence of endogenous insulin and exogenous hyperinsulinemia may impact muscle mass and function in people with T1D, limited data on this topic are available. Resting energy expenditure (REE) increases in T1D and correlates with hyperglycemia [16]. Insulin intensification decreases REE, inducing a net positive energy balance and weight gain. T1D is characterized by increased lipid oxidation at fasting and a reduced capacity to shift to carbohydrate oxidation during meals [17]. As a result, people with T1D and ow/ob might show fat deposition in the abdominal region and the liver, increasing the risk of developing liver steatosis also through an increased de novo lipogenesis [18], resulting in higher insulin resistance, dysregulated hepatokines’ release, and in a worse cardiometabolic profile [19]. A study conducted on people enrolled in the German Diabetes Study showed that an alteration of hepatic metabolism occurs in T1D already within the first 5 years after diagnosis, although the hepatic lipid content did not change despite a significant increase in BMI [20]. In this regard, an in-depth characterization of body composition, energy expenditure and substrate oxidation analysis across the range of body weight and glycemic control may help assess the cardiometabolic risk and deliver valuable data for T1D management.

2. Adipokines and incretin

Ow/ob often leads to an unbalance in adipose tissue-related factors critical for cardiometabolic health and, apparently, also for beta-cell function [21]. These include circulating and resident immune cells, adipokines, sphingolipids and microbiome modulation. The latter may have a metabolic connection in T1D based on short-chain fatty acids (SCFAs)’ positive role in glucose-stimulated insulin secretion (GSIS) and immunity. Adipokines seem to confirm their role in T1D too, with adiponectin showing a bivariate association with retinopathy and resistin being significantly associated with markers of atherosclerosis in T1D [22]. Some appetite-regulating hormones, such as incretins, also have an anti-inflammatory and beta-cells protective function, even though the latter have been consistently demonstrated only in animal models of T1D, but not in humans [23]. However, the role of incretins, amylin, and bile acids in T1D when ow/ob occurs needs to be clarified, especially because drug treatments for obesity may work on these pathways.

3. The vicious cycle between ow/ob and autoimmune diabetes

As T1D may create conditions favoring weight gain, also ow/ob might accelerate pancreatic autoimmunity and beta-cell loss [24]. T1D is a heterogeneous disease regarding the rate of beta-cell loss and clinical features, reflecting differences in pathophysiology among different cases [25,26]. According to the ‘accelerator’ hypothesis, ow/ob plays a central role in causing these differences, making beta-cells more vulnerable by inducing insulin resistance, by causing beta-cell stress and by inducing the low grade chronic pro-inflammatory milieu which often characterizes visceral adiposity [27]. In this regard, an imbalance between pro-inflammatory and anti-inflammatory cytokines has been extensively implicated in continuing autoimmune beta-cells aggression, representing a bridge between T1D and ow/ob-related low-grade inflammation. To date, most of the evidence concerning patterns of circulating inflammatory mediators in T1D derives from studies conducted mainly in normal weight people, with a lack of data derived from the population with ow/ob.

Furthermore, these mechanisms might also contribute to triggering pancreatic autoimmunity in people with milder genetic risk for T1D, resulting in the onset of slowly progressive forms of T1D [28].

4. Ow/ob and T1D progression

The vicious cycle between diabetic autoimmunity and ow/ob almost guarantees to bring about additional health problems. Ow/ob is likely to induce insulin-resistance in people with T1D, generating a novel expression of the disease known as ‘double diabetes,’ where features of both T1D and type 2 diabetes coexist [29]. Whether and to what extent fat accumulation influences metabolic control and response to therapy in people with T1D is unknown.

Furthermore, the risk of chronic diabetic complications may be enhanced by the concomitant ow/ob. While ow/ob is a recognized risk factor for vascular complications, this association has been mainly studied in type 2 diabetes, and very little is known about the implications of ow/ob in the progression toward chronic complications of T1D. As this is true for classical complications, even less is known about the newly recognized complications of T1D such as diabetic osteopathy, which frequently occur in adults with long-standing diabetes [30], i.e. those at higher odds of being ow/ob.

5. Expert opinion

The increasing prevalence of ow/ob in T1D is a novel issue with likely several adverse metabolic effects and probably with a high impact on the long-term risk of diabetic complications, yet still underappreciated and poorly understood. The lack of data about the features and consequences of ow/ob in people with diabetic autoimmunity is alarming considering the several dangerous effects of ow/ob on health outcomes and the size of the problem, which is higher than previously thought and increasing over time. Therefore, further research on this topic should be fostered. In our opinion the following research questions should be answered:

– What are the metabolic and phenotypic characteristics of ow/ob in T1D and do they differ from those without diabetes?

– Does ow/ob impact the natural history of T1D, from pancreatic autoimmunity to the appearance of complications?

– What are the unique behavioral, psychological, and social characteristics that underlie ow/ob in T1D?

– What are the biological phenomena that contribute to the ow/ob phenotype in T1D?

Integration of clinical data, such as beta-cell function, metabolic control, body composition, presence and extent of chronic complications, with molecular findings related to fat accumulation, such as the immune-metabolic and humoral signatures, could help in bridging such gaps in knowledge.

In definitive, new crucial insights about the relationship between ow/ob and autoimmune diabetes, revealing new potential targets for preventing the dangerous interaction between these two conditions, are needed and novel research in this field is claimed.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

European Union through Italian Ministry of University and Research (PRIN 2022NS7PRM).