Why does obesity cause diabetes?

Source: Cell Metabolism  2022. (Excerpt)

 

Summary

The accumulation of excessive body fat can cause type 2 diabetes, and the risk of type 2 diabetes increases rapidly, approximately exponentially, with increasing body mass index (BMI).

Accordingly, the global increase in the incidence of obesity parallels the increase in the prevalence of type 2 diabetes.

The cellular and physiological mechanisms responsible for the relationship between obesity and type 2 diabetes are complex and include obesity-induced changes in β-cell function, adipose tissue biology, and multi-organ insulin resistance, which are often mitigated or even normalized by appropriate weight loss.

Introduction

The accumulation of excessive body fat gives rise to a constellation of metabolic disorders and diseases, including insulin resistance, atherogenic dyslipidemia (high plasma triglyceride and low plasma HDL-cholesterol concentrations), nonalcoholic fatty liver disease (NAFLD), β-cell dysfunction, prediabetes, and type 2 diabetes.

In general, a progressive increase in BMI, which provides an index of adiposity, is associated with a progressive increase in the risk of developing type 2 diabetes (Colditz et al., 1995).

However, the distribution of fat and triglycerides modifies the risk of adiposity-induced metabolic dysfunction (Klein et al., 2002).

Obese individuals with predominantly increased upper body adipose tissue (abdominal subcutaneous and intra-abdominal fat), intrahepatic triglyceride content, intramyocellular lipid content, and pancreatic fat are at greater risk of developing type 2 diabetes than those with a lower body (gluteofemoral) fat phenotype.

Indeed, increased gluteofemoral body fat mass is associated with decreased plasma triglyceride and HDL-cholesterol concentrations, decreased fasting plasma glucose and insulin concentrations, increased oral glucose tolerance and insulin sensitivity, and decreased risk of type 2 diabetes in lean, overweight, or obese individuals (Manolopoulos et al., 2010).

Type 2 diabetes is caused by multi-organ insulin resistance, coupled with a decline in β-cell insulin secretory function (Bogardus and Tataranni, 2002).

The worldwide increase in obesity prevalence is likely responsible for the recent increase in type 2 diabetes prevalence because obesity affects both insulin action and β-cell function.

Adipose Tissue Biology and Insulin Resistance

(Summary)

Data from animal models and human studies indicate that obesity-induced changes in adipose tissue metabolism, extracellular matrix formation, immune cells (primarily macrophages), and inflammation (primarily SERPINE1 ) play a role in regulating the metabolic functions of other organs (Figure 1).

Differences in these factors among individuals likely contribute to the heterogeneity of obesity-related metabolic health in humans.

Figure 1: Changes in adipose tissue biology in metabolically dysfunctional obese individuals

 

Impact of Weight (Fat) Loss

Weight loss can have significant therapeutic effects on metabolic function, type 2 diabetes, and comorbidities associated with diabetes (Figure 2 ; Cohen et al., 2020 ; Gómez-Ambrosi et al., 2017 ; Klein et al., 2002).

Modest weight loss of 5%–10% improves glycemic control, plasma triglyceride and HDL-cholesterol levels, and blood pressure (Wing et al., 2011).

Greater weight loss can achieve diabetes remission, but the extent of remission depends primarily on the duration of diabetes, the ability of weight loss to improve β-cell function, and the criteria used to define remission (Camastra et al., 2011 ; Taylor et al., 2018).

The ability of weight loss to induce diabetes remission has been demonstrated in randomized, controlled trials comparing bariatric surgery with pharmacological therapy:

(1) 73% of patients with diabetes for less than 2 years achieved diabetes remission (glycated hemoglobin [HbA1c] < 6.2% without anti-diabetic medications) 24 months after laparoscopic adjustable gastric banding, with a 20% weight loss (Dixon et al., 2008 );

(2) 42% of patients with diabetes for an average of 8 years achieved diabetes remission (HbA1c ≤ 6.0% without anti-diabetic medications) 12 months after Roux-en-Y gastric bypass surgery, with a 28% weight loss (Schauer et al., 2012); and

(3) 75% of patients achieved diabetes remission (HbA1c < 6.5% without anti-diabetic medications) 24 months after Roux-en-Y gastric bypass surgery, with a 33% weight loss (Mingrone et al., 2012).

However, the durability of diabetes remission after bariatric surgery declines over time and is associated with weight regain; only about 50% of patients maintain diabetes remission (without anti-diabetic medications and either fasting plasma glucose < 100 mg/dl or < 126 mg/dl, or HbA1c < 6.0%) 5–10 years after surgery (Arterburn et al., 2013 ; Brethauer et al., 2013 ; Sjöström et al., 2004).

Figure 2: Therapeutic effects of weight loss on multiple organs

More recently, the DiRECT trial demonstrated that a structured weight management program, integrated into medical care, can achieve diabetes remission (Lean et al., 2018 , 2019).

This cluster-randomized trial was conducted in UK primary care practices and included patients diagnosed with the disease within the past 6 years (average 3 years) who were not treated with insulin.

Diabetes remission (HbA1c < 6.5% [<48 mmol/mol] without anti-diabetic medications) was achieved in 46% of patients at 12 months, with an average weight loss of approximately 10% (10 kg).

Remission varied depending on the extent of weight loss:

• 7% of those losing 0–5 kg,
• 34% of those losing 5–10 kg,
• 57% of those losing 10–15 kg,
• and 86% of those losing 15 kg or more.

In contrast to weight loss (fat loss) achieved through a negative energy balance induced by bariatric surgery, diet therapy, or pharmacotherapy, surgical removal of adipose tissue does not result in metabolic benefits.

For example, the removal of large amounts of subcutaneous abdominal adipose tissue (10 kg of adipose tissue, corresponding to a 12% body weight loss and a 20% reduction in total body fat mass) by liposuction does not improve insulin sensitivity of adipose tissue, liver, or skeletal muscle, or plasma lipids in obese women or women with type 2 diabetes (Klein et al., 2004), and the laparoscopic omentectomy removal of approximately 30% of intra-abdominal adipose tissue does not improve whole-body insulin sensitivity in obese individuals with type 2 diabetes (Fabbrini et al., 2010b).

These findings indicate that fat loss must be induced by a negative energy balance to achieve metabolic benefits.

Weight loss has a powerful effect on insulin action, and even 5% weight loss improves insulin sensitivity of multiple organs (adipose tissue, liver, and skeletal muscle) (Lim et al., 2011 ; Magkos et al., 2016).

However, the extent of functional improvement in response to a given amount of weight loss is not identical for all organs, nor is the extent of weight loss required to achieve maximal metabolic benefits across different organ systems clear and likely will vary among individuals depending on the severity and duration of metabolic dysfunction.

In general, hepatic (insulin-mediated suppression of glucose production) and adipose tissue (insulin-mediated suppression of lipolysis) insulin sensitivity are likely maximally improved at 5%–8% weight loss, whereas greater weight loss causes further increases in skeletal muscle insulin sensitivity (insulin-mediated increase in glucose disposal) (Magkos et al., 2016 ; Petersen et al., 2005).

 

Significant weight loss can result in type 2 diabetes remission

For example, in the DiRECT study, 57% of participants who lost 10%–15% and 86% of those who lost ≥15% achieved diabetes remission (Lean et al., 2018).

The cellular mechanisms responsible for the therapeutic effects of weight loss on metabolic functions are unclear.

Adipose tissue is highly sensitive to negative energy balance and weight loss.

A progressive increase in diet-induced weight loss causes a progressive decrease in whole-body, subcutaneous, and intra-abdominal adipose tissue mass, primarily due to a decrease in adipocyte size.

Progressive weight loss also causes progressive changes in adipose tissue biology, manifested by a gradual decrease in metabolic pathways and genes involved in lipid synthesis, extracellular matrix remodeling and collagen synthesis, PAI-1 production, and oxidative stress (Magkos et al., 2016).

However, the improvement in multi-organ insulin sensitivity after 5% weight loss is generally not associated with a decrease in inflammatory markers in either circulating or subcutaneous adipose tissue, suggesting that the beneficial effect of 5% weight loss on insulin action is not mediated by a decrease in systemic or adipose tissue inflammatory markers.

 

Progressive weight loss also causes a progressive decrease in intrahepatic triglyceride content and an improvement in the liver histological features of NAFLD

Indeed, intrahepatic triglyceride is particularly sensitive to negative energy balance; even a 48-hour low-calorie diet significantly reduces intrahepatic triglyceride content (Kirk et al., 2009).

The sensitivity of adipose tissue and liver to small amounts of weight loss suggests that the therapeutic effects of weight loss are at least partly mediated by changes in adipose tissue and liver physiology, as well as the effects of adipose tissue on systemic signaling mechanisms, such as adiponectin, PAI-1, and exosomes released from adipose tissue.

 

Conclusions

Obesity, – especially when associated with increased abdominal and intra-abdominal fat distribution and increased intrahepatic and intramuscular triglyceride content – is a major risk factor for prediabetes and type 2 diabetes because it causes both insulin resistance and β-cell dysfunction.

 

The worldwide increase in the prevalence of obesity has led to a concomitant increase in the prevalence of type 2 diabetes

A better understanding of the mechanisms responsible for the deleterious effects of excess body fat on factors involved in the pathogenesis of type 2 diabetes can lead to new therapeutic interventions for the prevention and treatment of this debilitating disease.

A series of studies in mouse models and humans have demonstrated changes in adipose tissue biology that link obesity to insulin resistance and β-cell dysfunction.

 

These changes include:

• adipose tissue fibrosis (increased expression of genes involved in fibrogenesis and extracellular matrix formation),
• inflammation (increased content of inflammatory macrophage and T cells, as well as PAI-1 production),
• and the production of exosomes that induce insulin resistance.

None of these factors can affect systemic metabolic function without a mechanism of communication between adipose tissue and other organs.

It is possible that several adipose tissue secreted products released into the bloodstream – including PAI-1, adiponectin, free fatty acids, and exosomes – are involved in this signaling process, but further research is needed to fully assess their clinical significance.

 

Additionally, it is also likely that crosstalk between adipose tissue, liver, muscle, and pancreatic islets contributes to insulin resistance and hepatic steatosis (Figure 3).

Figure 3: Organ crosstalk in the pathogenesis of metabolic dysfunction in obese individuals

• CO2: carbon dioxide
• HSC: hepatic stellate cell
• FFA: free fatty acid
• PAI-1: plasminogen activator inhibitor-1
• TG: triglyceride
• TGRL: triglyceride-rich lipoprotein
• VLDL: very low-density lipoprotein

 

 

Reducing body fat mass by inducing a negative energy balance – rather than surgical removal – can alleviate or normalize obesity-induced metabolic dysfunction and even achieve diabetes remission if β-cell function is adequately restored.