Type 2 Diabetes Mellitus (T2DM) is considered as a lifestyle disorder and obesity is one of the key risk factors that predispose to this metabolic syndrome. Several studies have proved that lifestyle and therapeutic interventions are beneficial in reducing weight that in turn improve insulin sensitivity and glycemic control. Individuals with body mass index (BMI) > 25 Kg/m2 and > 30 Kg/m2 are considered as overweight and obese respectively. Increased caloric intake and sedentary lifestyle are two most important factors that lead to increased body fat content that predispose to poor insulin sensitivity which in turn often progresses into T2DM.

Effect of obesity on insulin resistance Insulin resistance has different manifestations based on the location of the action. In muscles, insulin resistance leads to poor glucose uptake and reduced muscle glycogen synthesis; in the liver, it leads to impaired suppression of gluconeogenesis while maintaining the stimulation of fatty acid synthesis; in adipocytes, reduced insulin sensitivity results in decreased glucose uptake and impairment in the inhibition of lipolysis. Cumulative research over decades has revealed that obesity can cause insulin resistance through diverse mechanisms as discussed below: Glucose transporter type 4 (GLUT-4) Receptor abnormality: GLUT-4 receptors are responsible for glucose uptake. These receptors are present in the cytoplasm and translocate to the plasma membrane of the cell to import glucose molecules inside. In obese individuals, it has been often observed that GLUT-4 has reduced expression in adipocytes, leading to reduced glucose uptake despite normal insulin secretion. On the other hand, the expression of GLUT-4 remains unchanged in skeletal muscles of obese people, however, the fusion of these receptors to the plasma membrane is impaired leading to less glucose uptake despite normo- or hyperinsulinemia. Visceral adipocytes functionality: Research has confirmed that insulin resistance related to obesity depends on the location of the fat storage.

In fact, lipid accumulation in subcutaneous adipose tissue reduces the resistance to insulin. On the other hand, lipid accumulation and thereby increase in the visceral adipose tissue decreases insulin sensitivity. These adipose tissues are more lipolytically active that lead to increased intraportal free fatty acid levels resulting in insulin resistance and impairment of beta cell function. Enhanced lipid accumulation in these adipose tissues also increases the secretion of adipokine hormones that further increases insulin resistance in liver and muscle. Immunological factor of insulin resistance: Adipocytes are known to secrete inflammatory molecules such as tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) that can alter insulin signaling and reduce GLUT-4 expression leading to poor insulin sensitivity in the target cells. In obese individuals, hypertrophic adipocytes release chemoattractant molecules such as monocyte chemoattractant protein-1 (MCP-1) which leads to infiltration of macrophage and other immune cells in the adipose tissue resulting in secretion of more inflammatory molecules that further impair the action of insulin. Lifestyle modification for weight reduction and improvement of T2DM Lifestyle modifications are one of the earliest physician recommendations to overweight and obese patients with insulin resistance to prevent T2DM. Even in T2DM patients, lifestyle changes besides medications are extremely useful. Physical activity and maintaining well-planned diet are necessary steps for weight reduction.

Regular exercise helps in maintaining the energy balance in the body and helps offset excess caloric gain through food intake. Regular aerobic exercises are related to the reduction in visceral fat leading to improvement in glucose tolerance, insulin sensitivity, and glycemic control. Many studies have confirmed the insignificant effect on weight reduction through physical exercise if caloric restriction is not maintained. Low-fat and low-carbohydrate diets are highly beneficial dietary interventions in weight management. For T2DM patients or obese individuals with insulin resistance and risk of T2DM, the low-carbohydrate diet preferentially includes foods with low glycemic index. Several studies have shown that patients on low-carbohydrate diet are able to reduce significantly more weight compared to patients on a low-fat diet for initial 6 months. However, in long run, weight loss with both types of diets are similar. The benefits of lifestyle modifications in weight reduction are evident from clinical studies. The Diabetes Prevention Program randomized more than 3200 participants with insulin resistance to receive placebo or metformin or lifestyle modification and followed them for 2.8 years. The lifestyle modification included low-fat diet (1200-2000 Kcal/day depending on weight) and 150 min/week physical activity with a goal of 7% weight reduction from the baseline. After 2.8 years the lifestyle intervention group reduced an average 5.6 kg body weight, while the metformin and placebo groups lost 2.1 kg and 0.1 kg only. Pharmacological management for weight reduction In overweight and obese people with insulin resistance or T2DM, pharmacological management for weight loss can be considered only if lifestyle modifications are ineffective or inadequate.

The FDA has approved several drugs for weight loss: Intestinal lipase inhibitor Orlistat effectively decrease fat deposition in the body. Multiple randomized clinical trials have shown that Orlistat reduces an average 8-10% of initial weight which is 4% more reduction in weight compared to that of placebo and lifestyle change combination. Lorcaserin reduces appetite by activating serotonin receptor 5-HT2c. As per clinical studies, Lorcaserin reduces on average 5-6% of initial weight compared to 2-3% in Placebo treatments. Phentermine-Topiramate combination causes early satiety and thereby reduces dietary intake. The combination drug is found to reduce 8-10% of initial body weight compared to placebo (1-2%) as observed in randomized trials. Bupropion-naltrexone combination is found to reduce 5-6% of initial body weight compared to 1.3% that is achieved with placebo treatment. Besides the conventional drugs for weight loss, several antidiabetic drugs have also shown the promise. Since these drugs serve both the purposes (weight loss and glycemic control), patients need to take fewer medications. Selective sodium glucose co-transporter 2 (SGLT-2) inhibitors are effective drugs for T2DM management. However, Empagliflozin, an SGLT-2 inhibitor also effectively reduces body weight. In a randomized double-blind clinical trial with 3300 T2DM patients (HbA1c >7% – <10%), Empagliflozin (10mg and 25mg) significantly reduced (P<0.001 compared to placebo) body weight, waist circumference, estimated body fat, index of central obesity and visceral adiposity index.  Other studies also reported 2.2-4.0 Kg weight loss with Empagliflozin monotherapy or combination therapy (Metformin or insulin).

Besides Empagliflozin, other oral antidiabetic drugs such as Glucagon-like peptide 1 receptor agonist (GLP-1RA) Liraglutide & Exenatide, insulin-sensitizing drug Metformin, Dipeptidyl peptidase-4 inhibitors are also known to reduce body weight. Surgical management for weight reduction and its impact on T2DM remission For extremely obese patients (BMI > 35 Kg/m2), pharmacological therapy is often insufficient to achieve recommended weight loss and related glycemic improvement. For these patients, bariatric surgery has shown tremendous efficacy. It is now established that laparoscopic Roux-en-Y gastric bypass surgery leads to normoglycemia in more than 75% of these T2DM patients. Few other proposed mechanisms that are related to gastric bypass surgery and T2DM remission are as follows: The surgery stimulates the secretion of incretin peptides such as GLP-1 from L-cells resulting improved insulin secretion in a glucose-dependent Moreover, other incretins such as a gastric inhibitory peptide (GIP) also increases post-prandial insulin secretion. The surgery reduces the secretion of anti-incretin hormones resulting in improved blood glucose level. Adipocyte-derived hormone leptin causes insulin resistance while adiponectin improves insulin sensitivity.

Gastric bypass surgery reduces leptin level and improves adiponectin level. Moreover, clinical findings have shown the benefit of gastric bypass surgeries especially that offers caloric restriction in reducing body weight and T2DM remission. In a study with 1160 morbidly obese patients, Roux-en-Y gastric bypass surgery resulted in a normal level of fasting glucose and HbA1c levels in 83% cases and improved in remaining 17% cases. The surgery also reduced the need for oral antidiabetic drugs and insulin in 80% and 79% cases respectively. The remission of T2DM after the surgery was 95% in patients who had T2DM for less than 5 years, 75% (T2DM 6-10 years), 54% (T2DM more than 10 years).

Overall, more than 90% of the T2DM patients are either overweight or obese. BMI above normal is also associated with people with insulin resistance. Since obesity is an established predisposing factor for T2DM, effective remission of the disease requires thorough lifestyle management, pharmacological as well as surgical interventions to reduce body weight besides targeting better glycemic control.

References

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