Weight loss in obese subjects could reverse type 2 diabetes progression

Type 2 diabetes mellitus (T2DM) is caused by β-cell dysfunction in the endocrine pancreas and insulin resistance. This may be caused by environmental or epigenetic factors. A new paper explains a model of diabetes that centers on the role of obesity in glucose dysregulation.

Study: Modeling the progression of type 2 diabetes with underlying obesity. Image Source: goffkein.pro/Shutterstock


Mathematical models have been used to predict the long-term effects of antidiabetic drug use in different stages of T2DM. However, no model could predict this, given the influence of multiple diabetes-causing factors, such as an obesity-promoting environment.

Existing studies have shown that hyperinsulinemia worsens insulin resistance and vice versaSome scientists claim that beta cells overreact to fat or glucose, producing abnormally high insulin levels. This leads to insulin resistance as a protective mechanism against insulin-induced metabolic stress.

The model reported in the current paper appears in PLOS Computational Biologywhich analyzed the progression of diabetes in relation to multiple diabetogenic factors, including factors that increase diabetes risk in relation to individual obesity thresholds, race and tolerance in relation to factors that promote weight gain above obesity thresholds, and the effect of bariatric surgery on T2DM risk .

What did the research show?

Based on the research gap, the scientists developed a model to examine the effect of high insulin levels on insulin resistance. It will investigate the influence of multiple factors associated with the development of diabetes on beta cell dysfunction.

This general model constructed by the scientists was then narrowed down by specifying the diabetes-related factors associated with obesity. It examines how obesity affects glucose regulation in the body. It predicts changes in glucose and insulin levels over a lifetime in humans, showing how hepatic glucose production, insulin release rates, and the growth of functional beta-cell populations change when exposed to obesity-related diabetes-causing factors.

These long-term trends were shown to correlate well with actual longitudinal data when fitted to a specific population, in this case, Pima Indians. This group was chosen because of the availability of long-term follow-up data on the long-term changes and direction of glucose concentrations.

The model could distinguish hyperinsulinemic subjects without dysglycemia from those with prediabetes and overt diabetes. In a highly obesity-promoting setting, the mean time to progression to hyperinsulinemia was seven years. Ten years later, diabetes struck.

Over a period of about two decades, beta-cell failure begins to manifest as a drop in insulin levels, with true insulin deficiency developing over time.

The simulations also showed that the rate and severity of disease progression was significantly reduced when the same individuals were exposed to environments with only mild obesity-inducing risks.

This supports the finding that weight loss in obese patients helps alleviate diabetes

The results confirmed the scientists' guesses. With proper obesity management, T2DM can be reversed or delayed, or at least lessened in severity. This also explains the remarkable effect of bariatric Roux-en-Y surgery, which acts by reducing hepatic gluconeogenesis and reversing β-cell dysfunction, resulting in a rapid and durable return to normoglycemia. The model could help determine the right time and patient for such surgeries for optimal outcomes.

Second, individual-specific differences in levels of β-cell dysfunction and insulin resistance are reflected in changes in T2DM risk. Even with obesity, the person remains euglycemic as long as the diabetes-related factors associated with obesity remain below the threshold. As the threshold is crossed to a greater extent, diabetes begins to progress.

This personalized threshold provides a warning signal of obesity levels, allowing necessary interventions to prevent the onset of diabetes, which may be valuable for clinical decision-making

A concept called Personal Fat Threshold (PFT) is used to create an individualized eating plan for diabetics, using individualized sensitivities to specific types of excess lipids, and the amount of fat stored in the pancreas and liver.

Likewise, ethnic groups with basal hyperinsulinemia can successfully avoid diabetes by reducing exposure to obesogenic factors.

Finally, the scientists investigated the biological mechanisms of several key parameters specified in the model and found to be strongly related to the development of T2DM. Several interesting insights were gained, including improved predicted outcomes when treatments aimed at minimizing the adverse effects of diabetes risk factors on β cells compared to improving the diabetes-promoting environment. That is, beta cells are better able to control glucose levels when protected from harsh environments, rather than when treatment focuses on changing the environment through dietary modifications or exercise.

Likewise, some patients had poorer glycemic control despite increased insulin sensitivity, suggesting that insulin resistance is not the only necessary goal in treating diabetes. Some people rapidly develop severe diabetes after a long period of normal blood sugar. Previously good glucose control over long periods of time was traced to reduced glucose production in the liver, suggesting its importance as a therapeutic and preventive target.

What is the effect?

The research may encourage precise interventions to prevent diabetes and advance individualized patient care

Although used here to understand the progression of diabetes in an obesogenic setting, this model allows for the study of the influence of other factors, such as the effects of thyroid hormone or adrenaline hypersecretion on glucose regulatory systems in vivo.

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