Weight loss in obese subjects could reverse type 2 diabetes progression

By Dr. Liji Thomas, MDFeb 28 2023Reviewed by Aimee Molineux

Type 2 diabetes mellitus (T2DM) is caused by the dysfunction of beta cells in the endocrine pancreas, coupled with insulin resistance. This could be induced by environmental or epigenetic factors. A new paper explains a model of diabetes that centers on the role of obesity in glucose dysregulation.

Introduction

Mathematical models have been employed to predict the long-term effects of using anti-diabetic drugs at various stages of T2DM. However, there is no model to predict this condition considering the effect of multiple diabetogenic factors, such as an environment that promotes obesity.

Available research indicates that hyperinsulinemia worsens insulin resistance and vice versa. Some scientists claim that beta cells become hyper-responsive to fat or glucose, producing abnormally high insulin levels. This causes insulin resistance as a protective mechanism to prevent insulin-induced metabolic stress.

The model reported in the current paper, which appears in PLOS Computational Biology, analyzed diabetes progression regarding multiple diabetogenic factors, including those related to the individual’s obesity threshold for increased diabetes risk, those relating ethnicity to a tolerance of factors promoting weight gain above the obesity threshold, as well as the effect of bariatric surgery on T2DM risk.

What did the study show?

Based on the research gap, the scientists developed a model that examines the impact of high insulin levels on insulin resistance. It would investigate the effects of multiple factors linked to the development of diabetes in terms of beta cell dysfunction.

This generalized model constructed by the scientists was then narrowed down by specifying an obesity-related diabetogenic factor. It examined how obesity affects glucose regulation in the body. It predicted changes in glucose and insulin levels over a human lifetime, showing how liver glucose production, rate of insulin release, and growth of functional beta cell mass changed when exposed to the obesity-related diabetogenic factor.

These long-term trends showed a close correlation to actual longitudinal data when fitted to a specific population, in this case, Pima Indian individuals. This group was chosen because of the long follow-up data available on the long-term changes and direction of glucose concentrations.

The model could differentiate the hyperinsulinemic subject without blood glucose abnormality from those with prediabetes and overt diabetes. In an environment that highly promotes obesity, progression to hyperinsulinemia occurred in a mean of seven years. A decade later, diabetes set in.

In about two decades, beta cell failure began to manifest as declining insulin levels, with actual insulin deficiency setting in with time.

The simulation also showed that when the same individual was exposed to an environment with only a mild obesogenic risk, the rate of progression and severity of disease were markedly reduced.

This supports the finding that weight loss of obese patients helps alleviate diabetes.”

The results confirmed what the scientists suspected. With proper control of obesity, T2DM could be reversed or postponed, or at least its severity reduced. This also explains the dramatic effect of the bariatric Roux-en-Y procedure that acts via reduced liver gluconeogenesis and reversal of beta cell dysfunction, to produce a rapid and durable restoration of euglycemia. The model could help decide the right time and patient for such surgeries to have the best outcome.

Secondly, individual-specific differences in the level of beta-cell dysfunction and insulin resistance were reflected in the variation in T2DM risk. As long as the obesity-related diabetogenic factor remained subthreshold, the person remained euglycemic even though obese. As the threshold was crossed to greater degrees, diabetes began to progress.

Such individualized threshold values, which provide warning signs of obese levels for taking necessary interventions to prevent the commencement of diabetes, may be valuable for clinical decision making.”

A concept called personal fat threshold (PFT) is being used to personalize diet plans for diabetic patients, using individualized susceptibilities to excessive lipids of specific types, as well as the amount of fat stored in the pancreas and liver.

Similarly, ethnic groups with basal hyperinsulinemia could successfully stave off diabetes by reducing exposure to obesogenic factors.

Finally, the scientists looked at the biological mechanism of several key parameters specified in this model and found much of relevance to the development of T2DM. Some interesting insights were obtained, including the predicted improvement in prognosis when treatment was aimed at minimizing the adverse effect of a diabetes risk factor on the beta cells, compared to improving the environment that promoted diabetes. That is, beta cells controlled glucose levels better when shielded from a hostile environment, rather than when treatment efforts were focused on changing the environment through, for instance, dietary modifications or exercise.

Again, some patients showed poorer glucose control despite increased insulin sensitivity, indicating that insulin resistance is not the only target necessary in the treatment of diabetes. Certain individuals develop severe diabetes rapidly after a long period of euglycemia. This preceding prolonged period of excellent glucose control was traceable to lower glucose production in the liver, indicating the importance of this as a therapeutic and preventive target.

What are the implications?

This study may encourage precise interventions to prevent diabetes and facilitate individualized patient treatment.”

Though used here to understand how diabetes progresses in an obesogenic environment, the model can investigate the effects of other factors, such as thyroid hormone or epinephrine oversecretion on the glucose regulatory system in the body.