Natural history of β-cell adaptation and failure in type 2 diabetes

Abstract

Type 2 diabetes mellitus (T2D) is a complex disease characterized by β-cell failure in the setting of insulin resistance. The current evidence suggests that genetic predisposition, and environmental factors can impair the capacity of the β-cells to respond to insulin resistance and ultimately lead to their failure. However, genetic studies have demonstrated that known variants account for less than 10% of the overall estimated T2D risk, suggesting that additional unidentified factors contribute to susceptibility of this disease. In this review, we will discuss the different stages that contribute to the development of β-cell failure in T2D. We divide the natural history of this process in three major stages: susceptibility, β-cell adaptation and β-cell failure and provide an overview of the molecular mechanisms involved. Further research into mechanisms will reveal key modulators of β-cell failure and thus identify possible novel therapeutic targets and potential interventions to protect against β-cell failure.

Definition of a Skp2-c-Myc Pathway to Expand Human Beta-cells

“…Developmental differences, failure of adaptation and increased loss of β-cells via β-cell death or de-differentiation have emerged as the possible causes of this reduced β-cell mass. In rodents, β-cell proliferation contributes to the expansion of β-cell mass in non-diabetic obesity, and a failure to proliferate and/or an increased apoptosis seem to be the features of T2D123. In humans, data suggest that the proliferation in response to obesity is more limited or absent.…”

“…T2D (T2D) has traditionally been regarded to be the result of insulin resistance in liver, skeletal muscle and adipose tissue123. Recently, autopsy and genome-wide association studies (GWAS) suggest that it is also associated with β-cell deficiency and dysfunction45678910.…”

“…Recently, autopsy and genome-wide association studies (GWAS) suggest that it is also associated with β-cell deficiency and dysfunction45678910. The major factor associated with T2D is obesity, although not all obese subjects become diabetic1310. In autopsy studies, patients with T2D display a reduced β-cell mass as compared to non-diabetic patients with comparable BMI.…”

“…In contrast, β-cell mass is increased in non-diabetic obese subjects as compared to lean subjects81112. In rodents, β-cell expansion in obesity models is associated with replication of endogenous β-cells13. However, there is little evidence for β-cell replication in human obesity or T2D.…”

Regeneration of pancreatic insulin-producing cells by in situ adaptive cell conversion

“…Diabetes mellitus results from the impaired ability of either (i) the endocrine pancreas to produce the hormone insulin, or (ii) the target tissues (brain, liver, muscle…) to respond to it, or both. The two prevailing forms of diabetes, named Type 1 and Type 2 (T1D and T2D), are characterized by the loss of insulin-producing islet cells: total or near total in T1D, due to an autoimmune destruction, or variable and partial in T2D 1,2 . A cure for insulin-dependent diabetes requires the reconstitution of a functional β-cell mass, either through in situ regeneration or by cell-based replacement therapies, i.e.…”