Remission of pre-diabetes are driven by improvement in insulin resistance and loss of visceral fat mass

Abstract

Previous landmark studies have reported that the mechanism of remission of type 2 diabetes occurred as a results of weight loss which induced reduction in liver and pancreatic fat mass, leading to recovery of beta-cell function and insulin secretion. Such findings have led to interests in dietary, life-style and pharmacological intervention strategies to induce diabetes remission. Previous large scale randomized trials such as the diabetes prevention programme (DPP) have shown that life-style interventions was associated with a significant reduction in the risk of pre-diabetes progressing to diabetes state but the risks of relapse of pre-diabetes and subsequent progression to diabetes have not been studied. Furthermore, given that the beta-cell function in people with pre-diabetes remains intact (albeit being overworked), the mechanism of pre-diabetes remission remains unclear.

To investigate this, patients involved in the randomized, controlled, multicentre Prediabetes Lifestyle Intervention Study (PLIS) and who achieved weight loss-induced resolution of prediabetes was assessed and the results were validated against participants from the DPP study. The PLIS was conducted between between 1 March 2012 and 31 August 2016, and participants were recruited from eight clinical study centres (including seven university hospitals) in Germany. Patients were randomly assigned to receive either a control intervention, a standard lifestyle intervention (i.e., DPP-based intervention), or an intensified lifestyle intervention for 12 months. In a pre-specified post-hoc analysis of both PLIS and DPP, only participants who were randomly assigned to receive lifestyle intervention or placebo and who lost at least 5% of their bodyweight were included in this analysis. Responders or remission of pre-diabetes were defined as people who returned to normal fasting plasma glucose (FPG; <5.6 mmol/L), normal glucose tolerance (<7.8 mmol/L), and HbA_1c less than 39 mmol/mol after 12 months of lifestyle intervention or placebo or control intervention. Non-responders or those whose pre-diabetes relapsed were defined as people who had FPG, 2 h glucose, or HbA_1c more than these thresholds. The main outcomes for this analysis were insulin sensitivity, insulin secretion, visceral adipose tissue (VAT), and intrahepatic lipid content (IHL) and were evaluated via linear mixed models.

Of 1160 participants recruited to PLIS, 298 (25·7%) had weight loss of 5% with 128 (43%) of 298 participants were responders and 170 (57%) were non-responders. Interestingly, while BMI reduction was similar between responders and non-responders, whole-body insulin sensitivity increased more in responders than in non-responders. Crucially, unlike studies in people with type 2 diabetes, insulin secretion did not differ within groups over time or between groups. Visceral adipose tissue (VAT) however decreased more in responders than in non-responders. Responders had a 73% lower risk of developing type 2 diabetes than non-responders in the 2 years after the intervention ended.

This study in my opinion provided novel insight into the mechanism for the resolution of prediabetes—which appeared to be characterized by an improvement in insulin sensitivity and reduced VAT. This mechanism appears to be separate to total weight loss. Given that weight reduction per se were the same between responders and non-responders, it will be interesting to also investigate the role of muscle mass in the remission of pre-diabetes. This study was published in the journal Lancet, Diabetes & Endocrinology (1).