Aetiology of Type 2 diabetes in people with a 'normal' body mass index: testing the personal fat threshold hypothesis

Abstract

Weight loss in overweight or obese individuals with Type 2 diabetes (T2D) can normalize hepatic fat metabolism, decrease fatty acid oversupply to β cells and restore normoglycaemia. One in six people has BMI <27 kg/m2 at diagnosis, and their T2D is assumed to have different aetiology. The Personal Fat Threshold hypothesis postulated differing individual thresholds for lipid overspill and adverse effects on β-cell function. To test this hypothesis, people with Type 2 diabetes and body mass index <27kg/m2 (n = 20) underwent repeated 5% weight loss cycles. Metabolic assessments were carried out at stable weight after each cycle and after 12 months. To determine how closely metabolic features returned to normal, 20 matched normoglycemic controls were studied once. Between baseline and 12 months: BMI fell (mean ± SD), 24.8 ± 0.4 to 22.5 ± 0.4 kg/m2 (P<0.0001) (controls: 21.5 ± 0.5); total body fat, 32.1 ± 1.5 to 27.6 ± 1.8% (P<0.0001) (24.6 ± 1.5). Liver fat content and fat export fell to normal as did fasting plasma insulin. Post-meal insulin secretion increased but remained subnormal. Sustained diabetes remission (HbA1c < 48 mmol/mol off all glucose-lowering agents) was achieved by 70% (14/20) by initial weight loss of 6.5 (5.5-10.2)%. Correction of concealed excess intra-hepatic fat reduced hepatic fat export, with recovery of β-cell function, glycaemic improvement in all and return to a non-diabetic metabolic state in the majority of this group with BMI <27 kg/m2 as previously demonstrated for overweight or obese groups. The data confirm the Personal Fat Threshold hypothesis: aetiology of Type 2 diabetes does not depend on BMI. This pathophysiological insight has major implications for management.

Keywords: de novo lipogenesis; hepatic steatosis; remission; triglyceride; type 2 diabetes; weight loss.

Figure 1. Time course of change in major clinical parameters after each cycle of weight loss and at 12 months

Changes in mean (+SEM) BMI, weight, % body fat, waist circumference, visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) in the T2D group during the intervention at each time point. Numbers of participants and level of statistical significance vs. baseline are shown below each time point. The dotted line shows the mean control values for each parameter.

Figure 2. Major pathophysiological parameters at baseline, at the Clinical End Point of HbA1c <48mmol/mol (CEP) and at 12 months

Median (IQR) liver fat, very low-density lipoprotein-1 (VLDL) triglyceride, plasma triglycerides with palmitic acid content reflecting rate of de novo lipogenesis, total plasma triglyceride, and Disposition Index at baseline, the co-primary end points of CEP (clinical end point; HbA_1c <48 mmol/mol) and at 12 months in the T2D group. Numbers of participants and level of statistical significance vs. baseline are shown below CEP and 12 months. Non-diabetic control data are also shown with the level of significance vs. T2D at 12 months below ‘Control’.

Figure 3. Time course of change in glycaemic measures after each cycle of weight loss and at 12 months

Change in mean (+SEM) HbA_1c and fasting plasma glucose values in the T2D group during weight stability following each weight loss cycle and also after longer term follow up at 12 months. Numbers of participants and significance level versus baseline are shown below each time point.