Lipid-induced glucose intolerance is driven by impaired glucose kinetics and insulin metabolism in healthy individuals

Abstract

Aims: Hypertriglyceridemia is associated with an increased risk of type 2 diabetes. We aimed to comprehensively examine the effects of hypertriglyceridemia on major glucose homeostatic mechanisms involved in diabetes progression.

Methods: In this randomized, cross-over, single-blinded study, two dual-labeled, 3-hour oral glucose tolerance tests were performed during 5-hour intravenous infusions of either 20 % Intralipid or saline in 12 healthy subjects (age 27.9 ± 2.6 years, 11 men, BMI 22.6 ± 1.4 kg/m²) to evaluate lipid-induced changes in insulin metabolism and glucose kinetics. Insulin sensitivity, β cell secretory function, and insulin clearance were assessed by modeling glucose, insulin and C-peptide data. Intestinal glucose absorption, endogenous glucose production, and glucose clearance were assessed from glucose tracers. The effect of triglycerides on β-cell secretory function was examined in perifusion experiments in murine pseudoislets and human pancreatic islets.

Results: Mild acute hypertriglyceridemia impaired oral glucose tolerance (mean glucose: +0.9 [0.3, 1.5] mmol/L, p = 0.008) and whole-body insulin sensitivity (Matsuda index: -1.67 [-0.50, -2.84], p = 0.009). Post-glucose hyperinsulinemia (mean insulin: +99 [17, 182] pmol/L, p = 0.009) resulted from reduced insulin clearance (-0.16 [-0.32, -0.01] L min^-1 m^-2, p = 0.04) and enhanced hyperglycemia-induced total insulin secretion (+11.9 [1.1, 22.8] nmol/m², p = 0.02), which occurred despite a decline in model-derived β cell glucose sensitivity (-41 [-74, -7] pmol min^-1 m^-2 mmol^-1 L, p = 0.04). The analysis of tracer-derived glucose metabolic fluxes during lipid infusion revealed lower glucose clearance (-96 [-152, -41] mL/kg_FFM, p = 0.005), increased 2-hour oral glucose absorption (+380 [42, 718] μmol/kg_FFM, p = 0.04) and suppressed endogenous glucose production (-448 [-573, -123] μmol/kg_FFM, p = 0.005). High-physiologic triglyceride levels increased acute basal insulin secretion in murine pseudoislets (+11 [3, 19] pg/aliquot, p = 0.02) and human pancreatic islets (+286 [59, 512] pg/islet, p = 0.02).

Conclusion: Our findings support a critical role for hypertriglyceridemia in the pathogenesis of type 2 diabetes in otherwise healthy individuals and dissect the glucose homeostatic mechanisms involved, encompassing insulin sensitivity, β cell function and oral glucose absorption.

Keywords: Beta cell function; Fatty acids; Glucose absorption; Glucose intolerance; Glucose kinetics; Hypertriglyceridemia; Insulin clearance; Insulin resistance; Insulin secretion; Lipotoxicity.