The effects of increased acetate turnover on glucose-induced insulin secretion in lean and obese humans.

Kitt Falk Petersen,Anne Impellizeri,Gary W Cline,Gerald I Shulman

doi:10.1017/cts.2018.342

Abstract

Increased endogenous acetate production (Ra) in rodents has been shown to activate the parasympathetic nervous system and thereby promote increased glucose-stimulated insulin secretion (GSIS), increased ghrelin secretion, hyperphagia and obesity. To examine whether rates of acetate turnover are different in lean versus obese humans and whether increased acetate turnover promotes increased GSIS and increased ghrelin secretion in humans. Basal acetate Ra was measured following an overnight fast in lean (BMI: 21.3 ± 1.1 Kg/m2) and obese (30.2 ± 0.9 Kg/m2, P = 0.00001) individuals. The subjects underwent two hyperglycemic (10 mmol/L) clamp studies to measure GSIS during a basal acetate infusion and during a high-dose acetate infusion increasing plasma acetate concentrations ∼5-fold. Basal acetate Ra was 30% higher in the lean compared to the obese subjects (257 ± 27 vs. 173 ± 18 μmol/min; P = 0.025). Basal plasma insulin concentrations were 4-fold higher in the obese than the lean subjects (P = 0.008) and increased 5-fold during hyperglycemia in both groups, independent of changes in plasma acetate concentrations. Fasting plasma ghrelin concentrations were 35% lower in the obese compared to the lean subjects (P = 0.015). During the hyperglycemic clamp, plasma ghrelin decreased by 42% in the lean group (P < 0.022 vs. basal) and did not change in the obese group. Rates of endogenous acetate turnover are ∼30% higher in the lean subjects compared to the obese subjects, and increasing plasma acetate turnover does not promote increased GSIS or ghrelin secretion in either group.

Highlights

Increased endogenous acetate production (Ra) in rodents has been shown to activate the parasympathetic nervous system and thereby promote increased glucose-stimulated insulin secretion (GSIS), increased ghrelin secretion, hyperphagia and obesity
Perry et al went on to demonstrate that when acetate is infused in physiological amounts, to match endogenous rates of acetate turnover in HFF obese rats, this perturbation led to activation of the parasympathetic nervous system, which in turn promoted increased glucose-stimulated insulin secretion (GSIS), increased ghrelin secretion, hyperphagia and obesity [3]
Acetate has been shown to cross the blood–brain barrier [7], and increased plasma acetate concentrations have been associated with increased subjective satiety ratings [8] and reduction in body weight [9]; no studies have directly examined whether acetate turnover is increased in obese vs. lean humans and whether GSIS is affected by altering plasma acetate concentrations

Summary

Introduction

Increased endogenous acetate production (Ra) in rodents has been shown to activate the parasympathetic nervous system and thereby promote increased glucose-stimulated insulin secretion (GSIS), increased ghrelin secretion, hyperphagia and obesity. Conclusion: Rates of endogenous acetate turnover are ~30% higher in the lean subjects compared to the obese subjects, and increasing plasma acetate turnover does not promote increased GSIS or ghrelin secretion in either group. Perry et al assessed rates of endogenous acetate turnover in lean regular chow and highfat-fed (HFF) obese rats and found that high-fat feeding promoted increased rates of endogenous acetate turnover due to increased acetate production by the gut microbiota [3]. Consistent with these findings, studies in humans have found increased fecal acetate concentrations in obese individuals [4]. In order to examine the effects of increased plasma acetate concentrations on GSIS and ghrelin secretion, the subjects underwent two hyperglycemic clamps combined with a tracer infusion of [2-13C] acetate and a high-dose infusion of [2-13C]acetate designed to increase acetate turnover by ~5-fold and raise plasma acetate concentrations ~5-fold

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