Differential insulin sensitivity of NMR-based metabolomic measures in a two-step hyperinsulinemic euglycemic clamp study

Wenyi Wang,P Eline Slagboom,Raymond Noordam,Maarten P Rozing,Carolien A Wijsman,Diana Van Heemst,Simon P Mooijaart,Ko Willems Van Dijk,Marian Beekman,J Wouter Jukema

doi:10.1007/s11306-021-01806-2

Abstract

BackgroundInsulin is the key regulator of glucose metabolism, but it is difficult to dissect direct insulin from glucose-induced effects. We aimed to investigate the effects of hyperinsulemia on metabolomic measures under euglycemic conditions in nondiabetic participants.MethodsWe assessed concentrations of 151 metabolomic measures throughout a two-step hyperinsulinemic euglycemic clamp procedure. We included 24 participants (50% women, mean age = 62 [s.d. = 4.2] years) and metabolomic measures were assessed under baseline, low-dose (10 mU/m2/min) and high-dose (40 mU/m2/min) insulin conditions. The effects of low- and high-dose insulin infusion on metabolomic measures were analyzed using linear mixed-effect models for repeated measures.ResultsAfter low-dose insulin infusion, 90 metabolomic measures changed in concentration (p < 1.34e−4), among which glycerol (beta [Confidence Interval] = − 1.41 [− 1.54, − 1.27] s.d., p = 1.28e−95) and three-hydroxybutyrate (− 1.22 [− 1.36, − 1.07] s.d., p = 1.44e−61) showed largest effect sizes. After high-dose insulin infusion, 121 metabolomic measures changed in concentration, among which branched-chain amino acids showed the largest additional decrease compared with low-dose insulin infusion (e.g., Leucine, − 1.78 [− 1.88, − 1.69] s.d., P = 2.7e−295). More specifically, after low- and high-dose insulin infusion, the distribution of the lipoproteins shifted towards more LDL-sized particles with decreased mean diameters.ConclusionMetabolomic measures are differentially insulin sensitive and may thus be differentially affected by the development of insulin resistance. Moreover, our data suggests insulin directly affects metabolomic measures previously associated with increased cardiovascular disease risk.

Highlights

Insulin is an anabolic peptide hormone secreted by the pancreas in response to increased blood glucose levels to activate various mechanisms that decrease blood glucose levels (Tokarz et al, 2018)
Insulin sensitivity is frequently assessed on the basis of the ratio between fasting insulin and glucose levels calculated as the homeostatic model assessment for insulin resistance (HOMA-IR) index (Gutch et al, 2015)
This study explored the changes of blood metabolomic measures in 24 clinically healthy individuals during a hyperinsulinemic euglycemic clamp study

Summary

Introduction

Insulin is an anabolic peptide hormone secreted by the pancreas in response to increased blood glucose levels to activate various mechanisms that decrease blood glucose levels (Tokarz et al, 2018). Insulin increases glucose uptake by peripheral tissues such as muscle and fat, but insulin decreases endogenous glucose production through suppression of gluconeogenesis in the liver and both processes may be affected differentially by insulin resistance (Wallace et al, 2004). A two-step hyperinsulinemic euglycemic clamp analysis was used to assess whole-body insulin sensitivity and a glucose tracer was included to distinguish hepatic and peripheral insulin resistance (Finegood et al, 1987; Muniyappa et al, 2008; Steele, 1959). After high-dose insulin infusion, 121 metabolomic measures changed in concentration, among which branched-chain amino acids showed the largest additional decrease compared with low-dose insulin infusion (e.g., Leucine, − 1.78 [− 1.88, − 1.69] s.d., P = 2.7e−295). Our data suggests insulin directly affects metabolomic measures previously associated with increased cardiovascular disease risk

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