Background Insulin 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... Show moreBackground Insulin 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. Methods We 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/m(2)/min) and high-dose (40 mU/m(2)/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. Results After 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. Conclusion Metabolomic 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. Show less
Luo, J.; Meulmeester, F.L.; Martens, L.G.; Ashrafi, N.; Mutsert, R. de; Mook-Kanamori, D.O.; ... ; Heemst, D. van 2021
Background & aims: Damage induced by lipid peroxidation has been associated with impaired glucose homeostasis. Vitamin E (alpha-tocopherol, alpha-TOH) competitively reacts with lipid peroxyl... Show moreBackground & aims: Damage induced by lipid peroxidation has been associated with impaired glucose homeostasis. Vitamin E (alpha-tocopherol, alpha-TOH) competitively reacts with lipid peroxyl radicals to mitigate oxidative damage, and forms oxidized vitamin E metabolites. Accordingly, we aimed to investigate the associations between alpha-TOH metabolites (oxidized and enzymatic) in both circulation and urine and measures of glucose homeostasis in the general middle-aged population. Methods: This cross-sectional study was embedded in the population-based Netherlands Epidemiology of Obesity (NEO) Study. alpha-TOH metabolites in blood (alpha-TOH and alpha-CEHC-SO3) and urine [sulfate (SO3) and glucuronide (GLU) of both alpha-TLHQ (oxidized) and alpha-CEHC (enzymatic)] were quantified by liquid chromatography coupled with tandem mass spectrometry (LC/MSeMS). Measures of glucose homeostasis (HOMA-B, HOMA-IR, Insulinogenic index and Matsuda index) were obtained from fasting and postprandial blood samples. Multivariable linear regression analyses were performed to assess the associations of alpha-TOH metabolites and measures of glucose homeostasis. Results: We included 498 participants (45% men) with mean (SD) age of 55.8 (6.1) years who did not use glucose-lowering medication. While blood alpha-TOH was not associated with measures of glucose homeostasis, urinary oxidized metabolites (alpha-TLHQ-SO3/GLU) were associated with HOMA-IR and Matsuda index. For example, a one-SD higher alpha-TLHQ-SO3 was associated with 0.92 (95% CI: 0.87, 0.97) fold lower HOMA-IR and 1.06 (1.01, 1.11) fold higher Matsuda index, respectively. Similar results were obtained for the urinary alpha-TLHQ to alpha-CEHC ratio as a measure of oxidized-over-enzymatic conversion of alpha-TOH. Conclusion: Higher urinary levels of oxidized alpha-TOH metabolites as well as higher oxidized-to-enzymatic alpha-TOH metabolite ratio, but not circulating alpha-TOH or enzymatic metabolites, were associated with lower insulin resistance. Rather than circulating alpha-TOH, estimates of the conversion of alpha-TOH might be informative in relation to health and disease. (c) 2021 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/ Show less
