Glycerol and Fatty Acids in Serum Predict the Development of Hyperglycemia and Type 2 Diabetes in Finnish Men

Mahendran, Yuvaraj; Cederberg, Henna; Vangipurapu, Jagadish; Kangas, Antti J.; Soininen, Pasi; Kuusisto, Johanna; Uusitupa, Matti; Ala‐Korpela, Mika; Laakso, Markku

doi:10.2337/dc13-0800

Cited by 146 publications

(119 citation statements)

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“…However, in our study and in another Finnish study (12), circulating AA was inversely associated with risk, although most other studies did not find this association (9,10,13,14,31). In addition to the proinflammatory metabolites, AA is also a precursor to several anti-inflammatory metabolites (15).…”

Section: Discussioncontrasting

confidence: 50%

Serum n–6 polyunsaturated fatty acids, Δ5- and Δ6-desaturase activities, and risk of incident type 2 diabetes in men: the Kuopio Ischaemic Heart Disease Risk Factor Study

Yary

Voutilainen

Tuomainen

et al. 2016

The American Journal of Clinical Nutrition

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Background: The role of n-6 (v-6) polyunsaturated fatty acids (PUFAs) in type 2 diabetes (T2D) is inconclusive. In addition, little is known about how factors involved in PUFA metabolism, such as zinc, may affect the associations. Objectives: We investigated the associations of serum n-6 PUFAs and activities of enzymes involved in PUFA metabolism, D5 desaturase (D5D) and D6 desaturase (D6D), with T2D risk to determine whether serum zinc concentrations could modify these associations. Design: The study included 2189 men from the prospective Kuopio Ischaemic Heart Disease Risk Factor Study, aged 42-60 y and free of T2D at baseline in 1984-1989. T2D was assessed by selfadministered questionnaires, by fasting and 2-h oral-glucose-tolerance test blood glucose measurement at re-examination rounds 4, 11, and 20 y after baseline, and by record linkage to the hospital discharge registry and the reimbursement register on diabetes medication expenses. Multivariate-adjusted Cox proportional hazards regression models were used to analyze associations. Results: During the average follow-up of 19.3 y, 417 men developed T2D. Those with higher estimated D5D activity (extreme-quartile HR: 0.55; 95% CI: 0.41, 0.74; P-trend , 0.001) and higher concentrations of total n-6 PUFAs (HR: 0.54; 95% CI: 0.41, 0.73; P-trend , 0.001), linoleic acid (LA; HR: 0.52; 95% CI: 0.39, 0.70; P-trend , 0.001), and arachidonic acid (AA; HR: 0.62; 95% CI: 0.46, 0.85; P-trend = 0.007) had a lower risk and those with higher concentrations of g-linolenic acid (GLA; HR: 1.28; 95% CI: 0.98, 1.68; P = 0.021) and dihomog-linolenic acid (DGLA; HR: 1.38; 95% CI: 1.04, 1.84; P-trend = 0.005) and higher D6D activity had a higher (HR: 1.50; 95% CI: 1.14, 1.97; P-trend , 0.001) multivariate-adjusted risk of T2D. Zinc mainly modified the association with GLA on T2D risk, with a higher risk observed among those with serum zinc concentrations above the median (P-interaction = 0.04). Conclusions: Higher serum total n-6 PUFA, LA, and AA concentrations and estimated D5D activity were associated with a lower risk of incident T2D, and higher GLA and DGLA concentrations and estimated D6D activity were associated with a higher risk. In addition, a higher serum zinc concentration modified the association of GLA on the risk of T2D.Am J Clin Nutr 2016;103:1337-43.

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Section: Discussioncontrasting

confidence: 50%

Serum n–6 polyunsaturated fatty acids, Δ5- and Δ6-desaturase activities, and risk of incident type 2 diabetes in men: the Kuopio Ischaemic Heart Disease Risk Factor Study

Yary

Voutilainen

Tuomainen

et al. 2016

The American Journal of Clinical Nutrition

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“…Glycerol infusion at physiological concentrations stimulates glucose output from perfused mouse livers and cultured primary hepatocytes [8], and gluconeogenesis from glycerol accounts for approximately 10% of hepatic glucose production in type 2 diabetic patients [9]. Elevated circulating glycerol levels are predictive of type 2 diabetes in men [10] and glycerol gluconeogenesis is elevated in rat models of type 1 diabetes [11]. Furthermore, suppressing glycerol gluconeogenesis is a potential therapeutic strategy for treating diabetes, as deletion of glycerol transporters in the liver lowers blood glucose in diabetic db/db mice [12], and pharmacological inhibition of lipolysis reduces glycaemia in rats with streptozotocin (STZ)-induced diabetes [13].…”

Section: Introductionmentioning

confidence: 99%

Leptin induces fasting hypoglycaemia in a mouse model of diabetes through the depletion of glycerol

et al. 2015

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Aims/hypothesis Leptin has profound glucose-lowering effects in rodent models of type 1 diabetes, and is currently being tested clinically to treat this disease. In addition to reversing hyperglycaemia, leptin therapy corrects multiple lipid, energy and neuroendocrine imbalances in rodent models of type 1 diabetes, yet the precise mechanism has not been fully defined. Thus, we performed metabolic analyses to delineate the downstream metabolic pathway mediating leptin-induced glucose lowering in diabetic mice. Methods Mice were injected with streptozotocin (STZ) to induce insulin-deficient diabetes, and were subsequently treated with 20 μg/day recombinant murine leptin or vehicle for 5 to 14 days. Energy-yielding substrates were measured in the liver and plasma, and endogenous glucose production was assessed by tolerance to extended fasting. Results STZ-leptin-treated mice developed severe hypoketotic hypoglycaemia during prolonged fasting, indicative of suppressed endogenous ketone and glucose production. STZ-leptin mice displayed normal gluconeogenic and glycogenolytic capacity, but had depleted circulating glycerol and NEFA. The depletion of glycerol and NEFA correlated tightly with the kinetics of glucose lowering in response to chronic leptin administration, and was not mimicked by single leptin injection. Administration of glycerol acutely reversed fasting-induced hypoglycaemia in leptin-treated mice. Conclusions/interpretation The findings of this study suggest that the diminution of circulating glycerol reduces endogenous glucose production, contributing to severe fastinginduced hypoglycaemia in leptin-treated rodent models of type 1 diabetes, and support that depletion of glycerol contributes to the glucose-lowering action of leptin.

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“…We also demonstrated for the first time that ketone bodies predict the conversion to T2D by impairing insulin secretion (14). Noncholesterol sterols (desmosterol, avenasterol) (15), glycerol, free fatty acids, and monounsaturated and saturated fatty acids predicted incident T2D (16). Palmitoleic acid increased and linoleic acid measured from plasma (17) or erythrocyte membranes (18) decreased the risk of T2D.…”

Section: T2d and Hyperglycemiamentioning

confidence: 99%

The Metabolic Syndrome in Men study: a resource for studies of metabolic and cardiovascular diseases

Laakso

Kuusisto

Stančáková

et al. 2017

Journal of Lipid Research

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168

167

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The Metabolic Syndrome in Men (METSIM) study is a population-based study including 10,197 Finnish men examined in 2005-2010. The aim of the study is to investigate nongenetic and genetic factors associated with the risk of T2D and CVD, and with cardiovascular risk factors. The protocol includes a detailed phenotyping of the participants, an oral glucose tolerance test, fasting laboratory measurements including proton NMR measurements, mass spectometry metabolomics, adipose tissue biopsies from 1,400 participants, and a stool sample. In our ongoing follow-up study, we have, to date, reexamined 6,496 participants. Extensive genotyping and exome sequencing have been performed for essentially all METSIM participants, and >2,000 METSIM participants have been whole-genome sequenced. We have identified several nongenetic markers associated with the development of diabetes and cardiovascular events, and participated in several genetic association studies to identify gene variants associated with diabetes, hyperglycemia, and cardiovascular risk factors. The generation of a phenotype and genotype resource in the METSIM study allows us to proceed toward a "systems genetics" approach, which includes statistical methods to quantitate and integrate intermediate phenotypes, such as transcript, protein, or metabolite levels, to provide a global view of the molecular architecture of complex traits.

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Glycerol and Fatty Acids in Serum Predict the Development of Hyperglycemia and Type 2 Diabetes in Finnish Men

Cited by 146 publications

References 34 publications

Serum n–6 polyunsaturated fatty acids, Δ5- and Δ6-desaturase activities, and risk of incident type 2 diabetes in men: the Kuopio Ischaemic Heart Disease Risk Factor Study

Serum n–6 polyunsaturated fatty acids, Δ5- and Δ6-desaturase activities, and risk of incident type 2 diabetes in men: the Kuopio Ischaemic Heart Disease Risk Factor Study

Leptin induces fasting hypoglycaemia in a mouse model of diabetes through the depletion of glycerol

The Metabolic Syndrome in Men study: a resource for studies of metabolic and cardiovascular diseases

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