Abstract
BackgroundIt is commonly accepted that in obesity free fatty acids (FFA) cause insulin resistance and hyperglycemia, which drives hyperinsulinemia. However, hyperinsulinemia is observed in subjects with normoglycaemia and thus the paradigm above should be reevaluated.MethodsWe describe two studies: MD-Lipolysis, a case control study investigating the mechanisms of obesity-driven insulin resistance by a systemic metabolic analysis, measurements of adipose tissue lipolysis by microdialysis, and adipose tissue genomics; and POEM, a cohort study used for validating differences in circulating metabolites in relation to adiposity and insulin resistance observed in the MD-Lipolysis study.FindingsIn insulin-resistant obese with normal glycaemia from the MD-Lipolysis study, hyperinsulinemia was associated with elevated FFA. Lipolysis, assessed by glycerol release per adipose tissue mass or adipocyte surface, was similar between obese and lean individuals. Adipose tissue from obese subjects showed reduced expression of genes mediating catecholamine-driven lipolysis, lipid storage, and increased expression of genes driving hyperplastic growth. In the POEM study, FFA levels were specifically elevated in obese-overweight subjects with normal fasting glucose and high fasting levels of insulin and C-peptide.InterpretationIn obese subjects with normal glycaemia elevated circulating levels of FFA at fasting are the major metabolic derangement candidate driving fasting hyperinsulinemia. Elevated FFA in obese with normal glycaemia were better explained by increased fat mass rather than by adipose tissue insulin resistance. These results support the idea that hyperinsulinemia and insulin resistance may develop as part of a homeostatic adaptive response to increased adiposity and FFA.FundingSwedish-Research-Council (2016-02660); Diabetesfonden (DIA2017-250; DIA2018-384; DIA2020-564); Novo-Nordisk-Foundation (NNF17OC0027458; NNF19OC0057174); Cancerfonden (CAN2017/472; 200840PjF); Swedish-ALF-agreement (2018-74560).
Highlights
Excessive adiposity leads to hyperinsulinemia and insulin resistance, a major risk factor for diabetes mellitus and a cluster of related diseases collectively known as the metabolic syndrome [1]
Our results from the MD-Lipolysis study and the POEM study are consistent with the idea that elevated free fatty acids (FFA) levels, and not glucose, are the major metabolic derangement driving fasting hyperinsulinemia in obese insulin-resistant individuals with normal glycaemic control
The fact that fasting hyperinsulinemia was associated with high FFA levels in presence of normal fasting glycaemia is consistent with studies indicating that insulin controls hepatic glucose production mainly through its direct action in the hepatocyte [52,53] rather than by reducing circulating levels of FFA and glycerol driving hepatic glucose production [3,17,54,55]
Summary
Excessive adiposity leads to hyperinsulinemia and insulin resistance, a major risk factor for diabetes mellitus and a cluster of related diseases collectively known as the metabolic syndrome [1]. A major limitation of this model is that a marked hyperinsulinemia can be observed in subjects with normal glycemic control, suggesting that high blood glucose may not be the driver of hyperinsulinemia in these subjects [2] Along this line of reasoning, it has been proposed that hyperinsulinemia itself may be a cause of the resistance to insulin action in glucose metabolism instead of being a consequence of it, as elevated basal levels of insulin are expected to desensitize insulin target cells to insulin stimulation [2,4À7]. The general role of FFA as pathogenic drivers of insulin resistance has been questioned: data on 5790 individuals from the Paris Prospective Study and on 1591 individuals from the Oxford Biobank indicate that fasting levels of circulating FFA are not generally elevated in subjects with larger fat mass [26]; and it was reported that FFA release per 100 g of adipose tissue are downregulated in subjects with larger fat mass and negatively correlated with fasting circulating insulin levels [26]. Our results are consistent with the idea that insulin resistance may develop in the context of an adaptive homeostatic response restraining the increase of circulating levels of FFA driven by larger adipose mass of obese subjects
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