Hyperinsulinemia and insulin resistance in the obese may develop as part of a homeostatic response to elevated free fatty acids: A mechanistic case-control and a population-based cohort study

Emanuel Fryk, Josefin Olausson, Karin Mossberg, Lena Strindberg, Martin Schmelz, Helén Brogren, Li-Ming Gan, Silvano Piazza, Alessandro Provenzani, Barbara Becattini, Lars Lind, Giovanni Solinas, Per-Anders Jansson, Emanuel Fryk, Josefin Olausson, Karin Mossberg, Lena Strindberg, Martin Schmelz, Helén Brogren, Li-Ming Gan, Silvano Piazza, Alessandro Provenzani, Barbara Becattini, Lars Lind, Giovanni Solinas, Per-Anders Jansson

Abstract

Background: It 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.

Methods: We 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.

Findings: In 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.

Interpretation: In 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.

Funding: Swedish-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).

Keywords: Adaptive response; Adipose tissue; Free fatty acids; Insulin resistance; Lipolysis; Microdialysis; Obesity; RNA sequencing; Type 2 diabetes.

Conflict of interest statement

Declaration of Competing Interest L.M.G holds an employment at AstraZeneca R&D. All other authors declare no competing interest.

Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.

Figures

Fig. 1
Fig. 1
MD-Lipolysis study design and characteristics of subjects. (a) Illustration of the volunteer selection procedure for the MD-Lipolysis study by specific inclusion (green) and exclusion (red) criteria, which defined the experimental groups: Lean; Obese-IR; and Obese-T2D. (b) The experimental plan was implemented in three visits: screening and collection of information of participants was performed at visit-1; blood and abdominal subcutaneous adipose tissue interstitial dialysate fluids were collected after an overnight fasting and during an oral glucose tolerance test (OGTT), and abdominal subcutaneous adipose tissue blood flow (ATBF) measurements (by 133Xe-clearance technique) were performed at visit-2; EndoPAT (peripheral arterial tone) measurements of endothelial function and subcutaneous adipose tissue biopsies collection were performed at visit-3. (c) HbA1c values of participants, divided by experimental groups, at each study visit. (d) Weight of participants, divided by experimental groups, at each study visit. Data are presented as individual data points for each participant. n=9 for c and d, except for Visit-3 where one Obese-IR did not attend. Data in c, d [95% CI for mean slope of all curves].
Fig. 2
Fig. 2
Circulating concentrations of insulin and metabolites in Lean, Obese-IR, and Obese-T2D subjects. Overnight fasting levels of: (a) plasma glucose (fP-Glucose); (b) serum insulin (fS-Insulin); (c) plasma glycerol (fP-Glycerol); and (d) plasma free fatty acids (fP-FFA). During an oral glucose tolerance test (OGTT) we measured the levels of: (e) plasma glucose (P-Glucose), and (f) the area under the curves (AUC) in e; (g) serum insulin (S-Insulin) and (h) AUC of g; (i) plasma glycerol (P-Glycerol), and (j) AUC of i; (k) plasma free fatty acids (P-FFA), and (l) AUC of k. Maximum decrease from the baseline value during the OGTT of the levels of (m) P-Glycerol, and (n) P-FFA. (o) Fat mass of study participants. Data are presented as median and error bars indicate interquartile range (IQR) for each group. n=9 in each group for all panels [Mann-Whitney U-test for bars and time 180 in figure (g), mixed-effects models for curves].
Fig. 3
Fig. 3
Measurements of abdominal subcutaneous adipose tissue function in Lean, Obese-IR, and Obese-T2D subjects. During the OGTT in Fig. 2 we collected dialysates of abdominal subcutaneous adipose tissue and measured the concentrations of: (a) Interstitial glycerol (I-Glycerol); (b) interstitial insulin (I-Insulin); (c) interstitial lactate (I-Lactate); and (d) interstitial glucose (I-Glucose). (e) Maximum decrease in I-Glycerol from the baseline value during the OGTT. (f) Basal subcutaneous adipose tissue blood flow (ATBF) measured by 133Xe-clearance technique. (g) ATBF during the OGTT; and (h) ATBF area under the curve (AUC) of g. Data are presented as median and error bars indicate interquartile range (IQR) for each group. (i) Adipocyte size distribution curves of abdominal subcutaneous adipose tissue biopsies from Lean; Obese-IR; and Obese-T2D volunteers. Basal glycerol release rates from abdominal subcutaneous adipose tissue were calculated per: (j) 104 adipocytes; (k) 100 g of adipose tissue; and (l) adipocyte surface area. (a, c-e) n = 9 for Lean, n = 8 for Obese-IR and n = 9 for Obese-T2D. (b) n = 9 for Lean, Obese-IR and Obese-T2D. (f-i) n = 9 in Lean and Obese-IR, and n = 8 in Obese-T2D. (j-l) n = 9 for lean, n = 8 for obese-IR and n=8 for obese-T2D. [Mann-Whitney U-test for all bars and specific time points in curves a-c (mixed-effects models available in Supplementary Table 3), mixed-effects models for all time dependent curves (a-d, g). Mann-Whitney U-test for participant average cell size in (i)].
Fig. 4
Fig. 4
Adipose tissue RNA sequencing analysis in the MD-Lipolysis study. (a) Heat map showing the differentially expressed genes (log Fold change). Two main clusters of genes were obtained: one of genes upregulated and one of genes downregulated in the Obese groups. In the right panel, a box plot of these two gene clusters in the three categories [variance stabilizing transformation, FDR/Benjamini-Hochberg]. (b) Principal component analysis (PCA) of gene expression counts (normalized as in a). Groups and sex of participant are indicated. (c) Venn diagram of genes differentially expressed in the three comparisons. The number of differentially genes for each subgroup is indicated in red for downregulated and blue for upregulated. (d) Bar plots graph of the enrichment of ontology terms based on the combined score calculated by the EnrichR web tool. A selection of no more than the first five elements for each gene set databases is shown. Colour indicate the gene set database in Supplemental Material Figure 5a. All terms have multiple tests correction adjusted p-value less than 0.05 [FDR/Benjamini-Hochberg]. (e) Heat map of genes selected by literature search of all the core differentially expressed obesity genes identified by the Venn diagram (yellow area in c).
Fig. 5
Fig. 5
Study design and results on metabolic measurements from the POEM cohort. (a) Illustration of the volunteer selection procedure from the POEM study by specific inclusion (green) and exclusion (red) criteria, which defined the experimental groups: Lean NGT: lean normal glucose tolerance (lean insulin sensitive); ObOw-LI: obese-overweight normoglycaemic, with low insulin levels (obese-overweight insulin sensitive); and ObOw-HI: obese-overweight normoglycaemic, with high insulin levels (obese-overweight insulin resistant). Lean NGT were compared to ObOw-LI and ObOw-HI for: (b) body mass index (BMI); (c) fat mass; (d) fasting serum insulin levels; (e) fasting C-peptide levels; (f) fasting blood glucose levels; (g) fasting plasma FFA levels. n=148 for Lean NGT; n=69 for ObOw-LI; n=25 for ObOw-HI. Data are presented as mean ± 95% confidence intervals [two-way ANOVA for sex and metabolic group].

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