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Objective: Fasting hyperglycemia and hypertriglyceridemia are characteristic of insulin resistance (IR) and rodent work has suggested this may be due to selective hepatic IR, defined by increased hepatic gluconeogenesis and de novo lipogenesis (DNL), but this has not been shown in humans., Design: Cross-sectional study in men and women across a range of adiposity., Methods: Medication-free participants (n = 177) were classified as normoinsulinemic (NI) or hyperinsulinemic (HI) and as having low (LF) or high (HF) liver fat content measured by magnetic resonance spectroscopy. Fractional gluconeogenesis (frGNG) and hepatic DNL were measured using stable isotope tracer methodology following an overnight fast., Results: Although HI and HF groups had higher fasting plasma glucose and triglyceride concentrations when compared to NI and LF groups respectively, there was no difference in frGNG. However, HF participants tended to have lower frGNG than LF participants. HI participants had higher DNL compared to NI participants but there was no difference observed between liver fat groups., Conclusions: Taken together, we found no metabolic signature of selective hepatic IR in fasting humans. DNL may contribute to hypertriglyceridemia in individuals with HI but not those with HF. Glycogenolysis and systemic glucose clearance may have a larger contribution to fasting hyperglycemia than gluconeogenesis, especially in those with HF, and these pathways should be considered for therapeutic targeting., Competing Interests: Conflict of interest: None to declare., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Society of Endocrinology.)

Women with polycystic ovary syndrome (PCOS) exhibit reduced muscle insulin-mediated glucose uptake, potentially attributed to altered muscle mass; however, this is inconclusive. Altered muscle mass may aggravate PCOS complications. Our systematic review and meta-analysis evaluated whether PCOS alters muscle mass and function. Databases (MEDLINE, Web of Science, Scopus) were searched through September 2, 2020, for studies documenting skeletal muscle mass (lean tissue mass) and function (strength) in PCOS and control groups. The primary outcome was total lean body mass (LBM) or fat-free mass (FFM). Data were pooled by random-effects models and expressed as mean differences and 95% confidence intervals. Forty-five studies (n = 3676 participants) were eligible. Women with PCOS had increased total (0.83 [0.08,1.58] kg; p = 0.03; I 2  = 72.0%) yet comparable trunk (0.84 [-0.37,2.05] kg; p = 0.15; I 2  = 73.0%) LBM or FFM versus controls. Results of meta-regression analyses showed no associations between mean differences between groups in total testosterone or homeostatic model assessment of insulin resistance and total or trunk LBM or FFM (All: p ≥ 0.75). Mean differences in body mass index (BMI) were associated with total (0.65 [0.23,1.06] kg; p < 0.01; I 2  = 56.9%) and trunk (0.56 [0.11,1.01] kg; p = 0.02; I 2  = 42.8%) LBM or FFM. The PCOS subgroup with BMI ≥ 25 kg/m 2 had greater total LBM or FFM versus controls (1.58 [0.82,2.34] kg; p < 0.01; I 2  = 64.0%) unlike the PCOS subgroup with BMI < 25 kg/m 2 (-0.45 [-1.94,1.05] kg; p = 0.53; I 2  = 69.5%). Appendicular lean mass and muscle strength data were contradictory and described narratively, as meta-analyses were impossible. Women with PCOS have higher total and trunk lean tissue mass attributed to overweight/obesity, unlike hyperandrogenism or insulin resistance., (© 2021 World Obesity Federation.)

Key Points: We have recently shown that a high-fat, high-calorie (HFHC) diet decreases whole body glucose clearance without impairing skeletal muscle insulin signalling, in healthy lean individuals. These diets are also known to increase skeletal muscle IMTG stores, but the effect on lipid metabolites leading to skeletal muscle insulin resistance has not been investigated. This study measured the effect of 7 days' HFHC diet on (1) skeletal muscle concentration of lipid metabolites, and (2) potential changes in the perilipin (PLIN) content of the lipid droplets storing intramuscular triglyceride (IMTG). The HFHC diet increased PLIN3 protein expression and redistributed PLIN2 to lipid droplet stores in type I fibres. The HFHC diet increased IMTG content in type I fibres, while lipid metabolite concentrations remained the same. The data suggest that the increases in IMTG stores assists in reducing the accumulation of lipid metabolites known to contribute to skeletal muscle insulin resistance., Abstract: A high-fat, high-calorie (HFHC) diet reduces whole body glucose clearance without impairing skeletal muscle insulin signalling in healthy lean individuals. HFHC diets also increase skeletal muscle lipid stores. However, unlike certain lipid metabolites, intramuscular triglyceride (IMTG) stored within lipid droplets (LDs) does not directly contribute to skeletal muscle insulin resistance. Increased expression of perilipin (PLIN) proteins and colocalisation to LDs has been shown to assist in IMTG storage. We aimed to test the hypothesis that 7 days on a HFHC diet increases IMTG content while minimising accumulation of lipid metabolites known to disrupt skeletal muscle insulin signalling in sedentary and obese individuals. We also aimed to identify changes in expression and subcellular distribution of proteins involved in IMTG storage. Muscle biopsies were obtained from the m. vastus lateralis of 13 (11 males, 2 females) healthy lean individuals (age: 23 ± 2.5 years; body mass index: 24.5 ± 2.4 kg m -2 ), following an overnight fast, before and after consuming a high-fat (64% energy), high-calorie (+47% kcal) diet for 7 days. After the HFHC diet, IMTG content increased in type I fibres only (+101%; P < 0.001), whereas there was no change in the concentration of either total diacylglycerol (P = 0.123) or total ceramides (P = 0.150). Of the PLINs investigated, only PLIN3 content increased (+50%; P < 0.01) solely in type I fibres. LDs labelled with PLIN2 increased (+80%; P < 0.01), also in type I fibres only. We propose that these adaptations of LDs support IMTG storage and minimise accumulation of lipid metabolites to protect skeletal muscle insulin signalling following 7 days' HFHC diet., (© 2020 The Authors. The Journal of Physiology © 2020 The Physiological Society.)

Context: The mechanisms responsible for dietary fat-induced insulin resistance of skeletal muscle and its microvasculature are only partially understood., Objective: To determine the impact of high-fat overfeeding on postprandial glucose fluxes, muscle insulin signaling, and muscle microvascular endothelial nitric oxide synthase (eNOS) content and activation., Design: Fifteen non-obese volunteers consumed a high-fat (64%) high-energy (+47%) diet for 7 days. Experiments were performed before and after the diet. Stable isotope tracers were used to determine glucose fluxes in response to carbohydrate plus protein ingestion. Muscle insulin signaling was determined as well as the content and activation state of muscle microvascular eNOS., Results: High-fat overfeeding impaired postprandial glycemic control as demonstrated by higher concentrations of glucose (+11%; P = 0.004) and insulin (+19%; P = 0.035). Carbohydrate plus protein ingestion suppressed endogenous glucose production to a similar extent before and after the diet. Conversely, high-fat overfeeding reduced whole-body glucose clearance (-16%; P = 0.021) and peripheral insulin sensitivity (-26%; P = 0.006). This occurred despite only minor alterations in skeletal muscle insulin signaling. High-fat overfeeding reduced eNOS content in terminal arterioles (P = 0.017) and abolished the increase in eNOS Ser1177 phosphorylation that was seen after carbohydrate plus protein ingestion., Conclusion: High-fat overfeeding impaired whole-body glycemic control due to reduced glucose clearance, not elevated endogenous glucose production. The finding that high-fat overfeeding abolished insulin-mediated eNOS Ser1177 phosphorylation in the terminal arterioles suggests that impairments in the vasodilatory capacity of the skeletal muscle microvasculature may contribute to early dietary fat-induced impairments in glycemic control., (© Endocrine Society 2019. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Context and Objectives: Spillover of fatty acids (FAs) into the plasma nonesterified fatty acid (NEFA) pool, because of an inability of adipose tissue (AT) to accommodate sufficient fat uptake, has been suggested to contribute to obesity-related insulin resistance. Using specific labeling techniques, we compared the proportion of spillover-derived NEFA across a range of adiposity., Participants and Methods: Seventy-one healthy men and women were fed a mixed meal (40 g fat) containing [U13C]palmitate to assess the contribution of chylomicron-derived spillover FAs. To investigate subcutaneous abdominal-specific spillover, arteriovenous difference and stable-isotope methodologies were used in substudy (six men, six women)., Results: Chylomicron-derived FA spillover was higher in individuals with a BMI <25 kg/m2 (n = 18) compared with those with a BMI ≥25 kg/m2 (n = 53) (22.2 ± 1.6% vs 18.6 ± 0.7%, P = 0.02). Women had higher chylomicron-derived FA spillover than age- and BMI-matched men (21.9 ± 1.1% vs 15.0 ± 1.6%, P = 0.001). Assessing spillover across subcutaneous abdominal AT showed higher proportions in women than in men (28.5 ± 6.1% vs 9.9 ± 1.3%, P = 0.01)., Conclusion: There is a considerable degree of spillover FA into the systemic NEFA pool in the postprandial state; this process is greater and more dynamic in lean individuals and women. Contrary to general perception, spillover of chylomicron-derived FA into systemic circulation is a physiologically normal feature most easily observed in people with a higher capacity for clearance of plasma triglycerides, but does not appear to be a pathway providing excess NEFA in obesity., (Copyright © 2017 Endocrine Society)

Consuming excessive amounts of energy as dietary fat for several days or weeks can impair glycemic control and reduce insulin sensitivity in healthy adults. However, individuals who demonstrate binge eating behavior overconsume for much shorter periods of time; the metabolic consequences of such behavior remain unknown. The aim of this study was to determine the effect of a single day of high-fat overfeeding on whole-body insulin sensitivity. Fifteen young, healthy adults underwent an oral glucose tolerance test before and after consuming a high-fat (68% of total energy), high-energy (78% greater than daily requirements) diet for one day. Fasting and postprandial plasma concentrations of glucose, insulin, non-esterified fatty acids, and triglyceride were measured and the Matsuda insulin sensitivity index was calculated. One day of high-fat overfeeding increased postprandial glucose area under the curve (AUC) by 17.1% ( p < 0.0001) and insulin AUC by 16.4% ( p = 0.007). Whole-body insulin sensitivity decreased by 28% ( p = 0.001). In conclusion, a single day of high-fat, overfeeding impaired whole-body insulin sensitivity in young, healthy adults. This highlights the rapidity with which excessive consumption of calories through high-fat food can impair glucose metabolism, and suggests that acute binge eating may have immediate metabolic health consequences for the individual., Competing Interests: The authors declare no conflict of interest.