Objective: Alterations in lipids in muscle and plasma have been documented in insulin‐resistant people with obesity. Whether these lipid alterations are a reflection of insulin resistance or obesity remains unclear.Methods: Nondiabetic sedentary individuals not treated with lipid‐lowering medications were studied (n = 51). Subjects with body mass index (BMI) > 25 kg/m² (n = 28) were stratified based on median glucose infusion rate during a hyperinsulinemic‐euglycemic clamp into insulin‐sensitive and insulin‐resistant groups (above and below median, obesity/insulin‐sensitive and obesity/insulin‐resistant, respectively). Lean individuals (n = 23) served as a reference group. Lipidomics was performed in muscle and plasma by liquid chromatography electrospray ionization‐tandem mass spectrometry. Pathway analysis of gene array in muscle was performed in a subset (n = 35).Results: In muscle, insulin resistance was characterized by higher levels of C18:0 sphingolipids, while in plasma, higher levels of diacylglycerol and cholesterol ester, and lower levels of lysophosphatidylcholine and lysoalkylphosphatidylcholine, indicated insulin resistance, irrespective of overweight/obesity. The sphingolipid metabolism gene pathway was upregulated in muscle in insulin resistance independent of obesity. An overweight/obesity lipidomic signature was only apparent in plasma, predominated by higher triacylglycerol and lower plasmalogen species.Conclusions: Muscle C18:0 sphingolipids may play a role in insulin resistance independent of excess adiposity.

Impaired glucagon-like peptide (GLP-1) secretion or response may contribute to ineffective insulin release in type 2 diabetes. The conditionally esse

Context: The contribution of insulin resistance vs adiposity to bone mineral density (BMD), bone turnover, and fractures in humans remains unclear. Objective: To evaluate BMD and bone turnover markers (BTMs) in lean (n = 18) and overweight/obese individuals with (n = 17) and without (n = 34, insulin-sensitive [Ob_sensitive, n=15] or insulin-resistant [Ob_resistant, n=19] by homeostasis model assessment insulin resistance) diabetes mellitus. Design: Observational study. Outcome measures: Insulin sensitivity was assessed using the hyperinsulinemic-euglycemic clamp; whole body BMD and fat mass (FM) using dual energy X-ray absorptiometry; and by measurement of BTMs [osteocalcin (OC), procollagen type 1 N-terminal propeptide (P1NP), and collagen type 1 cross-linked C-terminal telopeptide (CTx)], with the patient fasting and during clamp hyperinsulinemia. Results: Fasting BTMs correlated with glucose infusion rate/fat-free mass (GIR/FFM) and adiponectin and, inversely, with fasting insulin and visceral fat (P ≤ 0.04 for all). Ob_sensitive, Ob_resistant, and diabetic individuals were matched by their FM percentage. Clamp GIR/FFM was similar in the lean and Ob_sensitive subjects (P = 1) and approximately twofold greater (P < 0.001) than in the Ob_resistant and diabetic subjects. BMD was greater in Ob_resistant than in Ob_sensitive (P = 0.04) and lean (P = 0.001) subjects. At baseline, compared with Ob_sensitive and lean subjects, Ob_resistant and diabetic individuals had lower OC, P1NP, and CTx levels. This reached statistical significance for Ob_resistant vs lean and Ob_resistant vs Ob_sensitive for both OC and CTx and for diabetic vs lean for CTx (P ≤ 0.04 for all). During hyperinsulinemia, lean individuals suppressed CTx more than did diabetic individuals (P = 0.03). On multiple regression analysis, visceral adiposity explained 16.7% and 19.3% of the baseline OC and CTx variability, respectively. Conclusions: Increased visceral adiposity and higher fasting insulin in insulin-resistant states are associated with lower fasting OC and CTx and failure to further suppress with more insulin.

Context: Whereas insulin resistance and obesity coexist, some obese individuals remain insulin sensitive. Objective: We examined phenotypic and metabolic factors associated with insulin sensitivity in both muscle and liver in obese individuals. Design and Participants: Sixty-four nondiabetic obese adults (29 males) underwent hyperinsulinemic (15 and 80 mU/m² · min)-euglycemic clamps with deuterated glucose. Top tertile subjects for glucose infusion rate during the high-dose insulin clamp were assigned Muscle_sen and those in the lower two tertiles were assigned Muscle_res. Secondarily, top tertile subjects for endogenous glucose production suppression during the low-dose insulin clamp were deemed Liver_sen and the remainder Liver_res. Main Outcomes Measures: Clinical and laboratory parameters and visceral, subcutaneous, liver, and pancreatic fat were compared. Results: Muscle_sen and Muscle_res had similar body mass index and total fat (P > .16), but Muscle_sen had lower glycated hemoglobin (P < .001) and systolic (P = .01) and diastolic (P = .03) blood pressure (BP). Despite similar sc fat (P = 1), Muscle_sen had lower visceral (P < .001) and liver (P < .001) fat. Liver_sen had lower visceral (P < .01) and liver (P < .01) fat and C-reactive protein (P = .02) than Liver_res. When subjects were grouped by both glucose infusion rate during the high-dose insulin clamp and endogenous glucose production suppression, insulin sensitivity at either muscle or liver conferred apparent protection from the adverse metabolic features that characterized subjects insulin resistant at both sites. High-density lipoprotein-cholesterol, 1-hour glucose, systolic BP, and triglycerides explained 54% of the variance in muscle insulin sensitivity. Conclusions: Obese subjects who were insulin sensitive at muscle and/or liver exhibited favorable metabolic features, including lower BP, liver and visceral adiposity. This study identifies factors associated with, and possibly contributing to, insulin sensitivity in obesity.