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Background and Aim: Angiopoietin-like 3 (ANGPTL3) and 4 (ANGPTL4) are regulators of triglyceride storage and utilization. Bariatric surgery (BS) leads to profound changes in adipose tissue composition and energy metabolism. We evaluated the impact of BS on plasma levels of ANGPTL3 and ANGPTL4., Methods and Results: Twenty-seven subjects affected by morbid obesity with or without type 2 diabetes (T2D) underwent Roux-en-Y gastric bypass (RYGB) and 18 patients with advanced T2D received Biliopancreatic Diversion (BPD). Fasting ANGPTL proteins levels, insulin sensitivity (evaluated by euglycemic hyperinsulinemic clamp), total bile acids (TBA) and free fatty acids (FFA) were measured at baseline and 1 year after surgery. Both surgical procedures resulted in the loss of fat mass, improved glucose control, and a ∼2-fold increase of insulin sensitivity. ANGPTL4 levels decreased significantly with both RYGB (26.6 ± 0.6 to 24.4 ± 0.3 ng/mL, p = 0.001) and BPD (27.9 ± 1.5 to 24.0 ± 0.5 ng/mL, p = 0.003). In contrast, ANGPTL3 concentrations did not change after RYGB but rose following BPD (225 ± 20 to 300 ± 15 ng/mL, p = 0.003). By multiple regression analysis, changes after BS in ANGPTL4 were independently associated with changes in blood glucose, (p = 0.0169) whereas changes in ANGPTL3 were associated with variations in FFA (p = 0.008) and insulin sensitivity (p = 0.043)., Conclusion: Circulating ANGPTL4 is reduced by BS, probably due to the loss of fat mass and improved insulin sensitivity. Conversely, ANGPTL3 levels increased after BPD, but not after RYGB, presumably because of the metabolic changes induced by the malabsorptive effect of BPD., Competing Interests: Declaration of competing interest LD has received personal fees for public speaking, consultancy or grant support from Amryt Pharmaceuticals, Akcea Therapeutics, Pfizer, Amgen and Sanofi; MA has received research grant support from Amryt Pharmaceutical, Amgen, IONIS, Akcea Therapeutics, Pfizer and Sanofi; has served as a consultant for Amgen, Aegerion, Akcea Therapeutics, Regeneron, Sanofi and Alfasigma and received lecturing fees from Amgen, Amryth Pharmaceutical, Pfizer, Sanofi and AlfaSigma. EF reports receiving consultancy/speaker fees, outside the present work, from Boehringer Ingelheim, Lilly&Co., AstraZeneca, and Sanofi. Other authors have declared no conflict of interest., (Copyright © 2022 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. All rights reserved.)

It is well-established that adipose tissue accumulation is associated with insulin resistance through multiple mechanisms. One major metabolic link is the classical Randle cycle: enhanced release of free fatty acids (FFA) from hydrolysis of adipose tissue triglycerides impedes insulin-mediated glucose uptake in muscle tissues. Less well studied are the different routes of this communication. First, white adipose tissue depots may be regionally distant from muscle (i.e., gluteal fat and diaphragm muscle) or contiguous to muscle but separated by a fascia (Scarpa's fascia in the abdomen, fascia lata in the thigh). In this case, released FFA outflow through the venous drainage and merge into arterial plasma to be transported to muscle tissues. Next, cytosolic triglycerides can directly, i.e., within the cell, provide FFA to myocytes (but also pancreatic ß-cells, renal tubular cells, etc.). Finally, adipocyte layers or lumps may be adjacent to, but not anatomically segregated, from muscle, as is typically the case for epicardial fat and cardiomyocytes. As regulation of these three main delivery paths is different, their separate contribution to substrate competition at the whole-body level is uncertain. Another important link between fat and muscle is vascular. In the resting state, blood flow is generally higher in adipose tissue than in muscle. In the insulinized state, fat blood flow is directly related to whole-body insulin resistance whereas muscle blood flow is not; consequently, fractional (i.e., flow-adjusted) glucose uptake is stimulated in muscle but not fat. Thus, reduced blood supply is a major factor for the impairment of in vivo insulin-mediated glucose uptake in both subcutaneous and visceral fat. In contrast, the insulin resistance of glucose uptake in resting skeletal muscle is predominantly a cellular defect., (© 2022. The Author(s).)

Objectives: Hepatic insulin resistance is a hallmark of type 2 diabetes and obesity. Insulin receptor signaling through AKT and FOXO has important metabolic effects that have traditionally been ascribed to regulation of gene expression. However, whether all the metabolic effects of FOXO arise from its regulation of protein-encoding mRNAs is unknown., Methods: To address this question, we obtained expression profiles of FOXO-regulated murine hepatic microRNAs (miRNAs) during fasting and refeeding using mice lacking Foxo1, 3a, and 4 in liver (L-Foxo1,3a, 4)., Results: Out of 439 miRNA analyzed, 175 were differentially expressed in Foxo knockouts. Their functions were associated with insulin, Wnt, Mapk signaling, and aging. Among them, we report a striking increase of miR-205-5p expression in L-Foxo1,3a,4 knockouts, as well as in obese mice. We show that miR-205-5p gain-of-function increases AKT phosphorylation and decreases SHIP2 in primary hepatocytes, resulting in FOXO inhibition. This results in decreased hepatocyte glucose production. Consistent with these observations, miR-205-5p gain-of-function in mice lowered glucose levels and improved pyruvate tolerance., Conclusions: These findings reveal a homeostatic miRNA loop regulating insulin signaling, with potential implications for in vivo glucose metabolism., (Copyright © 2018 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Bile acids (BAs) exert pleiotropic metabolic effects, and physicochemical properties of different BAs affect their function. In rodents, insulin regulates BA composition, in part by regulating the BA 12α-hydroxylase CYP8B1. However, it is unclear whether a similar effect occurs in humans. To address this question, we examined the relationship between clamp-measured insulin sensitivity and plasma BA composition in a cohort of 200 healthy subjects and 35 type 2 diabetic (T2D) patients. In healthy subjects, insulin resistance (IR) was associated with increased 12α-hydroxylated BAs (cholic acid, deoxycholic acid, and their conjugated forms). Furthermore, ratios of 12α-hydroxylated/non-12α-hydroxylated BAs were associated with key features of IR, including higher insulin, proinsulin, glucose, glucagon, and triglyceride (TG) levels and lower HDL cholesterol. In T2D patients, BAs were nearly twofold elevated, and more hydrophobic, compared with healthy subjects, although we did not observe disproportionate increases in 12α-hydroxylated BAs. In multivariate analysis of the whole dataset, controlling for sex, age, BMI, and glucose tolerance status, higher 12α-hydroxy/non-12α-hydroxy BA ratios were associated with lower insulin sensitivity and higher plasma TGs. These findings suggest a role for 12α-hydroxylated BAs in metabolic abnormalities in the natural history of T2D and raise the possibility of developing insulin-sensitizing therapeutics based on manipulations of BA composition.

Metabolomic screening of fasting plasma from nondiabetic subjects identified α-hydroxybutyrate (α-HB) and linoleoyl-glycerophosphocholine (L-GPC) as joint markers of insulin resistance (IR) and glucose intolerance. To test the predictivity of α-HB and L-GPC for incident dysglycemia, α-HB and L-GPC measurements were obtained in two observational cohorts, comprising 1,261 nondiabetic participants from the Relationship between Insulin Sensitivity and Cardiovascular Disease (RISC) study and 2,580 from the Botnia Prospective Study, with 3-year and 9.5-year follow-up data, respectively. In both cohorts, α-HB was a positive correlate and L-GPC a negative correlate of insulin sensitivity, with α-HB reciprocally related to indices of β-cell function derived from the oral glucose tolerance test (OGTT). In follow-up, α-HB was a positive predictor (adjusted odds ratios 1.25 [95% CI 1.00-1.60] and 1.26 [1.07-1.48], respectively, for each standard deviation of predictor), and L-GPC was a negative predictor (0.64 [0.48-0.85] and 0.67 [0.54-0.84]) of dysglycemia (RISC) or type 2 diabetes (Botnia), independent of familial diabetes, sex, age, BMI, and fasting glucose. Corresponding areas under the receiver operating characteristic curve were 0.791 (RISC) and 0.783 (Botnia), similar in accuracy when substituting α-HB and L-GPC with 2-h OGTT glucose concentrations. When their activity was examined, α-HB inhibited and L-GPC stimulated glucose-induced insulin release in INS-1e cells. α-HB and L-GPC are independent predictors of worsening glucose tolerance, physiologically consistent with a joint signature of IR and β-cell dysfunction.

Context: Bariatric surgery can induce remission in a high proportion of severely obese patients with type 2 diabetes mellitus (T2DM)., Objective: Our objective was to investigate predictors and mechanisms of surgery-induced diabetes remission., Patients and Setting: Forty-three morbidly obese subjects (body mass index = 45.6 ± 5.0 kg/m(2)), 32 with T2DM and 11 nondiabetic [normal glucose tolerance (NGT)], participated at a clinical research center., Intervention: Patients underwent Roux-en-Y gastric bypass., Main Outcome Measures: Diabetes remission and β-cell function were evaluated., Results: Subjects were tested before and 45 d and 1 yr after surgery. Weight decreased similarly in T2DM and NGT (-39 kg at 1 yr, P < 0.0001). Insulin sensitivity improved in both groups in proportion to the changes in body mass index but remained lower in T2DM than NGT (386 ± 91 vs. 479 ± 89 ml/min · m(2), P < 0.01). Based on glycosylated hemoglobin and oral glucose testing, diabetes had remitted in nine patients at 45 d and in an additional 16 at 1 yr. In T2DM, β-cell glucose sensitivity increased early after surgery but was no further improved and still abnormal at 1 yr [median, 48 (coefficient interval, 53) pmol/min · m(2) · mm vs. median, 100 (coefficient interval, 68) of NGT, P < 0.001]. Baseline β-cell glucose sensitivity was progressively worse in early remitters, late remitters, and nonremitters (median, 54[coefficient interval, 50] vs. median, 22[coefficient interval, 26] vs. median, 4[coefficient interval, 10] pmol/min · m(2) · mm) and, by logistic regression, was the only predictor of failure [odds ratio for bottom tertile = 7.9 (95% confidence interval = 1.2-51.9); P = 0.03]., Conclusions: In morbid obesity, Roux-en-Y gastric bypass causes rapid and profound metabolic adaptations; insulin sensitivity improves in proportion to the weight loss, and β-cell glucose sensitivity increases independently of weight loss. Over a period of 1 yr after surgery, diabetes remission depends on the starting degree of β-cell dysfunction.

Background: Insulin resistance is a risk factor for type 2 diabetes and cardiovascular disease progression. Current diagnostic tests, such as glycemic indicators, have limitations in the early detection of insulin resistant individuals. We searched for novel biomarkers identifying these at-risk subjects., Methods: Using mass spectrometry, non-targeted biochemical profiling was conducted in a cohort of 399 nondiabetic subjects representing a broad spectrum of insulin sensitivity and glucose tolerance (based on the hyperinsulinemic euglycemic clamp and oral glucose tolerance testing, respectively)., Results: Random forest statistical analysis selected alpha-hydroxybutyrate (alpha-HB) as the top-ranked biochemical for separating insulin resistant (lower third of the clamp-derived M(FFM) = 33 [12] micromol x min(-1) x kg(FFM) (-1), median [interquartile range], n = 140) from insulin sensitive subjects (M(FFM) = 66 [23] micromol x min(-1) x kg(FFM) (-1)) with a 76% accuracy. By targeted isotope dilution assay, plasma alpha-HB concentrations were reciprocally related to M(FFM); and by partition analysis, an alpha-HB value of 5 microg/ml was found to best separate insulin resistant from insulin sensitive subjects. alpha-HB also separated subjects with normal glucose tolerance from those with impaired fasting glycemia or impaired glucose tolerance independently of, and in an additive fashion to, insulin resistance. These associations were also independent of sex, age and BMI. Other metabolites from this global analysis that significantly correlated to insulin sensitivity included certain organic acid, amino acid, lysophospholipid, acylcarnitine and fatty acid species. Several metabolites are intermediates related to alpha-HB metabolism and biosynthesis., Conclusions: alpha-hydroxybutyrate is an early marker for both insulin resistance and impaired glucose regulation. The underlying biochemical mechanisms may involve increased lipid oxidation and oxidative stress.

Purpose: To compare the effects of equivalent weight loss induced by two bariatric surgical techniques on insulin action in severely obese patients., Methods: Eighteen nondiabetic patients with severe obesity (mean [+/- SD] body mass index: 53.5 +/- 9.0 kg/m(2)) and 20 sex- and age-matched lean subjects (body mass index: 23.8 +/- 3.0 kg/m(2)) underwent metabolic studies, including measurement of insulin sensitivity by the insulin clamp technique. Patients then underwent either vertical banded gastroplasty with Roux-en-Y gastric bypass, or biliopancreatic diversion, and were restudied at 5 to 6 months and again at 16 to 24 months postsurgery., Results: At baseline, patients were hyperinsulinemic (194 +/- 47 pmol/L vs. 55 +/- 25 pmol/L, P < 0.0001), hypertriglyceridemic (1.56 +/- 0.30 mmol/L vs. 0.78 +/- 0.32 mmol/L, P < 0.0001), and profoundly insulin resistant (insulin-mediated glucose disposal: 20.8 +/- 4.4 micromol/min/kg fat-free mass vs. 52.0 +/- 10.1 micromol/min/kg, P < 0.0001) as compared with controls. Weight loss by the two procedures was equivalent in both amount (averaging -53 kg) and time course. In the gastric bypass group, insulin sensitivity improved (23.8 +/- 6.0 micromol/min/kg at 5 months and 33.7 +/- 11.3 micromol/min/kg at 16 months, P < 0.01 vs. baseline and controls). In contrast, in the biliopancreatic diversion group, insulin sensitivity was normalized already at 6 months (52.5 +/- 12.4 micromol/min/kg, P = 0.72 vs. controls) and increased further at 24 months (68.7 +/- 9.5 micromol/min/kg, P < 0.01 vs. controls) despite a persistent obese phenotype (body mass index: 33.2 +/- 8.0 kg/m(2))., Conclusion: In surgically treated obese patients, insulin sensitivity improves in proportion to weight loss with use of predominantly restrictive procedures (gastric bypass), but is reversed completely by predominantly malabsorptive approaches (biliopancreatic diversion) long before normalization of body weight. Selective nutrient absorption and gut hormones may interact with one another in the genesis of the metabolic abnormalities of obesity.

Obesity is a frequent cause of insulin resistance and poses a major risk for diabetes. Abnormal fat deposition within skeletal muscle has been identified as a mechanism of obesity-associated insulin resistance. We tested the hypothesis that dietary lipid deprivation may selectively deplete intramyocellular lipids, thereby reversing insulin resistance. Whole-body insulin sensitivity (by the insulin clamp technique), intramyocellular lipids (by quantitative histochemistry on quadriceps muscle biopsies), muscle insulin action (as the expression of Glut4 glucose transporters), and postprandial lipemia were measured in 20 morbidly obese patients (BMI = 49 +/- 8 [mean +/- SD] kg x m(-2)) and 7 nonobese control subjects. Patients were restudied 6 months later after biliopancreatic diversion (BPD; n = 8), an operation that induces predominant lipid malabsorption, or hypocaloric diet (n = 9). At 6 months, BPD had caused the loss of 33 +/- 10 kg through lipid malabsorption (documented by a flat postprandial triglyceride profile). Despite an attained BMI still in the obese range (39 +/- 8 kg x m(-2)), insulin resistance (23 +/- 3 micromol/min per kg of fat-free mass; P < 0.001 vs. 53 +/- 13 of control subjects) was fully reversed (52 +/- 11 micromol/min per kg of fat-free mass; NS versus control subjects). In parallel with this change, intramyocellular-but not perivascular or interfibrillar-lipid accumulation decreased (1.63 +/- 1.06 to 0.22 +/- 0.44 score units; P < 0.01; NS vs. 0.07 +/- 0.19 of control subjects), Glut4 expression was restored, and circulating leptin concentrations were normalized. In the diet group, a weight loss of 14 +/- 12 kg was accompanied by very modest changes in insulin sensitivity and intramyocellular lipid contents. We conclude that lipid deprivation selectively depletes intramyocellular lipid stores and induces a normal metabolic state (in terms of insulin-mediated whole-body glucose disposal, intracellular insulin signaling, and circulating leptin levels) despite a persistent excess of total body fat mass.

Background: Hyperinsulinemia and insulin resistance may contribute to the development of cardiac hypertrophy. In humans, however, the evidence is inconclusive., Methods and Results: We studied 50 nondiabetic subjects covering a wide range of age (20 to 65 years), body mass index (BMI, 19 to 40 kg x m(-2)), and mean blood pressure (72 to 132 mm Hg). Plasma insulin concentrations and secretory rates were measured at baseline and during an oral glucose tolerance test; insulin sensitivity was measured by the insulin clamp technique. Left ventricular mass (LVM) (by 2D M-mode echocardiography) was distributed normally and was higher in obese (BMI >/=27 kg x m(-2), n=16) or hypertensive patients (blood pressure >140/90 mm Hg, n=21) (50+/-8 and 55+/-10 g x m(-2.7), respectively) than in 13 nonobese, normotensive subjects (40+/-8 g x m(-2.7), P:=0.0004). In a multivariate model adjusting for sex, age, BMI, and blood pressure, neither insulin concentrations (fasting or postglucose) nor insulin sensitivity or secretory rates were significant correlates of LVM. Systolic blood pressure (P:=0.003) and BMI (P:=0.01) were the only independent correlates of LVM. From the regression, the impact of hypertension (as a systolic pressure of 180 versus 140 mm Hg=+20%) was twice as large as that of obesity (as a BMI of 35 versus 25 kg x m(-2)=+11%), the two factors being additive., Conclusions: When adequate account is taken of body mass and blood pressure, insulin, as concentration, secretion, or action, is not an independent determinant of LVM in nondiabetic subjects.

Objective: To assess the impact of obesity and insulin sensitivity on resting (REE) and glucose-induced thermogenesis (GIT)., Design: Data from 322 studies carried out in non-diabetic subjects of either gender, covering a wide range of age (18-80y) and body mass index (BMI, 18-50 kg/m2)., Measurements: Insulin sensitivity and thermogenesis were measured by combining the euglycaemic insulin clamp technique with indirect calorimetry., Results: REE was inversely related to age (P = 0.001) and the respiratory quotient (P = 0.03), and positively related to BMI, lean body mass (LBM), fat mass, and percentage fat mass (all P<0.0001). In a multiple regression model, LBM-adjusted REE was estimated to decline by 9% between 18 and 80 y, independently of obesity and insulin sensitivity. In contrast, GIT was strongly associated with insulin sensitivity (P<0.0001) but not with gender, age or BMI. By multiple regression analysis, GIT was linearly related to insulin sensitivity after controlling for gender, age, BMI and steady-state plasma insulin levels. Furthermore, both of the main components of insulin-mediated glucose disposal (glucose oxidation and glycogen synthesis) correlated with GIT independently of one another. In the subset of subjects (n = 89) in whom waist-to-hip ratio (WHR) measurements were available, GIT was inversely associated with WHR (P<0.001 after adjustment by gender, age, BMI, insulin sensitivity and steady-state plasma insulin concentration). In this model, a significant interaction between WHR and gender indicated a stronger adverse effect on GIT of a high WHR in women than in men., Conclusions: In healthy humans, age, lean mass and respiratory quotient are the main independent determinants of resting thermogenesis. In contrast, insulin sensitivity and, to a lesser extent, abdominal obesity are the principal factors controlling glucose-induced thermogenesis.

An increased tissue content of PC-1, an inhibitor of insulin receptor signaling, may play a role in insulin resistance. Large scale prospective studies to test this hypothesis are difficult to carry out because of the need for tissue biopsies. The aim of this study was to investigate whether PC-1 is measurable in human plasma and whether its concentration is related to insulin sensitivity. A soluble PC-1, with mol wt and enzymatic activity similar to those of tissue PC-1, was measurable in human plasma by a specific enzyme-linked immunosorbent assay and was inversely correlated to skeletal muscle PC-1 content (r = -0.5; P < 0.01). The plasma PC-1 concentration was decreased (P < 0.05) in insulin-resistant (22.7 +/- 3.0 ng/mL; n = 25) compared to insulin-sensitive (36.7 +/- 4.5; n = 25) nondiabetic subjects and was correlated negatively with the waist/hip ratio (r = -0.48; P < 0.001) and mean blood pressure (r = -0.3; P < 0.05) and positively with high density lipoprotein/total cholesterol (r = 0.38; P < 0.01) and both the M value and the plasma free fatty acid level decrement at clamp studies (r = 0.28; n = 50; P = 0.05 and r = 0.43; n = 22; P < 0.05, respectively). A plasma PC-1 concentration of 19 ng/mL or less identified a cluster of insulin resistance-related alterations with 75% accuracy. In conclusion, PC-1 circulates in human plasma, and its concentration is related to insulin sensitivity. This may help to plan studies aimed at understanding the role of PC-1 in insulin resistance.

Objective: To investigate whether duration of obesity has an independent impact on insulin resistance., Design: Case-control study., Subjects: 30 non-diabetic obese subjects (age, 34+/-12 y, body mass index (BMI), 33.5+/-0.8 kg x m[-2]) with a range (1-35 y) of self-reported duration of obesity, and 12 age- and gender-matched non-obese controls (BMI, 22.1+/-0.6 kg x m[-2])., Measurements: Oral glucose tolerance (40 g x m[-2]), insulin sensitivity (by the euglycaemic insulin clamp technique), and insulin secretion (as the product of post-hepatic insulin clearance and plasma insulin concentration)., Results: The obese group presented hyperinsulinaemia in the basal state and after glucose loading (insulin area = 58+/-5 vs 33+/-3 nmol x I[-1] x 2 h, P = 0.005), insulin resistance (M value = 37.4+/-4.8 vs 50.6+/-2.6 micromol x min[-1] x kg FFM[-1], P = 0.002), and insulin hypersecretion (61.9+/-6.0 vs 33.9 +/- 4.0 nmol x 2 h, P = 0.007); endogenous glucose production was similar in the two groups. In the whole dataset, insulin resistance was directly related to BMI, the waist-to-hip ratio (WHR), endogenous glucose production, insulin secretion, and fasting serum triglycerides and uric acid concentrations. When the obese subjects were stratified by duration of obesity, insulin resistance was progressively lower with longer obesity duration (P = 0.04). When simultaneously adjusting by age, gender and BMI, obesity duration was independently associated with greater insulin sensitivity (P = 0.003), lower plasma insulin response to oral glucose (P = 0.001), and lower fasting and glucose-stimulated insulin release (P = 0.01 for both)., Conclusions: In obese subjects with preserved glucose tolerance, duration of obesity is associated with better insulin sensitivity irrespective of the degree of overweight.

Background: Insulin resistance and vascular abnormalities have both been described in patients with essential hypertension. Whether these defects are associated with one another in the same individual has not been established., Methods and Results: Whole-body insulin sensitivity (by the insulin clamp technique), forearm minimal vascular resistances, and the dose-response curve to acetylcholine, sodium-nitroprusside, and norepinephrine were measured in a group of 29 male patients with untreated essential hypertension. When the patients were divided into tertiles according to their level of insulin sensitivity, resistant and sensitive hypertensives were matched on several potential confounders of insulin action and vascular function. These subgroups showed similar minimal vascular resistances (2.5+/-0.2 versus 3.2+/-0.6 mm Hg per mL x min(-1) x dL(-1)) and superimposable responses to graded intraarterial infusions of acetylcholine, sodium-nitroprusside, and norepinephrine. No correlation was found between the vascular parameters (slope of the curve or maximal response) and insulin-mediated glucose uptake in the whole group. During the clamp, insulin sensitive patients tended to have greater increments in forearm blood flow when compared to their insulin resistant counterparts (+53+/-21 versus +9+/-7%, P=.06); in the whole group, clamp-induced vasodilatation was weakly related to insulin-mediated glucose uptake (r=.44, P<.02) as well as to the slope of the acetylcholine dose-response curve (r=.40, P<.04). Together, these two responses explained 30% (multiple r=.55, P<.01) of the variability in insulin-induced vasodilatation., Conclusions: Metabolic insulin resistance in essential hypertension is not associated with abnormalities in vascular structure, acetylcholine or nitroprusside-induced vasodilatation, or vascular adrenergic reactivity. Degree of insulin sensitivity and acetylcholine sensitivity explain a small portion of the variability of the clamp-induced vasodilatation in hypertensive patients.

Aim/hypothesis. To gain insight into the physiologic determinants of postabsorptive endogenous glucose output (EGO) in humans.¶Methods. We analysed the data of 344 non-diabetic subjects (212 men and 132 women) with a wide range of age (18–85 years) and body mass index (15–55 kg/m2) who participated in the European Group for the Study of Insulin Resistance (EGIR) project. Whole-body endogenous glucose output was measured by tracer ([3H]glucose) dilution at steady-state, peripheral insulin sensitivity (Ñ glucose clearance/Ñ insulin) was measured by the euglycaemic insulin (7 pmol × min–1× kg–1) clamp technique.¶Results. Whole-body endogenous glucose output showed a large variability (mean = 768 ± 202 μmol · min–1, range 209–1512) and was strongly related to lean body mass (r = 0.63, p < 0.0001). This association entirely explained the endogenous glucose output being higher in men than in women (827 ± 189 vs 674 × 187 μmol × min–1, p < 0.0001), its relation to body mass (+ 10 ± 2 per unit of body mass index, p < 0.0001) and its trend to decline with age (–1.1 ± 0.7 μmol · min–1 per year, p = 0.10). Although inversely related to one another (r = –0.41, p < 0.0001), peripheral insulin sensitivity and fasting plasma insulin were both independently associated with endogenous glucose output in an inverse fashion (with partial r's of 0.19 and 0.21, respectively, after adjusting for lean body mass and centre, p < 0.0001 for both).¶Conclusion/interpretation. Among non-diabetic subjects in the postabsorptive condition, total body endogenous glucose output variability is wide and is largely explained by the amount of lean mass; this, in turn, explains differences in total endogenous glucose output due to sex, obesity and age. Independently of the amount of lean mass, peripheral insulin resistance is associated with a higher endogenous glucose output independently of fasting plasma insulin concentration, suggesting coupled regulation of insulin action in peripheral tissues and the liver. [Diabetologia (2000) 43: 1266–1272] [ABSTRACT FROM AUTHOR]