We have separated the effect of insulin on glucose distribution/transport, glucose disposal, and endogenous production (EGP) during an intravenous glucose tolerance test (IVGTT) by use of a dualtracer dilution methodology. Six healthy lean male subjects (age 33 Ϯ 3 yr, body mass index 22.7 Ϯ 0.6 kg/m A new model described the kinetics of the two glucose tracers and native glucose with the use of a two-compartment structure for glucose and a onecompartment structure for insulin effects. Insulin sensitivities of distribution/transport, disposal, and EGP were similar (11.5 Ϯ 3.8 vs. 10.4 Ϯ 3.9 vs. 11.1 Ϯ 2.7 ϫ 10 Ϫ2 ml⅐kg Ϫ1 ⅐min Ϫ1per mU/l; P ϭ nonsignificant, ANOVA). When expressed in terms of ability to lower glucose concentration, stimulation of disposal and stimulation of distribution/transport accounted each independently for 25 and 30%, respectively, of the overall effect. Suppression of EGP was more effective (P Ͻ 0.01, ANOVA) and accounted for 50% of the overall effect. EGP was suppressed by 70% (52-82%) (95% confidence interval relative to basal) within 60 min of the IVGTT; glucose distribution/ transport was least responsive to insulin and was maximally activated by 62% (34-96%) above basal at 80 min compared with maximum 279% (116-565%) activation of glucose disposal at 20 min. The deactivation of glucose distribution/transport was slower than that of glucose disposal and EGP (P Ͻ 0.02) with half-times of 207 (84-510), 12 (7-22), and 29 (16-54) min, respectively. The minimal-model insulin sensitivity was tightly correlated with and linearly related to sensitivity of EGP (r ϭ 0.96, P Ͻ 0.005) and correlated positively but nonsignificantly with distribution/transport sensitivity (r ϭ 0.73, P ϭ 0.10) and disposal sensitivity (r ϭ 0.55, P ϭ 0.26). We conclude that, in healthy subjects during an IVGTT, the two peripheral insulin effects account jointly for approximately one-half of the overall insulin-stimulated glucose lowering, each effect contributing equally. Suppression of EGP matches the effect in the periphery.glucose kinetics; compartment modeling; D-[U-13 C]glucose; 3-O-methyl-D-glucose; insulin action; glucose transport; glucose disposal; endogenous glucose production; intravenous glucose tolerance test Glossary New Model EGP 0Endogenous glucose production extrapolated to zero insulin concentration (mmol/min) EGP b EGP at basal insulin concentration (mmol/min) F 01Total non-insulin-dependent glucose flux (mmol/min) g 1 (t), g 3 (t)Concentrations of D-[U-13 C]glucose and 3-O-methyl-D-glucose in the accessible compartment (mmol/l) G(t)Total glucose concentration in the accessible compartment (mmol/l) I(t), I b Plasma insulin and basal (preexperimental) plasma insulin (mU/l) k 03 Transfer rate constant of 3-O-methyl-D-glucose excretion (minTransfer rate constant from nonaccessible to accessible compart-Deactivation rate constants (minActivation rate constants (min Ϫ2per mU/l) q 1 (t), q 2 (t)Masses of D-[U-13 C]glucose in the two compartments (mmol) q 3 (t), q 4 (t)Masses of 3-O-methyl-D-glucose in ...

35Non-Alcoholic Fatty Liver Disease (NAFLD) is associated with multi-organ (hepatic, skeletal muscle, 36 adipose tissue) insulin resistance (IR). Exercise is an effective treatment for lowering liver fat but its 37 effect on insulin resistance in NAFLD is unknown. 38We aimed to determine whether supervised exercise in NAFLD would reduce liver fat and improve 51With exercise, peripheral insulin sensitivity significant increased (following high-dose insulin) despite 52 no significant change in hepatic glucose production (following low-dose insulin); no changes were 53 observed in the control group. 54Although supervised exercise effectively reduced liver fat, improving peripheral IR in NAFLD, the 55 reduction in liver fat was insufficient to improve hepatic IR.

Resistant starch (RS) has been shown to beneficially affect insulin sensitivity in healthy individuals and those with metabolic syndrome, but its effects on human type 2 diabetes (T2DM) are unknown. This study aimed to determine the effects of increased RS consumption on insulin sensitivity and glucose control and changes in postprandial metabolites and body fat in T2DM. Seventeen individuals with well-controlled T2DM (HbA1c 46.6±2 mmol/mol) consumed, in a random order, either 40 g of type 2 RS (HAM-RS2) or a placebo, daily for 12 weeks with a 12-week washout period in between. At the end of each intervention period, participants attended for three metabolic investigations: a two-step euglycemic–hyperinsulinemic clamp combined with an infusion of [6,6-2H2] glucose, a meal tolerance test (MTT) with arterio-venous sampling across the forearm, and whole-body imaging. HAM-RS2 resulted in significantly lower postprandial glucose concentrations (P=0.045) and a trend for greater glucose uptake across the forearm muscle (P=0.077); however, there was no effect of HAM-RS2 on hepatic or peripheral insulin sensitivity, or on HbA1c. Fasting non-esterified fatty acid (NEFA) concentrations were significantly lower (P=0.004) and NEFA suppression was greater during the clamp with HAM-RS2 (P=0.001). Fasting triglyceride (TG) concentrations and soleus intramuscular TG concentrations were significantly higher following the consumption of HAM-RS2 (P=0.039 and P=0.027 respectively). Although fasting GLP1 concentrations were significantly lower following HAM-RS2 consumption (P=0.049), postprandial GLP1 excursions during the MTT were significantly greater (P=0.009). HAM-RS2 did not improve tissue insulin sensitivity in well-controlled T2DM, but demonstrated beneficial effects on meal handling, possibly due to higher postprandial GLP1.

fatty liver disease (NAFLD) is an independent risk factor for cardiovascular disease (CVD). Endothelial dysfunction is an early manifestation of atherosclerosis and an important prognostic marker for future cardiovascular events. The aim of this study was twofold: to examine 1) the association between liver fat, visceral adipose tissue (VAT), and endothelial dysfunction in obese NAFLD patients and 2) the impact of supervised exercise training on this vascular defect. Brachial artery endothelial function was assessed by flow-mediated dilatation (FMD) in 34 obese NAFLD patients and 20 obese controls of similar age and cardiorespiratory fitness [peak oxygen uptake (V O2 peak)] (48 Ϯ 2 vs. 47 Ϯ 2 yr; 27 Ϯ 1 vs. 26 Ϯ 2 ml·kg Ϫ1 ·min Ϫ1Ϫ1 ). Magnetic resonance imaging and spectroscopy quantified abdominal and liver fat, respectively. Twenty-one NAFLD patients completed either 16 wk of supervised moderate-intensity exercise training (n ϭ 13) or conventional care (n ϭ 8). Differences between NAFLD and controls were compared using independent t-tests and effects of interventions by analysis of covariance. NAFLD patients had higher liver fat [11.6% (95% CI ϭ 7.4, 18.1), P Ͻ 0.0005] and VAT [1.6 liters (95% CI ϭ 1.2, 2.0), P Ͻ 0.0001] than controls and exhibited impaired FMD compared with controls [Ϫ3.6% (95% CI ϭ Ϫ4.9, Ϫ2.2), P Ͻ 0.0001]. FMD was inversely correlated with VAT (r ϭ Ϫ0.54, P ϭ 0.001) in NAFLD, although the impairment in FMD remained following covariate adjustment for VAT [3.1% (95% CI ϭ 1.8, 4.5), P Ͻ 0.001]. Exercise training, but not conventional care, significantly improved V O2 peak [9.1 ml·kg Ϫ1 ·min Ϫ1 (95% CI ϭ 4.1, 14.1); P ϭ 0.001] and FMD [3.6% (95% CI ϭ 1.6, 5.7), P ϭ 0.002]. Endothelial dysfunction in NAFLD cannot be fully explained by excess VAT but can be reversed with exercise training; this has potential implications for the primary prevention of CVD in NAFLD. nonalcoholic fatty liver disease; flow-mediated dilation; cardiovascular risk; exercise training NONALCOHOLIC FATTY LIVER DISEASE (NAFLD) is a disease spectrum ranging from simple steatosis, progressing to necroinflammatory changes (nonalcoholic steatohepatitis) and in a subset, to cirrhosis, fibrosis, and end-stage liver disease (20). NAFLD is the most common form of chronic liver disease in Western society, affecting 20 -30% of the general population (6) and up to ϳ60% of individuals with type 2 diabetes mellitus (43). NAFLD is regarded as the hepatic manifestation of the metabolic syndrome, coexisting with multiple cardiometabolic risk factors, including obesity, insulin resistance, hypertension, and dyslipidemia (34).NAFLD increases the risk of chronic liver disease, yet epidemiological studies suggest that cardiovascular disease (CVD) accounts for more deaths in NAFLD than liver disease, some reporting CVD to be the leading cause of mortality (10,23,34). Indeed, there is strong evidence that NAFLD patients are at greater risk of CVD than controls and that NAFLD is an independent predictor of cardiovascular morbidity and mortality ...

-We investigated the impact of growth hormone (GH) alone, testosterone (T) alone, and combined GH and T on whole body protein metabolism. Twelve hypopituitary men participated in two studies. Study 1 compared the effects of GH alone with GH plus T, and study 2 compared the effects of T alone with GH plus T. IGF-I, resting energy expenditure (REE), and fat oxidation (F ox) and rates of whole body leucine appearance (R a), oxidation (Lox), and nonoxidative leucine disposal (NOLD) were measured. In study 1, GH treatment increased mean plasma IGF-I (P Ͻ 0.001). GH did not change leucine R a but reduced Lox (P Ͻ 0.02) and increased NOLD (P Ͻ 0.02). Addition of T resulted in an additional increase in IGF-I (P Ͻ 0.05), reduction in Lox (P Ͻ 0.002), and increase in NOLD (P Ͻ 0.002). In study 2, T alone did not alter IGF-I levels. T alone did not change leucine R a but reduced Lox (P Ͻ 0.01) and increased NOLD (P Ͻ 0.01). Addition of GH further reduced L ox (P Ͻ 0.05) and increased NOLD (P Ͻ 0.05). In both studies, combined treatments on REE and Fox were greater than either alone. In summary, GH-induced increase of circulating IGF-I is augmented by T, which does not increase IGF-I in the absence of GH. T and GH exerted independent and additive effects on protein metabolism, Fox and REE. The anabolic effects of T are independent of circulating IGF-I.insulin-like growth factor I; protein turnover GROWTH HORMONE (GH) AND TESTOSTERONE are potent anabolic hormones. There is strong evidence in children that both hormones interact positively to enhance growth and body composition (2,22,35). The mechanistic basis of this interaction is poorly understood.Testosterone enhances the growth of boys with hypogonadism and those with hypopituitarism during GH treatment (2, 35). However, the effect of testosterone on somatic growth is poor in boys with hypopituitarism without concomitant GH treatment (2, 35). In hypopituitary adults who are not receiving GH replacement, testosterone exerts no effect on circulating IGF-I (18). These collective observations suggest that the growth promoting and anabolic effects of testosterone may be dependent on GH and possibly mediated in part by IGF-I.How GH and testosterone interact to regulate protein metabolism in adult life is also poorly understood. There is evidence that both hormones are necessary to exert an optimal effect. Even after adequate androgen replacement, lean body mass is reduced in GH-deficient men (15). The observation that the effects of GH replacement are more marked in men than in women (9) provides further evidence that testosterone might enhance the anabolic effects of GH. The anabolic effects of GH are mediated by IGF-I, but whether IGF-I also plays a role in mediating the anabolic effects of testosterone is unknown. The aim of the study was to investigate how GH and testosterone interact to regulate anabolism by studying the independent and combined effects of these two hormones on IGF-I and protein metabolism. SUBJECTS AND METHODSSubjects. Twelve hypopituitary men with GH d...