The present study sought to determine whether elevated plasma free fatty acids (FFAs) alter the ability of insulin and glucose to regulate splanchnic as well as muscle glucose metabolism. To do so, FFAs were increased in 10 subjects to ϳ1 mmol/l by an 8-h Intralipid/ heparin (IL/Hep) infusion, whereas they fell to levels near the detection limit of the assay (<0.05 mmol/l) in 13 other subjects who were infused with glycerol alone at rates sufficient to either match (n ‫؍‬ 5, low glycerol) or double (n ‫؍‬ 8, high glycerol) the plasma glycerol concentrations observed during the IL/Hep infusion. Glucose was clamped at ϳ8.3 mmol/l, and insulin was increased to ϳ300 pmol/l to stimulate both muscle and hepatic glucose uptake. Insulin secretion was inhibited with somatostatin. Leg and splanchnic glucose metabolism were assessed using a combined catheter and tracer dilution approach. Leg glucose uptake (21.7 ؎ 3.5 vs. 48.3 ؎ 9.3 and 57.8 ؎ 11.7 mol ⅐ kg ؊1 leg ⅐ min

To determine the mechanism(s) by which insulin inhibits endogenous glucose production (EGP) in nondiabetic humans, insulin was infused at rates of 0.25, 0.375, or 0.5 mU ⅐ kg ؊1 ⅐ min ؊1 and glucose was clamped at ϳ5.5 mmol/l. EGP, gluconeogenesis, and uridine-diphosphoglucose (UDP)-glucose flux were measured using [3-3 H]glucose, deuterated water, and the acetaminophen glucuronide methods, respectively. An increase in insulin from ϳ75 to ϳ100 to ϳ150 pmol/l (ϳ12.5 to ϳ17 to ϳ25 U/ml) resulted in progressive (ANOVA; P < 0.02) suppression of EGP (13.1 ؎ 1.3 vs. 11.7 ؎ 1.03 vs. 6.4 ؎ 2.15 mol ⅐ kg ؊1 ⅐ min ؊1 ) that was entirely due to a progressive decrease (ANOVA; P < 0.05) in the contribution of glycogenolysis to EGP (4.7 ؎ 1. The contribution of the direct (extracellular) pathway to UDP-glucose flux was minimal and constant during all insulin infusions. We conclude that higher insulin concentrations are required to suppress the contribution of gluconeogenesis of EGP than are required to suppress the contribution of glycogenolysis to EGP in healthy nondiabetic humans. Since suppression of glycogenolysis occurred without a decrease in UDP-glucose flux, this implies that insulin inhibits EGP, at least in part, by directing glucose-6-phosphate into glycogen rather than through the glucose-6-phosphatase pathway. Diabetes

Aims/hypothesis. The aim of this study was to determine whether rapid conversion to inactive and potentially antagonistic peptides could alter the response to GLP-1. Methods. We evaluated the ability of exendin-4, a GLP-1 analogue resistant to degradation by dipeptidyl peptidase IV, to modulate insulin-induced stimulation of glucose uptake and suppression of glucose production in eight healthy subjects during infusion of GLP-1 (1.2 pmol·kg -1 ·min -1 ), exendin-4 (0.12 pmol·kg -1 · min -1 ), or saline. Glucose was clamped at 5.3 mmol/l and insulin was infused to progressively increase insulin concentrations to about 65, 190 and 700 pmol/l, respectively. Endogenous insulin secretion was inhibited with somatostatin to ensure comparable portal insulin concentrations while glucagon and growth hormone were maintained at basal concentrations. Results. Glucose, insulin, C-peptide, glucagon and growth hormone concentrations did not differ on the three occasions. In contrast, cortisol concentrations were greater during both exendin-4 (25.1±4.4 mmol/l per 7 h; p<0.01) and GLP-1, (17.0±2.0 mmol/l 7 h; p<0.05) than saline (13.5±1.5 mmol/l per 7 h). While insulin-induced stimulation of glucose disappearance at the highest insulin concentrations tended to be greater and insulin-induced suppression of glucose production lower in the presence of exendin-4 or GLP-1 than saline, the differences were not significant. Conclusion/interpretation. Exendin-4 and GLP-1 increase cortisol secretion in human subjects. However, neither alters insulin action in non-diabetic human subjects. These data also suggest that the lack of an effect of GLP-1 on insulin action is not likely to be explained by rapid degradation to inactive or antagonistic peptides. [Diabetologia (2002[Diabetologia ( ) 45:1410[Diabetologia ( -1415 Keywords GLP-1, exendin-4, insulin action, glucose production, cortisol secretion. [11,12] and the liver [13]. GLP-1 (7-36) can increase glucose uptake in each of these tissues with its effects being additive to those of insulin [12,14,15,16]. In contrast, results from in vivo studies have been less consistent. GLP-1 (7-36) has been reported to increase glucose uptake during hyperglycaemia and hyperinsulinaemia in diabetic rats [17], pancreatectomized dogs [18] and in Type I (insulin-dependent) diabetic patients [19,20]. In contrast, GLP-1 (7-36) has been reported to have no effect on the insulin action in non-diabetic human subjects [21] GLP-1 (7-36) is actively being evaluated as a therapy for diabetes mellitus. GLP-1 (7-36) increases insulin secretion, decreases glucagon secretion and delays gastric emptying [1,2,3,4,5,6,7]. In vitro data suggest it might also enhance insulin action. Although controversial, GLP-1 receptors, to which Exendin-4

The authors identified several errors after their paper had been printed: 1. C-peptide values were inadvertently converted to nmol/l from ng/ml by multiplying by 0.331 twice. Correct values require division of reported values by 0.331. 2. Fig. 2: the Y-axis for growth hormone should be labelled as µg/l. 3. The mean growth hormone concentration at 0 min on the saline study day was incorrectly plotted. The correct value was 2.34 µg/l +/-1.64. 4. Fig. 2: the Y-axis for cortisol should be labelled as nmol/l

The present study sought to determine whether elevated plasma free fatty acids (FFAs) alter the splanchnic and muscle glucose metabolism in women. To do so, FFAs were increased in seven women by an 8-h Intralipid/heparin (IL/hep) infusion, and the results were compared with those observed in nine women who were infused with glycerol alone. Glucose was clamped at ϳ8.3 mmol/l and insulin was increased to ϳ300 pmol/l to stimulate both muscle and hepatic glucose uptake. Insulin secretion was inhibited with somatostatin. Leg and splanchnic glucose metabolism were assessed using a combined catheter and tracer dilution approach. The glucose infusion rates required to maintain target plasma glucose concentrations were lower (P < 0.01) during IL/hep than glycerol infusion (30.8 ؎ 2.6 vs. 65.0 ؎ 7.9 mol ⅐ kg ؊1 ⅐ min ؊1 ). Whole-body glucose disappearance (37.0 ؎ 2.2 vs. 70.9 ؎ 8.7 mol ⅐ kg ؊1 ⅐ min ؊1 ; P < 0.001) and leg glucose uptake (24.3 ؎ 4.2 vs. 59.6 ؎ 10.0 mol ⅐ kg fat-free mass of the leg ؊1 ⅐ min ؊1 ; P < 0.02) were also lower, whereas splanchnic glucose production (8.2 ؎ 0.8 vs. 4.3 ؎ 0.7 mol ⅐ kg ؊1 ⅐ min ؊1 ; P < 0.01) was higher during IL/hep than glycerol infusion. We conclude that in the presence of combined hyperinsulinemia and hyperglycemia, elevated FFAs impair glucose metabolism in women by inhibiting wholebody glucose disposal, muscle glucose uptake, and suppression of splanchnic glucose production. Diabetes 52: 38 -42, 2003 E levated plasma free fatty acid (FFA) concentrations are common in both obesity and type 2 diabetes (1-4). Currently, there is substantial evidence that FFAs may contribute to insulin resistance in both of these conditions (5-11). Elevated FFAs can decrease muscle glucose transport and muscle glycogen synthesis by inhibiting intracellular signaling (5,7,10,12). FFAs can also stimulate gluconeogenesis and impair insulin-induced suppression of hepatic glucose production (6,13). Therefore, the recent article by Frias et al. (14), showing that elevated FFAs lowered whole-body glucose uptake during a euglycemic-hyperinsulinemic clamp in men but not in women, was intriguing and potentially of considerable importance. In clinical settings hyperinsulinemia commonly occurs in conjunction with hyperglycemia and high FFA levels. The role of high FFAs in the above situation remains to be defined.It is well established that fat metabolism differs in men and women (15)(16)(17)(18). FFA release is greater and insulininduced suppression of lipolysis is less in upper body fat than in lower body fat (19). Men have a greater portion of visceral and upper body fat than women (20 -22). Insulin action, assessed using a variety of techniques, has been reported to be greater (15,23), lower (24), or no different (18,23,25,26) in women than men. On the other hand, hormone replacement therapy has been associated with increased (27), reduced (28), or unaltered (29) insulin concentrations.We have recently reported that, in the presence of hyperglycemia and hyperinsulinemia, elevated FFAs impair muscle gluc...