Reduction In Endogenous Glucose Production Research Articles

120-LB: Small Molecule Activator of Pyruvate Kinase Regulates In Vivo Glucose Homeostasis

Background: Nonalcoholic fatty liver disease (NAFLD) is a major factor in the pathogenesis of type-2 diabetes (T2D). Liver pyruvate kinase (PK) inactivating mutations are associated with diabetes in human subjects and PK deficiency associated with severe liver dysfunction and fat accumulation. Aim: To determine whether small molecule activators of PK (PKa) could improve liver metabolism in rats fed a high fat diet. Methods: Sprague Dawley regular chow (RC) or high fat diet (HFD) rats were either treated acutely (IV bolus 11mg/kg/min then primed continuous 0.06 mg/kg/min) or chronically (50 mg/kg/day x 3 weeks). Insulin sensitivity was assessed by hyperinsulinemic-euglycemic clamp studies. Results: PKa dose dependently suppressed glucose production from primary rat hepatocytes. Acute PKa infusion suppressed endogenous glucose production (EGP) by 20% in RC rats. Chronic PKa exposure did not affect body weight in HFD-fed rats. Three-week PKa treatment did not change activity, food intake, whole-body energy expenditure, or body weight in HFD-fed mice. Nevertheless, PKa improved whole-body insulin sensitivity compared with control HFD-fed rats (glucose infusion rate: control 11.8±1.4 vs. PKa 15.3±0.7 mg/(kg-min), P<0.05). Differences in whole-body insulin sensitivity were accounted for by a 15% reduction in EGP and increased insulin-stimulated peripheral glucose uptake (21.2±0.6 vs. 26.4±1.7 mg/(kg-min), P<0.05). Insulin-stimulated hepatic AKT phosphorylation was also significantly improved. Consistent with improving of peripheral insulin sensitivity, liver and muscle triglyceride content (liver: 27.2±2.6 vs. 16.9±1.5 mg/g, P<0.05. muscle: 9.8 ±1.4 vs. 6.7±1.0 mg/g, P<0.05) were improved in PKa-treated rats. In conclusion, activation of pyruvate kinase in rodents protects against HFD-induced insulin resistance. By reducing EGP and insulin resistance, activation of PK may be an exciting potential therapeutic target for T2D. Disclosure A. Abulizi: None. R.L. Cardone: None. S. Siebel: None. C. Kung: Employee; Self; Agios Pharmaceuticals. Stock/Shareholder; Self; Agios Pharmaceuticals. R. Kibbey: None. Funding American Diabetes Association (1-16-IBS-158 to R.K.); National Institutes of Health (R01DK108283-01A1)

Palmitic Acid Esters of Hydroxy Stearic Acids Are Hepatic Insulin Sensitizers in Chow and High-Fat Diet (HFD)–Fed Mice

Palmitic Acid esters of Hydroxy Stearic Acids (PAHSAs), bioactive lipids with potent anti-inflammatory and antidiabetic effects, reduce ambient glycemia and improve glucose tolerance and insulin sensitivity in insulin resistant HFD-fed mice. We aimed to determine the mechanisms by which PAHSAs improve insulin sensitivity. We treated chow- and HFD-fed mice with 5-PAHSA (0.1 mg/day) and 9-PAHSA (0.4 mg/day) by SQ osmotic minipumps for 13 weeks. Serum 5-PAHSA levels increased 3.5 fold and 9-PAHSA 2.5 fold in chow-fed mice, while 5-PAHSA levels increased 17 fold and 9-PAHSA 6 fold in HFD-fed mice. PAHSAs had no effect on weight gain or fat mass. We performed hyperinsulinemic euglycemic clamps (2.5 mU/Kg/min insulin infusion rate). PAHSA treatment increased systemic insulin sensitivity in both chow- [glucose infusion rate (GIR): vehicle 13±2 vs. PAHSA 27±4 mg/kg/min] and HFD-fed mice (GIR: vehicle 2±0.5 vs. PAHSA 10±3 mg/kg/min). Endogenous glucose production (EGP) was suppressed 28% by insulin in vehicle-treated mice and 55% in PAHSA-treated mice on chow diet. Remarkably, while insulin failed to suppress EGP in vehicle-treated HFD-fed mice, PAHSA treatment led to a 37% reduction in EGP. PAHSAs also decreased glycemia during a pyruvate tolerance test, indicating that suppression of hepatic gluconeogenesis contributes to the EGP improvement. Mechanistic studies showed that PAHSAs inhibit basal and glucagon-stimulated EGP and reduce cAMP in isolated hepatocytes. This effect is blocked by pertussis toxin indicating it is mediated by Gα/i protein-coupled receptors. PAHSAs also reduce G6pase activity and phosphorylation of CREB in liver. Sum: PAHSAs are systemic insulin sensitizers and augment insulin action on EGP in vivo. In vitro, PAHSAs reduce EGP through a cAMP dependent pathway involving Gα/i protein-coupled receptors. Thus, PAHSAs could be effective antidiabetic agents and the pathways they engage could provide novel drug targets for type 2 diabetes. Disclosure A. Santoro: None. P. Zhou: None. O.D. Peroni: None. I. Syed: None. A.T. Nelson: None. D. Siegel: None. A. Saghatelian: None. B. Kahn: Advisory Panel; Self; Janssen Research & Development. Research Support; Self; Janssen Research & Development. Advisory Panel; Self; Alterna Biotech.

Effect of fibre additions to flatbread flour mixes on glucose kinetics: a randomised controlled trial.

We previously found that guar gum (GG) and chickpea flour (CPF) added to flatbread wheat flour lowered postprandial blood glucose (PPG) and insulin responses dose dependently. However, rates of glucose influx cannot be determined from PPG, which integrates rates of influx, tissue disposal and hepatic glucose production. The objective was to quantify rates of glucose influx and related fluxes as contributors to changes in PPG with GG and CPF additions to wheat-based flatbreads. In a randomised cross-over design, twelve healthy males consumed each of three different 13C-enriched meals: control flatbreads (C), or C incorporating 15 % CPF with either 2 % (GG2) or 4 % (GG4) GG. A dual isotope technique was used to determine the time to reach 50 % absorption of exogenous glucose (T 50 %abs, primary objective), rate of appearance of exogenous glucose (RaE), rate of appearance of total glucose (RaT), endogenous glucose production (EGP) and rate of disappearance of total glucose (RdT). Additional exploratory outcomes included PPG, insulin, glucose-dependent insulinotropic peptide and glucagon-like peptide 1, which were additionally measured over 4 h. Compared with C, GG2 and GG4 had no significant effect on T 50 %abs. However, GG4 significantly reduced 4-h AUC values for RaE, RaT, RdT and EGP, by 11, 14, 14 and 64 %, respectively, whereas GG2 showed minor effects. Effect sizes over 2 and 4 h were similar except for significantly greater reduction in EGP for GG4 at 2 h. In conclusion, a soluble fibre mix added to flatbreads only slightly reduced rates of glucose influx, but more substantially affected rates of postprandial disposal and hepatic glucose production.

The hepatoselective glucokinase activator PF-04991532 ameliorates hyperglycemia without causing hepatic steatosis in diabetic rats.

Hyperglycemia resulting from type 2 diabetes mellitus (T2DM) is the main cause of diabetic complications such as retinopathy and neuropathy. A reduction in hyperglycemia has been shown to prevent these associated complications supporting the importance of glucose control. Glucokinase converts glucose to glucose-6-phosphate and determines glucose flux into the β-cells and hepatocytes. Since activation of glucokinase in β-cells is associated with increased risk of hypoglycemia, we hypothesized that selectively activating hepatic glucokinase would reduce fasting and postprandial glucose with minimal risk of hypoglycemia. Previous studies have shown that hepatic glucokinase overexpression is able to restore glucose homeostasis in diabetic models; however, these overexpression experiments have also revealed that excessive increases in hepatic glucokinase activity may also cause hepatosteatosis. Herein we sought to evaluate whether liver specific pharmacological activation of hepatic glucokinase is an effective strategy to reduce hyperglycemia without causing adverse hepatic lipids changes. To test this hypothesis, we evaluated a hepatoselective glucokinase activator, PF-04991532, in Goto-Kakizaki rats. In these studies, PF-04991532 reduced plasma glucose concentrations independent of changes in insulin concentrations in a dose-dependent manner both acutely and after 28 days of sub-chronic treatment. During a hyperglycemic clamp in Goto-Kakizaki rats, the glucose infusion rate was increased approximately 5-fold with PF-04991532. This increase in glucose infusion can be partially attributed to the 60% reduction in endogenous glucose production. While PF-04991532 induced dose-dependent increases in plasma triglyceride concentrations it had no effect on hepatic triglyceride concentrations in Goto-Kakizaki rats. Interestingly, PF-04991532 decreased intracellular AMP concentrations and increased hepatic futile cycling. These data suggest that hepatoselective glucokinase activation may offer glycemic control without inducing hepatic steatosis supporting the evaluation of tissue specific activators in clinical trials.

Glucose and fat metabolism in narcolepsy and the effect of sodium oxybate: a hyperinsulinemic-euglycemic clamp study.

Narcolepsy is associated with obesity though it is uncertain whether this is caused by changes in glucose and fat metabolism. Therefore, we performed a detailed analysis of systemic energy homeostasis in narcolepsy patients, and additionally, investigated whether it was affected by three months of sodium oxybate (SXB) treatment. Nine hypocretin deficient patients with narcolepsy-cataplexy, and nine healthy sex, age, and BMI matched controls were enrolled. A hyperinsulinemic-euglycemic clamp combined with stable isotopes ([6,6-(2)H2]-glucose and [(2)H5]- glycerol) was performed at baseline. In seven patients a second study was performed after three months of SXB treatment. Glucose disposal rate (GDR) per unit serum insulin was significantly higher in narcolepsy patients compared to matched controls (1.6 ± 0.2 vs. 1.1 ± 0.3 μmol/kgFFM/min/mU×L; P = 0.024), whereas β-cell function was similar (P = 0.50). Basal steady state glycerol appearance rate tended to be lower in narcolepsy patients (5.2 ± 0.4 vs. 7.5 ± 1.3 μmol/kgFM/min; P = 0.058), suggesting a lower rate of lipolysis. SXB treatment induced a trend in reduction of the GDR (1.4 ± 0.1 vs. 1.1 ± 0.2 μmol/kgFFM/min/mU×L; P = 0.063) and a reduction in endogenous glucose production (0.24 ± 0.03 vs. 0.16 ± 0.03 μmol/kgFFM/min/mU×L: P = 0.028) per unit serum insulin. After SXB treatment lipolysis increased (4.9 ± 0.4 vs. 6.5 ± 0.6 μmol/kgFM/min; P = 0.018), and body weight decreased in narcolepsy patients (99.2 ± 6.0 vs. 94.0 ± 5.4 kg; P = 0.044). We show that narcolepsy patients are more insulin sensitive and may have a lower rate of lipolysis than matched controls. SXB stimulated lipolysis in narcolepsy patients, possibly accounting for the weight loss after treatment. While sodium oxybate tended to decrease systemic insulin sensitivity, it increased hepatic insulin sensitivity, suggesting tissue-specific effects.

Hyperglucagonemia precedes a decline in insulin secretion and causes hyperglycemia in chronically glucose-infused rats

Islet damage from glucose toxicity is implicated in the pathogenesis of type 2 diabetes, but the sequence of events leading to islet cell dysfunction and hyperglycemia remains unclear. To examine the early stages of islet pathology resulting from increased basal glucose loads, normal awake rats were infused with glucose continuously for 10 days. Plasma glucose and markers of islet and liver function were monitored throughout the infusion. After initial hyperglycemia, rats adapted to the infusion and maintained euglycemia for approximately 4 days. Continued infusion led to worsening hyperglycemia in just 5% of rats after 6 days, but 69% after 8 days and 89% after 10 days, despite unchanged basal and stimulated plasma insulin and C-peptide concentrations. In contrast, plasma glucagon concentrations increased fivefold. Endogenous glucose production (EGP) was appropriately suppressed after 4 days (2.8 ± 0.7 vs. 6.1 ± 0.4 mg·kg(-1)·min(-1) on day 0, P < 0.001) but tripled between days 4 and 8 (9.9 ± 1.7 mg·kg(-1)·min(-1), P < 0.01). Surprisingly, the increase in EGP was accompanied by increased mitochondrial phosphoenolpyruvate carboxykinase expression with appropriate suppression of the cytosolic isoform. Infusion of anti-glucagon antibodies normalized plasma glucose to levels identical to those on day 4 and ∼300 mg/dl lower than controls. This improved glycemia was associated with a 60% reduction in EGP. These data support the novel concept that glucose toxicity may first manifest as α-cell dysfunction prior to any measurable deficit in insulin secretion. Such hyperglucagonemia could lead to excessive glucose production overwhelming the capacity of the β-cell to maintain glucose homeostasis.

ORIGINAL ARTICLE: Pioglitazone improvement of fasting and postprandial hyperglycaemia in Mexican‐American patients with Type 2 diabetes: a double tracer OGTT study

SummaryObjectives By using tracer techniques, we explored the metabolic mechanisms by which pioglitazone treatment for 16 weeks improves oral glucose tolerance in patients with type 2 diabetes when compared to subjects without diabetes.Methods In all subjects, before and after treatment, we measured rates of tissue glucose clearance (MCR), oral glucose appearance (RaO) and endogenous glucose production (EGP) during a (4‐h) double tracer oral glucose tolerance test (OGTT) (1‐14C‐glucose orally and 3‐3H‐glucose intravenously). Basal hepatic insulin resistance index (HepIR) was calculated as EGPxFPI. β‐cell function was assessed as the incremental ratio of insulin to glucose (ΔI/ΔG) during the OGTT.Results Pioglitazone decreased fasting plasma glucose concentration (10·5 ± 0·7 to 7·8 ± 0·6 mm, P &lt; 0·0003) and HbA1c (9·7 ± 0·7 to 7·5 ± 0·5%, P &lt; 0·003) despite increased body weight and no change in plasma insulin concentrations. This was determined by a decrease both in fasting EGP (20·0 ± 1·1 to 17·3 ± 0·8 μmol/kgffm min, P &lt; 0·005) and HepIR (from 8194 declined by 49% to 3989, P &lt; 0·002). During the OGTT, total glucose Ra during the 0‐ to 120‐min time period following glucose ingestion decreased significantly because of a reduction in EGP. During the 0‐ to 240‐min time period, pioglitazone caused only a modest increase in MCR (P &lt; 0·07) but markedly increased ΔI/ΔG (P = 0·003). The decrease in 2h‐postprandial hyperglycaemia correlated closely with the increase in ΔI/ΔG (r = −0·76, P = 0·004) and tissue clearance (r = −0·74, P = 0·006) and with the decrease in HepIR (r = 0·62, P = 0·006).Conclusions In diabetic subjects with poor glycaemic control, pioglitazone improves oral glucose tolerance mainly by enhancing the suppression of EGP and improving β‐cell function.

Effects of atazanavir/ritonavir and lopinavir/ritonavir on glucose uptake and insulin sensitivity

We read with interest the article by Noor et al. [1] examining the differential effects on glucose metabolism of the combinations of atazanavir/ritonavir versus lopinavir/ritonavir. Their paper deals with an important issue, having both theoretical interest and clinical impact. We think that some comments concerning aspects of the experimental procedure, data analysis and interpretation of the results could be helpful to other readers. The euglycemic hyperinsulinemic clamp is the golden standard for the assessment of insulin sensitivity. This experimental approach requires that the glucose concentration is maintained at a constant level throughout the study [2]. However, in the study by Noor et al.[1], the glucose concentration increased remarkably (up to 100 mg/dl) during the initial portion of the clamp (their fig. 3a), a defect which may influence the clamp-derived estimate of insulin sensitivity. During the clamp, it is assumed that endogenously secreted insulin is inhibited and only peripherally administered insulin contributes to insulin elevation. If the glycemic increase triggered an endogenous insulin response, this likely influenced the degree of inhibition of endogenous glucose production because the acute elevation of the portal insulin level has been shown to have a long-lasting effect on the liver [3]. As a result, the clamp-derived estimate of insulin sensitivity would also be affected. Additional data on the C-peptide would be welcome to verify the time course of endogenous insulin secretion, as a bias cannot otherwise be ruled out. In analyzing the oral glucose tolerance test (OGTT), Noor et al.[1] used plasma glucose and insulin levels to calculate insulin resistance for each time point of the OGTT by means of the homeostasis model assessment (HOMA) (their fig. 3c). That, however, is a misuse of the HOMA method, which has been developed to provide an index of insulin resistance from the concentrations of glucose and insulin measured at the basal steady state [4]. This method cannot be applied to nonsteady-state conditions when insulin and glucose concentrations continuously change. Thus, the authors had no methodological support for calculating the HOMA index at each time point during the OGTT and performing statistical comparisons among groups. In discussing their data obtained in vivo, Noor et al.[1] faced the problem of reconciling a discrepancy between the euglycemic, hyperinsulinemic clamp and OGTT results. Although the clamp revealed a significantly different reduction in insulin sensitivity between atazanavir/ritonavir and lopinavir/ritonavir, the OGTT did not (their table 2). The authors claimed that this discrepancy was due to the fact that the OGTT reflects both liver and peripheral insulin sensitivity, whereas the glucose clamp only reflects the latter component. This argument is questionable for the following reasons. First, a patent contradiction immediately emerges. If the OGTT reflects both liver and peripheral insulin sensitivity, whereas the clamp only reflects the latter, the OGTT would be expected to be more capable than the clamp of detecting differences in insulin sensitivity among the study groups. This contradicts the experimental evidence, which shows the opposite. Second, the claim that the clamp only reflects peripheral insulin sensitivity has no grounds. The index of clamp-based insulin sensitivity used by Noor et al.[1] is the ratio M/I, where M is the exogenous glucose infusion rate and I is the insulin concentration, both measured at the end of the clamp. It is worth emphasizing that the glucose infused during the clamp allows a constant plasma glucose concentration to be maintained because it balances exactly the increase in glucose disappearance (Rd) and the reduction in endogenous glucose production (EGP). Thus, the M-value measures the ability of insulin to stimulate peripheral glucose uptake, as well as to inhibit glucose production (M = ΔRd − ΔEGP, where Δ is the change from pretest level) [5]. In the study by Noor et al.[1], the inhibition of endogenous glucose production could not be assumed to be identical in the study groups because protease-inhibitors are known to affect liver insulin sensitivity [6]. The contribution of glucose uptake can only be isolated from that of endogenous glucose production if a glucose tracer is concurrently infused along with unlabeled glucose [5], but Noor et al.[1] did not use a tracer. It can be concluded that the true reason for the discrepancy between the clamp and OGTT results remains to be elucidated. In conclusion, we hope that the above considerations may prove useful to clinicians in the interpretation of studies assessing the effects of antiretroviral drugs on carbohydrate metabolism using methods such as the euglycemic hyperinsulinemic clamp, the HOMA, or the OGTT.

Metformin and Heart Failure

Throughout the world and for many years, metformin has been a mainstay of therapy for patients with type 2 diabetes. This highly effective and usually well-tolerated oral agent is, to date, the only one demonstrated to reduce cardiovascular disease (CVD) complications in newly diagnosed type 2 diabetic patients (1). It's precise mechanism of action remains enigmatic, although it clearly results in a reduction of endogenous glucose production, primarily hepatic gluconeogenesis, most likely involving the stimulation of AMP-activated protein kinase activity (2). A peripheral insulin-sensitizing effect in skeletal muscle has also been demonstrated by some, but not all, investigators (3). In small studies, metformin appears to exert benefit on various other fundamental biological processes that influence atherogenesis, such as lipid metabolism, inflammation, and vascular endothelial function (4). Another insulin sensitizer category, the thiazolidinediones (TZDs), has also been proposed to reduce CVD risk, but that class carries with it concerns of weight gain and fluid retention. As a result, TZDs remain more popular in combination therapy regimens. Perhaps of greatest import to clinicians is the recognition that metformin is the only oral antidiabetic agent associated with weight loss. Accordingly, metformin remains, in the eyes of many authorities, the optimal initial drug choice in most type 2 diabetic patients if diet and exercise have not succeeded in adequately reducing blood glucose levels (5). Approval of metformin in the U.S. was delayed because of previous experience with phenformin, which was associated with lactic acidosis. Although the risk of such metabolic decompensation with metformin was known to be significantly lower than with the earlier biguanide, a fair amount of debate occurred during the approval process (6). The Food and Drug Administration (FDA) eventually sanctioned metformin's use, with the stipulation that strong warnings be included in the package insert regarding potential risks (7). Since metformin …

Intensive Insulin Treatment in Critically Ill Trauma Patients Normalizes Glucose by Reducing Endogenous Glucose Production

Critical illness is associated with insulin resistance and hyperglycemia. Intensive insulin treatment to normalize blood glucose during feeding has been shown to improve morbidity and mortality in patients in intensive care. The mechanisms behind the glucose-controlling effects of insulin in stress are not well understood. Six previously healthy, severely traumatized patients (injury severity score > 15) were studied early (24-48 h) after trauma. Endogenous glucose production (EGP) and whole-body glucose disposal (WGD) were measured (6,6-(2)H(2)-glucose) at basal, during total parenteral nutrition (TPN), and during TPN plus insulin to normalize blood glucose (TPN+I). Six matched volunteers served as controls. At basal and TPN, concentrations of glucose and insulin were higher in patients (P < 0.05). During TPN+I, insulin concentrations were 30-fold higher in patients. At basal, WGD and EGP were 30% higher in patients (P < 0.05). During TPN, EGP decreased in both groups but less in patients, resulting in 110% higher EGP than controls (P < 0.05). Normoglycemia coincided with reduced EGP, resulting in similar rates in both groups. WGD did not change during TPN or TPN+I and was not different between the groups. In conclusion, in healthy subjects, euglycemia is maintained during TPN at physiological insulin concentrations by a reduction of EGP, whereas WGD is maintained at basal levels. In traumatized patients, hyperglycemia is due to increased EGP. In contrast to controls, normalization of glucose concentration during TPN needs high insulin infusion rates and is accounted for by a reduction in EGP, whereas WGD is not increased.

Increased hepatic insulin sensitivity together with decreased hepatic triglyceride stores in hormone-sensitive lipase-deficient mice.

Hormone-sensitive lipase (HSL) is a major enzyme for triglyceride (TG) lipolysis in adipose tissue. In HSL-knockout mice, plasma free fatty acid and TG levels are low, associated with low liver TG content. Because a decreased hepatic insulin sensitivity has been reported to be associated with high liver TG levels, our aim was to determine whether a hepatic TG content lower than normal, as observed in HSL-knockout mice, leads to increased hepatic insulin sensitivity. Therefore, hyperinsulinemic clamp experiments in combination with D-(3)H-glucose were used. Furthermore, hepatic insulin receptor and phosphorylated protein kinase B (PKB-P)/akt were analyzed by Western blotting. No significant differences where observed in insulin-mediated whole-body glucose uptake between HSL-knockout and control mice. Interestingly, hepatic insulin sensitivity of HSL-knockout mice was increased, because insulin caused a greater reduction in endogenous glucose production ( approximately 71% compared with approximately 31% in control mice; P < 0.05), despite decreased plasma adiponectin levels. PKB/akt phosphorylation and phosphatidylinositol-3-kinase activity was significantly higher in livers of HSL-knockout mice after insulin stimulation. In HSL-knockout mice, reduced hepatic TG stores result in an increased suppressive effect of insulin on hepatic glucose production, in line with an increased hepatic PKB-P/akt and phosphatidylinositol-3 kinase activity. Thus, hepatic insulin sensitivity is indeed increased after reducing hepatic TG stores below normal.

Vanadyl sulfate improves hepatic and muscle insulin sensitivity in type 2 diabetes.

Vanadyl sulfate (VOSO(4)) is an oxidative form of vanadium that in vitro and in animal models of diabetes has been shown to reduce hyperglycemia and insulin resistance. Small clinical studies of 2- to 4-week duration in type 2 diabetes (T2DM) have led to inconsistent results. To define its efficacy and mechanism of action, 11 type 2 diabetic patients were treated with VOSO(4) at a higher dose (150 mg/day) and for a longer period of time (6 weeks) than in previous studies. Before and after treatment we measured insulin secretion during an oral glucose tolerance test, and endogenous glucose production (EGP) and whole body insulin-mediated glucose disposal using the euglycemic insulin clamp technique combined [3-(3)H]glucose infusion. Treatment significantly improved glycemic control: fasting plasma glucose (FPG) decreased from 194 +/- 16 to 155 +/- 15 mg/dL, hemoglobin A(1c) decreased from 8.1 +/- 0.4 to 7.6 +/- 0.4%, and fructosamine decreased from 348 +/- 26 to 293 +/- 12 micromol/L (all P < 0.01) without any change in body weight. Diabetics had an increased rate of EGP compared with nondiabetic controls (4.1 +/- 0.2 vs. 2.7 +/- 0.2 mg/kg lean body mass.min; P< 0.001), which was closely correlated with FPG (r = 0.56; P< 0.006). Vanadyl sulfate reduced EGP by about 20% (P< 0.01), and the decline in EGP was correlated with the reduction in FPG (r = 0.60; P< 0.05). Vanadyl sulfate also caused a modest increase in insulin-mediated glucose disposal (from 4.3 +/- 0.4 to 5.1 +/- 0.6 mg/kg lean body mass x min; P< 0.03), although the improvement in insulin sensitivity did not correlate with the decline in FPG after treatment (r = -0.16; P = NS). Vanadyl sulfate treatment lowered the plasma total cholesterol (223 +/- 14 vs. 202 +/- 16 mg/dL; P < 0.01) and low density lipoprotein cholesterol (141 +/- 14 vs. 129 +/- 14 mg/dL; P < 0.05), whereas 24-h ambulatory blood pressure was unaltered. We conclude that VOSO(4) at maximal tolerated doses for 6 weeks improves hepatic and muscle insulin sensitivity in T2DM. The glucose-lowering effect of VOSO(4) correlated well with the reduction in EGP, but not with insulin-mediated glucose disposal, suggesting that liver, rather than muscle, is the primary target of VOSO(4) action at therapeutic doses in T2DM.

Effect of dietary energy restriction on glucose production and substrate utilization in type 2 diabetes.

A total of 8 obese subjects with type 2 diabetes were studied while on a eucaloric diet and after reduced energy intake (25 and then 75% of requirements for 10 days each). Weight loss was 2, 3, and 3 kg after 5, 10, and 20 days, respectively; all of the weight lost was body fat. Fasting blood glucose (FBG) levels fell from 11.9 +/- 1.4 at baseline to 8.9 +/- 1.6, 7.9 +/- 1.4, and 8.8 +/- 1.3 mmol/l at days 5, 10, and 20, respectively (P < 0.05, baseline vs. 5, 10, and 20 days). Endogenous glucose production (EGP) was 22 +/- 2, 18 +/- 2, 17 +/- 2, and 22 +/- 2 pmol x kg(-1) lean body mass (LBM) x min(-1) (P < 0.05, days 5 and 10 vs. baseline). Gluconeogenesis measured by mass isotopomer distribution analysis provided 31 +/- 4, 41 +/- 5, 40 +/- 4, and 33 +/- 4%, respectively, of the EGP (NS); absolute glycogenolytic contribution to the EGP was 15 +/- 2, 11 +/- 2, 11 +/- 2, and 15 +/- 2 pmol x kg(-1) LBM x min(-1), respectively (P < 0.001, baseline vs. days 5 and 10 and day 10 vs. day 20). The blood glucose clearance rate increased significantly at day 20 (P < 0.05). Neither lipolysis nor flux of plasma nonesterified fatty acids were altered compared with baseline. In conclusion, severe energy restriction per se independent of major changes in body composition reduces both FBG concentration and EGP in type 2 diabetes, the reduction in EGP results entirely from a reduction of glycogenolytic input into blood glucose, and the duration of reduced glycogenolysis is short-lived after relaxation of energy restriction even without weight gain, but effects on plasma glucose clearance persist and partially maintain the improvement in fasting glycemia.

Site of insulin resistance after surgery: the contribution of hypocaloric nutrition and bed rest.

1. Insulin resistance after surgery has been shown to be related to several important derangements in protein and fat metabolism. However, mechanisms of impaired glucose tolerance after surgery remain ill-defined. 2. Insulin sensitivity and glucose kinetics (6,6(2)H2-glucose) were studied in seven patients before and after elective surgery (surgery group), by two step-hyperinsulinaemic (0.3 and 0.8 munits kg-1 min-1), normoglycaemic (4.5 mmol/l) clamps. Six healthy subjects were studied, using the same protocol, before and after a similar period of bed rest and hypocaloric nutrition (fast/bed rest group) to delineate the effects of surgery per se. 3. Basal endogenous glucose production and whole-body glucose disposal was higher after surgery (P < 0.001), whereas no change was found after fast/bed rest. During glucose clamps, the glucose infusion rates required to maintain normoglycaemia and whole-body glucose disposal decreased (P < 0.001) after surgery, while endogenous glucose production increased (P < 0.001). In the control subjects, levels of endogenous glucose production remained unchanged after fast/bed rest. In contrast, glucose infusion rates and whole-body glucose disposal during glucose clamps also decreased after fast/bed rest (P < 0.01). However, the relative decrease in both these parameters was greater after surgery compared with after fast/bed rest (P < 0.01). 4. After surgery, energy expenditure and fat oxidation increased (P < 0.001), whereas glucose oxidation decreased (P < 0.05). No significant change was found in glucose utilization postoperatively. After fast/bed rest, no change was found in energy expenditure. However, fat oxidation increased (P < 0.01), whereas glucose oxidation and glucose utilization decreased (P < 0.05). 5. In conclusion, impaired glucose tolerance develops after surgery as a result of decreased insulin-stimulated whole-body glucose disposal as well as increased endogenous glucose release. Despite the increase in endogenous glucose production, the reduction in endogenous glucose production with each elevation of insulin was unaffected by surgery. Perioperative bed rest and/or hypocaloric nutrition contribute to the decrease in insulin-stimulated whole-body glucose disposal in the post-operative state, whereas these factors have no effects on endogenous glucose production.