Clearance Rate Of Glucose Research Articles

Usefulness of Insulin Sensitivity Indexes derived from Oral Glucose Tolerance Test in Women with Polycystic Ovary Syndrome

- Abstract Background: Insulin resistance is prevalent in women with polycystic ovary syndrome (PCOS), and it makes them to have high risk for development of type 2 diabetes. Evaluation of insulin sensitivity would be important to predict their risks. Although the euglycemic-hyperinsulinemic clamp technique is the gold standard for measuring insulin sensitivity, it is too hard to practice in large epidemiologic studies. The aim of this study is to verify the validity of various insulin sensitivity indexes f rom oral glucose tolerance test (OGTT) in women with PCOS. Methods: We performed euglycemic-hyperinsulinemic clamp (target glucose; 90 mg/dL, insulin ;~1 mU/kg․min) to obtain insulin-mediated glucose disposal rate (M-value) in 62 non-diabetic women with PCOS (BMI < 23 kg/m 2 ; n = 37, BMI ≥ 23 kg/m 2 ; n = 25). Homeostasis model assessment [HOMA(IR)], quantitative insulin sensitivity check index (QUICKI), glucose to insulin ratio (G/I ratio), whole body insu lin sensitivity index [ISI (COMP)], metabolic clearance rate of glucose [MCRest-OGTT 1,2 ], and insulin sensitivity indexes [ISIest-OGTT 1,2 ] were calculated from plasma glucose and insulin levels from standard 75-g OGTT. The correlations of various insulin sensitivity indexes f rom OGTT with M-value were evaluated. Results: In lean women with PCOS (BMI < 23 kg/m 2 , n = 37), ISI(COMP) (r = 0.36, P < 0.05), MCRest-OGTT 1 (r = 0.49, P < 0.01), ISIest-OGTT 1 (r = 0.50, P < 0.01), MCRest-OGTT 2 (r = 0.45, P < 0.01) and ISIest-OGTT 2 (r = 0.40, P < 0.05) were significantly correlated with M-value. In overweight and obese women with PCOS (BMI ≥ 23 kg/m 2 , n = 25), HOMA(IR) (r = -0.40, P < 0.05), QUICKI (r = 0.40, P < 0.05), MCRest-OGTT 1 (r = 0.76, P < 0.001), ISI est-OGTT 1 (r = 0.63, P < 0.001), MCRest-OGTT 2

Differential effects of pharmacological liver X receptor activation on hepatic and peripheral insulin sensitivity in lean andob/obmice

Liver X receptor (LXR) agonists have been proposed to act as anti-diabetic drugs. However, pharmacological LXR activation leads to severe hepatic steatosis, a condition usually associated with insulin resistance and type 2 diabetes mellitus. To address this apparent contradiction, lean and ob/ob mice were treated with the LXR agonist GW-3965 for 10 days. Insulin sensitivity was assessed by hyperinsulinemic-euglycemic clamp studies. Hepatic glucose production (HGP) and metabolic clearance rate (MCR) of glucose were determined with stable isotope techniques. Blood glucose and hepatic and whole body insulin sensitivity remained unaffected upon treatment in lean mice, despite increased hepatic triglyceride contents (61.7 +/- 7.2 vs. 12.1 +/- 2.0 nmol/mg liver, P < 0.05). In ob/ob mice, LXR activation resulted in lower blood glucose levels and significantly improved whole body insulin sensitivity. GW-3965 treatment did not affect HGP under normo- and hyperinsulinemic conditions, despite increased hepatic triglyceride contents (221 +/- 13 vs. 176 +/- 19 nmol/mg liver, P < 0.05). Clamped MCR increased upon GW-3965 treatment (18.2 +/- 1.0 vs. 14.3 +/- 1.4 ml x kg(-1) x min(-1), P = 0.05). LXR activation increased white adipose tissue mRNA levels of Glut4, Acc1 and Fasin ob/ob mice only. In conclusion, LXR-induced blood glucose lowering in ob/ob mice was attributable to increased peripheral glucose uptake and metabolism, physiologically reflected in a slightly improved insulin sensitivity. Remarkably, steatosis associated with LXR activation did not affect hepatic insulin sensitivity.

Reduced intrahepatic fat content is associated with increased whole-body lipid oxidation in patients with type 1 diabetes

Insulin resistance may be associated with ectopic fat accumulation potentially determined by reduced lipid oxidation. In patients with type 1 diabetes peripheral insulin resistance is associated with higher intramyocellular lipid content. We assessed whether these patients are also characterised by intrahepatic fat accumulation and abnormal fat oxidation. Nineteen patients with type 1 diabetes (6 women, 13 men, age 35+/-7 years, BMI 23+/-3 kg/m2), HbA1c 8.7+/-1.4%) and 19 healthy matched individuals were studied by (1) euglycaemic-hyperinsulinaemic clamp combined with [6,6-2H2]glucose infusion to assess whole-body glucose metabolism; (2) indirect calorimetry to assess glucose and lipid oxidation; and (3) localised 1H-magnetic resonance spectroscopy of the liver to assess intrahepatic fat content. Patients with type 1 diabetes showed a reduced insulin-stimulated metabolic clearance rate of glucose (4.3+/-1.3 ml kg(-1) min(-1)) in comparison with normal subjects (6.0+/-1.6 ml kg(-1) min(-1); p<0.001). Endogenous glucose production was higher in diabetic patients (p=0.001) and its suppression was impaired during insulin administration (66+/-30 vs 92+/-8%; p=0.047) in comparison with normal subjects. Plasma glucagon concentrations were not different between groups. The estimated hepatic insulin concentration was lower in diabetic patients than in normal subjects (p<0.05), as was the intrahepatic fat content (1.5+/-0.7% and 2.2+/-1.0% respectively; p<0.03), the latter in association with a reduced respiratory quotient (0.74+/-0.05 vs 0.84+/-0.06; p=0.01) and increased fasting lipid oxidation (1.5+/-0.5 vs 0.8+/-0.4 mg kg(-1) min(-1); p<0.01). In patients with type 1 diabetes, insulin resistance was not associated with increased intrahepatic fat accumulation. In fact, diabetic patients had reduced intrahepatic fat content, which was associated with increased fasting lipid oxidation. The unbalanced hepatic glucagon and insulin concentrations affecting patients with type 1 diabetes may be involved in this abnormality of intrahepatic lipid metabolism.

L-Arginine infusion increases glucose clearance during prolonged exercise in humans

Nitric oxide synthase (NOS) inhibition has been shown in humans to attenuate exercise-induced increases in muscle glucose uptake. We examined the effect of infusing the NO precursor L-arginine (L-Arg) on glucose kinetics during exercise in humans. Nine endurance-trained males cycled for 120 min at 72+/-1% Vo(2 peak) followed immediately by a 15-min "all-out" cycling performance bout. A [6,6-(2)H]glucose tracer was infused throughout exercise, and either saline alone (Control, CON) or saline containing L-Arg HCL (L-Arg, 30 g at 0.5 g/min) was confused in a double-blind, randomized order during the last 60 min of exercise. L-Arg augmented the increases in glucose rate of appearance, glucose rate of disappearance, and glucose clearance rate (L-Arg: 16.1+/-1.8 ml.min(-1).kg(-1); CON: 11.9+/- 0.7 ml.min(-1).kg(-1) at 120 min, P<0.05) during exercise, with a net effect of reducing plasma glucose concentration during exercise. L-Arg infusion had no significant effect on plasma insulin concentration but attenuated the increase in nonesterified fatty acid and glycerol concentrations during exercise. L-Arg infusion had no effect on cycling exercise performance. In conclusion, L-Arg infusion during exercise significantly increases skeletal muscle glucose clearance in humans. Because plasma insulin concentration was unaffected by L-Arg infusion, greater NO production may have been responsible for this effect.

Increased glucose tolerance in N-type Ca2+ channel α1B-subunit gene-deficient mice

The voltage-dependent N-type Ca2+ channel is localized in the plasma membrane of insulin-releasing beta-cells and glucagon-releasing alpha-cells in the islets of Langerhans in the pancreas. To examine the contribution of N-type Ca2+ channel to glucose homeostasis, we performed glucose tolerance and insulin tolerance tests with N-type Ca2+ channel alpha(1B)-subunit-deficient mice on a normal or high-fat diet. The fasting glucose level in homozygous mice on the normal diet was significantly lower than those in wild and heterozygous mice. In glucose tolerance tests, the homozygous mice showed a higher glucose clearance rate and a similar pattern of insulin levels to those of wild and heterozygous mice. In insulin tolerance tests, glucose clearance rates showed no significant difference among wild, heterozygous and homozygous mice. In animals on the high-fat diet, food consumption was the same among wild, heterozygous and homozygous mice, but body weight gain was reduced in homozygous mice. After 8 weeks of the high-fat diet, homozygous mice showed lower fasting glucose levels and exhibited higher glucose clearance and lower insulin levels than wild or heterozygous mice in glucose tolerance tests. Glucose clearance rates showed no significant difference among wild, heterozygous and homozygous mice in insulin tolerance tests. After 10 weeks of the high-fat diet, the alpha(1B)-deficient homozygous mice showed lower lipid deposition in liver and lower plasma glucagon, leptin and triglyceride levels than wild or heterozygous mice. These results suggest that N-type Ca2+ channels play a role in insulin and glucagon release, and that N-type Ca2+ channel alpha(1B)-subunit deficient mice show improved glucose tolerance without any change in insulin sensitivity. Thus, N-type Ca2+ channel blockers might be candidate anti-diabetic/anti-obesity agents.

Two days of a very low calorie diet reduces endogenous glucose production in obese type 2 diabetic patients despite the withdrawal of blood glucose–lowering therapies including insulin

The mechanism of the blood glucose–lowering effect of a 2-day very low calorie diet (VLCD; 1890 kJ/d) in combination with the cessation of all blood glucose–lowering agents was studied in 12 (7 women, 5 men) obese (body mass index, 36.3 ± 1.0 kg/m 2 [mean ± SEM]) type 2 diabetic patients (age, 55 ± 4 years; HbA 1c, 7.3% ± 0.4%) undergoing insulin therapy. Endogenous glucose production (EGP) and whole body glucose disposal (6,6 2H 2-glucose), lipolysis ( 2H 5-glycerol), and substrate oxidation (indirect calorimetry) rates were measured before and after the intervention in basal and hyperinsulinemic conditions. After 2 days of a VLCD and discontinuation of all blood glucose–lowering therapies, fasting plasma glucose levels did not increase (11.3 ± 1.3 vs 10.3 ± 1.0 mmol/L). Basal EGP significantly declined (14.2 ± 1.0 to 11.9 ± 0.7 μmol/kg per minute; P = .009). Basal metabolic clearance rate of glucose and rate of basal lipolysis did not change. During hyperinsulinemia, EGP (5.5 ± 0.8 to 5.2 ± 0.5 μmol/kg per minute), whole body glucose disposal (12.1 ± 0.7 to 11.3 ± 1.0 μmol/kg per minute), the metabolic clearance rate of glucose, and the rate of lipolysis did not change after the 2-day intervention. Cessation of blood glucose–lowering therapy in combination with a 2-day VLCD does not lead to hyperglycemia and is associated with a reduction in basal EGP. Insulin-stimulated whole body glucose disposal did not improve, nor did insulin suppressibility of EGP and lipolysis.

Prevailing hyperglycemia is critical in the regulation of glucose metabolism during exercise in poorly controlled alloxan-diabetic dogs

The separate impacts of the chronic diabetic state and the prevailing hyperglycemia on plasma substrates and hormones, in vivo glucose turnover, and ex vivo skeletal muscle (SkM) during exercise were examined in the same six dogs before alloxan-induced diabetes (prealloxan) and after 4-5 wk of poorly controlled hyperglycemic diabetes (HGD) in the absence and presence of approximately 300-min phlorizin-induced (glycosuria mediated) normoglycemia (NGD). For each treatment state, the approximately 15-h-fasted dog underwent a primed continuous 150-min infusion of [3-(3)H]glucose, followed by a 30-min treadmill exercise test (approximately 65% maximal oxygen capacity), with SkM biopsies taken from the thigh (vastus lateralis) before and after exercise. In the HGD and NGD states, preexercise hepatic glucose production rose by 130 and 160%, and the metabolic clearance rate of glucose (MCRg) fell by 70 and 37%, respectively, compared with the corresponding prealloxan state, but the rates of glucose uptake into peripheral tissues (Rd(tissue)) and total glycolysis (GF) were unchanged, despite an increased availability of plasma free fatty acid in the NGD state. Exercise-induced increments in hepatic glucose production, Rd(tissue), and plasma-derived GF were severely blunted by approximately 30-50% in the NGD state, but increments in MCRg remained markedly reduced by approximately 70-75% in both diabetic states. SkM intracellular glucose concentrations were significantly elevated only in the HGD state. Although Rd(tissue) during exercise in the diabetic states correlated positively with preexercise plasma glucose and insulin and GF and negatively with preexercise plasma free fatty acid, stepwise regression analysis revealed that an individual's preexercise glucose and GF accounted for 88% of Rd(tissue) during exercise. In conclusion, the prevailing hyperglycemia in poorly controlled diabetes is critical in maintaining a sufficient supply of plasma glucose for SkM glucose uptake during exercise. During phlorizin-induced NGD, increments in both Rd(tissue) and GF are impaired due to a diminished fuel supply from plasma glucose and a sustained reduction in increments of MCRg.

Long-Term Graft Function of Adult Rat and Human Islets Encapsulated in Novel Alginate-Based Microcapsules After Transplantation in Immunocompetent Diabetic Mice

We describe the results of the first study to show that adult rat and human islets can be protected against xenogenic rejection in immunocompetent diabetic mice by encapsulating them in a novel alginate-based microcapsule system with no additional permselective membrane. Nonencapsulated islets lost function within 4-8 days after being transplanted into diabetic Balb/c mice, whereas transplanted encapsulated adult rat or human islets resulted in normoglycemia for >7 months. When rat islet grafts were removed 10 and 36 weeks after transplantation, the mice became immediately hyperglycemic, thus demonstrating the efficacy of the encapsulated islets. The explanted capsules showed only a mild cellular reaction on their surface and a viability of >85%, and responded to a glucose stimulus with a 10-fold increase in insulin secretion. Furthermore, transplanted mice showed a slight decrease in the glucose clearance rate in response to intraperitoneal glucose tolerance tests 3-16 weeks after transplantation; after 16 weeks, the rate remained stable. Similar results were obtained for encapsulated human islets. Thus we provide the first evidence of successful transplantation of microencapsulated human islets. In conclusion, we have developed a novel microcapsule system that enables survival and function of adult rat and human islets in immunocompetent mice without immunosuppression for >7 months.

Dietary n-3 and n-6 fatty acids alter avian glucose metabolism

1. This investigation studied the effects of dietary saturated and polyunsaturated fatty acids (PUFAs) from the n-3 and n-6 series on insulin action and glucose uptake in broiler chickens. 2. One-day-old male chicks were fed on a commercial starter diet for 3 weeks, randomly divided into three groups (n = 6) and fed ad libitum on isonitrogenous experimental diets of equal energy density for a further 6 weeks. The diets contained 20·8 g/100 g protein and 80 g/kg of either edible tallow, fish oil or sunflower oil, giving diets high in saturated fatty acids, n-3 PUFAs or n-6 PUFAs, respectively. 3. Jugular catheterisation was performed under general anaesthesia during week 4 of the dietary treatments and the birds given 7 d post-surgery to recover. To estimate insulin action, a bolus glucose infusion (1 g/kg) was given to each chicken and sequential blood samples taken over a one-hour period. To estimate the disappearance rate of glucose from the plasma and its incorporation into tissues, 2-deoxy-D-3H glucose (2DG-3H glucose) was infused into each chicken (50 µCi) 2 d later. 4. Although there were no significant differences in glucose clearance rate following the glucose infusion, the maximal insulin release in response to the glucose infusion was higher in the tallow group than in either the n-3 or n-6 PUFA dietary groups. There were no significant differences in the clearance rate of 2DG-3H glucose. Labelled glucose incorporation into the breast muscle was greater in birds given fish oil than in birds given tallow and significantly greater than in birds given sunflower oil. 5. The data suggest that the type of dietary fat can influence glucose metabolism and that this change in glucose utilisation may alter the energy metabolism of the broiler.

Growth performance and nutrient utilization in black Bengal bucks (Capra hircus) supplemented with graded doses of chromium as chromium chloride hexahydrate

Black Bengal bucks (Capra hircus) were supplemented with 0, 0.2 or 0.4 mg elemental chromium (Cr) as chromium chloride hexahydrate per day for 70 days. Intake of dry matter (p<0.001), crude protein (p<0.001) and neutral detergent fiber (p<0.01) increased due to Cr supplementation. The apparent total tract digestibility of dry matter (p<0.01), organic matter (p<0.05), crude protein (p<0.001) and acid detergent fiber (p<0.01) improved and the total body weight gain and the live weight gain to feed intake ratio also increased (p<0.001) due to supplemental Cr feeding. The intake and apparent absorption (p<0.001) of Cr was enhanced due to its supplementation. The intake of copper, zinc, manganese and iron was also more (p<0.001) in the Cr supplemented bucks. As supplementation progressed, plasma glucose concentration was elevated particularly in 0.4 mg Cr supplemented bucks and a significant day x dose interaction effect (p<0.001) with this parameter. The activity of plasma alkaline phosphatase increased (p<0.001) and that of glutamate pyruvate transaminase in plasma decreased (p<0.01) in the Cr supplemented bucks. Supplemental Cr had minimal (p>0.05) effect on the plasma half life (k) and clearance rate of glucose (T1/2) during an intravenous glucose tolerance test. Area under the response curve from 0 to 180 minutes after glucose loading was lower (p<0.001) in the control group of bucks. The study revealed that Cr supplementation might promote growth and nutrient utilization in black Bengal bucks. However, little difference between the 0.2 and 0.4 mg Cr supplemented bucks suggested limited benefit of increasing the level of supplementation beyond 0.2 mg per day under the normal management regimes.

A comparison of the homeostasis model assessment (HOMA) with direct measurements of insulin resistance in pregnancy with and without gestational diabetes (GDM)

MEASUREMENTS OF INSULIN RESISTANCE IN PREGNANCY WITH AND WITHOUT GESTATIONAL DIABETES (GDM) MARTIN MONTORO, SIRI KJOS, ANNY XIANG, THOMAS A. BUCHANAN, University of Southern California, Women’s and Children’s Hospital, Dept. of OB/GYN, Los Angeles, California, HarborUCLA Med. Ctr., Dept. of OB/GYN (LA BioMed), Torrance, California, University of Southern California, Preventive Medicine, Los Angeles, California OBJECTIVE: To correlate third trimester HOMA [fasting serum glucose (mmol/L) ! fasting serum insulin (uU/mL)]/22.5 with insulin resistance and b-cell function in control and GDM women. STUDY DESIGN: 150 GDM and 25 non-diabetic women underwent (a) oral glucose tolerance test (OGTT), (b) intravenous glucose tolerance test (IVGTT) with minimal model analysis and (c) euglycemic clamps with measures of basal and steady state glucose turnover. Exclusion criteria included history of hypertension, previous insulin use and positive anti-pancreatic islet cell antibodies. Linear regression analysis was used to evaluate relationships between HOMA (dependent variable) and four direct measures of insulin sensitivity: (a) MINIMOD SI, (b) clamps steady state (SS) glucose requirements (GINF), (c) clamp ratio of SS/GINF: SS plasma insulin (GINF: ins), and (d) clamp SS glucose clearance rate. RESULTS: During pregnancy, the HOMA calculations were significantly but weakly correlated with MINIMOD SI (R = 0.34, R 2 = 0.12); clamp GINF (R = 0.454, R =0.21), clamp SS GINF: insulin (R = 0.377, R = 0.142) and clamp SS glucose clearance (R = 0.404, R = 0.163). Raw data demonstrate non-linear relationship between HOMA and direct measures of insulin sensitivity in pregnant women. CONCLUSION: The HOMA, an empirical calculation based on fasting insulin has a non-linear relationship to insulin sensitivity. During pregnancy the range of insulin sensitivity is truncated compared to non-pregnant individuals thus limiting the applicability of HOMA as a measure of insulin sensitivity in pregnancy.

High lipoprotein lipase activity increases insulin sensitivity in transgenic rabbits

Lipoprotein lipase (LPL) is the rate-limiting enzyme in the hydrolysis of triglyceride-rich lipoproteins and plays an important role in glucose metabolism. To examine the hypothesis that increased LPL activity may alter insulin sensitivity, we investigated glucose metabolism and insulin sensitivity in transgenic (Tg) rabbits expressing the human LPL gene under the control of a β-actin promoter. An intravenous glucose tolerance test showed that the plasma glucose clearance rate was not significantly different between Tg and non-Tg rabbits; however, the area under the curve for insulin and free fatty acids in Tg rabbits was significantly reduced compared with that of non-Tg rabbits ( P < .05). Using the intravenous insulin tolerance test, we found that the area of under the curve of glucose of Tg rabbits was also significantly reduced ( P < .01). Furthermore, euglycemic-hyperinsulinemic clamp test revealed that the mean glucose infusion rate in Tg rabbits was significantly higher than in non-Tg rabbits ( P < .05). These results demonstrate that systemic overexpression of LPL increases whole-body insulin sensitivity and genetic manipulation of LPL genes may be a potential target for the treatment of diabetic patients.

Enhanced glucose cycling and suppressed de novo synthesis of glucose-6-phosphate result in a net unchanged hepatic glucose output in ob/ob mice

Leptin-deficient ob/ob mice are hyperinsulinaemic and hyperglycaemic; however, the cause of hyperglycaemia remains largely unknown. Glucose metabolism in vivo in 9-h fasted ob/ob mice and lean littermates was studied by infusing [U-(13)C]-glucose, [2-(13)C]-glycerol, [1-(2)H]-galactose and paracetamol for 6 h, applying mass isotopomer distribution analysis on blood glucose and urinary paracetamol-glucuronide. When expressed on the basis of body weight, endogenous glucose production (109+/-23 vs 152+/-27 micromol.kg(-1).min(-1), obese versus lean mice, p<0.01) and de novo synthesis of glucose-6-phosphate (122+/-13 vs 160+/-6 micromol.kg(-1).min(-1), obese versus lean mice, p<0.001) were lower in ob/ob mice than in lean littermates. In contrast, glucose cycling was greatly increased in obese mice (56+/-13 vs 26+/-4 micromol.kg(-1).min(-1), obese versus lean mice, p<0.001). As a result, total hepatic glucose output remained unaffected (165+/-31 vs 178+/-28 micromol.kg(-1).min(-1), obese vs lean mice, NS). The metabolic clearance rate of glucose was significantly lower in obese mice (8+/-2 vs 18+/-2 ml.kg(-1).min(-1), obese versus lean mice, p<0.001). Hepatic mRNA levels of genes encoding for glucokinase and pyruvate kinase were markedly increased in ob/ob mice. Unaffected total hepatic glucose output in the presence of hyperinsulinaemia reflects hepatic insulin resistance in ob/ob mice, which is associated with markedly increased rates of glucose cycling. Hyperglycaemia in ob/ob mice primarily results from a decreased metabolic clearance rate of glucose.

Endogenous Glucose Production in Type 2 Diabetes: Basal and Postprandial. Role of Diurnal Rhythms

Glycemia in type 2 diabetes is characterized by a nonsteady but stable diurnal cycle. This leads to morning fasting hyperglycemia. It arises from an underlying circadian pattern in endogenous glucose production because the metabolic clearance rate of glucose is decreased but constant. Therefore, it is important to use appropriate nonsteady tracer methods to measure this rate even under basal conditions. Postprandially, in diabetes, the endogenous glucose production continues to decrease, with only minor deviations from the slope of the basal curve. This suggests a decoupling of endogenous glucose production from the regulatory factors (insulin, glucose) that prevail under normal circumstances. As the duration of diabetes increases, metabolic clearance of glucose continues to deteriorate. This may be partially compensated by a decrease in glucose production. This rate remains, however, inappropriate because its impact on glycemia does not decline.

Syntaxin 4 transgenic mice exhibit enhanced insulin-mediated glucose uptake in skeletal muscle.

Insulin-stimulated translocation of GLUT4 vesicles from an intracellular compartment to the plasma membrane in 3T3L1 adipocytes is mediated through a syntaxin 4 (Syn4)- and Munc18c-dependent mechanism. To investigate the impact of increasing Syn4 protein abundance on glucose homeostasis in vivo, we engineered tetracycline-repressible transgenic mice to overexpress Syn4 by fivefold in skeletal muscle and pancreas and threefold in adipose tissue. Increases in Syn4 caused increases in Munc18c protein, indicating that Syn4 regulates Munc18c expression in vivo. An important finding was that female Syn4 transgenic mice exhibited an increased rate of glucose clearance during glucose tolerance tests that was repressible by the administration of tetracycline. Insulin-stimulated glucose uptake in skeletal muscle was increased by twofold in Syn4 transgenic mice compared with wild-type mice as assessed by hyperinsulinemic-euglycemic clamp analysis, consistent with a twofold increase in insulin-stimulated GLUT4 translocation in skeletal muscle. Hepatic insulin action was unaffected. Moreover, insulin content and glucose-stimulated insulin secretion by islets isolated from Syn4 transgenic mice did not differ from that of wild-type mice. In sum, these data suggest that increasing the number of Syn4-Munc18c "fusion sites" at the plasma membrane of skeletal muscle increases the amount of GLUT4 available to increase the overall rate of insulin-mediated glucose uptake in vivo.

Manipulation of dietary carbohydrate and muscle glycogen affects glucose uptake during exercise when fat oxidation is impaired by beta-adrenergic blockade.

We have recently reported that, during moderate intensity exercise, low muscle glycogen concentration and utilization caused by a high-fat diet is associated with a marked increase in fat oxidation with no effect on plasma glucose uptake (R(d) glucose). It is our hypothesis that this increase in fat oxidation compensates for low muscle glycogen, thus preventing an increase in R(d) glucose. Therefore, the purpose of this study was to determine whether low muscle glycogen availability increases R(d) glucose under conditions of impaired fat oxidation. Six cyclists exercised at 50% peak O(2) consumption (Vo(2 peak)) for 1 h after 2 days on either a high-fat (HF, 60% fat, 24% carbohydrate) or control (CON, 22% fat, 65% carbohydrate) diet to manipulate muscle glycogen to low and normal levels, respectively. Two hours before the start of exercise, subjects ingested 80 mg of propanolol (betaB), a nonselective beta-adrenergic receptor blocker, to impair fat oxidation during exercise. HF significantly decreased calculated muscle glycogen oxidation (P < 0.05), and this decrease was partly compensated for by an increase in fat oxidation (P < 0.05), accompanied by an increase in whole body lipolysis (P < 0.05), despite the presence of betaB. Although HF increased fat oxidation, plasma glucose appearance rate, R(d) glucose, and glucose clearance rate were also significantly increased by 13, 15, and 26%, respectively (all P < 0.05). In conclusion, when lipolysis and fat oxidation are impaired, in this case by betaB, fat oxidation cannot completely compensate for a reduction in muscle glycogen utilization, and consequently plasma glucose turnover increases. These findings suggest that there is a hierarchy of substrate compensation for reduced muscle glycogen availability after a high-fat, low-carbohydrate diet, with fat being the primary and plasma glucose the secondary compensatory substrate. This apparent hierarchy likely serves to protect against hypoglycemia when endogenous glucose availability is low.

Small-molecule insulin mimetic reduces hyperglycemia and obesity in a nongenetic mouse model of type 2 diabetes.

Adiposity positively correlates with insulin resistance and is a major risk factor of type 2 diabetes. Administration of exogenous insulin, which acts as an anabolic factor, facilitates adipogenesis. Recently nonpeptidal insulin receptor (IR) activators have been discovered. Here we evaluate the effects of the orally bioavailable small-molecule IR activator (Compound-2) on metabolic abnormalities associated with type 2 diabetes using a nongenetic mouse model in comparison with the effects of a novel non-thiazolidinedione (nTZD) peroxisome proliferator-activated receptor-gamma agonist. Both Compound-2 and nTZD alleviated fasting and postprandial hyperglycemia; accelerated glucose clearance rate; and normalized plasma levels of nonesterified fatty acids, triglycerides, and leptin. Unlike nTZD, which increased body weight gain, and total fat mass, which is a common feature for PPARgamma agonists, Compound-2 prevented body weight gain and hypertrophy of brown, and white adipose tissue depots and the development of hepatic steatosis in the mouse model of type 2 diabetes. The effect of the two compounds on proximal steps in insulin signal transduction pathway was analyzed in tissues. Compound-2 enhanced insulin-stimulated phosphorylation of IR tyrosine and/or Akt in the liver, skeletal muscle, and white adipose tissue, whereas nTZD potentiated the phosphorylation of IR and Akt in the adipose tissue only. In conclusion, small-molecule IR activators have unique features as insulin sensitizers and hold potential utility in the treatment of type 2 diabetes and obesity.

Metabolic Responses of Periparturient Holstein Cows and Heifers Supplemented with Chromium Picolinate

Thirty-four Holstein cows, 18 primiparous and 16 multiparous, were used to determine the effects of supplemental Cr on carbohydrate and lipid metabolism during the transition period. From approximately 3 wk prior to anticipated calving date until parturition, Cr-treated cows were given 51mg Cr picolinate via a gelatin capsule bolus three times weekly, equivalent to an average daily intake of approximately 2ppm Cr. Control cows were given empty gelatin capsules. All cows were fed total mixed rations, with one ration fed to dry cows, a second to lactating cows for wk 1 of postpartum (transition), and a third to lactating cows thereafter. Blood samples were collected via jugular venipuncture at 1, 2, and 3 wk prior to anticipated calving date as well as immediately following calving, 3 d post calving, and 1, 2, and 3 wk post calving. Samples were analyzed for glucose, insulin, and nonesterified fatty acids (NEFA). Within 1 wk prior to calving, a frequently sampled intravenous glucose tolerance test was performed, and blood plasma samples were analyzed for concentrations of glucose and insulin. Plasma glucose response to the frequently sampled intravenous glucose tolerance test was evaluated by calculating the half-life and fractional turnover rate for the period from 2 to 19min after glucose infusion. Supplemental Cr did not affect circulating concentrations of glucose, insulin, or NEFA (P>0.1). Plasma NEFA concentrations were greater in primiparous cows (P<0.01) throughout the experiment, with the difference being most apparent during the 3 wk postpartum. Glucose concentrations reached a greater peak at time of calving in primiparous cows than in multiparous cows (P=0.07). There was an increase in glucose clearance rate (P=0.06) and a trend toward decreased glucose half-life (P<0.1) in primiparous cows supplemented with Cr. Insulin peak concentrations were unaffected by treatment or parity (P>0.1). Data suggest that Cr supplementation may alter carbohydrate metabolism in primiparous cows during the transition period.

Cold-induced PGC-1alpha expression modulates muscle glucose uptake through an insulin receptor/Akt-independent, AMPK-dependent pathway.

Peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha) participates in control of expression of genes involved in adaptive thermogenesis, muscle fiber type differentiation, and fuel homeostasis. The objective of the present study was to evaluate the participation of cold-induced PGC-1alpha expression in muscle fiber type-specific activity of proteins that belong to the insulin-signaling pathway. Rats were exposed to 4 degrees C for 4 days and acutely treated with insulin in the presence or absence of an antisense oligonucleotide to PGC-1alpha. Cold exposure promoted a significant increase of PGC-1alpha and uncoupling protein-3 protein expression in type I and type II fibers of gastrocnemius muscle. In addition, cold exposure led to higher glucose uptake during a hyperinsulinemic clamp, which was accompanied by higher expression and membrane localization of GLUT4 in both muscle fiber types. Cold exposure promoted significantly lower insulin-induced tyrosine phosphorylation of the insulin receptor (IR) and Ser473 phosphorylation of acute transforming retrovirus thymoma (Akt) and an insulin-independent increase of Thr172 phosphorylation of adenosine 5'-monophosphate-activated protein kinase (AMPK). Inhibition of PGC-1alpha expression in cold-exposed rats by antisense oligonucleotide treatment diminished glucose clearance rates during a hyperinsulinemic clamp and reduced expression and membrane localization of GLUT4. Reduction of PGC-1alpha expression resulted in no modification of insulin-induced tyrosine phosphorylation of the IR and Ser473 phosphorylation of Akt. Finally, reduction of PGC-1alpha resulted in lower Thr172 phosphorylation of AMPK. Thus cold-induced hyperexpression of PGC-1alpha participates in control of skeletal muscle glucose uptake through a mechanism that controls GLUT4 expression and subcellular localization independent of the IR and Akt activities but dependent on AMPK.

Inflexibility of energy substrate oxidation in type 1 diabetic patients

Obese, insulin-resistant patients have been shown to have metabolic inflexibility. The goal of this study was to examine the effect of insulin administration on energy metabolism in lean, type 1 diabetic (DM1) patients. Eleven DM1 patients without vascular complications and 11 healthy controls (C) were examined. We performed a 2-step hyperinsulinemic euglycemic clamp (240 minutes; period 1: 1 mU · kg −1 · min −1 and period 2: 10 mU · kg −1 · min −1) combined with indirect calorimetry during basal period B (B, −45 to 0 minutes), period 1, and period 2 of the clamp. The metabolic clearance rates of glucose (MCR) were lower in DM1 compared with C in period 1 (12.54 ± 3.38 v 17.41 ± 6.18 mL · kg −1 · min −1; P < .02), as well as in period 2 (21.63 ± 6.47 v 26.61 ± 4.45 mL · kg −1 · min −1; P < .05). Basal respiratory quotient (RQ) was lower in DM1 compared with C (0.72 ± 0.04 v 0.75 ± 0.04; P < .03). Insulin administration was accompanied by an increase in RQ in both groups, which was lower in DM1 compared with C (period 1: +0.09 ± 0.04 v +0.11 ± 0.07; P < .001; period 2: +0.13 ± 0.04 v +0.16 ± 0.04; P < .001). Glucose oxidation did not differ between the groups in period B; however, it was lower in DM1 compared with C in periods 1 (1.17 ± 0.67 v 3.28 ± 1.11 mg · kg −1 · min −1; P < .003); and 2 (2.10 ± 0.64 v 3.28 ± 0.93 mg · kg −1 · min −1; P < .009). Lipid oxidation was higher in DM1 in all periods compared with C; period B (3.28 ± 0.77 v 1.16 ± 0.55 mg · kg −1 · min −1; P < .001), period 1 (1.10 ± 0.41 v 0.67 ± 0.54 mg · kg −1 · min −1; P < .05), and period 2 (0.99 ± 0.29 v 0.52 ± 0.58 mg · kg −1 · min −1; P < .01). The groups did not differ in protein oxidation. In conclusion, DM1 patients with secondary insulin resistance (IR) are characterized by metabolic inflexibility manifesting itself by smaller increases in RQ and glucose oxidation after insulin administration during the euglycemic clamp.