Improved Glucose Disposal Research Articles

Acetyl- l-carnitine infusion increases glucose disposal in type 2 diabetic patients

Little information is available in the literature on the effect of L-carnitine to improve glucose disposal in healthy control subjects and type 2 diabetic patients. No data are reported on the pharmacological properties of acetyl-L-carnitine (ALC) in type 2 diabetes mellitus. The present study evaluates glucose uptake and oxidation rates with either ALC or placebo administration in 18 type 2 diabetic patients. On different days, each patient received both a primed-constant infusion of ALC (5 mg/kg body weight [BW] priming bolus and either 0.025, 0.1, or 1.0 mg/kg BW/min constant infusion) and a comparable placebo formulation. During the infusion period, continuous indirect calorimetric monitoring and a euglycemic-hyperinsulinemic clamp (EHC) study were performed. The total end-clamp glucose tissue uptake (M value) was significantly increased by the administration of ALC (from 3.8 to 5.2 mg/kg/min, P = .006), and the dose dependence of this effect reached borderline statistical significance (P = .037). The increase in the M/I ratio was also highly significant after ALC administration (from 3.9 to 5.8 x 10(-2) mg/kg/min/(microUI/mL, P < .001), while no statistically significant effect was attributable to the different dosages. The increase in the M value was related to increased glucose storage (highly significant effect of ALC) rather than increased glucose oxidation (no statistical significance). In conclusion, the effect of ALC on glucose disposal has no relationship to the amount administered. This could be due to an effect of ALC on the enzymes involved in both the glycolytic and gluconeogenetic pathways, and a possible reversibility of glycogen synthase inhibition in diabetic subjects.

The effect of urapidil and ramipril on hyperglycemia in streptozotocin diabetic rats.

Angiotensin-converting enzyme inhibitors and alpha1-adrenoceptor antagonists improve glucose disposal in diabetes mellitus. We compared the effect of the antihypertensive hybrid drug urapidil [alpha1-adrenoceptor antagonist serotonin 1A (5-hydroxytryptamine 1A, 5-HT1A) receptor agonist] on hyperglycemia in streptozotocin diabetic rats with the angiotensin-converting enzyme inhibitor ramipril. 5-HT1A receptor agonists induce hyperglycemia. This could be an important disadvantage during treatment of diabetes mellitus with urapidil. Diabetes was induced by streptozotocin (70 mg/kg i.p.). Treatment for 7 days (ramipril 10 mg/kg p.o.; urapidil 20 mg/kg p.o.) significantly decreased mean blood glucose values (urapidil: 15.7+/-0.9 mmol/l, P=0.007; ramipril: 15.0+/-0.8 mmol/l, P=0.038 vs. diabetic control group: 18.7+/-1.0 mmol/l). Both drugs reduced significantly blood pressure, urinary glucose, water consumption, and food requirement. Serotonin concentration in the brain (medulla oblongata, pituitary) was not affected. A normalization comparable with healthy control rats was observed only in a diabetic control group with insulin therapy. In conclusion, our results demonstrate that the antihypertensive drug urapidil has no detrimental effect on hyperglycemia compared with the angiotensin-converting enzyme inhibitor ramipril in experimental diabetes mellitus despite its 5-HT1A receptor agonistic properties.

Increased glucose disposal induced by adenovirus-mediated transfer of glucokinase to skeletal muscle in vivo.

In non-insulin-dependent diabetes mellitus, insulin-stimulated glucose uptake is impaired in muscle, contributing in a major way to development of hyperglycemia. We previously showed that expression of the glucose phosphorylating enzyme glucokinase (GK) in cultured human myocytes improved glucose storage and disposal, suggesting that GK delivery to muscle in situ could potentially enhance glucose clearance. Here we have tested this idea directly by intramuscular delivery of an adenovirus containing the liver GK cDNA (AdCMV-GKL) into one hind limb. We injected an adenovirus containing the beta-galactosidase gene (AdCMV-lacZ) into the hind limb of newborn rats. beta-Galactosidase activity was localized in muscle for as long as 1 month after delivery, with a large percentage of fibers staining positive in the gastrocnemius. Using the same approach with AdCMV-GKL, GK protein content was increased from zero to 50-400% of the GK in normal liver sample, and total glucose phosphorylating activity was increased in GK-expressing muscles relative to the counterpart uninfected muscle. Expression of GK in muscle improved glucose tolerance rather than changing basal glycemic control. Glucose levels were reduced by approximately 35% 10 min after administration of a glucose bolus to fed animals treated with AdCMV-GKL relative to AdCMV-lacZ-treated controls. The enhanced rate of glucose clearance was reflected in increases in muscle 2-deoxy glucose uptake and blood lactate levels. We conclude that restricted expression of GK in muscle leads to an enhanced capacity for muscle glucose disposal and whole body glucose tolerance under conditions of maximal glucose-insulin stimulation, suggesting that under these conditions glucose phosphorylation becomes rate-limiting. Our findings also show that gene delivery to a fraction of the whole body is sufficient to improve glucose disposal, providing a rationale for the development of new therapeutic strategies for treatment of diabetes.-Jiménez-Chillarón, J. C., Newgard, C. B., Gómez-Foix, A. M. Increased glucose disposal induced by adenovirus-mediated transfer of glucokinase to skeletal muscle in vivo.

L-Carnitine Improves Glucose Disposal in Type 2 Diabetic Patients

Objective: Aim of the present study is to evaluate the effects of L-carnitine on insulin-mediated glucose uptake and oxidation in type II diabetic patients and compare the results with those in healthy controls.Design: Fifteen type II diabetic patients and 20 healthy volunteers underwent a short-term (2 hours) euglycemic hyperinsulinemic clamp with simultaneous constant infusion of L-carnitine (0.28 μmole/kg bw/minute) or saline solution. Respiratory gas exchange was measured by an open-circuit ventilated hood system. Plasma glucose, insulin, non-esterified fatty acids (NEFA) and lactate levels were analyzed. Nitrogen urinary excretion was calculated to evaluate protein oxidation.Results: Whole body glucose uptake was significantly (p<0.001) higher with L-carnitine than with saline solution in the two groups investigated (48.66±4.73 without carnitine and 52.75±5.19 μmoles/kgffm/minute with carnitine in healthy controls, and 35.90±5.00 vs. 38.90±5.16 μmoles/kgffm/minute in diabetic patients). Glucose oxidation significantly increased only in the diabetic group (17.61±3.33 vs. 16.45±2.95 μmoles/kgffm/minute, p<0.001). On the contrary, glucose storage increased in both groups (controls: 26.36±3.25 vs. 22.79±3.46 μmoles/kgffm/minute, p<0.001; diabetics: 21.28±3.18 vs. 19.66±3.04 μmoles/kgffm/minute, p<0.001). In type II diabetic patients, plasma lactate significantly decreased during L-carnitine infusion compared to saline, going from the basal period to the end-clamp period (0.028±0.0191 without carnitine and 0.0759±0.0329 with carnitine, p<0.0003).Conclusions: L-carnitine constant infusion improves insulin sensitivity in insulin resistant diabetic patients; a significant effect on whole body insulin-mediated glucose uptake is also observed in normal subjects. In diabetics, glucose, taken up by the tissues, appears to be promptly utilized as fuel since glucose oxidation is increased during L-carnitine administration. The significantly reduced plasma levels of lactate suggest that this effect might be exerted through the activation of pyruvate dehydrogenase, whose activity is depressed in the insulin resistant status.

Effect of enalapril on insulin sensitivity in patients with hypertension and type 2 diabetes mellitus: a pilot study using the glucose clamp technique

Enalapril is the most widely used angiotensin-converting enzyme (ACE) inhibitor in Japan, but few studies have examined its effect on insulin sensitivity in Japanese patients. Therefore, we used the glucose clamp technique to study the effects of enalapril on insulin sensitivity in nine patients with hypertension and type 2 diabetes mellitus (non—insulin-dependent diabetes mellitus [NIDDM]). Sixteen weeks after beginning treatment with enalapril, systolic and diastolic blood pressures had decreased significantly compared with baseline values; no significant changes were seen in glycemic control, body-mass index, or heart rate. During treatment, glucose infusion rates (M values) increased significantly, reflecting the degree of insulin sensitivity during the low insulinemic, hyperglycemic glucose clamp phase. In contrast, rates did not increase significantly during the high insulinemic, euglycemic glucose clamp phase. No significant changes in either insulin secretion or metabolic insulin clearance were observed. In addition, ACE activity significantly decreased throughout the glucose clamp procedure. Enalapril treatment did not have a significant effect on plasma angiotensin II concentrations across the glucose clamp; plasma bradykinin levels increased significantly, but only immediately before the clamp. The results of this study suggest that enalapril may affect insulin sensitivity through its effect on bradykinin levels rather than insulin secretion, thus improving glucose disposal.

Zinc supplementation improves glucose disposal in patients with cirrhosis

Zinc deficiency is common in cirrhosis, and was proved to affect nitrogen metabolism. In experimental animals, zinc status may also affect glucose disposal, and acute zinc supplementation improves glucose tolerance in healthy subjects. This study was aimed at measuring the effects of long-term oral zinc supplements on glucose tolerance in cirrhosis. The time courses of glucose, insulin, and C-peptide in response to an intravenous (IV) glucose load were analyzed by the minimal-model technique before and after long-term oral zinc supplements (200 mg three times per day for 60 days) in 10 subjects with advanced cirrhosis and impaired glucose tolerance or diabetes. The test was performed using a simplified procedure, based on 20 blood samples collected within 4 hours from the glucose load. Normal values were obtained in 25 age-matched healthy subjects. Zinc levels were low to normal or reduced before treatment, and were normalized by oral zinc. Glucose disappearance improved by greater than 30% in response to treatment. There were no changes in pancreatic insulin secretion and systemic delivery, or in the hepatic extraction of insulin. Insulin sensitivity (S I), which was reduced by 80% before treatment, did not change. Glucose effectiveness (S G) was nearly halved in cirrhosis before treatment (0.013 [SD 0.007] min −1 v. 0.028 [SD 0.009] in controls; P < .001), and increased to 0.017 (SD 0.009) after zinc ( P < .05 v. baseline). The return to normal of plasma zinc levels after long-term zinc treatment in advanced cirrhosis improves glucose tolerance via an increase of the effects of glucose per se on glucose metabolism. Poor zinc status may contribute to the impaired glucose tolerance and diabetes of cirrhosis.

Metabolic effects of troglitazone in the Goto-Kakizaki rat, a non-obese and normolipidemic rodent model of non-insulin-dependent diabetes mellitus

Troglitazone (TRG) is an orally active antidiabetic agent that increases insulin sensitivity in models of non-insulin-dependent diabetes mellitus (NIDDM), subsequently reducing hyperinsulinemia and hyperglycemia. We examined the effects of TRG on the development and severity of diabetes in the Goto-Kakizaki (GK) rat, a spontaneous, non-obese model of NIDDM. TRG was administered at a dose of 30 mg/kg/d beginning at 4 weeks of age. TRG-treated GK rats were evaluated against Wistar and untreated GK rats at 8, 12, and 16 weeks of age. Untreated GK rats were nonketotic, normolipidemic, hyperglycemic, and had normal fasting insulin levels compared with Wistar rats. TRG treatment decreased glycosylated hemoglobin levels in the GK rat independently of its effects on plasma insulin. In untreated GK rats, intravenous glucose tolerance tests (IVGTTs) showed a hyperglycemic response to glucose loading with severely impaired glucose disposal relative to Wistar controls. TRG treatment was successful in decreasing the glucose area under the curve (AUC) ( P < .03) but did not improve glucose disposal, suggesting a direct hepatic effect. Ex vivo evaluation of hepatic glucose output (HGO) further supported a direct hepatic action, with 50% reduction in HGO in TRG-treated GK rats ( P < .004). A euglycemic-hyperinsulinemic clamp performed at 16 weeks of age showed severe insulin resistance in the untreated GK rat, with a glucose infusion rate (GIR) 33% lower than in Wistar rats ( P < .004). TRG treatment had no effect on this insulin resistance. These results indicate that TRG selectively decreases hepatic glucose production in this unique model of NIDDM independently of its action on peripheral insulin sensitivity or hyperlipidemia.

Potential Role of Bradykinin in Forearm Muscle Metabolism in Humans

Using the euglycemic-hyperinsulinemic glucose clamp and the human forearm technique, we have demonstrated that the improved glucose disposal rate observed after the administration of an angiotensin-converting enzyme (ACE) inhibitor such as captopril may be primarily due to increased muscle glucose uptake (MGU). These results are not surprising because ACE, which is identical to the bradykinin (BK)-degrading kininase II, is abundantly present in muscle tissue, and its inhibition has been observed to elicit the observed metabolic actions via elevated tissue concentrations of BK and through a BK B2 receptor site in muscle and/or endothelial tissue. These findings are supported by several previous studies. Exogenous BK applied into the brachial artery of the human forearm not only augmented muscle blood flow (MBF) but also enhanced the rate of MGU. In another investigation, during rhythmic voluntary contraction, both MBF and MGU increased in response to the higher energy expenditure, and the release of BK rose in the blood vessel, draining the working muscle tissue. Inhibition of the activity of the BK-generating protease in muscle tissue (kallikrein) with aprotinin significantly diminished these functional responses during contraction. Applying the same kallikrein inhibitor during the infusion of insulin into the brachial artery significantly reduced the effect of insulin on glucose uptake into forearm muscle. This is of interest, because in recent studies insulin has been suggested to elicit its actions on MBF and MGU via the accelerated release of endothelium-derived nitric oxide, the generation of which is also stimulated by BK in a concentration-dependent manner. This new evidence obtained from in vitro and in vivo studies sheds new light on the discussion of whether BK may play a role in energy metabolism of skeletal muscle tissue.

Magnesium supplementation reduces development of diabetes in a rat model of spontaneous NIDDM.

We examined the effects of a magnesium-supplemented (Mg-S) diet in the male obese Zucker diabetic fatty rat, a model of non-insulin-dependent diabetes mellitus (NIDDM). Obese rats were maintained on either a control (0.20% Mg) or magnesium-supplemented (Mg-S; 1% Mg) diet for 6 wk beginning at 6 wk of age. The rats maintained on the Mg-S diet had markedly lower fasting and fed-state blood glucose concentrations and an improved glucose disposal. By 12 wk of age, all of the eight animals on the control diet became diabetic, whereas diabetes developed in only one of eight animals on the Mg-S diet. Insulin and C-peptide concentrations, in addition to pancreatic GLUT-2 and insulin mRNA expression, were higher in the male obese Mg-S rats than in their control-fed counterparts. A subgroup of rats on the control diet with established diabetes was switched to a Mg-S diet for an additional 4 wk. The Mg-S diet did not reverse diabetes once already established. These data indicate that an increased dietary Mg intake in male obese rats prevents deterioration of glucose tolerance, thus delaying the development of spontaneous NIDDM.

Altered Metabolism and Mortality in Patients With Colon Cancer Receiving Chemotherapy

To identify the metabolic effects of 5-fluorouracil and hydrazine sulfate therapy, 22 patients with colon cancer were admitted prospectively to a Clinical Research Center for serial measurement of counter-regulatory hormones, fasting hepatic glucose production (HGP), intravenous glucose tolerance test, plasma leucine appearance (LA) and leucine oxidation. Combined therapy was associated with a significant reduction in fasting glucose level (98 +/- 2 mg/dL to 94 +/- 2, P < 0.025) without a significant fall in fasting HGP (2.09 +/- 0.11 mg/kg/min versus 2.03 +/- 0.13; P > 0.05). The decreased fasting glucose value was associated with a mild but not statistically improved glucose disposal rate in response to the intravenous glucose tolerance test (1.34 +/- 0.07 %/min vs 1.47 +/- 0.11, P = 0.15). Plasma leucine appearance was significantly reduced after 2 months of therapy (63.3 +/- 3.0 mumol/kg/hr vs 57.1 +/- 3.9 mumol/kg/hr; P < 0.025), but leucine oxidation (11.5 +/- 1.1 mumol/kg/hr vs 11.2 +/- 1.1 mumol/kg/hr) was not altered. Despite the fact that plasma triiodothyronine concentrations significantly increased with therapy, it was not associated with plasma LA. Half of the patients with cancer died 14 +/- 4 months after the study, and the other half were alive 58 +/- 2 months later. Survival time can be estimated with 59% accuracy using plasma LA, HGP, carcino-embryonic antigen, and insulin concentration. Multiple regression analysis identified that plasma LA was related directly to length of survival time, and baseline HGP, carcino-embryonic antigen, and insulin concentration were related inversely to length of survival.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of captopril on glucose transport activity in skeletal muscle of obese Zucker rats

This study tested whether the angiotensin-converting enzyme (ACE) inhibitor captopril can modify the glucose transport system in insulin-resistant skeletal muscle. Obese Zucker (fa/fa) rats (approximately 300 g)--a model of insulin resistance--were administered by gavage either a single dose (50 mg/kg body weight) or repeated doses (50 mg/kg/d for 14 consecutive days) of captopril. Corresponding groups of age-matched, vehicle-treated lean (Fa/-) littermates (approximately 170 g) were also studied. Glucose transport activity in the epitrochlearis muscle was assessed by in vitro 2-deoxyglucose (2-DG) uptake. The increase in 2-DG uptake due to insulin (2 mU/mL) in muscles from vehicle-treated obese rats was less than 50% (P < .05) of the increase observed in muscles from lean rats. Short-term captopril treatment improved insulin-stimulable 2-DG uptake in muscles from obese rats by 46% (P < .05), and this enhanced insulin action due to captopril was completely abolished by pretreatment with the bradykinin antagonist HOE 140 (100 micrograms/kg). Long-term treatment with captopril produced a 60% improvement in insulin-stimulated 2-DG uptake (P < .05). Contraction-stimulated 2-DG uptake was significantly impaired (-31%, P < .05) in the obese rat, but was not altered by long-term captopril treatment. These findings indicate that both short- and long-term treatments with captopril significantly improve insulin-stimulated glucose transport activity in skeletal muscle of the obese Zucker rat, and that this improvement involves bradykinin metabolism. These data therefore support the hypothesis that captopril-induced improvements in glucose disposal result in part from an enhancement of the skeletal muscle glucose transport system.

Insulin requirement for the antihyperglycaemic effect of metformin

1. Insulin-dependent diabetic BB/S rats with little or no endogenous insulin were used to determine whether insulin is required for the acute antihyperglycaemic effect of metformin (dimethylbiguanide). 2. Metformin (250 mg kg-1, intrajejunally) did not lower the hyperglycaemia in BB/S rats in the absence of exogenous insulin, but metformin increased by 69% (P < 0.05) the blood glucose-lowering effect of exogenous insulin. 3. Metformin (250 mg kg-1, intrajejunally) improved glucose disposal in rats with a normal insulin response to an intravenous glucose challenge. Plasma glucose disappearance was increased from 0.7 +/- 0.1 to 2.5 +/- 0.1% min-1 (P < 0.05). 3. When the insulin response to glucose was suppressed with somatostatin and diazoxide, metformin improved glucose disposal to a similar extent to that in rats with a normal insulin response. Plasma glucose disappearance was increased from 0.24 +/- 0.02 to 1.0 +/- 0.1% min-1 (P < 0.01). 5. The results indicate that insulin is required for the acute antihyperglycaemic effect of metformin, but the extent of this effect is not proportional to the prevailing insulin concentration.

Androgens and Body Fat Distribution in Men

M&in et al. (18) report in this issue of OBESITY RESEARCH that treatment of men with abdominal obesity, using moderate doses of testosterone delivered by a transdermal patch, will decrease visceral fat mass and improve glucose disposal, dyslipidemia, and diastolic blood pressure. Abdominal obesity is associated with increased risk of diabetes mellitus, hypertension, dyslipidemia. myocardial infarction, and stroke (23). In recent studies, it has been reported that there are metabolic differences between visceral and subcutaneous abdominal fat, with the interior visceral depot being more lipolytically active (20,5). Also, inmbdominal fat has been implicated in glucose homeostasis, with an increased

Short-term hyperglycemia and hyperinsulinemia improve insulin action but do not alter glucose action in normal humans.

Tissue glucose uptake occurs by insulin-dependent and insulin-independent mechanisms. To evaluate the effect of mild hyperglycemia and hyperinsulinemia on the parameters responsible for glucose disposal, glucose (1.17 mmol/min) or saline was infused into six healthy male subjects (age 25-38 yr, body mass index 22.1-26.3 kg/m2) for 24 h. Thereafter, while the infusion continued, indexes of insulin sensitivity (SI), glucose effectiveness at basal insulin (SG), basal insulin effect (BIE = SI x basal insulin), and glucose effectiveness at zero insulin (GEZI = SG - BIE) were measured using Bergman's minimal model of insulin action. GEZI provides a measure of the efficiency of glucose to accelerate its own disposal independent of insulin. Twenty-four hours of glucose infusion increased the basal plasma glucose (5.1 +/- 0.1 to 6.4 +/- 0.2 mM, P = 0.001) and insulin (79 +/- 8 to 174 +/- 31 pM, P less than 0.05) levels. Hyperglycemia was also associated with an increase in the insulin response, predominantly in the second-phase component (138 +/- 31 to 258 +/- 66 pM, P less than 0.05). SI (4.8 +/- 1.0 to 8.2 +/- 1.6 x 10(-5) min-1.pM-1, P less than 0.05) and SG (1.7 +/- 0.1 to 2.5 +/- 0.3 x 10(-2) min-1, P less than 0.05) both increased after glucose infusion. The increase in SG was entirely due to the combined increase in basal insulin and insulin sensitivity (BIE 0.4 +/- 0.1 to 1.2 +/- 0.1 x 10(-2) min-1, P = 0.001) since GEZI did not change at all (1.3 +/- 0.1 vs. 1.3 +/- 0.3 x 10(-2) min-1, P = not significant). From these data we conclude that, in normal subjects, the mild hyperglycemia and hyperinsulinemia occurring during a prolonged glucose infusion improves glucose disposal in the basal state by increasing insulin secretion and insulin sensitivity but does not enhance glucose effectiveness independent of insulin. Both of these changes thus tend to minimize the development of hyperglycemia.

Improvement of glucose-primed intravenous glucose tolerance and correction of acute insulin decrement by glipizide in type II diabetes

Improved glucose disposal after repeated intravenous (IV) glucose loads, known as the Staub effect, is absent in both type I and type II diabetes. Acute decrements of insulin secretion (AID) are observed following the early phase of insulin release on IV glucose stimulation in non-insulin-dependent diabetes mellitus (NIDDM). The AID cannot be corrected by acute infusions of glyburide or glipizide, or phentolamine, or by glycemic control after 2 weeks of intensive insulin treatments. Fifteen male subjects had 3 hourly successive IV glucose tolerance tests before and after 6 months of glipizide, at a final maintenance dose of 30 ± 3 mg/d. Before treatment, AID, defined as the difference of the lowest of post IV glucose 7- or 10-minute samples from the preceding baseline insulin levels, was detected in the three loads: −6.4 ± 1.9 μU/mL in the first, and then more consistently in the second and third loads, −11 ± 2 μU/mL, and −17 ± 9 μU/mL, respectively. There was a stepwise increase in insulin sums after each load. After glipizide therapy, the AIDs following all three IV glucose loads were no longer demonstrable; both insulin values, as well as insulin sums, were significantly elevated after all three glucose loads. While in the untreated state, the Staub effect was absent: serum glucose disappearances (K), corrected for glycosuria, were K1 = 0.52 ± 0.02, K2 = 0.50 ± 0.04, and K3 = 0.52 ± 0.03. After glipizide, fasting glucose decreased from 215 ± 12 mg/dL to 132 ± 9 mg/dL, glucose values during the triple IV tolerance tests were significantly lower, and the glycohemoglobin decreased from 9.9% ± 0.5% to 8.2% ± 0.03%. Furthermore, glucose disappearance rates were improved: K1 = 0.62 ± 0.02, K2 = 0.68 ± 0.02, and K3 = 0.77 ± 0.04, also defining a positive Staub effect. There was a positive correlation between the glucose disappearance rates and the treatment-induced improvement of early insulin release in the second and third glucose loads (the difference from baseline of the higher of either the 3-minute or the 5-minute post IV samples). There was also a positive correlation between improvement in glucose disappearance rates in the third load with the total insulin sums. Mean AID in untreated overt NIDDM is potentiated by IV glucose priming, even while insulin levels increase. After treatment with glipizide, the AID is either reverted or insignificant, and the Staub effect is restored, along with post IV glucose improvement in insulin levels. Chronic sulfonylurea administration appears at present to be the only known conventional treatment restoring post IV glucose Staub effect and ameliorating the AID of NIDDM.

Insulinomimetic Properties of Trace Elements and Characterization of Their In Vivo Mode of Action

Lithium and vanadate have insulinomimetic actions in vitro. In this study, we examined the in vivo effects of lithium and vanadate on glucose metabolism in diabetic (90% partial pancreatectomy) rats. Four groups of chronically catheterized rats were studied: control, diabetic, diabetic treated with lithium (plasma concn 1.0 +/- 0.1 meq/L) and vanadate (0.05 mg/ml in drinking water), and diabetic treated with lithium, vanadate, zinc, and magnesium. Postmeal plasma glucose was increased in diabetic versus control rats (18.7 vs. 7.7 mM, P less than 0.01) and was normalized by addition of lithium and vanadate (8 mM) or lithium, vanadate, zinc, and magnesium (7.4 mM). Euglycemic insulin-clamp studies were performed 2 wk posttreatment; insulin-mediated glucose uptake was reduced in diabetic compared with control rats (142 +/- 4 vs. 200 +/- 5 mumol.kg-1.min-1, P less than 0.01), returned to normal with lithium and vanadate (206 +/- 6 mumol.kg-1.min-1), or increased to supranormal levels with lithium, vanadate, zinc, and magnesium (238 +/- 6 mumol.kg-1.min-1). During the insulin clamp, muscle glycogenic rate was severely impaired in diabetic versus control rats (18 vs. 70 mumol.kg-1.min-1) and was normalized by lithium and vanadate (91 mumol.kg-1.min-1) or lithium, vanadate, zinc, and magnesium (93 mumol.kg-1.min-1).(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of metformin on insulin-stimulated glucose turnover and insulin binding to receptors in type II diabetes.

Euglycemic insulin glucose-clamp and insulin-binding studies on erythrocytes and monocytes were performed in seven type II (non-insulin-dependent) diabetic subjects before and after 4 wk of metformin treatment (850 mg 3 times/day) and in five obese subjects with normal glucose tolerance. Glucose turnover was also measured at basal insulin concentrations and during hyperinsulinemic euglycemic clamps. During euglycemic insulin-glucose clamps, diabetic subjects showed glucose disposal rates of 3.44 +/- 0.42 and 7.34 +/- 0.34 mg X kg-1 X min-1 (means +/- SD) before metformin at insulin infusion rates of 0.80 and 15.37 mU X kg-1 X min-1, respectively. With the same insulin infusion rates, glucose disposal was 4.94 +/- 0.55 (P less than .01) and 8.99 +/- 0.66 (P less than .01), respectively, after metformin treatment. Glucose disposal rates in normal obese subjects were 5.76 +/- 0.63 (P less than .01) and 10.92 +/- 1.11 (P less than .01) at 0.80 and 15.37 mU X kg-1 X min-1, respectively. Insulin maximum binding to erythrocytes in diabetics was 9.6 +/- 4.2 and 5.8 +/- 2.6 X 10(9) cells (means +/- SD) before and after metformin treatment, respectively (NS). Insulin maximum binding to monocytes in diabetics was 6.2 +/- 2.3 X 10(7) cells before and 5.0 +/- 1.6% after metformin. Hepatic glucose production was higher in the diabetic patients at basal insulin levels, but not at higher insulin concentrations, and was not significantly changed by drug treatment. Basal glucose and insulin concentrations decreased with metformin. Thus, metformin treatment improved glucose disposal rate without significant effect on insulin-binding capacity on circulating cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of exercise training on whole-body insulin sensitivity and responsiveness.

Exercise training causes a decline in basal and glucose-stimulated plasma insulin levels and improves glucose tolerance. Furthermore evidence has been presented for effects on both insulin receptors and postreceptor events. However, it is unclear how these changes affect the in vivo dose-response relationship between insulin levels and whole-body glucose utilization. The aim was to examine the effect of exercise training on this relationship and distinguish between changes in insulin sensitivity and responsiveness. Euglycemic clamps were performed in trained (ET, running 1 h/day for 7 wk), sedentary (CON), and sedentary food-restricted ( SFR ) rats. ET rats showed no increase in maximal net glucose utilization in response to insulin (ET 29.5 +/- 0.6 vs. CON 28.2 +/- 1.5 mg X kg-1 X min-1, NS), whereas insulin sensitivity was increased as indicated by the insulin concentration causing half-maximal stimulation (ED50) (49 +/- 20 for ET and 133 +/- 30 mU/l for CON). Thus 7 wk of moderate exercise training resulted in a significant shift of whole-body insulin sensitivity to place ED50 well within the physiological range of insulin concentrations. This would undoubtedly result in improved glucose disposal in the postprandial state and emphasizes the potential benefit of exercise in obesity and type II diabetes.

EFFECTS OF EXOGENOUS INSULIN ON GLUCOSE DISPOSAL OF LOW BIRTH WEIGHT (LBW) INFANTS

Hyperglycemia, is one of the complications of parenteral alimentation in LBW infants. The effectiveness of insulin administration to improve glucose disposal was evaluated in 7 infants (mean b.w. 1100 gms., mean gestation 29 wks) at age 5-14 days. At midpoint during a 4 hr constant glucose infusion (14 mg/Kg/min), a placebo (0.9% saline) was given (control); the next day, insulin (10 mU/Kg/min for 50 min) replaced the placebo (experimental). Plasma insulin (I) increased during glucose infusion induced hyperglycemia. Exogenous insulin results in further increase in I with significant fall in plasma glucose (G) and glucose insulin ratio (G/I). G remained normal 2 hours following conclusion of the 4 hr study. Hyperglycemia in LBW infants can be abolished by insulin treatment allowing 20 gm/Kg/day of glucose intake as a caloric source.