Search PubMed⌕ Search

Biomedical subjects

A D Baron

Publications and source records attributed to A D Baron.

At least 37 records · Page 2Linked to original sources
PubMed1998

Central nervous system nitric oxide synthase activity regulates insulin secretion and insulin action.

Systemic inhibition of nitric oxide synthase (NOS) with NG-monomethyl-L-arginine (L-NMMA) causes acute insulin resistance (IR), but the mechanism is unknown. We tested whether L-NMMA-induced IR occurs via NOS blockade in the central nervous system (CNS). Six groups of Sprague-Dawley rats were studied after chronic implantation of an intracerebroventricular (ICV) catheter into the lateral ventricle and catheters into the carotid artery and jugular vein. Animals were studied after overnight food deprivation, awake, unrestrained, and unstressed; all ICV infusion of L-NMMA or D-NMMA (control) were performed with artificial cerebrospinal fluid. ICV administration of L-NMMA resulted in a 30% rise in the basal glucose level after 2 h, while ICV D-NMMA had no effect on glucose levels. Insulin, epinephrine, and norepinephrine levels were unchanged from baseline in both groups. Tracer (3H-3-glucose)-determined glucose disposal rates during 2 h euglycemic hyperinsulinemic (300 microU/ml) clamps performed after ICV administration of L-NMMA were reduced by 22% compared with D-NMMA. Insulin secretory responses to a hyperglycemic clamp and to a superimposed arginine bolus were reduced by 28% in L-NMMA-infused rats compared with D-NMMA. In conclusion, ICV administration of L-NMMA causes hyperglycemia via the induction of defects in insulin secretion and insulin action, thus recapitulating abnormalities observed in type 2 diabetes. The data suggest the novel concept that central NOS-dependent pathways may control peripheral insulin action and secretion. This control is not likely to be mediated via adrenergic mechanisms and could occur via nonadrenergic, noncholinergic nitrergic neural and/or endocrine pathways. These data support previously published data suggesting that CNS mechanisms may be involved in the pathogenesis of some forms of insulin resistance and type 2 diabetes independent of adiposity.

Animals↗
PubMed1998

Evidence for defects in the trafficking and translocation of GLUT4 glucose transporters in skeletal muscle as a cause of human insulin resistance.

Insulin resistance is instrumental in the pathogenesis of type 2 diabetes mellitus and the Insulin Resistance Syndrome. While insulin resistance involves decreased glucose transport activity in skeletal muscle, its molecular basis is unknown. Since muscle GLUT4 glucose transporter levels are normal in type 2 diabetes, we have tested the hypothesis that insulin resistance is due to impaired translocation of intracellular GLUT4 to sarcolemma. Both insulin-sensitive and insulin-resistant nondiabetic subgroups were studied, in addition to type 2 diabetic patients. Biopsies were obtained from basal and insulin-stimulated muscle, and membranes were subfractionated on discontinuous sucrose density gradients to equilibrium or under nonequilibrium conditions after a shortened centrifugation time. In equilibrium fractions from basal muscle, GLUT4 was decreased by 25-29% in both 25 and 28% sucrose density fractions and increased twofold in both the 32% sucrose fraction and bottom pellet in diabetics compared with insulin-sensitive controls, without any differences in membrane markers (phospholemman, phosphalamban, dihydropyridine-binding complex alpha-1 subunit). Thus, insulin resistance was associated with redistribution of GLUT4 to denser membrane vesicles. No effects of insulin stimulation on GLUT4 localization were observed. In non-equilibrium fractions, insulin led to small GLUT4 decrements in the 25 and 28% sucrose fractions and increased GLUT4 in the 32% sucrose fraction by 2.8-fold over basal in insulin-sensitive but only by 1.5-fold in both insulin-resistant and diabetic subgroups. The GLUT4 increments in the 32% sucrose fraction were correlated with maximal in vivo glucose disposal rates (r = +0.51, P = 0.026), and, therefore, represented GLUT4 recruitment to sarcolemma or a quantitative marker for this process. Similar to GLUT4, the insulin-regulated aminopeptidase (vp165) was redistributed to a dense membrane compartment and did not translocate in response to insulin in insulin-resistant subgroups. In conclusion, insulin alters the subcellular localization of GLUT4 vesicles in human muscle, and this effect is impaired equally in insulin-resistant subjects with and without diabetes. This translocation defect is associated with abnormal accumulation of GLUT4 in a dense membrane compartment demonstrable in basal muscle. We have previously observed a similar pattern of defects causing insulin resistance in human adipocytes. Based on these data, we propose that human insulin resistance involves a defect in GLUT4 traffic and targeting leading to accumulation in a dense membrane compartment from which insulin is unable to recruit GLUT4 to the cell surface.

Adult↗
PubMed1998

Glucosamine infusion in rats mimics the beta-cell dysfunction of non-insulin-dependent diabetes mellitus.

Sustained hyperglycemia can cause peripheral insulin resistance and pancreatic beta-cell dysfunction and has been termed glucose toxicity or glucose-induced desensitization. Glucosamine, a product of glucose flux through the hexosamine biosynthetic pathway (HBP), causes insulin resistance in peripheral tissues and has been shown to cause abnormal glucose-insulin secretion coupling, and thus has been implicated in the pathogenesis of glucose toxicity. Here, we investigate whether glucosamine-induced insulin secretory dysfunction is specific to glucose or also extends to nonglucose secretagogues such as arginine. Two groups of 12 weight-matched Sprague-Dawley rats underwent hyperglycemic clamp studies (steady-state blood glucose, approximately 220 mg x dL(-1)) during infusion of normal saline or glucosamine 3.5 mg x kg(-1) x min(-1) over a 100-minute period. Insulin levels were measured at baseline and between 90 and 100 minutes. One hundred minutes into the hyperglycemic clamp, subgroups of seven rats each (saline- and glucosamine-infused rats) received a bolus of arginine (100 mg x kg(-1)) while the glucose infusion rate was unaltered. Glucose and insulin levels were measured at 1, 3, 5, 10, 15, and 30 minutes after the arginine bolus. Both groups had similar fasting glucose and insulin levels. At steady state (60 to 100 minutes), glucose levels were almost identical in both groups (223.58+/-3.94 v 224.58+/-4.34 mg x dL(-1)), but the glucose infusion rate (26.55+/-1.60 v 8.83+/-1.35 mg x kg(-1) x min(-1), P < .0001) and insulin level (41.36+/-6.47 v 18.04+/-2.95 mU x mL(-1), P < .0001) were markedly reduced in animals receiving glucosamine. Peak insulin levels 1 minute after the arginine bolus were lower in rats infused with glucosamine versus saline (274.00+/-30.38 v 176.25+/-20.12 microU x ml(-1), P=.0319). Total insulin secretion in response to arginine was significantly lower in the glucosamine group as determined by the area under the curve (1,268.09+/-142.27 v 706.77+/-84.79 microU x mL(-1) x min, P=.0054). In conclusion, glucosamine causes severe impairment in glucose-induced insulin secretion. Further, glucosamine-induced beta-cell secretory dysfunction extends to nonglycemic stimuli like arginine. This pattern of insulin secretory dysfunction is similar to that observed in patients with non-insulin-dependent diabetes mellitus (NIDDM). These data suggest that glucosamine may participate in the pathogenesis of glucose toxicity at the level of the beta cell in NIDDM patients.

Animals↗
PubMed1998

Postprandial hyperglycaemia and alpha-glucosidase inhibitors.

Fasting blood glucose level is usually used to diagnose diabetes, but is not a good predictor of postprandial hyperglycaemia, which is a more accurate measure of the metabolic defect underlying type 2 diabetes. Postprandial blood glucose levels may be elevated while fasting levels are normal, constituting an early stage in type 2 diabetes that can be termed 'postprandial diabetes'. Prevention of postprandial hyperglycaemia is important, as it is implicated in the development of macro- and microvascular complications associated with diabetes. The risk of cardiovascular disease is higher in individuals with postprandial hyperglycaemia, even without diabetes, than in individuals with normal postprandial blood glucose levels. Furthermore, postprandial hyperglycaemia is implicated in the development of type 2 diabetes. Even modest postprandial hyperglycaemia may lead to beta-cell dysfunction. Agents that reduce postprandial hyperglycaemia have a key role in the treatment of type 2 diabetes and pre-diabetic states. Most anti-diabetic agents that are currently available reduce fasting blood glucose levels, but have little impact on postprandial glycaemic excursions and thus do not normalize postprandial hyperglycaemia. However, new agents that control postprandial hyperglycaemia have been developed, for example, the alpha-glucosidase inhibitor acarbose. Such agents have a potential to reduce the progression of diabetes as well as macro- and microvascular complications.

Cardiovascular Diseases↗
PubMed1997

Intrapericardial delivery of L-arginine reduces the increased severity of ventricular arrhythmias during sympathetic stimulation in dogs with acute coronary occlusion: nitric oxide modulates sympathetic effects on ventricular electrophysiological properties.

BACKGROUND: Nitric oxide (NO) modulates autonomic effects on myocardial contractility and sinus and atrioventricular nodal function of the heart. Whether NO influences autonomic actions on ventricular electrophysiological properties and arrhythmogenesis is not known. METHODS AND RESULTS: Four groups consisting of 43 autonomically denervated dogs were studied. To "superfuse" sympathetic nerves innervating the ventricles, test drugs were introduced into the pericardial sac for 30 minutes, and their effects on ventricular effective refractory period (ERP) and arrhythmia development were assessed before and during sympathetic stimulation (SS). In group 1 (n=12), ventricular ERPs showed no significant difference between control and superfusion with L-arginine, a NO precursor (222+/-20 versus 222+/-19 ms, P=.485). However, L-arginine significantly reduced SS-induced ERP shortening compared with control (9+/-7 versus 13+/-7 ms, P<.001). Simultaneous administration of N(G)-monomethyl-L-arginine (2 mg/mL) abolished the inhibitory effects of L-arginine (13+/-7 versus 13+/-7 ms, P=.885). In group 2 (n=15), the severity of ventricular arrhythmias significantly increased during SS. L-Arginine reduced this increase caused by SS. In group 3 (n=8), plasma norepinephrine spillover measured from the coronary sinus significantly increased during SS and was reduced by pericardial superfusion with L-arginine compared with control (6005.2+/-1525.6 versus 8503.4+/-2044.5 pg/min, P=.012). In group 4 (n=8), L-arginine pericardial superfusion significantly increased NO overflow measured from the coronary sinus during SS (93.25+/-59.20 versus 114.82+/-74.92 nmol/min, P=.043). CONCLUSIONS: Pericardial L-arginine reduces ERP shortening and increased severity of ischemic ventricular arrhythmias during SS in dogs. NO-induced reduction of norepinephrine release in the heart may be one of the underlying mechanisms.

Animals↗
PubMed1997

Endothelial dysfunction is associated with cholesterol levels in the high normal range in humans.

BACKGROUND: The purpose of this study was to test the hypothesis that cholesterol levels in the high normal range are associated with impaired endothelium-dependent vasodilation. METHODS AND RESULTS: We studied leg blood flow (LBF) responses to graded intrafemoral artery infusions of the endothelium-dependent vasodilator methacholine chloride (MCh) or the endothelium-independent vasodilator sodium nitroprusside (SNP) in normal volunteers exhibiting a wide range of total cholesterol levels within the normal range (<75th percentile). LBF increased in a dose-dependent fashion in response to the femoral artery infusions of MCh and SNP (P<.001). LBF responses to MCh were significantly blunted (P<.001) in subjects with high normal cholesterol (195+/-6 mg/dL, n=13) compared with subjects with low normal cholesterol (146+/-5 mg/dL, n=20). Maximal endothelium-dependent vasodilation in the high normal group was decreased by nearly 50% compared with the low normal group (146+/-13% versus 268+/-34%, P<.01). There was a negative correlation between total cholesterol levels and maximal endothelium-dependent vasodilation (total cholesterol, r=-.41, P<.02; LDL cholesterol, r=-.42, P<.02). On the other hand, LBF responses to the endothelium-independent vasodilator SNP did not differ between groups. CONCLUSIONS: These data suggest that an inverse and continuous relationship exists between the prevailing cholesterol level and endothelium-dependent vasodilation. Moreover, cholesterol levels even in the normal range may be associated with endothelial dysfunction, thus potentially contributing to the increased risk of macrovascular disease conferred by cholesterol elevations.

Adult↗
PubMed1997

Elevated circulating free fatty acid levels impair endothelium-dependent vasodilation.

We have recently shown that insulin-resistant obese subjects exhibit impaired endothelial function. Here, we test the hypothesis that elevation of circulating FFA to levels seen in insulin-resistant subjects can impair endothelial function. We studied leg blood flow responses to graded intrafemoral artery infusions of the endothelium-dependent vasodilator methacholine chloride (Mch) or the endothelium-independent vasodilator sodium nitroprusside during the infusion of saline and after raising systemic circulating FFA levels exogenously via a low- or high-dose infusion of Intralipid plus heparin or endogenously by an infusion of somatostatin (SRIF) to produce insulinopenia in groups of lean healthy humans. After 2 h of infusion of Intralipid plus heparin, FFA levels increased from 562+/-95 to 1,303+/-188 micromol, and from 350+/-35 to 3,850+/-371 micromol (P < 0.001) vs. saline for both low- and high-dose groups, respectively. Mch-induced vasodilation relative to baseline was reduced by approximately 20% in response to the raised FFA levels in both groups (P < 0.05, saline vs. FFA, ANOVA). In contrast, similar FFA elevation did not change leg blood flow responses to sodium nitroprusside. During the 2-h SRIF infusion, insulin levels fell, and FFA levels rose from 474+/-22 to 1,042+/-116 micromol (P < 0.01); Mch-induced vasodilation was reduced by approximately 20% (P < 0.02, saline vs. SRIF, ANOVA). Replacement of basal insulin levels during SRIF resulted in a fall of FFA levels from 545+/-47 to 228+/-61 micromol, and prevented the impairment of Mch-induced vasodilation seen with SRIF alone. In conclusion, (a) elevated circulating FFA levels cause endothelial dysfunction, and (b) impaired endothelial function in insulin-resistant humans may be secondary to the elevated FFA concentrations observed in these patients.

Adult↗
PubMed1997

Role of blood flow in the regulation of muscle glucose uptake.

Insulin vasodilates skeletal muscle vasculature via an endothelium-derived nitric oxide-dependent mechanism. Data suggests that insulin interacts directly with the endothelium to cause nitric oxide release. This insulin-mediated increase in muscle perfusion accounts for approximately 30% of insulin's overall action to stimulate muscle glucose uptake, suggesting a role for insulin and glucose delivery as a determinant of insulin action. Hindlimb perfusion experiments, where perfusion rate is fixed, suggest that changes in distribution of microcirculatory perfusion can modulate substrate uptake. The potential role of insulin to enhance flow through capillary networks that are efficient at nutrient transfer to tissue (nutritive flow) relative to non-nutritive flow is discussed.

Animals↗
PubMed1997

Diabetic ketoacidosis charges relative to medical charges of adult patients with type I diabetes.

OBJECTIVE: To determine the medical charges for treating diabetic ketoacidosis (DKA) episodes relative to direct medical care charges of adult patients with type I diabetes. RESEARCH DESIGN AND METHODS: Using data from an electronic medical record system, we identified adult patients with type I diabetes who had received inpatient or outpatient care on at least two occasions between 1 January 1993 and 30 June 1994. Resources and charges for hospitalizations, emergency room visits, outpatient visits, and pharmaceuticals were recorded during this period. One additional year of information was collected to assess the resources and charges associated with multiple DKA episodes. RESULTS: A total of 200 patients were identified, of whom 72 (36.0%) experienced a total of 161 DKA episodes. The direct medical care charges associated with DKA episodes represented 28.1% of the direct medical care charges for the cohort of patients with type I diabetes. The average charge per DKA episode was $6,444. The estimated annual medical care charge for each patient was $7,855 ($13,096 per patient experiencing a DKA episode versus $4,907 per patient not experiencing an episode). Multiple DKA episodes were experienced by 24 (12.0%) of the study patients and accounted for 55.6% of the direct medical care charges for these patients. CONCLUSIONS: DKA episodes represented more than $1 of every $4 spent on direct medical care for adult patients with type I diabetes and $1 of every $2 in those patients experiencing multiple episodes. Interventions that are capable of even a modest reduction in the number of DKA episodes could produce substantial cost savings in a health care system and could be particularly cost-effective in adult patients with recurrent DKA.

Adult↗
PubMed1997

Ketoconazole retains activity in advanced prostate cancer patients with progression despite flutamide withdrawal.

PURPOSE: We tested the hypothesis that certain patients with hormone refractory prostate cancer retain hormonal sensitivity even after progression following antiandrogen withdrawal. The efficacy of ketoconazole and hydrocortisone in this patient population was evaluated. MATERIALS AND METHODS: A total of 50 consecutive patients with advanced prostate cancer received ketoconazole and hydrocortisone at progression after antiandrogen withdrawal. Prostate specific antigen (PSA) response was defined as greater than a 50% decrease in PSA from baseline that was maintained for at least 8 weeks. RESULTS: Overall, of 48 evaluable patients 30 (62.5%, 95% confidence interval 47.3 to 76.1%) had greater than a 50% decrease in PSA, while 23 (48%) had greater than an 80% decrease. The median duration of response was 3.5 months but 23 of 48 patients continue to exhibit a response, ranging from 3.25 to 12.75 or more months. The ketoconazole response rate in patients with no response to prior antiandrogen withdrawal was not different from that in patients with such a response (65 versus 40%, p = 0.35). Toxicity was mild. Grade 1 or 2 nausea, fatigue, edema, hepatotoxicity and rash occurred in 10.4 (5 of 48), 6.25, 6.25, 4.2 and 4.2% of patients, respectively, and anorexia occurred in 2%. CONCLUSIONS: Failure to respond to antiandrogen withdrawal does not identify patients with truly hormone refractory disease. Ketoconazole retains significant activity in this setting and is extremely well tolerated.

Aged↗
PubMed1996

Overexpression of glutamine:fructose-6-phosphate amidotransferase in transgenic mice leads to insulin resistance.

The hexosamine biosynthetic pathway has been hypothesized to be involved in mediating some of the toxic effects of hyperglycemia. Glutamine:fructose-6-phosphate amidotransferase (GFA), the first and rate limiting enzyme of the hexosamine biosynthetic pathway, was overexpressed in skeletal muscle and adipose tissue of transgenic mice. A 2.4-fold increase of GFA activity in muscle of the transgenic mice led to weight-dependent hyperinsulinemia in random-fed mice. The hyperinsulinemic-euglycemic clamp technique confirmed that transgenic mice develop insulin resistance, with a glucose disposal rate of 68.5 +/- 3.5 compared with 129.4 +/- 9.4 mg/kg per min (P < 0.001) for littermate controls. The decrease in the glucose disposal rate of the transgenic mice is accompanied by decreased protein but not mRNA levels of the insulin-stimulated glucose transporter (GLUT4). These data support the hypothesis that excessive flux through the hexosamine biosynthesis pathway mediates adverse regulatory and metabolic effects of hyperglycemia, specifically insulin resistance of glucose disposal. These mice can serve as a model system to study the mechanism for the regulation of glucose homeostasis by hexosamines.

Adipose Tissue↗
PubMed1996

Obesity/insulin resistance is associated with endothelial dysfunction. Implications for the syndrome of insulin resistance.

To test the hypothesis that obesity/insulin resistance impairs both endothelium-dependent vasodilation and insulin-mediated augmentation of endothelium-dependent vasodilation, we studied leg blood flow (LBF) responses to graded intrafemoral artery infusions of methacholine chloride (MCh) or sodium nitroprusside (SNP) during saline infusion and euglycemic hyperinsulinemia in lean insulin-sensitive controls (C), in obese insulin-resistant subjects (OB), and in subjects with non-insulin-dependent diabetes mellitus (NIDDM). MCh induced increments in LBF were approximately 40% and 55% lower in OB and NIDDM, respectively, as compared with C (P < 0.05). Euglycemic hyperinsulinemia augmented the LBF response to MCh by - 50% in C (P < 0.05 vs saline) but not in OB and NIDDM. SNP caused comparable increments in LBF in all groups. Regression analysis revealed a significant inverse correlation between the maximal LBF change in response to MCh and body fat content. Thus, obesity/insulin resistance is associated with (a) blunted endothelium-dependent, but normal endothelium-independent vasodilation and (b) failure of euglycemic hyperinsulinemia to augment endothelium-dependent vasodilation. Therefore, obese/insulin-resistant subjects are characterized by endothelial dysfunction and endothelial resistance to insulin's effect on enhancement of endothelium-dependent vasodilation. This endothelial dysfunction could contribute to the increased risk of atherosclerosis in obese insulin-resistant subjects.

Adult↗
PubMed1996

Lack of relationship between muscle sympathetic nerve activity and skeletal muscle vasodilation in response to insulin infusion.

Increases in plasma insulin concentration result in vasodilation in skeletal muscle but also in an increase in muscle sympathetic nerve activity (MSNA) which is thought to cause vasoconstriction. The increase in MSNA could therefore be a response to vasodilation (baroreflex), or MSNA could cause vasodilation via putative sympathetic vasodilatory fibres. To examine the relationship between vasodilation, MSNA and insulin action we studied nine non-diabetic Pima Indian men (age 29 +/- 7 years, weight 91 +/- 19 kg, 29 +/- 6% body fat, mean +/- SD) during sequential euglycaemic clamps at low and high insulin doses (80 and 600 mU.m-2.min-1). Leg blood flow was measured by thermodilution, leg glucose uptake by the balance technique, arterial pressure by invasive monitoring and MSNA by microneurography of the peroneal nerve. Whole body glucose uptake (M) ranged from 6.7 to 48.3 during low dose and from 9.4 to 67.7 mumol kg fat free mass-1.min-1 during high dose insulin infusion. At both insulin doses, incremental leg blood flow correlated with M (r = 0.63 and 0.71, respectively). No correlation was found between incremental MSNA and leg blood flow, M or leg glucose uptake. Blood pressure was unchanged throughout the study. MSNA increased after 15-40 min of insulin infusion in all the subjects, whereas leg blood flow started to increase only after 45 min in the most insulin sensitive but not in the most insulin resistant subjects. Thus, insulin stimulates MSNA more rapidly than vasodilation. In conclusion, insulin-mediated MSNA: 1) is neither a response to nor a cause of the vasodilation observed in insulin sensitive men, 2) has no net pressor effect even in the most insulin resistant men in whom insulin-mediated vasodilation was impaired. We conclude that the effect of insulin to stimulate MSNA is dissociated from its acute haemodynamic action.

Adult↗
PubMed1996

Effect of perfusion rate on the time course of insulin-mediated skeletal muscle glucose uptake.

To better define the time course of skeletal muscle glucose uptake and its modulation by changes in perfusion, we performed systemic euglycemic-hyperinsulinemic clamps (40 mU.m-2.min-1) for a 90-min period in a group of lean, insulin-sensitive subjects (n = 9) on two occasions (approximately 4 wk apart) with insulin-mediated vasodilation intact or inhibited. Insulin-mediated vasodilation was inhibited by an intrafemoral artery infusion of NG-monomethyl-L-arginine (L-NMMA), a specific inhibitor of nitric oxide synthase. During the study, leg blood flow (LBF) and arteriovenous glucose difference (AVG delta) were measured every 10 min; leg glucose uptake (LGU) was calculated as LGU = LBF x AVG delta. The systemic insulin infusion caused a time-dependent increase in LBF from 0.194 +/- 0.024 to 0.349 +/- 0.046 l/min (P < 0.01). The intrafemoral artery infusion of L-NMMA completely inhibited this increase in LBF. AVG delta, LGU, and whole body glucose disposal rates increased in a time-dependent manner in both studies. The maximum AVG delta was lower with insulin-mediated vasodilation intact than when inhibited (25.9 +/- 2.5 vs. 35.0 +/- 1.6 mg/dl, P < 0.001). The time to achieve half-maximal (T1/2) AVG delta was somewhat longer with insulin-mediated vasodilation intact compared with inhibited (35.6 +/- 4.1 vs. 29.7 +/- 1.6 min, P < 0.01). Maximal LGU was 93.9 +/- 26.8 and 57.2 +/- 11.6 mg/min (P < 0.005), and the T1/2 LGU was 50.2 +/- 16.0 and 36.3 +/- 8.8 min (P = 0.1) during intact and inhibited insulin-mediated vasodilation, respectively. Thus insulin-mediated vasodilation has a modest effect in slowing the time course at which insulin stimulates glucose uptake but has a marked effect in augmenting the maximal rate of insulin-stimulated glucose uptake in skeletal muscle. Impaired insulin-mediated vasodilation, as observed in patients with essential hypertension, may explain, at least in part, the insulin resistance observed in these patients.

Adult↗
PubMed1996

The coupling of glucose metabolism and perfusion in human skeletal muscle. The potential role of endothelium-derived nitric oxide.

Insulin-mediated glucose metabolism in skeletal muscle is associated with a commensurate increase in muscle perfusion. The link between insulin action and vasodilation may be mediated by endothelium-derived nitric oxide (EDNO). The evidence suggests that insulin causes an increase in the production of EDNO in insulin-sensitive but not insulin-resistant subjects. This defect in insulin-mediated vasodilation may contribute to 1) enhanced pressor sensitivity and 2) reduced rates of insulin-mediated glucose uptake. We propose that the endothelium is an insulin target tissue that exhibits an increase in the release of EDNO in response to insulin. We postulate that the insulin-resistant state of obesity is associated with insulin resistance at the level of the endothelium, reduced EDNO release, and impaired vasodilation. Thus EDNO may act as the mediator coupling glucose metabolism to vasodilation. The interaction between insulin and the endothelium to enhance EDNO release describes a novel insulin action that deserves further exploration.

Endothelium, Vascular↗
PubMed1996

Glucose and amino acid turnover in untreated gestational diabetes.

OBJECTIVE: Although gestational diabetes affects as many as 3% of all pregnant women, specific aspects of glucose and protein metabolism in this population have not been clearly delineated. We tested the hypothesis that gestational diabetes mellitus (GDM) results in increased glucose production and proteolysis during fasting. RESEARCH DESIGN AND METHODS: Using tracer isotope infusions, the rate of appearance (Ra) of glucose, leucine, phenylalanine and tyrosine, phenylalanine hydroxylation, leucine oxidation, and urea nitrogen excretion were determined after an overnight fast in 10 GDM subjects, within 2 weeks of diagnosis and before initiation of treatment, and in a matched control group of nine healthy nondiabetic pregnant women. RESULTS: Fasting glucose Ra was similar in GDM patients and control subjects (GDM, 12.8 +/- 1.1 vs. control subjects, 12.8 +/- 0.9 mumol . kg-1 . min-1). Leucine and phenylalanine Ra (reflecting proteolysis) also were not different between GDM patients and control subjects (GDM leucine Ra, 128 +/- 14 vs. control subjects, 124 +/- 5; phenylalanine Ra GDM, 35 +/- 4 vs. control subjects, 40 +/- 2 mumol . kg-1 . h-1). Furthermore, leucine oxidation and phenylalanine hydroxylation were not increased in GDM subjects, urea nitrogen excretion was actually lower in GDM patients. However, fasting insulin concentrations were significantly elevated in GDM subjects (GDM, 165 +/- 35 vs. control subjects, 30 +/- 5 pmol/l; P < 0.01). CONCLUSIONS: Hepatic glucose release and whole-body proteolysis in GDM patients were remarkably similar to matched pregnant control subjects. This was achieved with insulin concentrations three- to fivefold higher than normal, suggesting significant insulin resistance for both glucose and protein metabolism in GDM.

Adult↗