Timbe (Acaciella angustissima) Pods Extracts Reduce the Levels of Glucose, Insulin and Improved Physiological Parameters, Hypolipidemic Effect, Oxidative Stress and Renal Damage in Streptozotocin-Induced Diabetic Rats.

In Mexico one in 14 deaths are caused by diabetes mellitus (DM) or by the macro and microvascular disorders derived from it. A continuous hyperglycemic state is characteristic of DM, resulting from a sustained state of insulin resistance and/or a dysfunction of ß-pancreatic cells. Acaciella angustissima is a little studied species showing a significant antioxidant activity that can be used as treatment of this disease or preventive against the complications. The objective of this study was to explore the effect of oral administration of A. angustissima methanol extract on physiological parameters of streptozotocin-induced diabetic rats. The results indicated a significant reduction in blood glucose levels, an increase in serum insulin concentration, a decrease in lipid levels and an improvement in the parameters of kidney damage by applying a concentration of 100 mg/Kg B.W. However, glucose uptake activity was not observed in the adipocyte assay. Moreover, the extract of A. angustissima displayed potential for the complementary treatment of diabetes and its complications likely due to the presence of bioactive compounds such as protocatechuic acid. This study demonstrated that methanol extract of Acacciella angustissima has an antidiabetic effect by reducing the levels of glucose, insulin and improved physiological parameters, hypolipidemic effect, oxidative stress and renal damage in diabetic rats.

High-Dose, Diazoxide-Mediated Insulin Suppression Boosts Weight Loss Induced by Lifestyle Intervention.

Context: Obesity-related hyperinsulinism may impede lifestyle-initiated weight loss. Objective: Proof-of-concept study to investigate the amplifying effects of diazoxide (DZX)-mediated insulin suppression on lifestyle-induced weight loss in nondiabetic, hyperinsulinemic, obese men. Design: Twelve-month study comprising an initial 6-month, double-blind trial, followed by a partially de-blinded 6-month extension in men with obesity with a body mass index of 30 to 37.5 kg/m2 and a fasting serum C-peptide level >1.00 nM. Patients were randomized into three treatment groups: DZX + placebo (DZX + PL), DZX + metformin (DZX + MTF), and double PL (PL + PL). Results: At 6 months, DZX treatment was associated with a 6.1-kg PL-subtracted decline in fat mass (FM), and at 12 months, FM had decreased by a total of 15.7 ± 2.5 kg. Twelve months of DZX treatment was also associated with a significant decline in systolic (-6.6%) and diastolic (-8.6%) blood pressure and low-density lipoprotein-cholesterol (-18%) and triglycerides (-43%) and a 39% rise in high-density lipoprotein-cholesterol. These effects were achieved at the cost of a small rise in fasting glucose (95% CI: 0.2 to 1.0 mM) and hemoglobin A1c (95% CI: -0.08% to 0.44%). There were no differences between DZX monotherapy and the combination of DZX + MTF. Conclusion: High-dose DZX treatment of 1 year resulted in a substantial decrease in FM, blood pressure, and lipid levels at the cost of a small rise in blood glucose levels.

Effect of metformin by employing 2-hour postload insulin for measuring insulin resistance in Taiwanese women with polycystic ovary syndrome.

BACKGROUND/PURPOSE: Evidence on clinical effectiveness of metformin in ethnic Chinese women with polycystic ovary syndrome (PCOS) remains scarce. Standard diagnostic approaches to identify insulin resistance (IR) cases in PCOS patients might be invasive, labor intensive, and stressful for patients (i.e., euglycemic clamp), or somewhat complicated for clinicians to calculate and monitor in routine practice [i.e., the homeostatic model assessment (HOMA) and quantitative insulin sensitivity check index (QUICKI)]. The aim of this study was to evaluate the clinical effects of metformin in Taiwanese women with PCOS and identify the feasible diagnostic measures of IR for Taiwanese women with PCOS. METHODS: A total of 114 women from a medical center in Taiwan were studied. All were aged between 18 years and 45 years, diagnosed with PCOS according to the Rotterdam criteria, and treated with metformin. Outcome end points were body mass index (BMI) and 2-hour postload glucose and insulin levels from a 75-g oral glucose tolerance test. RESULTS: BMI in overweight patients were significantly improved with metformin treatment duration (p < 0.001). The 2-hour insulin level statistically improved after treatment (before: 80.7 ± 63.9 µIU/mL vs. after: 65.0 ± 60.4 µIU/mL; p = 0.009). The improved 2-hour insulin level was significantly greater in IR patients than in non-IR patients. Compared with the 2-hour postload insulin level, the fasting insulin level provided 18.15% sensitivity and 94.12% specificity, the HOMA yielded 40% sensitivity and 70.58% specificity, and the QUICKI achieved 63.63% sensitivity and 11.76% specificity. CONCLUSION: Clinical outcomes in Taiwanese PCOS women were improved with metformin treatment, especially in overweight and IR patients. The 2-hour postload insulin level appears to be a convenient tool for screening IR in Taiwanese patients.

Effects of subcutaneous, low-dose glucagon on insulin-induced mild hypoglycaemia in patients with insulin pump treated type 1 diabetes.

AIM: To investigate the dose-response relationship of subcutaneous (s.c.) glucagon administration on plasma glucose and on counter-regulatory hormone responses during s.c. insulin-induced mild hypoglycaemia in patients with type 1 diabetes treated with insulin pumps. METHODS: Eight insulin pump-treated patients completed a blinded, randomized, placebo-controlled study. Hypoglycaemia was induced in the fasting state by an s.c. insulin bolus and, when plasma glucose reached 3.4 mmol/l [95% confidence interval (CI) 3.2-3.5], an s.c. bolus of either 100, 200, 300 µg glucagon or saline was administered. Plasma glucose, counter-regulatory hormones, haemodynamic variables and side effects were measured throughout each study day. Peak plasma glucose level was the primary endpoint. RESULTS: Plasma glucose level increased significantly by a mean (95% CI) of 2.3 (1.7-3.0), 4.2 (3.5-4.8) and 5.0 (4.3-5.6) mmol/l to 6.1 (4.9-7.4), 7.9 (6.4-9.3) and 8.7 (7.8-9.5) vs 3.6 (3.4-3.9) mmol/l (p < 0.001) after the three different glucagon doses as compared with saline, and the increase was neither correlated with weight nor insulin levels. Area under the plasma glucose curve, peak plasma glucose, time to peak plasma glucose and duration of plasma glucose level above baseline were significantly enhanced with increasing glucagon doses; however, these were not significantly different between 200 and 300 µg glucagon. Free fatty acids and heart rates were significantly lower initially after glucagon than after saline injection. Other haemodynamic variables, counter-regulatory hormones and side effects did not differ between interventions. CONCLUSIONS: An s.c. low-dose glucagon bolus effectively restores plasma glucose after insulin overdosing. Further research is needed to investigate whether low-dose glucagon may be an alternative treatment to oral carbohydrate intake for mild hypoglycaemia in patients with type 1 diabetes.

Insulin degludec and insulin degludec/insulin aspart: a review of their use in the management of diabetes mellitus.

Insulin degludec (Tresiba(®)) is an ultra-long-acting insulin analogue that is also available as a coformulation with rapid-acting insulin aspart (insulin degludec/insulin aspart) [Ryzodeg(®)]. Insulin degludec has a flat, stable glucose-lowering profile with a duration of action of >42 h, and less within-patient day-to-day variability in glucose-lowering effect than the long-acting insulin analogue insulin glargine. In clinical trials, insulin degludec achieved similar glycaemic control to that seen with insulin glargine in patients with type 1 or 2 diabetes, but with a lower risk of nocturnal hypoglycaemia. In addition, trials examining a flexible dosing regimen of insulin degludec in patients with type 1 or 2 diabetes show the potential for adjusting the injection time, without compromising glycaemic control or safety. A 200 U/mL formulation of insulin degludec is also available for use in patients who require large volumes of basal insulin. Insulin degludec/insulin aspart was noninferior to the long-acting insulin analogue insulin detemir in patients with type 1 diabetes and has the potential to reduce the number of daily injections. Trial results also indicate that insulin degludec/insulin aspart may be an appropriate option for initiating insulin therapy in patients with type 2 diabetes inadequately controlled with oral antidiabetic drugs. Subcutaneous insulin degludec was generally well tolerated in patients with type 1 or 2 diabetes. In conclusion, insulin degludec and insulin degludec/insulin aspart represent a useful advance in the treatment of type 1 or 2 diabetes.

Arcuate nucleus injection of an anti-insulin affibody prevents the sympathetic response to insulin.

Accumulating evidence suggests that insulin acts within the hypothalamus to alter sympathetic nerve activity (SNA) and baroreflex function. Although insulin receptors are widely expressed across the hypothalamus, recent evidence suggests that neurons of the arcuate nucleus (ARC) play an important role in the sympathoexcitatory response to insulin. The purpose of the present study was to determine whether circulating insulin acts directly in the ARC to elevate SNA. In anesthetized male Sprague-Dawley rats (275-425 g), the action of insulin was neutralized by microinjection of an anti-insulin affibody (1 ng/40 nl). To verify the efficacy of the affibody, ARC pretreatment with injection of the anti-insulin affibody completely prevented the increase in lumbar SNA produced by ARC injection of insulin. Next, ARC pretreatment with the anti-insulin affibody attenuated the lumbar sympathoexcitatory response to intracerebroventricular injection of insulin. Third, a hyperinsulinemic-euglycemic clamp increased lumbar, but not renal, SNA in animals that received ARC injection of a control affibody. However, this sympathoexcitatory response was absent in animals pretreated with the anti-insulin affibody in the ARC. Injection of the anti-insulin affibody in the adjacent ventromedial hypothalamus did not alter the sympathoexcitatory response to insulin. The ability of the anti-insulin affibody to prevent the sympathetic effects of insulin cannot be attributed to a general inactivation or nonspecific effect on ARC neurons as the affibody did not alter the sympathoexcitatory response to ARC disinhibition by gabazine. Collectively, these findings suggest that circulating insulin acts within the ARC to increase SNA.

Systemic inhibition of nitric oxide synthesis in non-diabetic individuals produces a significant deterioration in glucose tolerance by increasing insulin clearance and inhibiting insulin secretion.

AIMS/HYPOTHESIS: Endogenous NO inhibits insulin release in isolated beta cells and insulin-degrading enzyme activity in hepatocytes, while NO release from endothelial cells has been suggested to enhance insulin action. We assessed the overall effect of systemic inhibition of endogenous NO synthesis on glucose homeostasis in humans. METHODS: Twenty-four non-diabetic volunteers underwent two hyperglycaemic (+7 mmol/l) clamps with either saline or L-NG-nitroarginine methyl ester (L-NAME, at rates of 2.5, 5, 10 and 20 µg min⁻¹ kg⁻¹) infusion. Another five volunteers underwent an OGTT with either saline or L-NAME (20 µg min⁻¹ kg⁻¹) infusion. Blood pressure and heart rate were measured to monitor NO blockade; during the OGTT, endothelial function was assessed by peripheral arterial tonometry and insulin secretion by C-peptide deconvolution and insulin secretion modelling. RESULTS: Compared with saline, L-NAME at the highest dose raised mean blood pressure (+20 ± 2 mmHg), depressed heart rate (-12 ± 2 bpm) and increased insulin clearance (+50%). First-phase insulin secretion was impaired, but insulin sensitivity (M/I index) was unchanged. During the OGTT, L-NAME raised 2 h plasma glucose by 1.8 mmol/l (p < 0.01), doubled insulin clearance and impaired beta cell glucose sensitivity while depressing endothelial function. CONCLUSIONS/INTERPRETATION: In humans, systemic NO blockade titrated to increase blood pressure and induce endothelial dysfunction does not affect insulin action but significantly impairs glucose tolerance by increasing plasma insulin clearance and depressing insulin secretion, namely first-phase and beta cell glucose sensitivity.

Obesity-related hypertension and the role of insulin and leptin in high-fat-fed rabbits.

Feeding a high-fat diet (HFD) to rabbits results in increased blood pressure and renal sympathetic nerve activity (RSNA) and marked increases in plasma leptin and insulin. We determined the contribution of insulin and leptin signaling in the central nervous system to the increased blood pressure and RSNA during a HFD using specific antagonists. New Zealand White rabbits were implanted with an intracerebroventricular (ICV) catheter and RSNA electrode and placed on a normal or 13.5% HFD for 1 or 3 weeks. Blood pressure, heart rate, and RSNA were recorded before and for 90 minutes after ICV administration of a leptin antagonist (100 µg), insulin antagonist (0.5 U), or vehicle (50 µL) on separate days. Rabbits had higher blood pressure (+8%, +17%) and RSNA (+55%, +71%), at 1 and 3 weeks, respectively, of HFD compared with controls (n=7-11). ICV leptin antagonist reduced blood pressure by 9% and RSNA by 17% (P<0.001) after 3 weeks of HFD but had no effect at week 1. ICV administration of the insulin antagonist reduced blood pressure by ≈5% at both times (P<0.05) but there was no effect on RSNA. Leptin and insulin antagonist doses were confirmed to effectively block the pressor responses to ICV leptin and insulin, respectively. The elevation of blood pressure and RSNA induced by a HFD is predominantly mediated by central actions of leptin. Central actions of insulin contribute a smaller proportion of the hypertension but independently of RSNA.

Congenital hyperinsulinism in an infant with paternal uniparental disomy on chromosome 11p15: few clinical features suggestive of Beckwith-Wiedemann syndrome.

Beckwith-Wiedemann syndrome (BWS) is the most common congenital overgrowth syndrome involving tumor predisposition. BWS is caused by various epigenetic or genetic alterations that disrupt the imprinted genes on chromosome 11p15.5 and the clinical findings of BWS are highly variable. Hyperinsulinemic hypoglycemia is reported in about half of all babies with BWS. We identified an infant with diazoxide-unresponsive congenital hyperinsulinism (HI) without any apparent clinical features suggestive of BWS, but diagnosed BWS by molecular testing. The patient developed severe hyperinsulinemic hypoglycemia within a few hours after birth, with macrosomia and mild hydronephrosis. We excluded mutations in the K(ATP) channel genes on chromosome 11p15.1, but found a rare homozygous single nucleotide polymorphism (SNP) of ABCC8. Parental SNP pattern suggested paternal uniparetal disomy in this region. By microsatellite marker analysis on chromosome 11p15, we could diagnose BWS due to the mosaic of paternal uniparental disomy. Our case suggests that some HI of unknown genetic etiology could involve undiagnosed BWS with no apparent clinical features, which might be diagnosed only by molecular testing.

Islet ß-cell ghrelin signaling for inhibition of insulin secretion.

Ghrelin, an acylated 28-amino acid peptide, was isolated from the stomach, where circulating ghrelin is produced predominantly. In addition to its unique role in regulating growth-hormone release, mealtime hunger, lipid metabolism, and the cardiovascular system, ghrelin is involved in the regulation of glucose metabolism. Ghrelin is expressed in pancreatic islets and released into pancreatic microcirculations. Ghrelin inhibits insulin release in mice, rats, and humans. Pharmacological and genetic blockades of islet-derived ghrelin markedly augment glucose-induced insulin release. The signal transduction mechanisms of ghrelin in islet ß-cells are very unique, being distinct from those utilized for growth-hormone release. Ghrelin attenuates the glucose-induced cAMP production and PKA activation, which drives activation of Kv channels and suppression of the glucose-induced [Ca(2+)](i) increase and insulin release in ß-cells. Insulinostatic function of the ghrelin-GHS-R system in islets is a potential therapeutic target for type 2 diabetes.

Mechanisms of diabetes mellitus induced with FK506 in SD rats models.

BACKGROUND: Tacrolimus causes post-transplant diabetes mellitus, however the pathogenetic mechanisms remain controversial. In this study we probed into the mechanisms of tacrolimus-induced diabetes mellitus in rats. METHODS: Glucose levels were determined on whole blood samples using a glucose oxidase method. Levels of serum insulin and C-peptide were measured with ELISA. Histological damage of ultra-structure and apoptosis of beta cells of the pancreas were assayed with electric microscope and tunnel methods respectively.--Ultra-structure were assayed with electric microscope and apoptosis of beta cells of the pancreas were assayed with tunnel methods. Immunohistochemistry was utilized to detect the sum of insulin receptors of hepatic cells. RESULTS: Compared to control group, insulin and C peptide levels in serum decreased in rats of diabetes mellitus models induced with FK506(P<0.05). Compared to the control group, the sum of apoptosis body in pancreatic islets increased in rats of diabetes mellitus models induced with FK506 (P<0.05). Compared to the control group, electron microscopy showed cytoplasm swelling and vacuolization, and marked decrease or absence of dense-core secretory granules in beta cells in rats with diabetes mellitus induced with FK506.Compared to the control group, expression of insulin receptor of hepatic cell decreased in rats of diabetes mellitus models induced with FK506 (P<0.05). CONCLUSION: Pathogenetic mechanisms of rats of diabetes mellitus models induced with FK506 including reduction of secretion of insulin in beta cells of pancreatic islets, damages of ultra-structure of beta cells of pancreatic islets, increasing of apoptosis of beta cells of pancreatic islets and decreasing of expression of insulin receptors in hepatic cells.

Insulin-stimulated release of D-chiro-inositol-containing inositolphosphoglycan mediator correlates with insulin sensitivity in women with polycystic ovary syndrome.

Some actions of insulin are mediated by inositolphosphoglycan (IPG) mediators. Deficient release of a putative D-chiro-inositol-containing (DCI) IPG mediator may contribute to insulin resistance in women with polycystic ovary syndrome (PCOS). Previously, we demonstrated that oral DCI supplementation improved ovulation and metabolic parameters in women with PCOS. However, whether oral DCI mediates an increase in the release of the DCI-IPG mediator and an improvement in insulin sensitivity in women with PCOS is unknown. We conducted a randomized controlled trial of DCI supplementation vs placebo in 11 women with PCOS who were assessed at 2 time points 6 weeks apart. Plasma DCI, DCI-IPG release during oral glucose tolerance test (AUC(DCI-IPG)), and insulin sensitivity (S(i)) by frequently sampled intravenous glucose tolerance test were assessed at baseline and end of study. The study was terminated early because of a sudden unavailability of the study drug. However, in all subjects without regard to treatment assignment, there was a positive correlation between the change in AUC(DCI-IPG)/AUC(insulin) ratio and the change in S(i) during the 6-week period (r = 0.69, P = .02), which remained significant after adjustment for body mass index (P = .022) and after further adjustment for body mass index and treatment allocation (P = .0261). This suggests that, in women with PCOS, increased glucose-stimulated DCI-IPG release is significantly correlated with improved insulin sensitivity. The significant relationship between DCI-IPG release and insulin sensitivity suggests that the DCI-IPG mediator may be a target for therapeutic interventions in PCOS.

Insulinización basal y enfermedad aterosclerótica en la diabetes mellitus tipo 2 / Basal insulinization and atherosclerotic disease in type 2 diabetes mellitus

Las complicaciones macrovasculares son la causa principal de morbilidad y mortalidad en la diabetes mellitus tipo 2. Y como sustrato fundamental se encuentra la enfermedad aterosclerótica, que en el paciente diabético tiene unas características diferenciadas y responde peor al tratamiento. Por ello, la prevención de la macroangiopatía diabética debe ser la principal estrategia para estos pacientes. Si bien ha quedado demostrado que la mejora del control metabólico (HbA1c < 8%) disminuye la incidencia de complicaciones microvasculares, ello no ocurre igualmente para la enfermedad aterosclerótica, debido, en parte, al carácter multifactorial de ésta. Por tanto, es necesario un control metabólico más estricto y desde las fases iniciales de la diabetes, e incluso en los estados prediabéticos. En este contexto, la insulinización basal es una alternativa fisiológica, que puede permitir enlentecer el deterioro de la célula beta, mejorar el control metabólico y, posiblemente, reducir la incidencia de episodios cardiovasculares. La mayoría de los estudios de insulinización basal se han realizado con insulina glargina, que ha demostrado ser al menos igual de eficaz que otras insulinas, pero con una reducción significativa de efectos adversos, en concreto de las hipoglucemias graves y las hipoglucemias nocturnas (AU)

Macrovascular complications are the main cause of morbidity and mortality in type 2 diabetics. And as the fundamental substrate we find atherosclerosis, which in the diabetic patient has characteristic differentiations and a worse response to treatment. This is the principal reason why diabetic macroangiopathy prevention is our main goal in these patients. It has been proved that good metabolic control reduces microvascular complications, however, this does not occur with atherosclerosis most likely due to a multifactorial origin. We need a more strict metabolic control in the initial phases of diabetes and even in the pre-diabetes stages. In this context basal insulinization is a physiological alternative that may allow a slower deterioration of beta cells, a better metabolic control and even a decrease in the incidence of cardiovascular events. The majority of the basal insulinization studies have been undertaken with Glargin Insulin, which has proved to be at least as effective as other insulins, but with a significant reduction in adverse events, especially severe hypoglycemias and night hypoglycemias (AU)

Kisspeptin-13 inhibits insulin secretion without affecting glucagon or somatostatin release: study in the perfused rat pancreas.

Kisspeptins are a family of peptides encoded by the KISS1 gene, which binds to G-protein-coupled receptor (GPR54), an orphan GPR54 related to galanin receptors. Endogenous forms composed of 54, 14, and 13 amino acids have been identified. Kisspeptin and GPR54 mRNAs have been detected in pancreatic B and A cells. Furthermore, kisspeptin-54 has been shown to slightly stimulate the last phase of glucose-induced insulin secretion in mouse and human islets and to inhibit insulin release in MIN6 cells. We have investigated the effect of kisspeptin-13 on insulin, glucagon, and somatostatin secretion. The study was performed in the perfused rat pancreas. Glucose, arginine, carbachol, and exendin-4 were used as secretagogues. Hormones were measured by RIA. Kisspeptin-13 reduced glucose-induced insulin secretion in a dose-dependent manner (IC(50)=1.2 nM) and inhibited the insulin responses to both carbachol and exendin-4. Kisspeptin-13 blocked arginine-induced insulin secretion without affecting the glucagon or somatostatin responses to this amino acid, thus indicating that kisspeptin-13 influences B cells directly, rather than through an A- or D-cell paracrine effect. The reduction of the insulin response to exendin-4 induced by kisspeptin-13 was also observed in pertussis toxin-treated rats, thus suggesting an inhibition independent of G(i) proteins. In view of the potent insulinostatic effect of kisspeptin-13, it is tempting to speculate that kisspeptins may be implicated in the regulation of B-cell secretion.

Effects of diet supplementation with olive oil and guar upon fructose-induced insulin resistance in normal rats.

Exposure of normal rats to fructose-containing drinking water represents a current model of insulin resistance. The major aim of the present study was to assess the possible effect of diet supplementation with either olive oil or guar upon the metabolic consequences of exposure to exogenous fructose. For this purpose, the changes in body weight, plasma D-glucose and insulin concentrations, and D-glucose infusion rate during a hyperinsulinemic-euglycemic clamp were measured after 65 days exposure to exogenous fructose and either olive oil- or guar-enriched diet. The results were compared to those previously collected in control animals exposed for the same period to either tap water or the fructose-containing drinking water and a standard diet. Diet supplementation with olive oil or guar failed to affect the increase in the insulinogenic index and the decrease in insulin sensitivity and fasted/fed ratio for plasma insulin concentration caused by exogenous fructose. In the rats exposed to exogenous fructose, the olive oil-fed rats differed from other animals by the absence of a decrease in food intake and body weight gain, whilst the guar-fed rats differed from other animals in a lower plasma D-glucose concentration in fed state and an absence, at day 65, of a higher plasma D-glucose concentration than that at day 0 measured in after overnight fasting state. These findings argue in favour of guar, rather than olive oil, to oppose the effect of exogenous fructose on glucose homeostasis.

Fatty acids attenuate insulin regulation of 5'-AMP-activated protein kinase and insulin cardioprotection after ischemia.

The cardioprotective effect of insulin during ischemia-reperfusion has been associated with stimulation of glucose uptake and glycolysis. Although fatty acids and 5'-AMP activated protein kinase (AMPK) are regulators of glucose metabolism, it is unknown what effect insulin has on postischemic function and AMPK activity in the presence of high levels of fatty acid. Isolated ejecting mouse hearts were perfused with Krebs-Henseleit solution containing 5 mmol x L(-1) glucose and 0, 0.2, or 1.2 mmol x L(-1) palmitate, with or without 100 microU/mL insulin. During aerobic perfusion in the absence of palmitate, insulin stimulated glycolysis by 73% and glucose oxidation by 54%, while inhibiting AMPK activity by 43%. In the presence of 0.2 or 1.2 mmol x L(-1) palmitate, insulin stimulated glycolysis by 111% and 105% and glucose oxidation by 72% and 274% but no longer inhibited AMPK activity. During reperfusion of hearts in the absence of palmitate, insulin increased recovery of cardiac power by 47%. This was associated with a 97% increase in glycolysis and a 160% increase in glucose oxidation. However, in the presence of 1.2 mmol x L(-1) palmitate, insulin now decreased recovery of cardiac power by 42%. During reperfusion, glucose oxidation was inhibited by high fat, but insulin-stimulated glycolysis remained high, resulting in increased proton production. In the absence of fatty acids, insulin blunted the ischemia-induced activation of AMPK, but this effect was lost in the presence of fatty acids. We demonstrate that the cardioprotective effect of insulin and its ability to inhibit AMPK activity are lost in the presence of high concentrations of fatty acids.

Tumor necrosis factor-alpha inhibits insulin's stimulating effect on glucose uptake and endothelium-dependent vasodilation in humans.

BACKGROUND: Inflammatory mechanisms could be involved in the pathogenesis of both insulin resistance and atherosclerosis. Therefore, we aimed at examining whether the proinflammatory cytokine tumor necrosis factor (TNF)-alpha inhibits insulin-stimulated glucose uptake and insulin-stimulated endothelial function in humans. METHODS AND RESULTS: Healthy, lean male volunteers were studied. On each study day, 3 acetylcholine (ACh) or sodium nitroprusside (SNP) dose-response studies were performed by infusion into the brachial artery. Before and during the last 2 dose-response studies, insulin and/or TNF-alpha were coinfused. During infusion of insulin alone for 20 minutes, forearm glucose uptake increased by 220+/-44%. This increase was completely inhibited during coinfusion of TNF-alpha (started 10 min before insulin) with a more pronounced inhibition of glucose extraction than of blood flow. Furthermore, TNF-alpha inhibited the ACh forearm blood flow response (P<0.001), and this inhibition was larger during insulin infusion (P=0.01) but not further increased by NG-monomethyl-L-arginine acetate (P=0.2). Insulin potentiated the SNP response less than the ACh response and the effect of TNF-alpha was smaller (P<0.001); TNF-alpha had no effect on the SNP response without insulin infusion. Thus, TNF-alpha inhibition of the combined response to insulin and ACh was likely mediated through inhibition of NO production. CONCLUSIONS: These results support the concept that TNF-alpha could play a role in the development of insulin resistance in humans, both in muscle and in vascular tissue.

Influence of long term cyclosporine therapy on insulin and its precursors secretion in patients after heart transplantation.

Diabetes mellitus is a very well recognized risk factor for coronary artery disease in non-transplant patients. With the introduction of new immunosuppressive agents in solid organ recipients, there is an interest in medical complications of immunosuppressive therapy. An influence of long-term cyclosporine-A (CyA) therapy on glucose metabolism was analyzed in a group of 122 heart transplant recipients who developed hyperglycemia after heart transplantation. Based on WHO criteria for diagnosis of diabetes two groups were identified: group 1 (102 pts) included pts with impaired glycemic control and group 2 (20 pts) with clinical diabetes. Fasting insulin, proinsulin, C-peptide, HbA1c and cyclosporine-A trough levels were determined 12-18 months post surgery in clinically stable period without transplant rejection. The immunosuppressive treatment in both groups was the same and consisted of cyclosporine A, azathioprine and prednisone. We observed a statistically significant negative correlation between CyA concentration and insulin in both groups, a statistically significant negative correlation between CyA concentration and proinsulin, C-peptide blood level in group 1 and statistically significant positive correlation between CyA and glucose blood level in both groups.

Central leptin gene therapy suppresses body weight gain, adiposity and serum insulin without affecting food consumption in normal rats: a long-term study.

The weight-reducing effects of leptin are predominantly mediated through the hypothalamus in the brain. Gene therapy strategies designed for weight control have so far tested the short-term effect of peripherally delivered viral vectors encoding the leptin gene. In order to circumvent the multiple peripheral effects of hyperleptinemia and to overcome the age-related development of leptin resistance due to multiple factors, including defective leptin transport across the blood brain barrier, we determined whether delivery of viral vectors directly into the brain is a viable therapeutic strategy for long-term weight control in normal wild-type rats. A recombinant adeno-associated virus (rAAV) vector encoding rat leptin (Ob) cDNA was generated (rAAV-betaOb). When administered once intracerebroventricularly (i.c.v.), rAAV-betaOb suppressed the normal time-related weight gain for extended periods of time in adult Sprague-Dawley rats. The vector expression was confirmed by immunocytochemical localization of GFP and RT-PCR analysis of leptin in the hypothalamus. This sustained restraint on weight gain was not due to shifts in caloric consumption because food-intake was similar in rAAV-betaOb-treated and rAAV-GFP-treated control rats throughout the experiment. Weight gain suppression, first apparent after 2 weeks, was a result of reduced white fat depots and was accompanied by drastically reduced serum leptin and insulin concentrations in conjunction with normoglycemia. Additionally, there was a marked increase in uncoupling protein-1 (UCP1) mRNA expression in brown adipose tissue, thereby indicating increased energy expenditure through thermogenesis. Seemingly, a selective enhancement in energy expenditure following central delivery of the leptin gene is a viable therapeutic strategy to control the age-related weight gain and provide protection from the accompanying multiple peripheral effects of hyperleptinemia and hyperinsulinemia.

Inhibition of insulin release by intraduodenally infused enterostatin-VPDPR in rats.

Enterostatin, an amino-terminal pentapeptide produced in the intestinal lumen after cleavage of pancreatic procolipase, has been shown to suppress fat intake in rats after intraduodenal infusion. In this study, female Sprague-Dawley rats fitted with a duodenal catheter were intestinally infused with enterostatin (Val-Pro-Asp-Pro-Arg, 11.3 and 22.6 nmol/kg/min) plus 20% Intralipid for 30 min. Plasma insulin levels were significantly reduced, whereas plasma glucose concentrations were not altered by enterostatin-VPDPR. The tripeptide Asp-Pro-Arg was also found to decrease the levels of plasma insulin. However, the pentapeptide with the sequence Val-Pro-Gly-Pro-Arg, des-Arg-enterostatin Val-Pro-Asp-Pro and the tripeptide Pro-Asp-Pro failed to cause the reduction of plasma insulin levels in rats following intestinal infusion of these peptides. Radiolabeled enterostatin ([3H]VPDPR) was identified in plasma by HPLC following intraduodenal infusion of the peptide, indicating that the appearance of an intact enterostatin-VPDPR in blood. It is concluded that intestinally administered enterostatin-VPDPR and its metabolites reduce plasma levels of insulin stimulated by Intralipid.