Effect of pioglitazone on endothelial function in impaired glucose tolerance

Aim: Flow-mediated dilation (FMD) is a surrogate marker of endothelial function, which has been proposed as a barometer of vascular health. Impaired microvascular response to reactive hyperaemia is thought to be the mechanism behind reduced shear stress and subsequently impaired FMD, which has been associated with cardiovascular events. This study aims to assess the effect of pioglitazone on the vasculature of patients with impaired glucose tolerance (IGT).

Materials and Methods: Forty IGT patients with no cardiovascular disease were compared with 24 healthy age- and sex-matched controls. Endothelial function was assessed using FMD of the brachial artery. Adiponectin (ADN) levels were measured and insulin sensitivity was calculated using homeostasis model assessment of insulin resistance (HOMA-IR). A randomised double-blind placebo-controlled trial of the IGT subjects was then performed, with subjects receiving either pioglitazone 30 mg od or matched placebo for 12 weeks before the measurements were repeated.

Results: The IGT subjects had a significantly impaired FMD compared with the controls (p < 0.001). Diastolic shear stress (DSS) was also significantly reduced in IGT (p = 0.04). High molecular weight (HMW) ADN was significantly lower in the IGT group than in controls (p = 0.03). On analysis of the IGT group after 12 weeks treatment, FMD was significantly increased in the pioglitazone group compared with placebo (p = 0.03) as was endothelium-independent dilation (EID) (p = 0.03). A significant increase in total ADN (p < 0.001), HMW ADN (p < 0.001) and HMW/total ratio (p = 0.001) occurred in the pioglitazone group compared with placebo.

Conclusions: Pioglitazone improved endothelial function in IGT. Treatment with pioglitazone may reduce the risk of cardiovascular disease in this patient group.

Ocular blood flow analysis detects microvascular abnormalities in impaired glucose tolerance.

Objective: Waveform analysis has been used to assess vascular resistance and predict cardiovascular events. We aimed to identify microvascular abnormalities in patients with impaired glucose tolerance (IGT) using ocular waveform analysis. The effects of pioglitazone were also assessed. Methods: Forty patients with IGT and twenty-four controls were studied. Doppler velocity recordings were obtained from the central retinal, ophthalmic and common carotid arteries, and sampled at 200 Hz. A discrete wavelet-based analysis method was employed to quantify waveforms. The resistive index (RI),was also determined. Patients with IGT were randomised to pioglitazone or placebo and measurements repeated after 12 weeks treatment. Results: In the ocular waveforms, significant differences in power spectra were observed in frequency band four (corresponding to frequencies between 6.25 and 12.50 Hz) between groups (p

Predicting the need for insulin therapy in late onset (40-69 years) diabetes mellitus

A six-year prospective study of 144 newly diagnosed, symptomatic diabetic patients aged 40-69 years showed that 21 (15%) required insulin therapy, commencing 1-61 months after diagnosis. The plasma insulin response to oral glucose was assessed at the time of diagnosis. All 12 patients with very low peak insulin response (less than or equal to 6 mU/l) required insulin therapy. Thirty-six patients had an intermediate insulin response (greater than 6 less than or equal to 18 mU/l); of these, 7 with a mean weight 88% (range 73-96%) of average body weight required insulin, while 29 with a mean weight 117% (range 98-158%) of average body weight, did not. Ninety-six patients had a peak insulin response (greater than 18 mU/l); 2 patients whose weights were 96% and 100% of average body weight, required insulin, while the remainder did not. Consideration of initial body weight and peak insulin response provides a useful prediction of the eventual need for insulin.

Novel loci for adiponectin levels and their influence on type 2 diabetes and metabolic traits: a multi-ethnic meta-analysis of 45,891 individuals.

Circulating levels of adiponectin, a hormone produced predominantly by adipocytes, are highly heritable and are inversely associated with type 2 diabetes mellitus (T2D) and other metabolic traits. We conducted a meta-analysis of genome-wide association studies in 39,883 individuals of European ancestry to identify genes associated with metabolic disease. We identified 8 novel loci associated with adiponectin levels and confirmed 2 previously reported loci (P = 4.5×10(-8)-1.2×10(-43)). Using a novel method to combine data across ethnicities (N = 4,232 African Americans, N = 1,776 Asians, and N = 29,347 Europeans), we identified two additional novel loci. Expression analyses of 436 human adipocyte samples revealed that mRNA levels of 18 genes at candidate regions were associated with adiponectin concentrations after accounting for multiple testing (p<3×10(-4)). We next developed a multi-SNP genotypic risk score to test the association of adiponectin decreasing risk alleles on metabolic traits and diseases using consortia-level meta-analytic data. This risk score was associated with increased risk of T2D (p = 4.3×10(-3), n = 22,044), increased triglycerides (p = 2.6×10(-14), n = 93,440), increased waist-to-hip ratio (p = 1.8×10(-5), n = 77,167), increased glucose two hours post oral glucose tolerance testing (p = 4.4×10(-3), n = 15,234), increased fasting insulin (p = 0.015, n = 48,238), but with lower in HDL-cholesterol concentrations (p = 4.5×10(-13), n = 96,748) and decreased BMI (p = 1.4×10(-4), n = 121,335). These findings identify novel genetic determinants of adiponectin levels, which, taken together, influence risk of T2D and markers of insulin resistance.

Impact de l’insuffisance rénale chronique sur les transporteurs de glucose et les effets subséquents sur la résistance à l’insuline

Parmi l’ensemble des désordres métaboliques retrouvés en insuffisance rénale chronique (IRC), la résistance à l’insuline demeure l’un des plus importantes à considérer en raison des risques de morbidité et de mortalité qu’elle engendre via les complications cardiovasculaires. Peu d’études ont considéré la modulation de transporteurs de glucose comme mécanisme sous-jacent à l’apparition et à la progression de la résistance à l’insuline en IRC. Nous avons exploré cette hypothèse en étudiant l’expression de transporteurs de glucose issus d’organes impliqués dans son homéostasie (muscles, tissus adipeux, foie et reins) via l’utilisation d’un modèle animal d’IRC (néphrectomie 5/6e). La sensibilité à l’insuline a été déterminée par un test de tolérance au glucose (GTT), où les résultats reflètent une intolérance au glucose et une hyperinsulinémie, et par les études de transport au niveau musculaire qui témoignent d’une diminution du métabolisme du glucose en IRC (~31%; p<0,05). La diminution significative du GLUT4 dans les tissus périphériques (~40%; p<0,001) peut être à l’origine de la résistance à l’insuline en IRC. De plus, l’augmentation de l’expression protéique de la majorité des transporteurs de glucose (SGLT1, SGLT2, GLUT1; p<0,05) au niveau rénal en IRC engendre une plus grande réabsorption de glucose dont l’hyperglycémie subséquente favorise une diminution du GLUT4 exacerbant ainsi la résistance à l’insuline. L’élévation des niveaux protéiques de GLUT1 et GLUT2 au niveau hépatique témoigne d’un défaut homéostatique du glucose en IRC. Les résultats jusqu’ici démontrent que la modulation de l’expression des transporteurs de glucose peut être à l’origine de la résistance à l’insuline en IRC. L’impact de la parathyroïdectomie (PTX) sur l’expression du GLUT4 a été étudié étant donné que la PTX pourrait corriger l’intolérance au glucose en IRC. Nos résultats démontrent une amélioration de l’intolérance au glucose pouvant être attribuable à la moins grande réduction de l’expression protéique du GLUT4 dans les tissus périphériques et ce malgré la présence d’IRC. L’excès de PTH, secondaire à l’hyperparathyroïdie, pourrait alors être à l’origine de la résistance à l’insuline en IRC en affectant l’expression du GLUT4. L’IRC partage de nombreuses similitudes avec le prédiabète quant aux défaillances du métabolisme du glucose tout comme l’hyperinsulinémie et l’intolérance au glucose. Aucune étude n’a tenté d’évaluer si l’IRC pouvait ultimement mener au diabète. Nos résultats ont par ailleurs démontré que l’induction d’une IRC sur un modèle animal prédisposé (rats Zucker) engendrait une accentuation de leur intolérance au glucose tel que constaté par les plus hautes glycémies atteintes lors du GTT. De plus, certains d’entre eux avaient des glycémies à jeun dont les valeurs surpassent les 25 mmol/L. Il est alors possible que l’IRC puisse mener au diabète via l’évolution de la résistance à l’insuline par l’aggravation de l’intolérance au glucose.

Diabetes relacionada a la fibrosis quística (DRFQ)

Importancia: el paciente con fibrosis quística después de las complicaciones gastrointestinales y pulmonares debe enfrentar otras comorbilidades como la diabetes relacionada a su condición . Dado el aumento en la esperanza de vida y el hecho de que virtualmente todas los pacientes con esta enfermedad pueden desarrollar alteración en el metabolismo de los carbohidratos, se requiere una sensibilización frente al tema que posibilite una detección temprana de esta entidad y un tratamiento óptimo que evite las complicaciones microvasculares e impacte entre otros el crecimiento pondo-estatural en pacientes en desarrollo y la función pulmonar. Objetivo : realizar una revisión actualizada de la literatura sobre la diabetes relacionada a la fibrosis quística, destacando las indicaciones de tamización y tratamiento. Conclusión : la FQ dentro de su abordaje requiere la detección temprana de la alteración del metabolismo de los carbohidratos con una prueba de tolerancia a la glucosa , el daño del islote pancreático , la disfunción inmune, la resistencia a la insulina, el estrés oxidativo entre otros elementos fisiopatológicos conllevan a un estado de depleción de insulina que producirán un efecto negativo microvascular así como a una reducción marcada de la función pulmonar, mayores tasa de infección e incremento de la mortalidad. La piedra angular del tratamiento en pacientes con o sin hiperglicemia es la insulina que mejora tanto el estado nutricional como la función pulmonar ; nuevos antidiabéticos orales con efecto incretinas y fármacos modificadores de la enfermedad se vislumbran como alternativas al corto plazo

Mobilisation of enterocyte fat stores by oral glucose in humans

Background and aims: When a high fat oral load is followed several hours later by further ingestion of nutrients, there is an early postprandial peak in plasma triacylglycerol (TG). The aim of this study was to investigate the location and release of lipid from within the gastrointestinal tract. Methods: Ten healthy patients undergoing oesopho-gastro-duodenoscopy (OGD) were recruited. At t=0, all patients consumed a 50 g fat emulsion and at t=5 hours they consumed either water or a 38 g glucose solution. OGD was performed at t=6 hours and jejunal biopsy samples were evaluated for fat storage. A subgroup of five subjects then underwent a parallel metabolic study in which postprandial lipid and hormone measurements were taken during an identical two meal protocol. Results: Following oral fat at t=0, samples from patients that had subsequently ingested glucose exhibited significantly less staining for lipid within the mucosa and submucosa of the jejunum than was evident in patients that had consumed only water (p=0.028). There was also less lipid storage within the cytoplasm of enterocytes (p=0.005) following oral glucose. During the metabolic study, oral glucose consumed five hours after oral fat resulted in a postprandial peak in plasma TG, chylomicron-TG, and apolipoprotein B48 concentration compared with oral water. Conclusion: After a fat load, fat is retained within the jejunal tissue and released into plasma following glucose ingestion, resulting in a peak in chylomicron-TG which has been implicated in the pathogenesis of atherosclerosis.

Insulin, glucagon-like peptide 1, glucose-dependent insulinotropic polypeptide and insulin-like growth factor I as putative mediators of the hypolipidemic effect of oligofructose in rats

The addition of oligofructose as a dietary fiber decreases the serum concentration and the hepatic release of VLDL-triglycerides in rats. Because glucose, insulin, insulin-like growth factor I (IGF-I) and gut peptides [i.e., glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1)]) are factors involved in the metabolic response to nutrients, this paper analyzes their putative role in the hypolipidemic effect of oligofructose. Male Wistar rats were fed a nonpurified diet with or without 10% oligofructose for 30 d. Glucose, insulin, IGF-I and GIP concentrations were measured in the serum of rats after eating. GIP and GLP-1 contents were also assayed in small intestine and cecal extracts, respectively. A glucose tolerance test was performed in food-deprived rats. Serum insulin level was significantly lower in oligofructose-fed rats both after eating and in the glucose tolerance test, whereas glycemia was lower only in the postprandial state. IGF-I serum level did not differ between groups. GIP concentration was significantly higher in the serum of oligofructose-fed rats. The GLP-1 cecal pool was also significantly higher. In this study, we have shown that cecal proliferation induced by oligofructose leads to an increase in GLP-1 concentration. This latter incretin could be involved in the maintenance of glycemia despite a lower insulinemia in the glucose tolerance test in oligofructose-fed rats. We discuss also the role of hormonal changes in the antilipogenic effect of oligofructose.

A low glycaemic load breakfast can attenuate cognitive impairments observed in middle aged obese females with impaired glucose tolerance.

Increased central adiposity and abnormalities in glucose tolerance preceding type 2 diabetes can have demonstrable negative effects on cognitive function, even in ostensibly healthy, middle-aged females. The potential for GL manipulations to modulate glycaemic response and cognitive function in type 2 diabetes and obesity merits further investigation..