Nocturnal free fatty acids are uniquely elevated in the longitudinal development of diet-induced insulin resistance and hyperinsulinemia

Obesity is strongly associated with hyperinsulinemia and insulin resistance, both primary risk factors for type 2 diabetes. It has been thought that increased fasting free fatty acids (FFA) may be responsible for the development of insulin resistance during obesity, causing an increase in plasma glucose levels, which would then signal for compensatory hyperinsulinemia. But when obesity is induced by fat feeding in the dog model, there is development of insulin resistance and a marked increase in fasting insulin despite constant fasting FFA and glucose. We examined the 24-h plasma profiles of FFA, glucose, and other hormones to observe any potential longitudinal postprandial or nocturnal alterations that could lead to both insulin resistance and compensatory hyperinsulinemia induced by a high-fat diet in eight normal dogs. We found that after 6 wk of a high-fat, hypercaloric diet, there was development of significant insulin resistance and hyperinsulinemia as well as accumulation of both subcutaneous and visceral fat without a change in either fasting glucose or postprandial glucose. Moreover, although there was no change in fasting FFA, there was a highly significant increase in the nocturnal levels of FFA that occurred as a result of fat feeding. Thus enhanced nocturnal FFA, but not glucose, may be responsible for development of insulin resistance and fasting hyperinsulinemia in the fat-fed dog model.     

Hyperglycemia and hyperlipidemia are associated with endothelial dysfunction during the development of type 2 diabetes

Diabetes mellitus impairs endothelial function, which can be considered as the hallmark in the development of cardiovascular diseases. Hyperglycemia, hyperinsulinemia, and hyperlipidemia are believed to contribute to endothelial dysfunction. In the present study, we investigated the possible links among these plasma metabolic markers and endothelial function in a mouse model during the development of type 2 diabetes. C57BL/6J-Lepob/ob mice at 8, 12, and 16 weeks were used to study endothelial function during the establishment of type 2 diabetes. Endothelial function was accessed in vitro in the thoracic aorta by measuring acetylcholine (ACh)-stimulated vasodilatation. Blood plasma was obtained for the measurements of glucose, insulin, triglycerides, and cholesterol levels. Correlation and multiple regression analysis revealed strong negative associations between the ACh responsiveness and the plasma levels of glucose, insulin, and lipid profiles at the age of 8 weeks. Associations were observed at neither older age nor in C57BL/6J mice. In conclusion, the increase in plasma levels of glucose, insulin, and lipids is associated with the impairment of the endothelial function during the early stage of the development of type 2 diabetes. The loss of correlation at an older age suggests multifactorial regulation of endothelial function and cardiovascular complications at later stages of the disease.     

二甲双胍联合西格列汀对2型糖尿病患者氧化应激、胰岛素抵抗的影响

目的:探讨二甲双胍联合西格列汀对2型糖尿病患者氧化应激、胰岛素抵抗的影响。方法:收集我院就诊或住院治疗的80例2型糖尿病患者,随机分为实验组和对照组,每组40例。两组患者入院后均给予相应的治疗措施,对照组患者给予二甲双胍250 mg/次,2次/d;实验组患者在对照组的基础上给予西格列汀100 mg/次,1次/d,治疗均连续8周。治疗结束后对患者血清丙二醛(MDA)、8异前列腺素F2α(8-iso-PGF2α)、空腹血糖(FBG)、空腹胰岛素(FINS)、胰岛素抵抗指数(HOMA-IR)以及患者临床治疗效果进行检测并比较。结果:与治疗前相比,治疗后两组患者MDA、8-iso-PGF2α、FBG、FINS以及HOMA-IR水平均下降(P0.05);与对照组相比,实验组患者MDA、8-iso-PGF2α、FBG、FINS以及HOMA-IR水平较低(P0.05),临床治疗总有效率较高(P0.05)。结论:二甲双胍联合西格列汀能够降低2型糖尿病患者血糖水平,降低MDA、8-iso-PGF2α水平,减轻氧化应激反应,降低胰岛素抵抗,临床疗效较好。     

甘精胰岛素联合不同降糖药稳定2 型糖尿病血糖水平的效果

目的:评价甘精胰岛素联合沙格列汀或格列美脲稳定2型糖尿病血糖水平的作用效果。方法:将我院2收治的228例2型糖尿病患者按照随机数字表法分为研究组和对照组,每组114人。研究组给予沙格列汀联合甘精胰岛素进行治疗,对照组给予格列美脲联合甘精胰岛素进行治疗。全部病例在治疗前4 d及治疗满16周时应用动态血糖监测仪实施72 h动态血糖监测。对比两组治疗前后血糖水平相关指标及血糖水平浮动相关指标的变化。结果:研究组治疗后体质指数显著低于对照组(P0.05)。两组治疗后空腹血糖均比本组治疗前显著下降(P0.05)。两组治疗后糖化血红蛋白均比本组治疗前显著下降(P0.05)。两组治疗后胰岛素用量无显著差异。两组平均血糖水平治疗前后无显著差异(P0.05)。研究组治疗后血糖标准差、日内血糖平均波动幅度、日内血糖波动次数、日间血糖平均绝对差改善幅度显著优于对照组。两组高血糖治疗后均比治疗前显著改善,改善幅度无显著差异(P0.05)。两组低血糖曲线下面积治疗前后无显著差异(P0.05)。结论:甘精胰岛素并用沙格列汀更能在显著控制2型糖尿病患者血糖的同时,还可使其血糖水平保持持久稳定,且不增加其低血糖的发生风险。     

Effect of dietary Platycodon grandiflorum on the improvement of insulin resistance in obese Zucker rats

The effect of dietary Platycodon grandiflorum on the improvement of insulin resistance and lipid profile was investigated in lean (Fa/-) and obese (fa/fa) Zucker rats, a model for noninsulin dependent diabetes mellitus. Dietary Platycodon grandiflorum feeding for 4 weeks resulted in a significant decrease in the concentration of plasma triglyceride in both lean and obese Zucker rats. Furthermore, dietary Platycodon grandiflorum markedly decreased both plasma cholesterol and fasting plasma insulin levels, and significantly decreased the postprandial glucose level at 30 min during oral glucose tolerance test in obese Zucker rats. Although there was no statistical significance, the crude glucose transporter 4 protein level of obese rats fed Platycodon grandiflorum tended to increase when compared with that of obese control rats. Therefore, the present results suggested that dietary Platycodon grandiflorum may be useful in prevention and improvement of metabolic disorders characterized by hyperinsulinemia states such as noninsulin dependent diabetes mellitus, syndrome X, and coronary artery disease.     

Effects of pioglitazone and metformin on beta-cell function in nondiabetic subjects at high risk for type 2 diabetes

Thiazolidinediones (TZDs) and metformin decreased the incidence of diabetes in subjects at risk for developing diabetes and improved peripheral or hepatic insulin sensitivity, respectively. Whether they also directly improved beta-cell function is not clear. In vitro studies showed improved beta-cell function in response to TZDs and metformin; however, the effects of TZDs or metformin on beta-cell function in humans are still uncertain. We hypothesized that both TZDs and metformin directly affect beta-cell function. We evaluated beta-cell function and insulin sensitivity (S(I)) in subjects with impaired glucose tolerance or a history of gestational diabetes using oral and intravenous glucose tolerance tests in addition to the glucose-potentiated arginine stimulation test. In contrast to metformin, pioglitazone improved S(I), glucose tolerance, and insulin-independent glucose disposal [glucose effectiveness (S(G))]. Neither pioglitazone nor metformin significantly improved beta-cell compensation for insulin resistance [disposition index (DI)], but the change in DI significantly correlated with baseline S(I). Insulin secretion in response to arginine at maximally potentiating glucose levels (AIR(max)) tended to increase after metformin and to decrease after pioglitazone; however, when adjusted for S(I), the changes were not significant. Our results demonstrate that, in nondiabetic subjects at risk for diabetes, pioglitazone, but not metformin, significantly improved glucose tolerance by improving S(I) and S(G). We did not find any evidence that either pioglitazone or metformin improved beta-cell function. Improved beta-cell compensation was observed primarily in the subgroup of subjects that had the lowest S(I) at baseline.     

Apolipoprotein A-II, genetic variation on chromosome 1q21-q24, and disease susceptibility

PURPOSE OF REVIEW: Apolipoprotein (apo) A-II is the second most abundant HDL apolipoprotein; however its function remains largely unknown. Owing to the lack of consequences of apoA-II deficiency in humans, it has long been considered an apolipoprotein of minor importance. Overexpression of apoA-II in transgenic mice, however, causes combined hyperlipidemia and, in some cases, insulin resistance. This, and the location of the apoA-II gene in chromosome 1q23, a hot region in the search for genes associated with familial combined hyperlipidemia, insulin resistance and type 2 diabetes mellitus, has greatly increased interest in this protein. RECENT FINDINGS: ApoA-II is biochemically and genetically linked to familial combined hyperlipidemia. Given that the chromosome 1q21-q24 region is associated with insulin resistance or type 2 diabetes, this region is a now a focus of interest in the study of these complex, often overlapping diseases. However, no polymorphisms that increase apoA-II levels have been identified to date in humans. Other nonstructural loci may regulate apoA-II plasma concentration. Further, plasma apoA-II concentration is increased by saturated fat intake. Several reports have added to our understanding of the relationship between apoA-II mutations and amyloidosis both in humans and mice. SUMMARY: An increased plasma concentration of apoA-II might contribute to familial combined hyperlipidemia or type 2 diabetes mellitus expression, which emphasizes the need to understand its function and metabolism. Genetic studies in well characterized patients and genomic and proteomic approaches in cell and mouse models may help to achieve this understanding.     

Metabolic efficacy and safety of once-daily pioglitazone monotherapy in patients with type 2 diabetes: a double-blind, placebo-controlled study.

Pioglitazone is a novel oral anti-diabetic agent belonging to the thiazolidinedione class. Pioglitazone has been shown to be effective and well tolerated in the treatment of patients with type 2 diabetes, as it reduces insulin resistance and improves glycaemic control and abnormal lipid profiles. This double-blind, randomised, placebo-controlled study was conducted for further evaluation of the efficacy and tolerability of once-daily administration of pioglitazone monotherapy alongside dietary measures in patients with type 2 diabetes. Following a 10-week washout period, 251 patients received one of three treatment regimens for 26 weeks: placebo + diet (n = 84), pioglitazone 15 mg once-daily + diet (n = 89), or pioglitazone 30 mg once-daily + diet (n = 78). Pioglitazone, both 15 and 30 mg/day, in addition to dietary control, was associated with significant reductions (vs. placebo) in mean levels of both glycosylated haemoglobin (HbA 1C ) and fasting blood glucose (FBG). HbA 1C was reduced by 0.92 % and 1.05 %, respectively, and FBG was reduced by 34.3 and 36.0 mg/dl, respectively, compared with the control group. Pioglitazone at 15 and 30 mg/day significantly reduced postprandial blood glucose levels at all visits (- 163 and - 165 mg/dl/hour, respectively) compared with an increase of 47.7 mg/dl/hour on placebo. The profile and frequency of adverse events were similar in all treatment groups. These results indicate that pioglitazone monotherapy together with dietary control is both effective and safe in patients with type 2 diabetes.     

有机铬、炎症与胰岛素抵抗的相关性

目的研究有机铬、炎症、他汀类药物与胰岛素抵抗,及其与心、脑血管疾病方面的关系。方法筛选40岁以上的糖耐量异常(IGT)合并高血压患者60人、糖耐量异常合并高脂血症患者60人、糖耐量异常合并冠心病患者60人和非胰岛素依赖性糖尿病(T2DM)患者60人,进行分组,每一组随机分为3个小组:2个治疗组及对照组。治疗一组在原治疗方案基础上给予唐安一号(有机铬制剂)口服,治疗二组在原治疗方案基础上给予阿乐(阿托伐他汀钙片)口服,对照组维持原治疗方案,治疗4周。结果治疗一组空腹血糖(FBG)、空腹血清胰岛素(FINS)、甘油三酯(TG)、血清总胆固醇(TC)和血清低密度脂蛋白胆固醇(LDL-C)均低于对照组(P0.05),血清高密度脂蛋白胆固醇(HDL-C)高于对照组(P0.05)。治疗二组FINS、TG、TC、LDL-C和C-反应蛋白(CRP)低于对照组(P0.05),HDL-C高于对照组(P0.05)。4周治疗后,治疗一组、治疗二组HOMA-IR均低于对照组(P0.05)。结论有机铬及他汀类药物能增强胰岛素的生物学效应,调节糖脂代谢,改善胰岛素抵抗。     

Adenoviral insulin gene therapy prolongs survival of IDDM model BB rats by improving hyperlipidemia.

Diabetes is frequently associated with hyperlipidemia, which results in atherogenic complications. Insulin-dependent diabetes mellitus (IDDM) model BB/Wor//Tky (BB) rats exhibit both hyperglycemia and hyperlipidemia and die within 3 weeks after the onset of diabetes unless insulin therapy is given. We performed insulin gene therapy in BB rats with adenovirus vectors through the tail vein. After infusion, plasma triglyceride levels dropped quickly and maintained low levels for 1 week, whereas blood glucose levels showed a slight decrease. The survival period of diabetic BB rats was prolonged to up to 75 days by infusing insulin gene-expressing adenoviral vectors. We suggest that the control of hyperlipidemia can be a life-saving measure when combined with hyperglycemia control in the treatment of diabetes.     

Familial type C syndrome of insulin resistance and short stature with possible autosomal dominant transmission

We describe a 17-yr-old girl with insulin resistant diabetes, acanthosis nigricans, hirsutism and short stature. At the age of 14 she was found to have glycosuria and diagnosed as diabetes mellitus. No endocrinological abnormality except transient amenorrhea and exaggerated LH response to LHRH was found. Insulin resistance was demonstrated by fasting hyperinsulinemia, insulin tolerance test and euglycemic glucose clamp test, and large doses of insulin with CSII were not effective in controlling blood glucose. Insulin binding to erythrocytes was normal, suggesting a postbinding defect. The same phenotype of insulin resistant diabetes and short stature was found in her mother who was diagnosed as diabetes mellitus at the age of 31 and died of diabetic nephropathy at the age of 41. Her maternal grandfather and uncle were reportedly affected with the same phenotype. Her father had impaired glucose tolerance, but no hyperinsulinemia. Two sisters had essentially normal glucose tolerance. Insulin binding to erythrocytes of her father and mother was also in the normal range. These results suggest that the present case may be a rare syndrome present together with type C syndrome of insulin resistance, and with short stature which was inherited autosomal dominantly.     

Pioglitazone ameliorates insulin resistance and diabetes by both adiponectin-dependent and -independent pathways

Thiazolidinediones have been shown to up-regulate adiponectin expression in white adipose tissue and plasma adiponectin levels, and these up-regulations have been proposed to be a major mechanism of the thiazolidinedione-induced amelioration of insulin resistance linked to obesity. To test this hypothesis, we generated adiponectin knock-out (adipo-/-) ob/ob mice with a C57B/6 background. After 14 days of 10 mg/kg pioglitazone, the insulin resistance and diabetes of ob/ob mice were significantly improved in association with significant up-regulation of serum adiponectin levels. Amelioration of insulin resistance in ob/ob mice was attributed to decreased glucose production and increased AMP-activated protein kinase in the liver but not to increased glucose uptake in skeletal muscle. In contrast, insulin resistance and diabetes were not improved in adipo-/-ob/ob mice. After 14 days of 30 mg/kg pioglitazone, insulin resistance and diabetes of ob/ob mice were again significantly ameliorated, which was attributed not only to decreased glucose production in the liver but also to increased glucose uptake in skeletal muscle. Interestingly, adipo-/-ob/ob mice also displayed significant amelioration of insulin resistance and diabetes, which was attributed to increased glucose uptake in skeletal muscle but not to decreased glucose production in the liver. The serum-free fatty acid and triglyceride levels as well as adipocyte sizes in ob/ob and adipo-/-ob/ob mice were unchanged after 10 mg/kg pioglitazone but were significantly reduced to a similar degree after 30 mg/kg pioglitazone. Moreover, the expressions of TNFalpha and resistin in adipose tissues of ob/ob and adipo-/-ob/ob mice were unchanged after 10 mg/kg pioglitazone but were decreased after 30 mg/kg pioglitazone. Thus, pioglitazone-induced amelioration of insulin resistance and diabetes may occur adiponectin dependently in the liver and adiponectin independently in skeletal muscle.     

Secretin-stimulated amylase release into blood is impaired in type 1 diabetes mellitus.

BACKGROUND: Prior studies have provided data indicating the existence of close interaction between pancreatic endocrine and exocrine function, but few clinical studies have explored this relationship in depth. We compared pancreatic exocrine function non-endoscopically in individuals with type 1 diabetes mellitus, type 2 diabetes mellitus, and normal glucose tolerant controls, to assess the importance of local insulin production to pancreatic exocrine function. METHODS: The plasma amylase response to intravenous secretin challenge was measured in men with type 1 diabetes mellitus (n = 5), type 2 diabetes mellitus (n = 5), and normal controls (n = 3). Patients were characterized by their urinary excretion of c-peptide and albumin over 24 hours. Autonomic neuropathy was non-invasively assessed by measuring RR variation (with deep respiration on EKG). RESULTS: Post-secretin amylase responses were generally absent with low baseline levels in the patients with type 1 diabetes mellitus. Patients with type 2 diabetes mellitus and controls showed similar twofold increases over baseline after secretin administration. When normal glucose tolerant and type 2 diabetic patients were pooled and compared against type 1 diabetes mellitus, the differences were statistically significant (p < 0.03). Total amylase response correlated positively, but weakly, with 24 h urinary C-peptide excretion (r = 0.507; p < 0.112), but not with glycemic control, duration of diabetes, or indices of autonomic neuropathy. CONCLUSIONS: Patients with type 1 diabetes mellitus, but not type 2 diabetes mellitus, have reduced pancreatic exocrine function, supporting the concept of a local paracrine effect of insulin on pancreatic acinar cells. Further studies are needed to determine the clinical impact of this deficiency, and whether such patients with type 1 diabetes mellitus would benefit from therapy with pancreatic enzyme supplementation.     

Influence of diadenosine tetraphosphate (Ap4A) on lipid metabolism

Diadenosine polyphosphates (Ap(x)A) are physiologically released and may be partly involved in the pathogenesis of diabetes mellitus. Ap(4)A (diadenosine tetraphosphate) leads to an increase in blood glucose while it decreases insulin levels in plasma. A possible link between Ap(x)A and diabetes mellitus-associated diseases such as insulin resistance and hyperlipidemia (plasma free fatty acids, cholesterol and its biosynthesis, triacylglycerols) has not been investigated yet. Parameters such as free fatty acid and cholesterol content in blood were determined enzymically. The biosynthesis of cholesterol and triacylglycerols was determined in HepG2 cells using the radioactive precursor [(14)C]-acetate and by using gas chromatography. Plasma free fatty acids were significantly decreased 5 and 10 min after an Ap(4)A bolus (0.75 mg kg(-1) b.w.) given to rats. Plasma cholesterol was reduced 5 and 60 min after Ap(4)A administration. LPDS (lipoprotein-deficient serum)-stimulated cholesterol biosynthesis in HepG2 cells was significantly reduced after 1 h incubation with Ap(4)A. Triacylglycerol (TAG) biosynthesis in HepG2 cells was not significantly influenced by Ap(4)A; there was just a tendency for a concentration-dependent decrease in TAG levels. In conclusion Ap(4)A as a diabetogenetic compound is not likely to be responsible for the development of insulin resistance or of hyperlipidemia. Parameters such as free fatty acids, cholesterol and triacylglycerols are not elevated by Ap(4)A, but are even decreased. Ap(4)A seems to be involved in the development of diabetes mellitus by increasing blood glucose and decreasing plasma insulin as shown earlier, but not in diabetes mellitus-associated diseases such as insulin resistance or hyperlipidemia.     

Mechanisms of oleic acid deterioration in insulin secretion: role in the pathogenesis of type 2 diabetes

Obesity is highly associated with type 2 diabetes where free fatty acids (FFAs) may be a trigger factor. To examine this hypothesis, in this study, we investigated the role of FFAs in the pathogenic development of type 2 diabetes. The release of insulin, the expression of preproinsulin (PPI), glucose transporter2 (GLUT2) and pancreatic duodenal homeobox-1 (PDX-1), and levels of intracellular free Ca++([Ca++]i) were measured in rat pancreatic islets treated with or without high concentrations of FFA (0.1 and 1.0 mM oleic acid) for 24 h. In comparison with untreated control, islets exposed to oleic acid showed an increase in basal insulin release and a decrease in glucose induced insulin secretion (GSIS). Elevated expression of PPI, PDX-1 and GLUT2 was also observed after treatment of the islets with oleic acid, which may partially contribute to the increased basal insulin secretion. Moreover, [Ca++]i levels increased after oleic acid exposure, which most likely accounts for the decrease of GSIS. Our findings, thus strongly suggest, that the increased levels of basal insulin secretion involved in glucose sensing, insulin producing and insulin secreting induced by high levels of FFAs may cause hyperinsulinemia in patients with type 2 diabetes, and thus long-term hyperinsulinemia could desensitize insulin receptors. We hypothesize that hyperinsulinemia may be a primary and independent event in the pathogenesis of diabetes. If proven, it may be possible to create novel and effective approaches for the prevention and treatment of type 2 diabetes.     

Successful treatment of prediabetes in clinical practice: targeting insulin resistance and β-cell dysfunction

ObjectiveTo determine the effectiveness of targeted pharmacologic interventions to reverse documented pathophysiologic abnormalities in prediabetes.MethodsPatients with impaired glucose tolerance (IGT) and/or impaired fasting glucose (IFG) were treated with insulin sensitizers (pioglitazone + metformin) or insulin sensitizers + exenatide on the basis of oral glucose tolerance testing-derived indices of insulin resistance and impaired b-cell function. Patients who declined pharmacologic therapy received lifestyle modification only.ResultsOne hundred five patients with IGT and/or IFG were treated with insulin sensitizers (pioglitazone + metformin) (n = 40), insulin sensitizers + exenatide (n = 47), or lifestyle modification only (n = 18). After a mean follow-up period of 8.9 months, the lifestyle modification group demonstrated no significant changes in fasting plasma glucose, plasma glucose area under the curve during oral glucose tolerance testing, insulin sensitivity, or b-cell function. In the pioglitazone + metformin group (24 hours off medication), fasting plasma glucose fell from 109 to 102 mg/dL; plasma glucose area under the curve decreased by 12.0%; insulin sensitivity and b-cell function improved by 42% and 50%, respectively (all P < .001); 14.3% converted to normal glucose tolerance; and no patient developed diabetes. In the pioglitazone + metformin + exenatide group (24 hours off medication), fasting plasma glucose fell from 109 to 98 mg/dL; plasma glucose area under the curve decreased by 21.2%; insulin sensitivity and b-cell function improved by 52% and 109%, respectively (all P < .001); 59.1% of patients with IGT reverted to normal glucose tolerance; and no patient developed diabetes.ConclusionsTargeted pathophysiologic therapy based on oral glucose tolerance test-derived measures of insulin sensitivity and b-cell function can be implemented in general internal medicine and endocrine practice and is associated with marked improvement in glucose tolerance and reversion of prediabetes to normal glucose tolerance in more than 50% of patients. (Endocr Pract. 2012;18: 342-350)     

Plasma proinsulin-like components and insulin in chronic liver disease.

In order to explain the increase of total IRI frequently observed at basal status, and after glucose administration, in patients with chronic liver disease, plasma proinsulin-like component and insulin levels have been studied in fourteen patients with liver cirrhosis associated or not with clinical or subclinical diabetes mellitus. A significative increase of plasma insulin was observed at basal status and after a glucose load not only in subjects with clinical or subclinical diabetes but also in those patients without carbohydrate abnormalities. This increase is apparently not correlated to any clinical characteristic and is associated in fasting and after glucose load with increased proinsulin-like component levels especially in patients with clinical or subclinical diabetes.     

Apolipoprotein B gene variants are involved in the determination of blood glucose and lipid levels in patients with non-insulin dependent diabetes mellitus

We have examined the frequency of the EcoRI, XbaI and MspI RFLPs of the apolipoprotein B (apo B) gene in 110 type 2 diabetic patients and 91 healthy control subjects in order to ascertain whether variation in this gene may influence the development of non-insulin dependent diabetes mellitus (type 2 diabetes). Serum lipids including total-cholesterol (T-Chol), triacylglycerol (TAG), apolipoprotein E (apo E), apolipoprotein AI (apo AI), apolipoprotein B and lipoprotein (a) (Lp(a)) were analysed. Genomic DNA was extracted and the apo B polymorphic regions amplified by the polymerase chain reaction. Regions carrying EcoRI, XbaI, and MspI restriction sites present in the apo B gene were amplified and digested separately by the respective enzymes. No significant difference for genotypic frequencies was observed for the EcoRI, XbaI and MspI restriction sites in type 2 diabetic patients as compared to controls. Type 2 diabetic patients and controls with EcoRI +/+ and XbaI +/+ genotypes had higher apo E levels. The MspI +/+ genotype is more frequent in the patient and control groups with elevated T-Chol. Furthermore, the EcoRI -/-, XbaI -/-, and MspI +/+ genotypes were found to be significantly more frequent in type 2 diabetic patients with higher blood glucose levels. This study identifies the apo B gene polymorphisms in modulating plasma lipid/lipoprotein and glucose levels in patients with type 2 diabetes.     

Comparative evaluation of atenolol and metoprolol on cardiovascular complications associated with streptozotocin-induced diabetic rats

Recently, various clinical studies have indicated that lipophilic beta-blockers reduce the coronary mortality in diabetic patients; however, systematic studies have not been reported. The objective of the present investigation was to compare the effects of chronic treatment with metoprolol and atenolol on cardiovascular complications in streptozotocin (STZ)-induced diabetic rats. Injection of STZ produced hyperglycemia, hypoinsulinemia, hyperlipidemia, increased blood pressure, cardiac hypertrophy, reduction in heart rate, and structural alterations in cardiac tissues. Metoprolol and atenolol effectively prevented the development of hypertension in diabetic rats. Metoprolol treatment produced a slight but significant reduction in serum glucose levels with elevation in serum insulin levels, while atenolol produced a slight increase in glucose levels but no effect on insulin levels. Moreover, neither metoprolol nor atenolol treatment reduced the elevated cholesterol levels in diabetic rats. Metoprolol treatment significantly prevented STZ-induced increase in triglyceride levels, but atenolol failed to produce this effect. Metoprolol exhibited a minimal improvement in STZ-induced bradycardia, whereas atenolol produced a further reduction in heart rate. Histological examination showed metoprolol treatment also prevented STZ-induced hypertrophy and some of the alterations in cardiomyocytes. In conclusion, our data suggest that metoprolol has some beneficial effects over atenolol with respect to cardiovascular complications associated with diabetes mellitus.     

Pioglitazone acutely influences glucose-sensitive insulin secretion in normal and diabetic human islets

We have studied acute effects of the PPARgamma agonist pioglitazone in vitro on human islets from both non-diabetic and type 2 diabetic subjects. In 5 mM glucose, pioglitazone caused a transient increase in insulin secretion in non-diabetic, but not diabetic, islets. Continuous presence of the drug suppressed insulin release in both non-diabetic and diabetic islets. In islets from non-diabetic subjects, both high glucose and tolbutamide-stimulated insulin secretion was inhibited by pioglitazone. When islets were continuously perifused with 5 mM glucose, short-term pretreatment with pioglitazone caused approximately 2-fold increase in insulin secretion after drug withdrawal. Pioglitazone pretreatment of diabetic islets restored their glucose sensitivity. Examination of cytosolic free Ca(2+) concentration ([Ca(2+)](i)) in non-diabetic islets revealed slight Ca(2+) transient by pioglitazone at 3 mM glucose with no significant changes at high glucose. Our data suggest that short-term pretreatment with pioglitazone primes both healthy and diabetic human islets for enhanced glucose-sensitive insulin secretion.