The dual peroxisome proliferator-activated receptor alpha/gamma activator muraglitazar prevents the natural progression of diabetes in db/db mice

There are two major defects in type 2 diabetes: 1) insulin resistance and 2) insulin deficiency due to loss of beta-cell function. Here we demonstrated that treatment with muraglitazar (a dual peroxisome proliferator-activated receptor alpha/gamma activator), when initiated before or after the onset of diabetes in mice, is effective against both defects. In study 1, prediabetic db/db mice were treated for 12 weeks. The control mice developed diabetes, as evidenced by hyperglycemia, hyperinsulinemia, reduced insulin levels in the pancreas, blunted insulin response to glucose, and impaired glucose tolerance. The muraglitazar-treated mice had normal plasma glucose, and insulin levels, equivalent or higher pancreatic insulin content than normal mice, showed a robust insulin response to glucose and exhibited greater glucose tolerance. In study 2, diabetic db/db mice were treated for 4 weeks. The control mice displayed increased glucose levels, severe loss of islets, and their isolated islets secreted reduced amounts of insulin in response to glucose and exendin-4 compared with baseline. In muraglitazar-treated mice, glucose levels were reduced to normal. These mice showed reduced loss of islets, and their isolated islets secreted insulin at levels comparable to baseline. Thus, muraglitazar treatment decreased both insulin resistance and preserved beta-cell function. As a result, muraglitazar treatment, when initiated before the onset of diabetes, prevented development of diabetes and, when initiated after the onset of diabetes, prevented worsening of diabetes in db/db mice.     

Telmisartan improves lipid metabolism and adiponectin production but does not affect glycemic control in hypertensive patients with type 2 diabetes

Angiotensin II receptor blockers as a class are reported to act as insulin sensitizers. Of these, telmisartan has been shown to have additional unique peroxisome proliferator-activated receptor-gamma-mediated, insulin-sensitizing properties. In this study, investigators explored the effects of telmisartan on glycemic control and lipid metabolism in hypertensive patients with type 2 diabetes who had switched to telmisartan from another angiotensin II receptor blocker. The study subjects were 42 hypertensive outpatients with type 2 diabetes who were being treated with candesartan 8 mg/d and who agreed to switch to treatment with telmisartan 40 mg/d. Relevant laboratory variables were measured 6 mo before treatment switching, at the time of switching, and 6 mo after switching. No significant differences were noted in blood pressure, body mass index, or glycosylated hemoglobin among subjects before and after therapy was switched. No adverse reactions such as edema or hepatic toxicity were noted. No significant changes in fasting plasma glucose, fasting insulin, HOMA-R (insulin resistance as measured by the homeostasis model), preheparin lipoprotein lipase mass, high-density lipoprotein cholesterol, and free fatty acids were noted. Triglyceride levels were significantly decreased, however, and adiponectin levels were significantly increased (8.1+/-3.1 microg/mL at switching; 8.6+/-3.0 microg/mL 6 mo after switching; P<.01) after the switch to telmisartan therapy. Study results show that telmisartan did not affect glycemic control, but it improved lipid metabolism and adiponectin production in patients with type 2 diabetes, suggesting that AT(1)-receptor antagonism and selective peroxisome proliferator-activated receptor-gamma activation by telmisartan combine to account for observed effects on lipid metabolism and adiponectin production.     

山奈酚对2型糖尿病大鼠糖脂代谢及胰岛素抵抗的影响

目的探讨PPARγ激动剂山奈酚对糖尿病大鼠血糖、胰岛素抵抗及血脂生化水平的影响。方法高糖高脂饲料喂养加腹腔注射链脲佐菌素建立2型糖尿病大鼠模型,实验组灌胃给予山奈酚50、100、200 mg/(kg.d),灌胃给药10周后,葡萄糖氧化酶法进行空腹血糖测定,放射免疫法进行血浆胰岛素水平测定,酶法测定血浆总胆固醇、甘油三酯、尿素氮和肌酐含量。结果与模型组相比,山奈酚治疗组空腹血糖值及胰岛素抵抗均有所下降,血脂生化水平也有所降低,与模型组比较存在显著性差异。结论山奈酚可有效降低空腹血糖和胰岛素抵抗,改善糖脂代谢紊乱。     

初诊2型糖尿病患者前列环素与胰岛素抵抗的相关分析

目的分析初诊2型糖尿病(T2DM)患者血浆前列环素(PGI2)水平变化及其与胰岛素抵抗(IR)的相关性。方法选择初诊T2DM患者60例及健康对照组60例,测定体质量、身高、血脂、空腹血糖(FPG)、餐后2h血糖(2hPG)、空腹胰岛素(FINS)、餐后2h胰岛素(2hINS),计算胰岛素抵抗指数(HOMA-IR),测定血浆PGI2的稳定代谢产物6-酮-前列腺素F1α(6-keto-PGF1α)浓度,并作相关性分析。结果 T2DM组体质量指数(BMI)、三酰甘油(TG)、总胆固醇(TC)、FPG、2hPG、FINS、2hINS、HOMA-IR均高于健康对照组,差异有统计学意义(P0.05);T2DM组血浆6-keto-PGF1α水平较健康对照组明显下降(P0.01);血浆6-keto-PGF1α水平与HOMA-IR呈负相关(r=-0.82,P0.01)。结论 T2DM患者存在IR,血浆PGI2的代谢终末产物6-keto-PGF1α水平与IR密切相关。     

The glitazones: a new treatment for type 2 diabetes mellitus.

The glitazones are a new class of anti-diabetic drugs that act by improving sensitivity to insulin and are indicated in the treatment of type 2 diabetes. The glitazones have effects on carbohydrate and lipid metabolism and hold the promise of being able to influence the many components of the insulin resistance syndrome seen in type 2 diabetes. It is possible that the glitazones may be able to prevent or delay the cardiovascular disease which accompanies type 2 diabetes, long-term studies are required to determine if this is the case. In addition to drug treatment patients with type 2 diabetes should be strongly encouraged to make life style changes which will improve glycaemic control such as weight reduction and increase exercise.     

Comparison of insulin aspart and lispro: pharmacokinetic and metabolic effects

OBJECTIVE: To compare insulin levels and actions in patients with type 1 diabetes after subcutaneous injection of the rapid-acting insulin analogs aspart and lispro. RESEARCH DESIGN AND METHODS: Seven C-peptide-negative patients with type 1 diabetes (two men and five women) were studied at the General Clinical Research Center at Temple University Hospital two times, 1 month apart. Their plasma glucose was normalized overnight by intravenous infusion of insulin. The next morning, they received subcutaneous injections of either aspart or lispro (9.4 +/- 1.9 U) in random order. For the next 4-5 h, their plasma glucose was clamped at approximately 5.5 mmol/l with a variable infusion of 20% glucose. The study was terminated after 8 h. RESULTS: Both insulin analogs produced similar serum insulin levels (250-300 pmol/l) at approximately 30 min and disappeared from serum after approximately 4 h. Insulin aspart and lispro had similar effects on glucose and fat metabolism. Effects on carbohydrate metabolism (glucose uptake, glucose oxidation, and endogenous glucose production) peaked after approximately 2-3 h and disappeared after approximately 5-6 h. Effects on lipid metabolism (plasma free fatty acid, ketone body levels, and free fatty acid oxidation) appeared to peak earlier (at approximately 2 h) and disappeared earlier (after approximately 4 h) than the effects on carbohydrate metabolism. CONCLUSIONS: We conclude that both insulin aspart and lispro are indistinguishable from each other with respect to blood levels and that they are equally effective in correcting abnormalities in carbohydrate and fat metabolism in patients with type 1 diabetes.     

Dysfunctional fat cells, lipotoxicity and type 2 diabetes

Type 2 diabetes is characterized by insulin resistance and impaired insulin secretion. Considerable evidence implicates altered fat topography and defects in adipocyte metabolism in the pathogenesis of type 2 diabetes. In individuals who develop type 2 diabetes, fat cells tend to be enlarged. Enlarged fat cells are resistant to the antilipolytic effects of insulin, leading to day-long elevated plasma free fatty acid (FFA) levels. Chronically increased plasma FFA stimulates gluconeogenesis, induces hepatic and muscle insulin resistance, and impairs insulin secretion in genetically predisposed individuals. These FFA-induced disturbances are referred to as lipotoxicity. Enlarged fat cells also have diminished capacity to store fat. When adipocyte storage capacity is exceeded, lipid 'overflows' into muscle and liver, and possibly the beta-cells of the pancreas, exacerbating insulin resistance and further impairing insulin secretion. In addition, dysfunctional fat cells produce excessive amounts of insulin resistance-inducing, inflammatory and atherosclerosis-provoking cytokines, and fail to secrete normal amounts of insulin-sensitizing cytokines. As more evidence emerges, there is a stronger case for targeting adipose tissue in the treatment of type 2 diabetes. Peroxisome-proliferator activated receptor gamma (PPARgamma) agonists, for example the thiazolidinediones, redistribute fat within the body (decrease visceral and hepatic fat; increase subcutaneous fat) and have been shown to enhance adipocyte insulin sensitivity, inhibit lipolysis, reduce plasma FFA and favourably influence the production of adipocytokines. This article examines in detail the role of adipose tissue in the pathogenesis of type 2 diabetes and highlights the potential of PPAR agonists to improve the management of patients with the condition.     

Hypertension and abnormal fat distribution but not insulin resistance in mice with P465L PPARgamma

Peroxisome proliferator-activated receptor gamma (PPARgamma), the molecular target of a class of insulin sensitizers, regulates adipocyte differentiation and lipid metabolism. A dominant negative P467L mutation in the ligand-binding domain of PPARgamma in humans is associated with severe insulin resistance and hypertension. Homozygous mice with the equivalent P465L mutation die in utero. Heterozygous mice grow normally and have normal total adipose tissue weight. However, they have reduced interscapular brown adipose tissue and intra-abdominal fat mass, and increased extra-abdominal subcutaneous fat, compared with wild-type mice. They have normal plasma glucose levels and insulin sensitivity, and increased glucose tolerance. However, during high-fat feeding, their plasma insulin levels are mildly elevated in association with a significant increase in pancreatic islet mass. They are hypertensive, and expression of the angiotensinogen gene is increased in their subcutaneous adipose tissues. The effects of P465L on blood pressure, fat distribution, and insulin sensitivity are the same in both male and female mice regardless of diet and age. Thus the P465L mutation alone is sufficient to cause abnormal fat distribution and hypertension but not insulin resistance in mice. These results provide genetic evidence for a critical role for PPARgamma in blood pressure regulation that is not dependent on altered insulin sensitivity.     

S-Allyl cysteine improves nonalcoholic fatty liver disease in type 2 diabetes Otsuka Long-Evans Tokushima Fatty rats via regulation of hepatic lipogenesis and glucose metabolism

It is important to prevent and improve diabetes mellitus and its complications in a safe and low-cost manner. S-Allyl cysteine, an aged garlic extract with antioxidant activity, was investigated to determine whether S-allyl cysteine can improve type 2 diabetes in Otsuka Long-Evans Tokushima Fatty rats with nonalcoholic fatty liver disease. Male Otsuka Long-Evans Tokushima Fatty rats and age-matched Long-Evans Tokushima Otsuka rats were used and were divided into two groups at 29 weeks of age. S-Allyl cysteine (0.45% diet) was administered to rats for 13 weeks. Rats were killed at 43 weeks of age, and detailed analyses were performed. S-Allyl cysteine improved hemoglobinA1c, blood glucose, triglyceride, and low-density lipoprotein cholesterol levels. Furthermore, S-allyl cysteine normalized plasma insulin levels. S-Allyl cysteine activated the mRNA and protein expression of both peroxisome proliferator-activated receptor α and γ, as well as inhibiting pyruvate dehydrogenase kinase 4 in Otsuka Long-Evans Tokushima Fatty rat liver. Sterol regulatory element-binding protein 1c and forkhead box O1 proteins were normalized by S-allyl cysteine in Otsuka Long-Evans Tokushima Fatty rat liver. In conclusions, these findings support the hypothesis that S-allyl cysteine has diabetic and nonalcoholic fatty liver disease therapeutic potential as a potent regulating agent against lipogenesis and glucose metabolism.     

Identifying the links between obesity,insulin resistance and beta-cell function: potential role of adipocyte-derived cytokines in the pathogenesis of type 2 diabetes

A combination of insulin resistance and pancreatic beta-cell dysfunction underlies most cases of type 2 diabetes. While the interplay of these two impairments is believed to be important in the development and progression of type 2 diabetes, the mechanisms involved are unclear. A number of factors have been suggested as possibly linking insulin resistance and beta-cell dysfunction in the pathogenesis of type 2 diabetes mellitus. Pro-inflammatory cytokines such as tumour necrosis factor-alpha (TNF-alpha) have deleterious effects on both glucose homeostasis and beta-cell function, and can disrupt insulin signalling pathways in both pancreatic beta cells and liver and adipose tissue. The anti-inflammatory activity of the thiazolidinedione anti-diabetic agents is potentially beneficial, given the possible role of pro-inflammatory cytokines in linking insulin resistance with beta-cell dysfunction.     

Genetic factors and insulin resistance

Diabetes is characterized by impaired insulin secretion from pancreatic beta-cell and/or insulin resistance in peripheral tissues. Genetic factors affecting the insulin sensitivities have been described, including the mutations of genes of insulin receptor, insulin receptor substrate-1, glycogen synthase, uncoupling proteins, beta3-adrenergic receptor, and peroxisome proliferator-activated receptor gamma. Mutant insulin receptors might act as a monogenic factor, but most of the others act as one of the genetic factors of a polygenetic disease.     

Improved insulin-sensitivity in mice heterozygous for PPAR-gamma deficiency

The thiazolidinedione class of insulin-sensitizing, antidiabetic drugs interacts with peroxisome proliferator-activated receptor gamma (PPAR-gamma). To gain insight into the role of this nuclear receptor in insulin resistance and diabetes, we conducted metabolic studies in the PPAR-gamma gene knockout mouse model. Because homozygous PPAR-gamma-null mice die in development, we studied glucose metabolism in mice heterozygous for the mutation (PPAR-gamma(+/-) mice). We identified no statistically significant differences in body weight, basal glucose, insulin, or FFA levels between the wild-type (WT) and PPAR-gamma(+/-) groups. Nor was there a difference in glucose excursion between the groups of mice during oral glucose tolerance test, but insulin concentrations of the WT group were greater than those of the PPAR-gamma(+/-) group, and insulin-induced increase in glucose disposal rate was significantly increased in PPAR-gamma(+/-) mice. Likewise, the insulin-induced suppression of hepatic glucose production was significantly greater in the PPAR-gamma(+/-) mice than in the WT mice. Taken together, these results indicate that - counterintuitively - although pharmacological activation of PPAR-gamma improves insulin sensitivity, a similar effect is obtained by genetically reducing the expression levels of the receptor.     

Pioglitazone: beyond glucose control

Pioglitazone is an oral antidiabetic agent that decreases insulin resistance in adipose tissue, liver and muscles. This action is mediated by its link to a nuclear receptor called peroxisome proliferator-activated receptor-γ. By improving insulin sensitivity, hepatic glucose production decreases and glucose uptake increases in the peripheral tissues. Beyond these effects on glucose metabolism, pioglitazone has positive effects on lipid metabolism, blood pressure, endothelial function, adiponectin and C-reactive protein levels. These make pioglitazone treatment effective beyond glucose control. In this article, current evidence concerning pioglitazone in the treatment of Type 2 diabetes will be reviewed.     

Telmisartan at 80 mg/Day Increases High-Molecular-Weight Adiponectin Levels and Improves Insulin Resistance in Diabetic Patients

Introduction

The clinical dose of telmisartan necessary for activation of peroxisome proliferator-activated receptor gamma (PPAR-gamma) has not been established. The authors investigated the effect of high-dose telmisartan on serum levels of the high-molecular-weight (HMW) adiponectin in patients with diabetes and hypertension.

Methods

In this open-label, prospective, randomized study, patients with type 2 diabetes and hypertension with poor control of blood pressure by 40 mg/day telmisartan were randomly assigned into the telmisartan 80 mg/day (Tel80) group (dose increase from 40 to 80 mg/day) or the telmisartan 40 mg + amlodipine 5 mg (Tel40 + Aml5) group. Serum levels of HMW adiponectin and parameters of glucose and lipid metabolism were measured at baseline and end of 3-months of treatment.

Results

Although the antihypertensive effects of the two doses of telmisartan were similar, a significant increase in HMW adiponectin levels was noted only in the Tel80 group. The increase was evident particularly in a group of patients whose HMW adiponectin levels were less than 4.0 ??g/dL. A significant improvement in homeostasis model assessment of insulin resistance (HOMA-IR), a measure of insulin resistance, was also observed in the Tel80 group only.

Conclusions

In diabetic patients with hypertension, high-dose telmisartan increased HMW adiponectin levels and improved insulin resistance through activation of PPAR-gamma.     

Protective effect of selenium on certain hepatotoxic and pancreotoxic manifestations of subacute cadmium administration.

Administration of cadmium chloride (1.0 mg/kg s.c.) to rats, twice a day for 7 days, significantly stimulated the activities of hepatic pyruvate carboxylase, phosphoenolpyruvate carboxykinase, fructose 1,6-diphosphatase and glucose 6-phosphatase, markedly increased the concentration of hepatic cyclic adenosine monophosphate and circulating blood glucose and significantly reduced serum insulin levels. Furthermore, subacute exposure to cadmium induced glucose intolerance that was associated with a decreased pancreatic secretory activity as evidenced by lowered insulinogenic indices and marked inhibition of phentolamine-stimulated insulin release. In contrast to cadmium, administration of selenium dioxide (2 X 1.0 mg/kg/day s.c., 7 days) failed to alter significantly the activities of gluconeogenic enzymes, hepatic cyclic adenosine monophosphate, blood glucose or serum insulin levels, glucose tolerance or the pancreatic secretory activity. However, administration of selenium concurrently with cadmium completely prevented the cadmium-induced increases of hepatic gluconeogenic enzymes. Treatment with selenium ameliorated the cadmium-induced hyperglycemia, hypoinsulinemia, glucose intolerance and the suppression of pancreatic secretory activity, whereas it failed to alter significantly the cadmium-induced elevation of hepatic cyclic AMP levels. Data provide evidence suggesting that subacute exposure to cadmium alters several parameters of carbohydrate metabolism and suppresses pancreatic secretory activity and that administration of selenium alone is without any appreciable effect on the above parameters. However, administration of selenium concurrently with cadmium prevents, to varying degrees, several of the cadmium-induced metabolic and functional changes.     

Lipid reducing and antioxidant action of mexicor in patients with diabetes mellitus type 2

AIM: To study mexicor effects on functional activity of beta-cells, insulin resistance, lipid metabolism and lipid peroxidation in patients with diabetes mellitus (DM) type 2. MATERIAL AND METHODS: Twenty patients with DM type 2 participated in a double blind randomized trial of mexicor vs placebo. Before and after therapy the following parameters were studied: plasma glucose before meal, immunoreactive insulin, glycosilated hemoglobin, cholesterol, triglycerides, LDLP and HDLP cholesterol, malonic dialdehyde, dienic conjugates, superoxide dismutase, catalase, glutathione peroxidase and alpha-tocopherol. RESULTS: Mexicor significantly improved compensation of carbohydrate metabolism by glucose and glycosylated hemoglobin in the blood, insulin resistance value, lipid metabolism and lipid peroxidation in activation of antioxidant enzymes. CONCLUSION: Mexicor in therapy of DM type 2 improves carbohydrate and lipid metabolism, lipid peroxidation, activates antioxidant defence enzymes, functional activity of beta-cells, reduces insulin resistance.