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 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. Insulin resistance is an early and major feature in the development of non-insulin-dependent diabetes mellitus (NIDDM), but it is also associated with hyperlipidaemia, hypertension, obesity and cardiovascular disease, the so-called 'insulin-resistance syndrome' (Syndrome X). 2. There is a strong genetic determination of NIDDM and insulin resistance, but the environmental factors of calorie excess, reduced activity and obesity also make a major contribution. 3. Central (abdominal) obesity is much more strongly associated with insulin resistance than is overall obesity. From twin studies, there appears to be specific genetic determinants of central abdominal fat, independent of overall obesity. 4. Calorie restriction and weight loss improve insulin sensitivity in overweight humans. Isocaloric alteration of macronutrients substantially affects insulin sensitivity in rats but not, at least in the short-term, in humans. 5. Exercise training improves insulin sensitivity via increased oxidative enzymes, glucose transporters (GLUT4) and capillarity in muscle as well as by reducing abdominal fat. 6. Metformin has been the only available drug that has been used clinically to significantly improve insulin sensitivity, but the new 'glitazones' (thiazolidinediones) have a more specific effect via altered lipid metabolism.
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PMID:Pathogenesis of the insulin resistance syndrome (syndrome X). 931 89

Although low-density lipoprotein (LDL) cholesterol is a critically important factor in the development of atherosclerosis, nearly half the patients with coronary artery disease have LDL cholesterol levels within the National Cholesterol Education Program (NCEP) guidelines. Therefore, attention has focused on other modifiable risk factors that could strongly impact the development of coronary artery disease. Type 2 diabetics have a 3-fold increased risk of coronary artery disease; prediabetics, without chronic hyperglycemia, have a 2-fold increased risk compared with normal subjects. Insulin resistance has also been implicated as the cause of atherosclerosis. Insulin resistance is associated with hyperinsulinemia and a constellation of other factors, some of which are themselves independent risk factors for coronary artery disease. These include reduced levels of high-density lipoprotein (HDL) cholesterol, hypertriglyceridemia, increased small dense LDL particles, hypertension, visceral obesity, and increased levels of plasminogen activator inhibitor-1 (PAI-1). Hyperinsulinemia and insulin resistance at the vascular level also may contribute to vascular injury and the atherosclerotic process. Current studies suggest that controlling hyperglycemia, LDL cholesterol, and blood pressure are important to protect the diabetic from atherosclerosis. A key question, particularly in type 2 diabetes, is to define the best regimen for glucose control that will protect the vasculature. Sulfonylureas, metformin, and troglitazone have direct vascular actions. Metformin lowers LDL cholesterol and triglycerides, while troglitazone reverses many of the components associated with the insulin resistance syndrome. Clinical trials focusing on coronary artery disease outcomes are now warranted to prevent coronary artery disease, the major vascular complication and cause of mortality in diabetes.
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PMID:Cardiovascular risk continuum: implications of insulin resistance and diabetes. 970 62

Metformin, an antihyperglycemic agent used for treatment of type 2 diabetes mellitus, lowers blood pressure in humans and experimental animals. We recently demonstrated that short-term administration of metformin may lower blood pressure by reducing sympathetic neural outflow. The present studies were initiated to determine whether long-term administration of metformin blunts salt-induced hypertension, a condition characterized by elevated sympathetic activity. Male spontaneously hypertensive rats, in which radiotelemeters had been implanted for continuous monitoring of heart rate and blood pressure, were randomly assigned to groups that received vehicle (drinking water) or metformin (500 mg/kg per day) and ate a normal 0.3% NaCl diet and to groups that received vehicle or metformin and ate a high 8.0% NaCl diet for a period of 4 weeks. Although metformin did not affect blood pressure in the animals that ate the normal-salt diet (vehicle, 130+/-3 mm Hg; metformin, 133+/-5 mm Hg; mean+/-SEM), drug treatment blunted the rise in pressure caused by a high-salt diet (vehicle, 153+/-4 mm Hg; metformin, 140+/-5 mm Hg; P<0.001). In agreement, during direct pressure recordings in anesthetized rats, the animals that ate the high-salt diet had higher pressures (136+/-13 mm Hg) than those in the control (98+/-5 mm Hg, P<0.01), metformin (100+/-7 mm Hg, P<0.01), and metformin/high-salt groups (92+/-3 mm Hg, P<0.01). Finally, metformin lowered heart rate in rats that ate the normal- and high-salt diets (310+/-3 and 305+/-4 bpm) compared with rats that ate normal- and high-salt diets given vehicle (332+/-3 and 324+/-2 bpm, P<0.01). These data indicate that the chronic depressor actions of metformin are enhanced in animals with hypertension exacerbated by a high-salt diet.
Hypertension 1999 May
PMID:Metformin attenuates salt-induced hypertension in spontaneously hypertensive rats. 1033

Hyperglycemia may lead to atherosclerosis by different pathogenic mechanisms. Nonenzymatic glycation and oxidation of LDL may increase its atherogenicity. Glycation may modify some arterial wall structural proteins. Increased blood glucose leads to hypertriglyceridemia which results in decrease of HDL-cholesterol level and in increase of atherogenic dense LDL particles. Hyperglycemia also adversely affects processes of platelet aggregation, hemocoagulation and fibrinolysis. It accelerates the development of diabetic nephropathy--a condition with a high prevalence of macrovascular diseases. Prospective epidemiologic studies have shown that diabetic patients in worse metabolic control had an increased cardiovascular morbidity and mortality. Therapeutic randomized studies in type 1 (DCCT) and type 2 (UKPDS) diabetic patients have shown that better diabetes control had a preventive effect against development of microvascular complications. The incidence of macrovascular complications both in type 1 diabetic patients on intensive insulin or sulfonylurea treatment has been decreased on the level of borderline statistical significance. Metformin lead to a significant decrease in myocardial infarction incidence in the subgroup of obese type 2 diabetic patients. In conclusion, maximal possible metabolic control of diabetes prevents the development of microvascular complication, but more impressive decrease in macrovascular disease incidence probably requires to affect another important risk factors for atherosclerosis, such as dyslipidemia and hypertension.
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PMID:[Hyperglycemia and atherosclerosis. Causal relation or association?]. 1095 84

The discovery that insulin resistance has a key role in the pathophysiology of PCOS has led to a novel and promising form of therapy in the form of the insulin-sensitizing drugs. Although no extremely large trials using these drugs for this indication have been performed, more than 18 trials have specifically examined the effects of these drugs on ovulation, hyperandrogenemia, and dysmetabolic features in PCOS. Table 1 summarizes the results of previous trials using each of the insulin-sensitizing drugs discussed herein. Among the various agents (i.e., thiazolidinediones, [table: see text] metformin, and D-chiro-inositol), metformin is the most widely tested. Metformin may have the added benefit of improving at least some features of syndrome X, such as hypertension and obesity. All of the evidence to date suggests that metformin is a safe drug to administer to women who may become pregnant. In contrast, the two thiazolidinediones currently available, rosiglitazone and pioglitazone, are category C drugs that have been demonstrated to retard fetal development in animal studies. Overall, insulin-sensitizing therapy presents a promising and unique therapeutic intervention for the treatment of PCOS, offering metabolic and gynecologic benefits for women who sustain this syndrome.
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PMID:Insulin-lowering drugs in polycystic ovary syndrome. 1129

Polycystic ovary syndrome (PCOS) is classically characterised by ovarian dysfunction (oligomenorrhoea, anovulation and infertility), androgen excess (hirsutism and acne), obesity, and morphological abnormalities of the ovaries (cystic enlargement and stromal expansion). More recently, insulin resistance has been found to be common in PCOS, along with an increased prevalence of other features of the "metabolic syndrome", namely glucose intolerance, type 2 diabetes mellitus, and hyperlipidaemia. Hyperinsulinaemia is likely to contribute to the disordered ovarian function and androgen excess of PCOS. Reducing insulin resistance by lifestyle modifications such as diet and exercise improves endocrine and menstrual function in PCOS. These lifestyle modifications are the best initial means of improving insulin resistance. Metformin, an oral hypoglycaemic agent that increases insulin sensitivity, has been shown to reduce serum concentrations of insulin and androgens, to reduce hirsutism, and to improve ovulation rates. The effect of metformin alone on fertility rates is unknown. Some studies suggest that metformin will reduce total body weight to a small extent, but with a predominant effect on visceral adipose reduction. The effects of metformin on lipid abnormalities, hypertension or premature vascular disease are unknown, but the relative safety, moderate cost, and efficacy in reducing insulin resistance suggest that metformin may prove to be of benefit in combating these components of the "metabolic" syndrome in PCOS. Further properly planned randomised controlled trials are required.
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PMID:Metformin and intervention in polycystic ovary syndrome. Endocrine Society of Australia, the Australian Diabetes Society and the Australian Paediatric Endocrine Group. 1145 23

Obesity has been shown to be an independent risk factor for coronary heart disease. The insulin resistance associated with obesity contributes to the development of other cardiovascular risk factors, including dyslipidemia, hypertension, and type 2 diabetes. The coexistence of hypertension and diabetes increases the risk for macrovascular and microvascular complications, thus predisposing patients to cardiac death, congestive heart failure, coronary heart disease, cerebral and peripheral vascular diseases, nephropathy, and retinopathy. Body weight reduction increases insulin sensitivity and improves both blood glucose and blood pressure control. Metformin therapy also improves insulin sensitivity and has been associated with decreases in cardiovascular events in obese diabetic patients. Antihypertensive treatment in diabetics decreases cardiovascular mortality and slows the decline in glomerular function. However, pharmacological treatment should take into account the effects of the antihypertensive agents on insulin sensitivity and lipid profile. Diuretics and beta-blockers are reported to reduce insulin sensitivity and increase triglyceride levels, whereas calcium channel blockers are metabolically neutral and ACE inhibitors increase insulin sensitivity. For the high-risk hypertensive diabetic patients, ACE inhibition has proven to confer additional renal and vascular protection. Because hypertension and glycemic control are very important determinants of cardiovascular outcome in obese diabetic hypertensive patients, weight reduction, physical exercise, and a combination of antihypertensive and insulin sensitizers agents are strongly recommended to achieve target blood pressure and glucose levels.
Hypertension 2001 Sep
PMID:Treatment of obesity hypertension and diabetes syndrome. 1156 61

The aim of this study was to examine the effects of long-term continuous intracerebroventricular (icv) infusion of metformin on blood pressure (BP) in spontaneously hypertensive rats (SHR). To accelerate the development of hypertension, SHR were fed a 8% NaCl diet during the 3-week study period. Metformin was given in the following doses: 0 (isotonic saline; n = 7), 25 (n = 8), 50 (n = 6), 100 (n = 6), and 200 microg/day icv (n = 5). Mean arterial pressure (MAP) and heart rate (HR) were measured by radiotelemetry, and as a measure of the contribution of sympathetic nerve activity to BP, the decrease in MAP in response to ganglionic blockade with hexamethonium, 30 mg/kg iv, was determined once weekly. In vehicle treated rats, MAP increased by 27+/-4 mm Hg, whereas in rats treated with a low dose of metformin (25 microg/day), MAP increased only by 7+/-3 mm Hg (P < .01). The hypotensive response to hexamethonium was attenuated by all doses of metformin suggesting that chronic icv metformin decreased central sympathetic outflow. The highest doses of metformin (100 and 200 microg/day) also prevented development of hypertension, but these doses were highly neurotoxic as demonstrated by histologic evaluation post mortem. Fast-Fourier transformation of MAP revealed increased variability within the 0.15 to 0.6 Hz frequency range in rats treated with neurotoxic doses of metformin, suggesting impaired sympathetic control of BP in these animals. In conclusion, long-term icv infusion with apparently nontoxic doses of metformin attenuates hypertension and decreases the hypotensive responses to ganglionic blockade in SHR, suggesting a centrally elicited sympathoinhibitory action.
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PMID:Intracerebroventricular metformin attenuates salt-induced hypertension in spontaneously hypertensive rats. 1172 10

Basing on the key role of the hyperinsulinemia in the etiopathogenesis of the Polycystic ovary syndrome, the authors treat the affected women with Metformin. In an 1 year prospective study, including 30 women, they assess the effect of the application of Metformin in relation to some indexes--BMI, WHR, IRI, LH, LH/FSH ratio. After analysing the results, it is reported for a decrease in the absolute values of BMI, WHR and a tendency for redistribution of the adipose tissue from visceral to gynoid type. They report for a statistical reliability in the decrease of LH and LH/FSH ratio. The level of IRI decreases pointedly at every stage of the study. 28 of the patients influence favourably in one or other degree, regarding the menstrual cycles. A good results is also reported in reference to Arterial Hypertension. According to the authors, Mtformin is a good alternative in the treatment of the PCOS.
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PMID:[Our experience in the treatment of polycystic ovary syndrome with Metformin]. 1178 62

The etiology, natural history, and relationship of insulin resistance to type 2 diabetes mellitus and the effects of insulin-sensitizing agents are described. Insulin resistance results from a combination of genetic and environmental factors and contributes to type 2 diabetes mellitus, dyslipidemia, hypertension, central (abdominal) obesity, and cardiovascular disease. Insulin resistance does not necessarily progress to impaired glucose tolerance or diabetes because insulin secretion by normal pancreatic beta cells can increase to compensate for reduced physiological activity. Diabetes may develop in insulin-resistant persons with inherited secretory and glucose-sensing defects in beta cells. The pathogenesis of diabetes appears to involve a progressive decrease in beta-cell mass, potentially triggered by abnormalities in adipocytokine release from intraabdominal fat cells. Metformin and the thiazolidinediones are used to treat insulin resistance, but their actions differ. Metformin reduces free-fatty-acid efflux from fat cells, thereby suppressing hepatic glucose production, and indirectly improves peripheral insulin sensitivity and endothelial function. Thiazolidinediones improve peripheral insulin sensitivity by reducing circulating free fatty acids but also by suppressing adipocytokines, which increase insulin resistance. Thiazolidinediones also improve endothelial function and may prevent or delay the onset of diabetes. Insulin is intrinsically antiatherogenic but may mediate arterial inflammation in insulin-resistant patients. Unlike metformin, the thiazolidinediones suppress this inflammatory pathway and may indirectly help preserve beta-cell function. Insulin resistance, resulting from a combination of genetic and environmental factors, plays a central role in type 2 diabetes mellitus. Diabetes may develop in insulin-resistant persons with inherited secretory and glucose-sensing defects in beta cells. Metformin and thiazolidinediones are insulin-sensitizing agents with different mechanisms of action and effects in patients with type 2 diabetes mellitus.
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PMID:Insulin resistance, diabetes, and the adipocyte. 1248 80


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