Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Metformin reduces the incidence of progression to type 2 diabetes in humans with obesity or impaired glucose tolerance. We used an animal model to investigate whether metformin could prevent acute lipid-induced insulin resistance and the mechanisms involved. Metformin or vehicle was administered to rats daily for 1 week. Rats were studied basally, after 3.75 h of intralipid-heparin or glycerol infusion, or after 5 h of infusion with a hyperinsulinemic-euglycemic clamp between 3 and 5 h. Metformin had no effect on plasma triacylglycerol or nonesterified fatty acid concentrations and did not alter glucose turnover or gluconeogenic enzyme mRNA after lipid infusion. However, metformin normalized hepatic glucose output and increased liver glycogen during lipid infusion and clamp. Basal liver (but not muscle or fat) AMP-activated protein kinase activity was increased by metformin (by 310%; P < 0.01), associated with increased phosphorylation of acetyl CoA carboxylase. Postclamp liver but not muscle phosphorylated/total Akt protein was increased, whereas basal c-Jun NH2-terminal kinase-1 and -2 protein expression were reduced (by 39 and 53%, respectively; P < 0.05). Metformin also increased hepatic basal IkappaBalpha levels (by 260%; P < 0.001) but had no effect on tyrosine phosphorylation or expression of insulin receptor substrate-1 (IRS-1). In summary, metformin opposes the development of acute lipid-induced insulin resistance in the liver through alterations in multiple signaling pathways.
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PMID:Metformin prevents the development of acute lipid-induced insulin resistance in the rat through altered hepatic signaling mechanisms. 1556 58

Type 2 diabetes mellitus is a progressive and complex disorder that is difficult to treat effectively in the long term. The majority of patients are overweight or obese at diagnosis and will be unable to achieve or sustain near normoglycaemia without oral antidiabetic agents; a sizeable proportion of patients will eventually require insulin therapy to maintain long-term glycaemic control, either as monotherapy or in conjunction with oral antidiabetic therapy. The frequent need for escalating therapy is held to reflect progressive loss of islet beta-cell function, usually in the presence of obesity-related insulin resistance. Today's clinicians are presented with an extensive range of oral antidiabetic drugs for type 2 diabetes. The main classes are heterogeneous in their modes of action, safety profiles and tolerability. These main classes include agents that stimulate insulin secretion (sulphonylureas and rapid-acting secretagogues), reduce hepatic glucose production (biguanides), delay digestion and absorption of intestinal carbohydrate (alpha-glucosidase inhibitors) or improve insulin action (thiazolidinediones). The UKPDS (United Kingdom Prospective Diabetes Study) demonstrated the benefits of intensified glycaemic control on microvascular complications in newly diagnosed patients with type 2 diabetes. However, the picture was less clearcut with regard to macrovascular disease, with neither sulphonylureas nor insulin significantly reducing cardiovascular events. The impact of oral antidiabetic agents on atherosclerosis--beyond expected effects on glycaemic control--is an increasingly important consideration. In the UKPDS, overweight and obese patients randomised to initial monotherapy with metformin experienced significant reductions in myocardial infarction and diabetes-related deaths. Metformin does not promote weight gain and has beneficial effects on several cardiovascular risk factors. Accordingly, metformin is widely regarded as the drug of choice for most patients with type 2 diabetes. Concern about cardiovascular safety of sulphonylureas has largely dissipated with generally reassuring results from clinical trials, including the UKPDS. Encouragingly, the recent Steno-2 Study showed that intensive target-driven, multifactorial approach to management, based around a sulphonylurea, reduced the risk of both micro- and macrovascular complications in high-risk patients. Theoretical advantages of selectively targeting postprandial hyperglycaemia require confirmation in clinical trials of drugs with preferential effects on this facet of hyperglycaemia are currently in progress. The insulin-sensitising thiazolidinedione class of antidiabetic agents has potentially advantageous effects on multiple components of the metabolic syndrome; the results of clinical trials with cardiovascular endpoints are awaited. The selection of initial monotherapy is based on a clinical and biochemical assessment of the patient, safety considerations being paramount. In some circumstances, for example pregnancy or severe hepatic or renal impairment, insulin may be the treatment of choice when nonpharmacological measures prove inadequate. Insulin is also required for metabolic decompensation, that is, incipient or actual diabetic ketoacidosis, or non-ketotic hyperosmolar hyperglycaemia. Certain comorbidities, for example presentation with myocardial infarction during other acute intercurrent illness, may make insulin the best option. Oral antidiabetic agents should be initiated at a low dose and titrated up according to glycaemic response, as judged by measurement of glycosylated haemoglobin (HbA1c) concentration, supplemented in some patients by self monitoring of capillary blood glucose. The average glucose-lowering effect of the major classes of oral antidiabetic agents is broadly similar (averaging a 1-2% reduction in HbA1c), alpha-glucosidase inhibitors being rather less effective. Tailoring the treatment to the individual patient is an important principle. Doses are gradually titrated up according to response. However, the maximal glucose-lowering action for sulphonylureas is usually attained at appreciably lower doses (approximately 50%) than the manufacturers' recommended daily maximum. Combinations of certain agents, for example a secretagogue plus a biguanide or a thiazolidinedione, are logical and widely used, and combination preparations are now available in some countries. While the benefits of metformin added to a sulphonylurea were initially less favourable in the UKPDS, longer-term data have allayed concern. When considering long-term therapy, issues such as tolerability and convenience are important additional considerations. Neither sulphonylureas nor biguanides are able to appreciably alter the rate of progression of hyperglycaemia in patients with type 2 diabetes. Preliminary data suggesting that thiazolidinediones may provide better long-term glycaemic stability are currently being tested in clinical trials; current evidence, while encouraging, is not conclusive. Delayed progression from glucose intolerance to type 2 diabetes in high-risk individuals with glucose intolerance has been demonstrated with troglitazone, metformin and acarbose. However, intensive lifestyle intervention can be more effective than drug therapy, at least in the setting of interventional clinical trials. No antidiabetic drugs are presently licensed for use in prediabetic individuals.
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PMID:Oral antidiabetic agents: current role in type 2 diabetes mellitus. 1566 80

Type 2 diabetes is a serious, costly, and increasingly common disease. Several conditions commonly seen in family medicine settings confer increased risk of developing diabetes. Among these conditions are impaired glucose tolerance, impaired fasting glucose, obesity, gestational diabetes, hypertension, hyperlipidemia, and menopause. We here present the results of a systematic review of the literature examining the evidence for different strategies aimed at preventing type 2 diabetes in patients with these conditions. The strongest evidence supports an intensive lifestyle intervention designed to induce modest weight loss. The greatest degree of prevention, based on lesser quality evidence, may be imparted by bariatric surgery. Metformin and troglitazone have appreciable evidence in specific populations, and orlistat and acarbose have slightly less evidence among obese patients, for preventing diabetes. Ramipril, captopril, losartan, pravastatin, and estrogens show some very preliminary promise for preventing diabetes in patients treated for hypertension, hyperlipidemia, and menopause, but each needs a more rigorous evaluation. Although more questions remain to be answered, family physicians now have tools available to help our patients lead lives free of diabetes.
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PMID:Preventing type 2 diabetes mellitus. 1570 62

Increases in subclinical inflammation (C-reactive protein [CRP]) and impaired coagulation have been associated with increased obesity and insulin resistance. Only a few small studies have examined the effect of lifestyle changes, such as weight loss, increased physical activity, and insulin-sensitizing intervention on inflammation and coagulation. The Diabetes Prevention Program (DPP) clinical trial studied the effect of an intensive lifestyle intervention or metformin on progression to diabetes relative to placebo in 3,234 adults with impaired glucose tolerance. The effects of these interventions on CRP and fibrinogen at 12 months are examined in this report. Metformin reduced CRP in women compared with the placebo group. In men, the median changes in CRP from baseline to 1 year were -33% in the lifestyle group, -7% in the metformin group, and +5% in the placebo group. In women, the changes in CRP from baseline to follow-up were -29% in the lifestyle group, -14% in the metformin group, and 0% in the placebo group. In the lifestyle group weight loss rather than increased physical activity seems to account for most of the changes in CRP. Only modest reductions (although significant) were seen in fibrinogen levels in the lifestyle group relative to the metformin and placebo group. Lifestyle intervention reduced levels of nontraditional cardiovascular risk factors relative to both placebo and to a lesser degree to metformin.
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PMID:Intensive lifestyle intervention or metformin on inflammation and coagulation in participants with impaired glucose tolerance. 1585 47

Accumulating evidence suggests that high concentrations of leptin observed in obesity and diabetes may contribute to their adverse effects on cardiovascular health. Metformin monotherapy is associated with reduced macrovascular complications in overweight patients with type 2 diabetes. It is uncertain whether such improvement in the cardiovascular outcome is related to specific vasculoprotective effects of this drug. In the present study, we determined the effect of leptin on human aortic smooth muscle cell (HASMC) proliferation and matrix metalloproteinase (MMP)-2 expression, the signaling pathways mediating these effects, and the modulatory effect of metformin on these parameters. Incubation of HASMCs with leptin enhanced the proliferation and MMP-2 expression in these cells and increased the generation of intracellular reactive oxygen species (ROS). These effects were abolished by vitamin E. Inhibition of NAD(P)H oxidase and protein kinase C (PKC) suppressed the effect of leptin on ROS production. In HASMCs, leptin induced PKC, extracellular signal-regulated kinase (ERK)1/2, and nuclear factor-kappaB (NF-kappaB) activation and inhibition of these signaling pathways abrogated HASMC proliferation and MMP-2 expression induced by this hormone. Treatment of HASMCs with metformin decreased leptin-induced ROS production and activation of PKC, ERK1/2, and NF-kappaB. Metformin also inhibited the effect of leptin on HASMC proliferation and MMP-2 expression. Overall, these results demonstrate that leptin induced HASMC proliferation and MMP-2 expression through a PKC-dependent activation of NAD(P)H oxidase with subsequent activation of the ERK1/2/NF-kappaB pathways and that therapeutic metformin concentrations effectively inhibit these biological effects. These results suggest a new mechanism by which metformin may improve cardiovascular outcome in patients with diabetes.
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PMID:Signaling pathways involved in human vascular smooth muscle cell proliferation and matrix metalloproteinase-2 expression induced by leptin: inhibitory effect of metformin. 1598 26

Nonalcoholic fatty liver disease (NAFLD) is increasingly recognized as one of the most common causes of chronic liver damage in the western world. It is strongly associated with insulin resistance, obesity and other features of the metabolic syndrome. The entity NAFLD embraces a clinical spectrum from benign steatosis over steatohepatitis to hepatic cirrhosis with its complications liver failure and hepatocellular carcinoma. Treatment is currently based on prescriptive diet and physical exercise. A well-defined pharmacotherapy of NAFLD still remains to be established due to the lack of randomized, controlled trials. Yet, for several drugs such as Metformin and Thiazolidinediones, smaller trials report promising results.
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PMID:[Therapeutic options for nonalcoholic fatty liver disease and steatohepatitis]. 1624 33

Atypical endometrial hyperplasia has been associated with progression to endometrial cancer, the most common genital malignancy. There are multiple risk factors for endometrial cancer, such as early menarche, exogenous estrogen exposure, obesity and diabetes. Diabetics have a 3-4 fold relative risk of endometrial cancer. Also, several studies have demonstrated an association between insulin resistance and endometrial cancer. There is known the first description of atypical endometrial hyperplasia resistant to progestogen therapy, which was subsequently treated with an insulin-sensitizng agent, metformin. Metformin is a biguanide antihyperglycemic agent used in the treatment of adult-onset diabetes. Unlike the sulfonylureas, metformin does not act primarily by increasing insulin secretion. In contrast, metformin lowers the rate of gluconeogenesis in the presence of insulin. Therefore, it is considered an insulin-sensitizer. Increased insulin sensitivity may improve the metabolic effect of insulin and decrease its mitogenic effect by tissue-specific mechanisms. One explanation for tissue specific differences in insulin binding and action may be through the relative expression of the insulin receptor (IR) isoforms. The IR isoforms IR-A and IR-D differ by 12 amino acid residues, owing to the alternative splicing of exon. The IR-A is predominantly expressed in malignant tissues and may lead to mitogenic effects within the cell. The relative expressions of IR-A and IR-B in normal and malignant endometrial tissue is not known. Besides direct effects on the IR, several additional mechanisms have been proposed for the mitogenic effect of insulin in endometrial cancer. In addition to the possible direct mitogenic effects of insulin through the IR-A, insulin resistance may be associated with alterations in expression of insulin-like growth factors (IGFs) and the IGF binding proteins (IGFBPs) or may inhibit the protective effect of progestagens. Binding sites for IGF-1 and IGF-2 have been confirmed in both normal and malignant endometrium. Binding of IGF-1 is significantly higher in endometrial cancer compared to normal endometrium. In the Ishikawa human endometrial cancer cell line IGF-1 was a more potent mitogen than insulin or IGF-2. Insulin may increase mitogenicity by regulating the expression of IGFBPs. The IGFBPs are a family of proteins that have both proliferative and anti-proliferative effects. While all six high-affinity IGFBPs are expressed in the endometrium, IGFBP-1 is the best characterized. Hyperinsulinemia can decrease IGFBP-1 even in the presence of progesterone, perhaps inhibiting progesterone's protective effects. Interestingly, IGFBP-1 was undetectable or minimally expressed in endometrial cancers. Nestler discussed results of a 6-month treatment of 100 nonebese women with PCOS, which showed a somewhat greater effect of metformin than rosiglitazone and no benefit of administering both agents in combination. Long-term treatment with oral contraceptives decreases endometrial cancer, with a reduction in serum androgens and a decreases in hirsutism and acne, but may worsen insulin resistance and lead to deteriration in glucose tolerance. Insulin sensitizers, on the other hand, should decrease endometrial hyperplasia by inducing regular menses, but may not be as beneficial in improving androgen - related symptoms. Note that the Nurses Health Study (NHS) showed increased risk of diabetes in oral contraceptive users. These considerations may be related to the finding that women who used oral contraceptives have increased risk of myocardial infarction. Thus, in view of the particular increase in CVD risk among women with PCOS, one might be less likely to recommend oral contraceptives, while insulin sensitizers may be of particular benefit, decreasing androgens, improving ovulation and fertility, and reducing the risk of diabetes and CVD. Theoretically, metformin, a treatment which is now widely used to treat infertile women with PCOS, may have a role in preventing endometrial hyperstimulation by lowering insulin concentrations and restoring ovulation. However, the long-term effects of this drug in women with PCOS are not known and more studies are required before suggesting its use for preventing endometrial cancer.
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PMID:[Molecular action of insulin-sensitizing agents]. 1635 Jul 24

Polycystic ovary syndrome (PCOS) is a heterogeneous disorder characterized by hirsutism, obesity, hyperandrogenism and insulin resistance. The syndrome is often accompanied by infertility because of anovulation. Many approaches have been proposed to solve this problem, with the most commonly used therapies being ovarian drilling and pharmacological ovulation induction. Ovarian drilling is a procedure in which a laser fiber or electro-surgical needle punctures the ovary four to ten times. Side-effects are rare and often related to surgery itself. Pharmacological strategies include administration of metformin and insulin-sensitizing agents, clomiphene citrate (CC), gonadotropins and aromatase inhibitors. Metformin appears valuable in increasing ovulation rate, menstrual cyclicity and pregnancy rate. CC is an oral estrogen antagonist that raises circulating concentrations of follicle-stimulating hormone (FSH) and induces follicular growth in most women with PCOS and anovulation. Failure to respond is associated with high body mass index and high androgen levels. Aromatase inhibitors mimic the central reduction of negative feedback through which CC works. Ovulation induction with recombinant FSH has proved successful, but treatment requires skill and experience to avoid multiple pregnancies and ovarian hyperstimulation syndrome. The hypothetical deleterious effects of the high luteinizing hormone concentrations observed in PCOS patients seem to be related to the concomitant hyperinsulinemia (and/or insulin resistance). A thorough understanding of the syndrome and a careful assessment of each patient are the mainstays for choosing an appropriate treatment regimen.
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PMID:Therapeutic strategies for ovulation induction in infertile women with polycystic ovary syndrome. 1639 Jul 83

The pharmacokinetic disposition of metformin in late pregnancy was studied together with the level of fetal exposure at birth. Blood samples were obtained in the third trimester of pregnancy from women with gestational diabetes or type 2 diabetes; 5 had a previous diagnosis of polycystic ovary syndrome. A cord blood sample also was obtained at the delivery of some of these women, and also at delivery of others who had been taking metformin during pregnancy but from whom no blood had been taken. Plasma metformin concentrations were assayed by a new, validated, reverse-phase HPLC method. A 2-compartment, extravascular maternal model with transplacental partitioning of drug to a fetal compartment was fitted to the data. Nonlinear mixed-effects modeling was performed in NONMEM using FOCE with INTERACTION. Variability was estimated using logarithmic interindividual and additive residual variance models; the covariance between clearance and volume was modeled simultaneously. Mean (range) metformin concentrations in cord plasma and in maternal plasma were 0.81 (range, 0.1-2.6) mg/L and 1.2 (range, 0.1-2.9) mg/L, respectively. Typical population values (interindividual variability, CV%) for allometrically scaled maternal clearance and volume of distribution were 28 L/h/70 kg (17.1%) and 190 L/70 kg (46.3%), giving a derived population-wide half-life of 5.1 hours. The placental partition coefficient for metformin was 1.07 (36.3%). Neither maternal age nor weight significantly influenced the pharmacokinetics. The variability (SD) of observed concentrations about model-predicted concentrations was 0.32 mg/L. The pharmacokinetics were similar to those in nonpregnant patients and, therefore, no dosage adjustment is warranted. Metformin readily crosses the placenta, exposing the fetus to concentrations approaching those in the maternal circulation. The sequelae to such exposure, eg, effects on neonatal obesity and insulin resistance, remain unknown.
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PMID:Population pharmacokinetics of metformin in late pregnancy. 1641 96

We assessed whether hypofibrinolytic plasminogen activator inhibitor 1 (PAI-1 activity) showed an independent association with first-trimester miscarriage in the 430 women with polycystic ovary syndrome (PCOS) who had previous pregnancies (from a cohort of 967 women with PCOS). Prospectively, we hypothesized that Glucophage (Bristol-Myers Squibb, Princeton, NJ) promotes successful live births in women with PCOS by lowering PAI-1 activity before conception and maintaining further reductions of PAI-1 activity during the first trimester of pregnancy. We also assessed whether PAI-1 activity levels were independently related to PAI-1 genotype and to modifiable risk factors body mass index (BMI), insulin, and triglyceride. By stepwise logistic regression, with the dependent variable being previous pregnancy outcomes at 3 levels (live birth pregnancies only [n = 208]; both > or =1 live birth and > or =1 first-trimester miscarriage [n = 111]; or first-trimester miscarriages only [n = 71]) and explanatory variables PAI-1 genotype, PAI-1 activity, insulin, homeostasis model assessment of insulin resistance, BMI, and triglyceride, PAI-1 activity was positively associated with first-trimester miscarriage (P = .004). For each 5 IU/mL increment in PAI-1 activity, the risk being in an adverse first-trimester miscarriage category increased (odds ratio, 1.12; 95% confidence interval, 1.04-1.20). Prospectively, from pretreatment to the last preconception visit on Glucophage, in 30 women who subsequently had live births, PAI-1 activity fell 44%, but rose 19% in 23 women with first-trimester miscarriage (P = .03). In the 30 women with live birth pregnancies, median PAI-1 activity fell continuously from pretreatment through the first trimester (from 16.8 to 6.7 IU/mL), whereas PAI-1 activity was either unchanged or rose in women with first-trimester miscarriage. Of the 921 women with PCOS who had 4G5G data, 718 (78%) had 4G4G-4G5G genotypes vs 87 (69%) of 126 normal female controls (chi(2) = 4.95, P = .026). The 4G allele frequency was 53% in women with PCOS vs 46% in controls (chi(2) = 4.3, P = .04). Of the 866 women with PCOS who had PAI-1 activity data, by stepwise regression, positive independent determinants of PAI-1 activity included BMI (partial R(2) = 10.6%, P < .0001), insulin (partial R(2) = 2.8%, P < .0001), triglyceride (partial R(2) = 1.1%, P = .0009), and the 4G4G-4G5G genotype (partial R(2) = 1%, P = .0011). The PAI-1 gene 4G polymorphism is more common in women with PCOS than in normal women and, in concert with obesity, hyperinsulinemia, and hypertriglyceridemia, contributes to treatable, hypofibrinolytic, miscarriage-promoting, high PAI-1 activity. Preconception and first-trimester decrements in PAI-1 activity on Glucophage are associated with live births, whereas increments or no change in PAI-1 activity despite Glucophage appears to be associated with first-trimester miscarriage.
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PMID:Plasminogen activator inhibitor activity, 4G5G polymorphism of the plasminogen activator inhibitor 1 gene, and first-trimester miscarriage in women with polycystic ovary syndrome. 1648 78


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