Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Metformin, a drug widely used in the treatment of type 2 diabetes, has recently been shown to act on skeletal muscle and liver in part through the activation of AMP-activated protein kinase (AMPK). Whether metformin or the satiety factor leptin, which also stimulates AMPK in muscle, regulates this enzyme in pancreatic islets is unknown. We have recently shown that forced increases in AMPK activity inhibit insulin secretion from MIN6 cells (da Silva Xavier G, Leclerc I, Varadi A, Tsuboi T, Moule SK, and Rutter GA. Biochem J 371: 761-774, 2003). Here, we explore whether 1) glucose, metformin, or leptin regulates AMPK activity in isolated islets from rodent and human and 2) whether changes in AMPK activity modulate insulin secretion from human islets. Increases in glucose concentration from 0 to 3 and from 3 to 17 mM inhibited AMPK activity in primary islets from mouse, rat, and human, confirming previous findings in insulinoma cells. Incubation with metformin (0.2-1 mM) activated AMPK in both human islets and MIN6 beta-cells in parallel with an inhibition of insulin secretion, whereas leptin (10-100 nM) was without effect in MIN6 cells. These studies demonstrate that AMPK activity is subject to regulation by both glucose and metformin in pancreatic islets and clonal beta-cells. The inhibitory effects of metformin on insulin secretion may therefore need to be considered with respect to the use of this drug for the treatment of type 2 diabetes.
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PMID:Metformin, but not leptin, regulates AMP-activated protein kinase in pancreatic islets: impact on glucose-stimulated insulin secretion. 1487 85

Burgeoning obesity is increasing the prevalence of type II diabetes mellitus. As a consequence, there will be an even greater burden of cardiovascular disease, end-stage renal disease, blindness, and lower extremity amputations. If diagnosed, impaired glucose tolerance presents an opportunity for intervention that potentially could delay or prevent the development of diabetes. Recent prospective studies document the effectiveness of exercise and weight reduction in preventing diabetes. Metformin is less effective than intense lifestyle interventions. Acarbose, losartan, orlistat, pravastatin, ramipril, and hormone replacement therapy are associated with lower rates of the development of diabetes. The Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication (DREAM) trial and the Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) trial were designed to assess not only the prevention of diabetes but also the impact on cardiovascular morbidity and mortality.
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PMID:Preventing type II diabetes mellitus. 1505 49

Metformin is a biguanide commonly used in type 2 diabetes and considered to be a safe drug with minimal side effects. Approximately 2% of cases of acute pancreatitis may be caused by drugs, but it is not a known complication of metformin therapy. To date only one case of pancreatitis has been reported in association with metformin, but that was secondary to metformin poisoning (overdose). This is the first reported case of pancreatitis caused by a therapeutic dose of metformin (although in this case renal failure precipitated the metformin toxicity). Severe lactic acidosis is a rare but life threatening complication of metformin, which occurs particularly in patients with renal failure.
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PMID:Metformin induced acute pancreatitis precipitated by renal failure. 1508 49

To investigate the anti-atherogenic effect of metformin, we prospectively evaluated the effect of metformin treatment on common carotid intima-media thickness (CCA-IMT) in patients with type 2 diabetes. A 2-year open prospective study was performed. Thirty-six patients were treated with metformin (500-750 mg per day). CCA-IMT was measured after 1- and 2-year treatment. Changes in CCA-IMT were compared with control patients. After 2-year metformin therapy, the progression of CCA-IMT was significantly less than 56 control patients (0.02+/-0.08 mm versus 0.07+/-0.08 mm, P<0.01). Metformin therapy did not alter body weight, blood pressure, HbA1c, and serum lipids relative to the control. Thus, metformin attenuates the progression of CCA-IMT. This anti-atherogenic effect is not mediated through changes in classical cardiovascular risk factors.
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PMID:Metformin attenuates progression of carotid arterial wall thickness in patients with type 2 diabetes. 1512 12

Metformin is widely used in the treatment of type 2 diabetes, though it is recognized to be associated with the risk of lactic acidosis. A case of pronounced lactic acidosis with cardiac arrest (pH 6.60, lactate 17.5 mmol/l, base excess - 30, standard bicarbonate 2.5 mmol/l, core body temperature 27.8 degrees C) is presented in a 61-year-old woman under metformin therapy. The key laboratory abnormalities observed during the intensive care treatment including repeated hemodialysis are described. The patient showed a complete recovery with residually reduced mental capabilities. Furthermore, an explorative data analysis of our poison center database from 1995 until 2003 concerning metformin was performed. In 109 inquiries for metformin a lactic acidosis (mean pH 6.87 +/- 0.11, mean lactate 20.9 +/- 8.1 mmol/l) was present in 14 cases (9 female, 5 male, average age 57.7 years) with 8 patients under regular metformin therapy and 6 patients who ingested large amounts of metformin to attempt suicide. 4 patients did not survive the severe metabolic disturbance. The present report demonstrates that metformin-associated lactic acidosis is a rare but critical complication of metformin therapy of type 2 diabetes as well as in acute suicidal ingestion of metformin. Early diagnosis and rapid correction of the metabolic acidosis using hemodialysis provides the possibility of a positive outcome even in severe cases. If metformin-associated lactic acidosis is suspected we recommend early involvement of a poison center.
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PMID:Experiences of a poison center with metformin-associated lactic acidosis. 1512 22

We present an 84-year-old man with a history of chronic obstructive pulmonary disease, type 2 diabetes, hypertension, glaucoma, and bladder cancer who presented to the emergency department after the police found him disoriented and confused. Metformin therapy began 3 days before, and he denied any overdose or suicidal ideation. Other daily medications included glipizide, fluticasone, prednisone, aspirin, furosemide, insulin, and potassium supplements. In the emergency department, his vital signs were significant for hypertension (168/90), tachycardia (120 bpm), and Kussmaul respirations at 24 breaths per minute. Oxygen saturation was 99% on room air, and a fingerstick glucose was 307 mg/dL. He was disoriented to time and answered questions slowly. Metformin was discontinued, and by day 3, the patient's vital signs and laboratory test results normalized. He has been asymptomatic at subsequent follow-up visits. Metformin-associated lactic acidosis is a well-known phenomenon. Respiratory alkalosis may be an early adverse event induced by metformin prior to the development of lactic acidosis.
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PMID:Metformin-associated respiratory alkalosis. 1513 41

The sulphonylureas act by triggering insulin release from the pancreatic beta cell. A specific site on the adenosine triphosphate (ATP)-sensitive potassium channels is occupied by sulphonylureas leading to closure of the potassium channels and subsequent opening of calcium channels. This results in exocytosis of insulin. The meglitinides are not sulphonylureas but also occupy the sulphonylurea receptor unit coupled to the ATP-sensitive potassium channel. Glibenclamide (glyburide), gliclazide, glipizide and glimepiride are the primary sulphonylureas in current clinical use for type 2 diabetes mellitus. Glibenclamide has a higher frequency of hypoglycaemia than the other agents. With long-term use, there is a progressive decrease in the effectiveness of sulphonylureas. This loss of effect is the result of a reduction in insulin-producing capacity by the pancreatic beta cell and is also seen with other antihyperglycaemic agents. The major adverse effect of sulphonylureas is hypoglycaemia. There is a theoretical concern that sulphonylureas may affect cardiac potassium channels resulting in a diminished response to ischaemia. There are now many choices for initial therapy of type 2 diabetes in addition to sulphonylureas. Metformin and thiazolidinediones affect insulin sensitivity by independent mechanisms. Disaccharidase inhibitors reduce rapid carbohydrate absorption. No single agent appears capable of achieving target glucose levels in the majority of patients with type 2 diabetes. Combinations of agents are successful in lowering glycosylated haemoglobin levels more than with a single agent. Sulphonylureas are particularly beneficial when combined with agents such as metformin that decrease insulin resistance. Sulphonylureas can also be given with a basal insulin injection to provide enhanced endogenous insulin secretion after meals. Sulphonylureas will continue to be used both primarily and as part of combined therapy for most patients with type 2 diabetes.
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PMID:The role of sulphonylureas in the management of type 2 diabetes mellitus. 1520 Mar 48

Insulin resistance is a characteristic feature of obesity and type 2 diabetes mellitus, but it is also present in up to 25% of healthy nonobese individuals. The molecular mechanisms causing insulin resistance are not yet fully understood. Recently, overexpression of several potential inhibitors of the insulin receptor tyrosine-kinase activity, a key step in insulin signaling, has been described in insulin-resistant subjects . PC-1 is expressed in many tissues and inhibits insulin signaling either at the level of the insulin receptor or downstream at a postreceptor site. An elevated PC-1 content in insulin target tissues may play an important role in the development of insulin resistance in obesity and type 2 diabetes mellitus. A polymorphism in PC-1 has been demonstrated to be associated with insulin resistance. This was a DNA polymorphism in exon 4 that causes an amino acid change from lysine to glutamine at codon 121 (K121Q). PC-1 121Q allele might predispose independently of other well established risk factors for early myocardial infarction. Testing for the PC-1 K121Q polymorphism might be valuable in patients with a family history of atherosclerotic vascular disease and myocardial infarction. There is growing evidence that genetic factors play an important role in the development of diabetic nephropathy (DN). Efforts to identify these factors rely primarily on the candidate gene approach; candidate genes for insulin resistance may be considered candidates for DN as well. In a stratified analysis according to duration of diabetes, the risk of early-onset end-stage renal disease (ESRD) for carriers of the Q variant was 2.3 times that for noncarriers. The cellular mechanisms for the insulin resistance of pregnancy and gestational diabetes mellitus (GDM) are unknown. Women with GDM have an increased PC-1 content and excessive phosphorylation of serine/threonine residues in muscle insulin receptors. The postreceptor defects in insulin signaling may contribute to the pathogenesis of GDM and the increased risk for type 2 diabetes later in life. Although widely explored, the true cause of insulin resistance in uremic patients is not entirely elucidated yet. During the last decade it was found that erythropoietin (EPO) therapy, used for correction of anemia in patients with end stage renal failure, ameliorates insulin resistance. An increased lymphocyte PC-1 activity over control was found in hemodialysis patients. A two-month EPO therapy significantly decreased PC-1 activity to the control values, suggesting that an effect on PC-1 expression could be implicated in the amelioration of insulin resistance in uremic patients treated with EPO. Current investigations implicate that therapeutic modification of PC-1 expression would be of great benefit for insulin-resistant type 2 diabetics. Metformin, a biguanide oral antidiabetic agent, was shown to affect insulin resistance by decreasing enzymatic activity of overexpressed PC-1 molecules in obese type 2 diabetics. Thiazolidinedione (TZD) insulin-sensitizing drugs are a class of compounds that improve insulin action in vivo. Treatment of patients with TZDs seems to have a beneficial effect on most, if not all, components of metabolic syndrome. TZDs have also been used in the treatment of nondiabetic human insulin-resistant states, and have demonstrated an improvement in insulin sensitivity. Although much remains to be learned about PPAR gamma receptor and TZD action, the advent of TZD insulin-sensitizing agents has an enormous impact on our understanding of insulin resistance. The great potential of insulin resistance therapy illuminated by the TZDs will continue to catalyze research in this area directed toward the discovery of new insulin-sensitizing agents that work through other mechanisms.
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PMID:Plasma cell membrane glycoprotein 1 (PC-1): a marker of insulin resistance in obesity, uremia and diabetes mellitus. 1520 35

Metformin extended release [Glumetza, metformin hydrochloride, metformin gastric retention, metformin GR] is a proprietary once-a-day formulation of metformin hydrochloride under development with DepoMed for the treatment of diabetes. In May 2002, DepoMed licensed manufacturing and marketing rights for its proprietary formulation of metformin extended release (500mg dose) to Biovail Corporation for the US (including Puerto Rico) and Canada. Under the terms of the agreement, Biovail would pay a $25 million milestone fee upon approval and also customary royalties on the net sales in the US and Canada. Biovail also agreed to acquire approximately 2.4 million of additionally issued DepoMed shares for $12.3 million. Biovail has subsequently developed a 1000mg dose of metformin extended release. In April 2004, Depomed and Biovail amended their original license agreement of May 2002. Under the terms of the amended agreement, Depomed will receive royalties on sales of Biovail's 1000mg tablet in the US and Canada. In turn, Biovail acquired access to Depomed's clinical data for the metformin 500mg tablet that will be used to accelerate regulatory filings for Biovail's 1000mg tablet and establish equivalence between the two dosages. Metformin GR is available for partnership in Europe and Asia (Bio-Square-2004, Basel, Switzerland). In April 2004, Depomed and Biovail filed an NDA with the US FDA for the once-daily, extended-release formulation of metformin extended release (Glumetza), 500mg and 1000mg tablets. The 500mg dosage was developed by Depomed using its patented drug delivery GR technology, while Biovail developed the metformin 1000mg dose using its proprietary Smartcoat delivery technology. Depomed completed two double-blind, pivotal, phase III clinical trials with metformin extended release 500mg at 60 sites in the US in more than 1000 patients with type 2 diabetes. In three different dosing regimens, metformin extended release significantly decreased the glycosylated haemoglobin level similarly to that of metformin immediate release. Biovail successfully compared the metformin extended release 1000mg dose with Depomed's 500mg dose in multiple equivalence studies. In these studies, metformin extended release was well tolerated and demonstrated an excellent safety profile in terms of gastrointestinal adverse events. The licensee, Biovail, has submitted an application for metformin extended release with Health Canada. Bristol-Myers Squibb is marketing a proprietary, once-daily extended-release formulation of metformin (Glucophage XR). Several companies are developing controlled-release and extended release formulations of metformin.
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PMID:Metformin extended release--DepoMed: metformin, metformin gastric retention, metformin GR. 1523 Jun 31

We present a case of metabolic acidosis in a man, recently diagnosed with type 2 diabetes mellitus under treatment with metformin. Metformin (along with Fenformin and Butformin) is an oral antihyperglycemic agent belonging to the biguanide group employed in the treatment of non insulin dependent diabetes (NIDDM). Its main use is in association with other oral agents in obese diabetic patients with difficult metabolic control. In some of these patients, clearly beneficial developed lactic acidosis, specially in those who have predisposing factors (respiratory failure, liver disease or cardiovascular disease) and/or those who require high doses. For this reason we describe its pharmacokinetics, therapeutic indications and its correct use in this type of diabetic patient.
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PMID:[Lactic acidosis in diabetic patient treated with metformin]. 1528 44


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