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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Metformin and acarbose are novel antihyperglycemic agents indicated for the treatment of non-insulin-dependent diabetes mellitus. These agents offer new therapeutic options to control hyperglycemia that were previously unavailable. Common to both agents is a relatively high incidence of gastrointestinal adverse effects. Initiating therapy at a low dose and slowly titrating to therapeutic response may be the most effective way to minimize associated adverse effects. Recognition and proper management of these possible adverse effects can optimize therapy and maximize the potential for successful outcomes with these agents while limiting drug noncompliance.
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PMID:Managing therapy and adverse effects with antihyperglycemic agents: a focus on metformin and acarbose. 1017 8

Recently there has been growing interest in the effects of antioxidants on insulin activity. In the present study, we investigated the effect of metformin on free radical activity and insulin sensitivity in high fructose-fed rats, a diet that leads to insulin resistance. The animals were divided into four groups (n = 16 per group; experiment duration = 6 weeks): the control (C) group received a standard diet; the control metformin (CM) group was fed a control diet and received metformin (200 mg x kg(-1) x day(-1) in water); the fructose control (FT) group was fed a diet in which fructose composed 56.8% of the total carbohydrates; and the fructose metformin (FM) group received high-fructose diet and metformin (200 mg x kg(-1) x day(-1) in water). The glucose clamp technique was used to determine insulin sensitivity in eight animals per group. Metabolic and oxidative stress parameters were measured in the remaining rats. In the FT rats, insulin resistance, lower red cell CuZn superoxide dismutase activity and lower blood reduced glutathione were observed. Metformin treatment improved both the insulin activity and the antioxidant defense system. In the CM group, metformin had no effect on metabolic parameters, but improved red cell antioxidant enzyme activities and the blood GSH level, which suggests that it has an antioxidant activity independent of its effect on insulin activity.
Diabetes 1999 Feb
PMID:An insulin sensitizer improves the free radical defense system potential and insulin sensitivity in high fructose-fed rats. 1033 13

To better define the modifications of liver gluconeogenesis and citric acid cycle, or Krebs' cycle, activity induced by insulin deficiency and the effects of metformin on these abnormalities, we infused livers isolated from postabsorptive or starved normal and streptozotocin-induced diabetic rats with pyruvate and lactate (labeled with [3-13C]lactate) with or without the simultaneous infusion of metformin. Lactate and pyruvate uptake and glucose production were calculated. The 13C-labeling pattern of liver glutamate was used to calculate, according to Magnusson's model, the relative fluxes through Krebs' cycle and gluconeogenesis. These relative fluxes were converted into absolute values using substrate balances. In normal rats, starvation increased gluconeogenesis, the flux through pyruvate carboxylase-phosphoenolpyruvate carboxykinase (PC-PEPCK), and the ratio of PC to pyruvate dehydrogenase (PDH) flux (P < 0.05); metformin induced only a moderate decrease in the PC:PDH ratio. Livers from postabsorptive diabetic rats had increased lactate and pyruvate uptakes (P < 0.05); their metabolic fluxes resembled those of starved control livers, with increased gluconeogenesis and flux through PC-PEPCK. Starvation induced no further modifications in the diabetic group. Metformin decreased glucose output from the liver of starved diabetic rats (P < 0.05). The flux through PC-PEPCK and also pyruvate kinase were decreased (P < 0.05) by metformin in both groups of diabetic rats. In conclusion, insulin deficiency increased in this model of diabetes gluconeogenesis through enhanced uptake of substrate and increased flux through PC-PEPCK; metformin decreased glucose production by reducing the flux through PC-PEPCK.
Diabetes 1999 Jun
PMID:Modifications of citric acid cycle activity and gluconeogenesis in streptozotocin-induced diabetes and effects of metformin. 1034 12

Metformin has been used for over 40 years as an effective glucose-lowering agent in type 2 (noninsulin-dependent) diabetes mellitus. Typically it reduces basal and postprandial hyperglycaemia by about 25% in more than 90% of patients when either given alone or coadministered with other therapies including insulin during a programme of managed care. Metformin counters insulin resistance and offers benefits against many features of the insulin resistance syndrome (Syndrome X) by preventing bodyweight gain, reducing hyperinsulinaemia and improving the lipid profile. In contrast to sulphonylureas, metformin does not increase insulin secretion or cause serious hypoglycaemia. Treatment of type 2 diabetes mellitus with metformin from diagnosis also offers greater protection against the chronic vascular complications of type 2 diabetes mellitus. The most serious complication associated with metformin is lactic acidosis which has an incidence of about 0.03 cases per 1000 patients years of treatment and a mortality risk of about 0.015 per 1000 patient-years. Most cases occur in patients who are wrongly prescribed the drug, particularly patients with impaired renal function (e.g. serum creatinine level > 130 micromol/L or > 1.5 g/L). Other major contraindications include congestive heart failure, hypoxic states and advanced liver disease. Serious adverse events with metformin are predictable rather than spontaneous and are potentially preventable if the prescribing guidelines are respected. Gastrointestinal adverse effects, notably diarrhoea, occur in less than 20% of patients and remit when the dosage is reduced. The life-threatening risks associated with metformin are rare and could mostly be avoided by strict adherence to the prescribing guidelines. Given the 4 decades of clinical experience with metformin, its antihyperglycaemic efficacy and benefits against Syndrome X, metformin offers a very favourable risk-benefit assessment when compared with the chronic morbidity and premature mortality among patients with type 2 diabetes mellitus.
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PMID:A risk-benefit assessment of metformin in type 2 diabetes mellitus. 1039 66

The UKPDS was a 20-year study involving 23 centres in the United Kingdom. More than 5000 patients with Type 2 diabetes were recruited. The aim of the study was to determine the impact of intensive blood glucose control on 21 predetermined clinical endpoints using, in the care of blood glucose control, sulphonylureas or insulin therapy or, in the overweight patient, treatment with metformin. In addition, the study investigated the impact of intensive blood pressure control on macro- and microvascular complications of diabetes and compared captopril treatment with atenolol. UKPDS found that improved control of blood glucose or blood pressure reduced the risk of major diabetic eye disease by one quarter, serious deterioration of vision by nearly one half, early kidney damage by one third, strokes by one third, and death from diabetes-related causes by one third. Blood glucose control had little or no effect on macrovascular events. There was no evidence of a major detrimental effect of the drugs or insulin on survival or outcome other than the expected risk of hypoglycaemia. Metformin appeared to be the drug of choice in obese diabetic patients. The targets of glucose and blood pressure control were often achieved by using several drugs. Many patients at the end of the studies were on four or five drugs for blood glucose and blood pressure treatment. The results and implications of the study are discussed. It is proposed that the results of UKPDS herald a new era of more focused therapy of Type 2 diabetes.
Diabetes Metab Res Rev
PMID:United Kingdom prospective diabetes study (UKPDS): what now or so what? 1039 49

Many recent data provide new, original insights into the mechanisms of action of the antidiabetic Metformin. Careful selection of most relevant data in terms of dosage prompted this original review, largely devoted to the drug action at the cell level and whose hypotheses/conclusions are tentatively interpreted according to corresponding basic scientific knowledge. Metformin interferes with several processes linked to HGP (gluconeogenesis, glycogenolysis and their regulatory mechanisms), lowering glucose production and resensitizing the liver to insulin. The hepatic drug effect is largely favoured by prevailing glycemia. In peripheral tissues, metformin potentiates the effects of both hyperglycemia and hyperinsulinemia. Increase in glucose-mediated glucose transport is mainly mediated by an improvement in the glucose transporter's intrinsic activity. Potentiation of the hormone effect relates to an increase in insulin receptor tyrosine kinase activity. Both mechanisms (insulin signalling and glucose transport) result in the activation of glycogen synthase, a limiting enzyme in the causal defects of NIDDM. Exciting findings show that, conversely, priming cells with very low insulin concentrations also leads to full expression of metformin's antidiabetic activity. Specific investigations confirm a working hypothesis defining the site of action as the cell membrane level. Indeed metformin corrects membrane fluidity and protein configuration disturbed by the diabetic state and which interfere with normal protein-protein or protein-lipid interactions required for proper functioning of the processes regulating glucose transport/metabolism. It is proposed that membrane changes largely represent a common denominator explaining metformin effects on various systems involved in receptor signalling and related functions.
Diabetes Metab 1999 Jun
PMID:Membrane physiology as a basis for the cellular effects of metformin in insulin resistance and diabetes. 1044 22

We have recently demonstrated that adult rat ventricular myocytes maintained in a high glucose (HG) culture medium exhibit abnormalities in excitation-contraction coupling similar to myocytes from diabetic rats. Metformin, an insulin-sensitizing biguanide, enhances peripheral insulin action and lowers blood pressure in hyperinsulinemic animals, but its direct impact on cardiac function is not fully understood. To examine the role of metformin on HG-induced cardiac dysfunction at the cellular level, normal adult ventricular myocytes were cultured for 1 day in a serum-free insulin-containing medium with either normal glucose (5.5 mmol/l glucose) or HG (25.5 mmol/l glucose) in the presence or absence of metformin or the sulfonylurea glyburide. Mechanical properties were evaluated using a high-speed video-edge detection system, and intracellular Ca2+ transients were recorded in fura-2-loaded myocytes. As previously reported, culturing myocytes in HG depresses peak shortening, prolongs time to 90% relengthening, and slows Ca2+ transient decay. Culturing cells with metformin (50 micromol/l) prevented the HG-induced abnormalities in relaxation without ameliorating depressed peak-shortening amplitudes. Incubation of the cells with metformin also prevented slower intracellular Ca2+ clearing induced by HG. However, the HG-induced relaxation defects were not improved by glyburide (50-300 micromol/l). Interestingly, metformin also improved HG-induced relaxation abnormalities in the absence of insulin, whereas it failed to protect against HG in the presence of the tyrosine kinase inhibitor genistein (50 micromol/l). These data demonstrate that, unlike glyburide, metformin provides cardioprotection against HG-induced abnormalities in myocyte relaxation, perhaps through tyrosine kinase-dependent changes in intracellular Ca2+ handling, independent of its insulin sensitizing action.
Diabetes 1999 Oct
PMID:Metformin but not glyburide prevents high glucose-induced abnormalities in relaxation and intracellular Ca2+ transients in adult rat ventricular myocytes. 1051 74

Metformin structure and mechanisms of action were presented. Metformin plays a particularly important role in the treatment of diabetes mellitus type 2 by decreasing insulin resistance. Indications of its use include diabetes mellitus type 2 in obese patients without systemic complications or disordered blood supply in large body areas. It may be used as a monotherapy or combined with other oral drugs.
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PMID:[Renaissance of metformin]. 1055 68

The effects of streptozotocin (STZ) diabetes and the antihyperglycaemic agent metformin on the contractile characteristics of the limb skeletal muscles and on erythrocyte volume were examined in rats. After 8 weeks of diabetes, the tetanic tension of the extensor digitorum longus (EDL) muscle decreased and the half-relaxation time of the soleus muscle increased. Endurance decreased in both muscles. Metformin treatment of the diabetic rats did not prevent the development of these contractile changes. Diabetes induced depolarisation in the EDL and soleus muscles. Following exposure to insulin, both muscles repolarized. Metformin treatment of control rats induced depolarisation in the EDL and soleus muscles, but in the depolarised EDL and soleus muscles of the diabetic rats metformin treatment caused no further depolarisation. The muscles of metformin-treated control and diabetic rats hyperpolarized in the presence of insulin. Diabetes caused an increase in the volume of the blood erythrocytes. This was prevented by metformin treatment.
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PMID:The influence of streptozotocin diabetes and metformin on erythrocyte volume and on the membrane potential and the contractile characteristics of the extensor digitorum longus and soleus muscles in rats. 1056 2

This study was undertaken to assess the effect of metformin as a second-line oral antihyperglycemic agent in a defined population with type 2 diabetes mellitus. We measured the extent and circumstances of metformin use in the 15,000-person diabetes registry of a large, group-model health maintenance organization (HMO). Among subsets of patients in whom adequate glycemic control could not be maintained with sulfonylurea (SU) therapy, we compared glycemic control before and after metformin use to glycemic control during a similar interval before metformin was introduced. Metformin users were significantly more likely than nonusers to have had poor glycemic control at baseline. Nearly two thirds (63.8%) of patients with a glycosylated hemoglobin (Hb A1c) level >10% switched to metformin, as did 46.3% of those with an Hb A1c level of 8% to 10%. In all patients (metformin users and nonusers) in whom SU therapy failed to maintain glycemic control, Hb A1c levels decreased 0.9% after metformin was introduced, compared with a decrease of 0.4% during the control period. In a group-model HMO that promoted the use of metformin as second-line therapy in patients unable to maintain glycemic control with SU therapy, metformin reduced hyperglycemic levels.
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PMID:Metformin as secondary therapy in a defined population with type 2 diabetes. 1056 64


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