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

The patient with type II, or non-insulin-dependent, diabetes mellitus (NIDDM) is characterized by obesity and insulin resistance, with resultant hyperinsulinemia and hyperglycemia. Sulfonylureas are the chief therapy for patients with NIDDM; for a limited time, these agents stimulate increased insulin secretion. With chronic administration, sulfonylureas improve the diabetic patient's insulin activity by increasing cellular insulin receptors and reducing insulin postreceptor defects. Metformin, a drug in the biguanide class, is now approved for use in the United States. This drug does not stimulate insulin release but works by lowering glucose in peripheral tissues. It can be used alone or in combination with a sulfonylurea. With sulfonylureas and metformin, therapy for the patient with NIDDM can be more effectively tailored.
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PMID:Oral hypoglycemic agents in type II diabetes mellitus. 748 7

Patients with diabetes mellitus are at a higher risk to undergo surgical intervention compared with the non-diabetic population, and additionally, they have an increased perioperative morbidity and mortality. Insulin deficiency and insulin resistance are aggravated by surgery and anaesthesia. The consequences of hyperglycemia are glycosuria, volume depletion from osmotic diuresis, impairment of wound healing and leucocyte function and exacerbation of ischemic brain damage. Depending on the extent of hypoinsulinemia, lipolysis and ketogenesis are enhanced which may result in metabolic acidosis with subsequent electrolyte disturbances. Protein catabolism is increased because of increased breakdown and decreased synthesis. Insulin administration reverts or overcomes most of these disturbances. The preoperative assessment includes the diagnoses of the long-term complications to judge the intraoperative risks. Long-acting insulins, such as ultralente of animal origin should be stopped preoperatively and substituted by protamine and lente insulins. In type-2-diabetic patients, long-acting sulfonylurea drugs such as chlorpropamide should be stopped and substituted by short-acting agents. Metformin must always be stopped. Type-2-diabetic patients with marked hyperglycemia under oral treatment should be switched to insulin before operation. The insulin requirements in diabetic patients during surgery vary from 0.25-0.40 U per gram glucose in normal weight patients, 0.4-0.8 U per gram glucose in case of obesity, liver disease, steroid therapy or sepsis, to 0.8-1.2 U per gram glucose in patients undergoing cardiopulmonary bypass surgery. Therefore, the appropriate dose has to be determined individually. The regimen nowadays preferred by most authors is based on variable rate insulin infusion.(ABSTRACT TRUNCATED AT 250 WORDS)
Exp Clin Endocrinol Diabetes 1995
PMID:Perioperative management of the diabetic patient. 758 26

The objective of the U.K. Prospective Diabetes Study is to determine whether improved blood glucose control in type II diabetes will prevent the complications of diabetes and whether any specific therapy is advantageous or disadvantageous. The study will report in 1998, when the median duration from randomization will be 11 years. This report is on the efficacy of therapy over 6 years of follow-up and the overall incidence of diabetic complications. Subjects comprised 4,209 newly diagnosed type II diabetic patients who after 3 months' diet were asymptomatic and had fasting plasma glucose (FPG) 6.0-15.0 mmol/l. The study consists of a randomized controlled trial with two main comparisons: 1) 3,867 patients with 1,138 allocated to conventional therapy, primarily with diet, and 2,729 allocated to intensive therapy with additional sulfonylurea or insulin, which increase insulin supply, aiming for FPG < 6 mmol/l; and 2) 753 obese patients with 411 allocated to conventional therapy and 342 allocated to intensive therapy with metformin, which enhances insulin sensitivity. In the first comparison, in 2,287 subjects studied for 6 years, intensive therapy with sulfonylurea and insulin similarly improved glucose control compared with conventional therapy, with median FPG at 1 year of 6.8 and 8.2 mmol/l, respectively (P < 0.0001). and median HbA1c of 6.1 and 6.8%, respectively (P < 0.0001). During the next 5 years, the FPG increased progressively on all therapies (P < 0.0001) with medians at 6 years in the conventional and intensive groups, FPG 9.5 and 7.8 mmol/l, and HbA1c 8.0 and 7.1%, respectively. The glycemic deterioration was associated with progressive loss of beta-cell function. In the second comparison, in 548 obese subjects studied for 6 years, metformin improved glucose control similarly to intensive therapy with sulfonylurea or insulin. Metformin did not increase body weight or increase the incidence of hypoglycemia to the same extent as therapy with sulfonylurea or insulin. A high incidence of clinical complications occurred by 6-year follow-up. Of all subjects, 18.0% had suffered one or more diabetes-related clinical endpoints, with 12.1% having a macrovascular and 5.7% a microvascular endpoint. Sulfonylurea, metformin, and insulin therapies were similarly effective in improving glucose control compared with a policy of diet therapy. The study is examining whether the continued improved glucose control, obtained by intensive therapy compared with conventional therapy (median over 6 years HbA1c 6.6% compared with 7.4%), will be clinically advantageous in maintaining health.
Diabetes 1995 Nov
PMID:U.K. prospective diabetes study 16. Overview of 6 years' therapy of type II diabetes: a progressive disease. U.K. Prospective Diabetes Study Group. 758 20

The biguanide metformin (dimethylbiguanide) is an oral antihyperglycaemic agent used in the management of non-insulin-dependent diabetes mellitus (NIDDM). It reduces blood glucose levels, predominantly by improving hepatic and peripheral tissue sensitivity to insulin without affecting the secretion of this hormone. Metformin also appears to have potentially beneficial effects on serum lipid levels and fibrinolytic activity, although the long term clinical implications of these effects are unclear. Metformin possesses similar antihyperglycaemic efficacy to sulphonylureas in obese and nonobese patients with NIDDM. Additionally, interim data from the large multicentre United Kingdom Prospective Diabetes Study (UKPDS) indicated similar antihyperglycaemic efficacy for metformin and insulin in newly diagnosed patients with NIDDM. Unlike the sulphonylureas and insulin, however, metformin treatment is not associated with increased bodyweight. Addition of metformin to existing antidiabetic therapy confers enhanced antihyperglycaemic efficacy. This may be of particular use in improving glycaemic control in patients with NIDDM not adequately controlled with sulphonylurea monotherapy, and may serve to reduce or eliminate the need for daily insulin injections in patients with NIDDM who require this therapy. The acute, reversible gastrointestinal adverse effects seen with metformin may be minimised by administration with or after food, and by using lower dosages, increased slowly where necessary. Lactic acidosis due to metformin is rare, and the risk of this complication may be minimised by observance of prescribing precautions and contraindications intended to avoid accumulation of the drug or lactate in the body. Unlike the sulphonylureas, metformin does not cause hypoglycaemia. Thus, metformin is an effective antihyperglycaemic agent which appears to improve aberrant plasma lipid and fibrinolytic profiles associated with NIDDM. Possible long term clinical benefits of this drug with regard to cardiovascular mortality and morbidity are not yet established but are being assessed in a major ongoing study. Since metformin does not promote weight gain or hypoglycaemia it should be considered first-line pharmacotherapy in obese patients with NIDDM inadequately controlled by nonpharmacological measures. Metformin appears similarly effective for the pharmacological management of NIDDM in nonobese patients.
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PMID:Metformin. A review of its pharmacological properties and therapeutic use in non-insulin-dependent diabetes mellitus. 760 Oct 13

Metformin has been demonstrated to lower blood glucose in vivo by a mechanism which increases peripheral glucose uptake. Furthermore, the therapeutic concentration of metformin has been estimated to be in the order of 0.01 mmol/l. We investigated the effect of metformin on insulin-stimulated 3-0-methylglucose transport in isolated skeletal muscle obtained from seven patients with non-insulin-dependent diabetes mellitus (NIDDM) and from eight healthy subjects. Whole body insulin-mediated glucose utilization was decreased by 45% (p < 0.05) in the diabetic subjects when studied at 8 mmol/l glucose, compared to the healthy subjects studied at 5 mmol/l glucose. Metformin, at concentrations of 0.1 and 0.01 mmol/l, had no effect on basal or insulin-stimulated (100 microU/ml) glucose transport in muscle strips from either of the groups. However, the two control subjects and three patients with NIDDM which displayed a low rate of insulin-mediated glucose utilization (< 20 mumol.kg-1.min-1), as well as in vitro insulin resistance, demonstrated increased insulin-stimulated glucose transport in the presence of metformin at 0.1 mmol/l (p < 0.05). In conclusion, the concentration of metformin resulting in a potentiating effect on insulin-stimulated glucose transport in insulin-resistant human skeletal muscle is 10-fold higher than the therapeutic concentrations administered to patients with NIDDM. Thus, it is conceivable that the hypoglycaemic effect of metformin in vivo may be due to an accumulation of the drug in the extracellular space of skeletal muscle, or to an effect of the drug distal to the glucose transport step.
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PMID:Effect of metformin on insulin-stimulated glucose transport in isolated skeletal muscle obtained from patients with NIDDM. 798 85

To establish the antihyperglycemic mechanisms of metformin in non-insulin-dependent diabetes mellitus (NIDDM) independently of the long-term, aspecific effects of removal of glucotoxicity, 21 NIDDM subjects (14 obese, 7 nonobese) were studied on two separate occasions, with an isoglycemic (plasma glucose approximately 9 mM) hyperinsulinemic (two-step insulin infusion, 2 h each, at the rate of 4 and 40 mU.m-2.min-1) clamp combined with [3-3H]glucose infusion and indirect calorimetry, after administration of either metformin (500 mg per os, at -5 and -1 h before the clamp) or placebo. Compared with placebo, hepatic glucose production (HGP) decreased approximately 30% more after metformin (from 469 +/- 50 to 330 +/- 54 mumol/min), but glucose uptake did not increase. Metformin suppressed free fatty acids (FFAs) by approximately 17% (from 0.42 +/- 0.04 to 0.35 +/- 0.04 mM) and lipid oxidation by approximately 25% (from 4.5 +/- 0.4 to 3.4 +/- 0.4 mumol.kg-1.min-1) and increased glucose oxidation by approximately 16% (from 16.2 +/- 1.4 to 19.3 +/- 1.3 mumol.kg-1.min-1) compared with placebo (P < 0.05), but did not affect nonoxidative glucose metabolism, protein oxidation, or total energy expenditure. Suppression of FFA and lipid oxidation after metformin correlated with suppression of HGP (r = 0.70 and r = 0.51, P < 0.001). The effects of metformin in obese and nonobese subjects were no different. We conclude that the specific, antihyperglycemic effects of metformin in the clinical condition of hyperglycemia in NIDDM are primarily due to suppression of HGP, not stimulation of glucose uptake, and are mediated, at least in part, by suppression of FFA and lipid oxidation.
Diabetes 1994 Jul
PMID:Acute antihyperglycemic mechanisms of metformin in NIDDM. Evidence for suppression of lipid oxidation and hepatic glucose production. 801 58

Obesity is a well-known risk factor for non-insulin-dependent (or Type 2) diabetes mellitus. Consequently, reduction of weight excess comes to the front line in the prevention and management of NIDDM. It is only when diet and physical exercise fail that drug treatment should be considered. Pharmacological treatment of obesity should favour drugs which not only promote weight loss, by reducing caloric intake and/or increasing thermogenesis and energy expenditure, but also, and especially, improve insulin sensitivity. Serotoninergic anorectic compounds (dexfenfluramine, fluoxetine) appear to possess, to some extent, all these properties. Metformin significantly reduces insulin resistance and improves glycaemic control without inducing weight gain, and even favouring some weight loss. This biguanide is now considered as the first line drug for the obese diabetic patient. Alpha-glucosidase inhibitors may help to reduce post-prandial glucose excursions but do not promote weight loss per se. Sulfonylureas can be prescribed to an obese patient when hyperglycaemia persists despite diet and the above-mentioned oral agents, but their use should be associated with reinforcement of dietary advices in order to prevent further weight increase; it is also the case for insulin therapy. Finally, drugs specifically stimulating thermogenesis and energy expenditure, new agents sensitizing tissues to the action of insulin and various compounds interfering with lipid metabolism are currently under extensive investigation with promising preliminary results in the obese diabetic patient. In conclusion, obesity remains a major problem in the management of Type 2 diabetes mellitus and this justifies the search for new, safe and effective, pharmacological approaches.
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PMID:Pharmacological treatment of the obese diabetic patient. 802 6

Recently, we demonstrated that approximately 60% of GLUT 1 in a crude membrane fraction of rat skeletal muscle originates from perineurial sheaths. To study the in vivo regulation of GLUT 1 expression in different tissues in muscles, we measured the level of GLUT 1 in crude muscle membranes and in perineurial sheaths in diabetic (fa/fa) Zucker rats and lean controls, with and without metformin treatment. The GLUT 1 concentration in perineurial sheaths was identical in all four groups of rats, both when measured by quantitative immunofluorescence and by immunoblotting and densitometry. In a fraction of crude membranes of soleus muscles GLUT 1 expression was more than two-fold higher in (fa/fa) rats than in lean controls (p < 0.005). Metformin treatment significantly elevated GLUT 1 in control rats (p < 0.05) and tended to decrease GLUT 1 in diabetic rats (p < 0.075). The expressions of GLUT 1 and GLUT 4 in crude muscle membranes were inversely correlated (p < 0.01), and GLUT 1 expression correlated positively with fasting glucose (p < 0.05). In conclusion, GLUT 1 expression in perineurial sheaths is unaffected by alterations in glucose homeostasis and by the genes responsible for obesity and diabetes in the Zucker rat. GLUT 1 expression in a crude membrane fraction of soleus muscle is increased in the diabetic animals, likely due to an increased expression in muscle cells proper.
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PMID:Elevated GLUT 1 level in crude muscle membranes from diabetic Zucker rats despite a normal GLUT 1 level in perineurial sheaths. 805 80

The effects of glucose and glucagon on the anti-gluconeogenic action of metformin were investigated in normal and diabetic hepatocytes. Glucose production from lactate was elevated by 88% in hepatocytes from fasted normal rats compared with hepatocytes from fed animals. Diabetes caused 3.5- and 2.1-fold increases in hepatic gluconeogenesis under fasting and fed conditions, respectively. Metformin (250 microM) suppressed glucose production by 37% in normal and by 30% in diabetic hepatocytes from fed rats. This drug was more effective (up to 67%) with increasing concentrations of glucose in the medium. Potentiation by metformin of insulin action on gluconeogenesis was elevated significantly (P < 0.01 to 0.001) by glucose in vitro. Metformin (75-250 microM) also counteracted the effects of glucagon at optimal concentrations in normal (32-68%) as well as diabetic (8-46%) hepatocytes. The findings of this study indicate that (i) the anti-gluconeogenic effect of metformin is enhanced by glucose in vivo and in vitro; and (ii) the suppression of glucagon-induced gluconeogenesis by metformin could play a role in its glucose-lowering effects in diabetic conditions.
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PMID:Effects of metformin on glucose and glucagon regulated gluconeogenesis in cultured normal and diabetic hepatocytes. 809 7

We investigated the mechanisms of the effects of the biguanides metformin and buformin on hepatic gluconeogenesis in hepatocytes isolated from normal rats. Both 10 nM glucagon and 50 microM dibutyryl cAMP increased [3H]alanine uptake in isolated hepatocytes of normal rats by about 150% and 55%, respectively, compared with the effect of 5 mM alanine alone. Metformin (3 mM) reduced glucagon-stimulated [3H]alanine uptake to the level seen with alanine alone; buformin (3 mM) inhibited glucagon-stimulated [3H]alanine uptake by about 69%. The effects of biguanides on dibutyryl cAMP-stimulated [3H]alanine uptake were similar, but of smaller magnitude compared with those observed in the presence of glucagon. Ouabain (3 mM) had a stronger inhibitory effect on [3H]alanine uptake than the biguanides. However, 3 mM tolbutamide failed to suppress [3H]alanine uptake in the presence or absence of glucagon or dibutyryl cAMP. Our results suggest that the inhibition of alanine uptake, related to a reduction in the Na+/L-alanine transport system, is a possible mechanism of biguanide-related inhibition of hepatic gluconeogenesis.
Diabetes Res Clin Pract
PMID:Biguanides may produce hypoglycemic action in isolated rat hepatocytes through their effects on L-alanine transport. 813 11


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