The oral antihyperglycemic drug metformin has a unique mechanism of action and controls glycemia in both obese and normal-weight NIDDM patients without inducing hypoglycemia, insulin stimulation or hyperinsulinemia. Metformin used in combination with sulfonylureas has a synergistic effect in lowering fasting and postprandial glucose and hemoglobin A1c levels, and improving the lipid profile. Metformin does not increase lactate production from skeletal muscle and has little clinically significant effect on vitamin B12 and folic acid absorption. Lactic acidosis associated with metformin use is extremely rare (reported incidence of 0.03/1,000 patient-years exposure) and has occurred predominantly in patients for whom the drug was contraindicated. Observance of prescribing guidelines will greatly minimize risk, since risk factors have been identified. Metformin can be safely used in the elderly, provided prescribing precautions are followed. Dosing in the elderly should be conservative, with dose adjustment designed to achieve normal blood sugar levels.

Acidosis, Lactic↗

PubMed1996

Interactions between the sorbitol pathway, non-enzymatic glycation, and diabetic vascular dysfunction.

BACKGROUND: Many lines of evidence attest to a multifactorial pathogenesis of diabetic complications in humans and in animal models of diabetes. Increased sorbitol pathway metabolism and non-enzymatic glycation products have been implicated by many investigators in the pathogenesis of vascular and neural dysfunction as well as early vascular structural changes in animal models of diabetes. The present studies were undertaken to assess the mechanisms that mediate vascular dysfunction associated with these biochemical imbalances. METHODS: Three different animal models of diabetes were used: (1) rats with diabetes induced by injection of streptozotocin; (2) non-diabetic rats with acute hyperglycaemia of 5 h duration induced by i.v. glucose infusion at a rate sufficient to produce plasma glucose levels comparable to those in diabetic rats; and (3) the skin chamber granulation tissue model in which vessels in the chamber are exposed to buffer containing 5 or 30 mM glucose +/- pharmacological agents or 0.1 microM glycated rat serum albumin +/- pharmacological agents. Vascular function was assessed by injection of 11.3 microns 46Sc microspheres for quantification of blood flow and by injection of [125I] and [131I]bovine serum albumin for quantification of vascular albumin permeation. RESULTS: Vascular dysfunction induced by elevated glucose levels (increased blood flow and increased albumin permeation) in all three models was prevented by inhibitors of sorbitol pathway metabolism, inhibitors of nitric oxide synthesis and inhibitors of prostaglandin synthesis. In the skin chamber model vascular dysfunction induced by elevated glucose levels and by glycated rat serum albumin was prevented by superoxide dismutase, probucol and inhibitors of nitric oxide synthase. CONCLUSIONS: These observations suggest that vascular dysfunction induced by increased sorbitol pathway metabolism (caused by elevated glucose levels) and by products of non-enzymatic glycation (at normal glucose levels) is mediated by a common final pathway consistent with a scenario in which: increases superoxide production-->increases intracellular calcium levels-->increases nitric oxide synthesis-->increases blood flow and increases vascular permeability.

Animals↗

PubMed1994

Neural dysfunction and metabolic imbalances in diabetic rats. Prevention by acetyl-L-carnitine.

The rationale for these experiments is that administration of L-carnitine and/or short-chain acylcarnitines attenuates myocardial dysfunction 1) in hearts from diabetic animals (in which L-carnitine levels are decreased); 2) induced by ischemia-reperfusion in hearts from nondiabetic animals; and 3) in nondiabetic humans with ischemic heart disease. The objective of these studies was to investigate whether imbalances in carnitine metabolism play a role in the pathogenesis of diabetic peripheral neuropathy. The major findings in rats with streptozotocin-induced diabetes of 4-6 weeks duration were that 24-h urinary carnitine excretion was increased approximately twofold and L-carnitine levels were decreased in plasma (46%) and sciatic nerve endoneurium (31%). These changes in carnitine levels/excretion were associated with decreased caudal nerve conduction velocity (10-15%) and sciatic nerve changes in Na(+)-K(+)-ATPase activity (decreased 50%), Mg(2+)-ATPase (decreased 65%), 1,2-diacyl-sn-glycerol (DAG) (decreased 40%), vascular albumin permeation (increased 60%), and blood flow (increased 65%). Treatment with acetyl-L-carnitine normalized plasma and endoneurial L-carnitine levels and prevented all of these metabolic and functional changes except the increased blood flow, which was unaffected, and the reduction in DAG, which decreased another 40%. In conclusion, these observations 1) demonstrate a link between imbalances in carnitine metabolism and several metabolic and functional abnormalities associated with diabetic polyneuropathy and 2) indicate that decreased sciatic nerve endoneurial ATPase activity (ouabain-sensitive and insensitive) in this model of diabetes is associated with decreased DAG.

Acetylcarnitine↗

PubMed1993

Endoneurial blood flow changes in diabetic rats.

Explore the source record for details and available documents.

Animals↗

PubMed1993

Hyperglycemic pseudohypoxia and diabetic complications.

Vasodilation and increased blood flow are characteristic early vascular responses to acute hyperglycemia and tissue hypoxia. In hypoxic tissues these vascular changes are linked to metabolic imbalances associated with impaired oxidation of NADH to NAD+ and the resulting increased ratio of NADH/NAD+. In hyperglycemic tissues these vascular changes also are linked to an increased ratio of NADH/NAD+, in this case because of an increased rate of reduction of NAD+ to NADH. Several lines of evidence support the likelihood that the increased cytosolic ratio of free NADH/NAD+ caused by hyperglycemia, referred to as pseudohypoxia because tissue partial pressure oxygen is normal, is a characteristic feature of poorly controlled diabetes that mimics the effects of true hypoxia on vascular and neural function and plays an important role in the pathogenesis of diabetic complications. These effects of hypoxia and hyperglycemia-induced pseudohypoxia on vascular and neural function are mediated by a branching cascade of imbalances in lipid metabolism, increased production of superoxide anion, and possibly increased nitric oxide formation.

Animals↗

PubMed1992

A multisite physician's office laboratory evaluation of an immunological method for the measurement of HbA1c.

OBJECTIVE: To evaluate the clinical performance of a new immunological HbA1c method in physicians' office laboratories. RESEARCH DESIGN AND METHODS: Three physicians' offices participated in the evaluations. The clinicians routinely use HbA1c test results to monitor their patients' long-term blood glucose control. Precision and interlaboratory variability were assessed using three levels of lyophilized controls. Correlation of the method's results to currently available laboratory methods was made. Comparison of finger-stick (capillary) results to venous EDTA whole blood results was made on 134 patients. Physician and laboratory personnel input was evaluated with regard to the clinical utility of the system. RESULTS: The CVW and CVB were a maximum of 4.5 and 4.4% for the immunoassay system on three levels of control materials at the three sites. Interlaboratory variability among the control means was found to be 4.9-5.4, 8.0-8.3, and 11.7-12.0% HbA1c. Correlation coefficients (r) ranged from 0.95 to 0.99. There was a positive bias by the DCA 2000 compared with the in-house method at site 1. Minimal negative biases were seen by the DCA 2000 with comparative methods used at sites 2 and 3. Median percentage differences with the comparative methods were 12, -1.4, and -5.6%. Comparison of capillary to venous sample results, from the DCA 2000, showed no clinically significant differences. Operator and physician feedback were positive with respect to technical ease in performance of the test and accuracy of results. CONCLUSIONS: Precision was acceptable and interlaboratory variability was low. The immunological method correlated well with manual ion-exchange and automated HPLC methods. The small sample size and good comparison between capillary and venous sample results make fingerstick sampling acceptable. The method provided immediate test results (within 9 min) to the clinicians.

Blood Specimen Collection↗

PubMed1991

Evaluation of the efficacy and safety of Diamicron in non-insulin-dependent diabetic patients.

The efficacy and safety of gliclazide (Diamicron) were studied in 29 NIDDM patients (19 men and 10 women aged 25-68 years) who failed to improve with diet or with diet plus a sulfonylurea. All patients were overweight and had fasting blood glucose levels consistently above 150 mg/dl (8.24 mmol/l). After withdrawal of oral hypoglycemics where applicable, they received 40 mg Diamicron three times daily with meals. The dose was increased by 40-80 mg/day until optimum control was obtained or up to a maximum of 320 mg/day. Treatment lasted for 12 months. At the end of this period the mean fasting blood glucose level had fallen by 35% from 238 to 154 mg/dl and the mean 2-h postprandial blood glucose level had fallen by 28% from 237.7 to 195 mg/dl. The mean glycosylated hemoglobin level also fell by 30% from 10.10 to 7.02%, i.e. within the normal range. In addition, there was a 19% fall in triglyceride and a 10% fall in cholesterol levels, with no change in body weight. No changes were observed for serum insulin, C-peptide and glucagon levels, thyroid function tests, blood counts, liver and kidney function tests, uric acid, electrolytes, blood pressure or heart rate. No clinical or ECG abnormalities were observed in patients with or without cardiovascular disease. There were two presumptive hypoglycemic reactions, but these did not require treatment. Adverse effects were reported by 22 patients, including dizziness and light-headedness, diarrhea, nausea, palpitations and pruritus, but none required modification of Diamicron therapy. The results therefore show that Diamicron is safe, effective and well tolerated in suitably selected NIDDM patients.

Adult↗

PubMed1991

Duplication of the colon: a case report.

Colonic duplication is a rare anomaly. The authors present a case of duplication in an adult to introduce a brief discussion of the embryology, classification, symptoms and radiology of the condition.

Aged↗

PubMed1990

Vascular filtration function in galactose-fed versus diabetic rats: the role of polyol pathway activity.

These studies were undertaken to assess the effects of increased galactose (v increased glucose) metabolism via the polyol pathway on vascular filtration function in the kidneys, eyes, nerves, and aorta. Quantitative radiolabeled tracer techniques were used to assess glomerular filtration rate (GFR) and regional tissue vascular clearance of plasma 131I-bovine serum albumin (BSA) in five groups of male Sprague-Dawley rats: nondiabetic controls, streptozotocin-diabetic rats, nondiabetic rats fed a 50% galactose diet, diabetic rats treated with sorbinil (an aldose reductase inhibitor), and galactose-fed rats treated with sorbinil. Sorbinil was added to the diet to provide a daily dose of approximately .2 mmol/kg body weight. After 2 months of diabetes or galactose ingestion, albumin clearance was increased twofold to fourfold in the eye (anterior uvea, choroid, and retina), sciatic nerve, aorta, and kidney; GFR was increased approximately twofold and urinary excretion of endogenous albumin and IgG were increased approximately 10-fold. Sorbinil treatment markedly reduced or completely prevented all of these changes in galactose-fed, as well as in diabetic rats. These observations support the hypothesis that increased metabolism of glucose via the sorbitol pathway is of central importance in mediating virtually all of the early changes in vascular filtration function associated with diabetes in the kidney, as well as in the eyes, nerves, and aorta. On the other hand, renal hypertrophy in diabetic rats and polyuria, hyperphagia, and impaired weight gain in galactose-fed and in diabetic rats were unaffected by sorbinil and therefore are unlikely to be mediated by increased polyol metabolism.

Animals↗

PubMed1990

Visual field defects in patients with insulin-dependent and noninsulin-dependent diabetes.

Automated perimetry (Humphrey 30-2) was used to quantitate visual field sensitivity in diabetic patients with either little or no retinopathy (n = 38) or mild background diabetic retinopathy (n = 19) and in visually normal controls (n = 40). Foveal thresholds were unaffected in the diabetic patients but significant reductions in visual field sensitivity, measured by both the mean deviation and the pattern standard deviation indices of visual field sensitivity, were observed in the diabetic patients. Subgroup analyses showed that this sensitivity reduction primarily occurred in noninsulin-dependent diabetic patients. Among the diabetic patients, 26.3% of the visual fields were flagged as "probably abnormal." This percentage was greatest among the noninsulin-dependent patients with mild background diabetic retinopathy (72.3%). The sensitivity reductions observed in the noninsulin-dependent patients with mild background diabetic retinopathy tended to be localized in the superior quadrants and correlated with the extent of retinal vascular compromise evident from vitreous fluorophotometry (r = 0.603). These findings imply that in diabetic patients visual field defects (1) often can be detected in patients with at most moderate retinopathy, (2) occur more frequently in noninsulin-dependent patients than in insulin-dependent patients, and (3) may result from subclinical microangiopathy.

Adult↗

PubMed1990

Glucose-induced microvascular functional changes in nondiabetic rats are stereospecific and are prevented by an aldose reductase inhibitor.

Exposure of skin chamber granulation tissue vessels in nondiabetic rats to 11 or 15 mM D-glucose (but not L-glucose or 3-O-methylglucose) twice daily for 10 d induces vascular functional changes (increased albumin permeation and blood flow) identical to those in animals with mild or severe streptozotocin diabetes, respectively. These vascular changes are strongly linked to increased metabolism of glucose via the sorbitol pathway and are independent of nonenzymatic glycosylation as well as systemic metabolic and hormonal imbalances associated with the diabetic milieu. (J. Clin. Invest. 1990. 85:1167-1172.)

Aldehyde Reductase↗

PubMed1990

Modulation of hemodynamic and vascular filtration changes in diabetic rats by dietary myo-inositol.

To assess the potential of myo-inositol-supplemented diets to prevent diabetes-induced vascular functional changes, we examined the effects of diets supplemented with 0.5, 1, or 2% myo-inositol on blood flow and vascular filtration function in nondiabetic control rats and rats with streptozocin-induced diabetes (STZ-D). After 1 mo of diabetes and dietary myo-inositol supplementation, 1) 131I-labeled bovine serum albumin (BSA) permeation of vessels was assessed in multiple tissues, 2) glomerular filtration rate (GFR) was estimated as renal plasma clearance of 57Co-labeled EDTA, 3) regional blood flows were measured with 15-microns 85Sr-labeled microspheres, and 4) endogenous albumin and IgG urinary excretion rates were quantified by radial immunodiffusion assay. In STZ-D rats, 131I-BSA tissue clearance increased significantly (2- to 4-fold) in the anterior uvea, choroid-sclera, retina, sciatic nerve, aorta, new granulation tissue, diaphragm, and kidney but was unchanged in skin, forelimb muscle, and heart. myo-Inositol-supplemented diets reduced diabetes-induced increases in 131I-BSA clearance (in a dose-dependent manner) in all tissues; however, only in new granulation tissue and diaphragm did the 2% myo-inositol diet completely normalize vascular albumin permeation. Diabetes-induced increases in GFR and in urinary albumin and IgG excretion were also substantially reduced or normalized by dietary myo-inositol supplements. Increased blood flow in anterior uvea, choroid-sclera, kidney, new granulation tissue, and skeletal muscle in STZ-D rats also was substantially reduced or normalized by the 2% myo-inositol diet. myo-Inositol had minimal if any effects on the above parameters in control rats. These observations indicate that diabetes-induced increases in regional blood flow, 131I-BSA permeation, GFR, and urinary protein excretion can be markedly reduced or normalized by consumption of myo-inositol-supplemented diets that raise plasma myo-inositol levels approximately fivefold. The failure of the 2% myo-inositol diet to normalize GFR and blood flow and albumin permeation in several tissues despite markedly elevated plasma myo-inositol levels and normal or elevated tissue myo-inositol levels indicates that if vascular functional changes in these tissues are linked to altered myo-inositol levels, they are resistant to normalization by elevation of plasma myo-inositol levels. These results suggest that other factors independent of changes in relative or absolute tissue myo-inositol levels may play an important role in the pathogenesis of diabetes-induced vascular functional changes in these tissues.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1990

Effects of islet isografts on hemodynamic and vascular filtration changes in diabetic rats.

To assess the reversibility of diabetes-induced increases in regional vascular albumin permeation and blood flow and changes in kidney filtration function, islet isografts were given via the portal vein after 2 mo of streptozocin-induced diabetes in male Lewis rats. One month later, vascular function was assessed in control rats, islet-transplanted diabetic rats, and untreated diabetic rats (6-9 rats/group). Untreated diabetic rats were markedly hyperglycemic, hyperphagic, and polyuric. Transplanted rats were euglycemic within 6 days; 24-h urine volumes were virtually normalized by 2 wk and food consumption was normalized 4 wk after transplantation. Vascular albumin permeation in diabetic rats was significantly increased 1.4- to 1.7-fold in anterior uvea, choroid, retina, sciatic nerve, new granulation tissue, and kidney and was increased 1.1- to 1.3-fold in diaphragm, cecum, and optic nerve. Albumin permeation was not increased in aorta, brain, heart, or forelimb skeletal muscle. Islet transplants significantly reduced but did not completely normalize vascular albumin permeation in most tissues in which it was increased by diabetes but had no effect on albumin permeation in optic nerve, sciatic nerve, and diaphragm. Urinary excretion of endogenous albumin and IgG in diabetic rats was significantly increased 19- and 14-fold, respectively, and was virtually normalized 4 days after islet transplantation. Marked (1.8-fold) increases in glomerular filtration rate (GFR) in diabetic rats were also substantially reduced by islet transplants but remained elevated 1.4-fold control values. Likewise, diabetes-induced increases in regional blood flow were reduced in general but not normalized by islet transplants. These observations indicate that 1) diabetes-induced hemodynamic changes and alterations in vascular filtration function are not rapidly reversed by euglycemia after islet transplantation, 2) diabetes-induced increases in urinary albumin and IgG excretion are more readily normalized by euglycemia than increases in GFR and renal 125I-labeled bovine serum albumin (125I-BSA) filtration, and 3) significant increases in GFR and renal 125I-BSA filtration may not be manifested by albuminuria.

Animals↗