Showing papers in "Diabetes, Obesity and Metabolism in 2000"

Weight loss with sibutramine improves glycaemic control and other metabolic parameters in obese patients with type 2 diabetes mellitus.

Abstract: Summary Aim: To determine the efficacy and tolerability of sibutramine hydrochloride in obese patients whose type 2 diabetes was poorly controlled on diet alone or with an oral antidiabetic agent Methods: This study was a 24-week, double-blind, multicentre trial following a 5-week placebo run-in period. One hundred and seventy-five obese (body mass index (b.m.i.) ≥27 kg/m2) patients with poorly controlled type 2 diabetes mellitus were randomized either to sibutramine (n = 89; mean age 53.5 years; mean weight 99.3 kg) or placebo (n = 86; mean age 55 years; mean weight 98.2 kg) at 16 participating centres. To achieve moderate calorie restriction (deficit ≥ 250–500 kcal/day), individual dietary counselling was accompanied by either placebo or sibutramine (initial dosage of 5 mg/day titrated up by 5 mg biweekly through week 6, and maintained at 20 mg through week 24). The main outcome measures included changes in weight, b.m.i., waist and hip circumference, glycaemic control, lipid profile, and quality of life, and evaluation of reported adverse events. Results: Sixty-seven per cent of sibutramine patients and 71% of placebo patients completed the study. At week 24 when comparing those who completed the course, sibutramine compared with placebo patients showed significantly greater (p < 0.001) absolute (−4.3 vs. −0.4 kg) and percentage (−4.5% vs. −0.5%) weight loss. Weight loss ≥5% or 10% was achieved by 33% and 8% of sibutramine patients, respectively, but no placebo patients (p < 0.03 or better). Improvement in glycaemic control was correlated with weight loss (p < 0.001). In 5% and 10% weight-loss responders, mean treatment differences were −0.53% and −1.65% (p ≤ 0.05), respectively, for HbA1c, and −1.4 mmol/l (p ≤0.05) and −3.8 (p ≤0.05) mmol/l for fasting plasma glucose. Sibutramine patients also showed improvements in fasting insulin, triglycerides, HDL cholesterol, and quality-of-life assessments. Overall, sibutramine was well tolerated compared with the placebo. Sibutramine treatment was associated with small mean increases in blood pressure (BP) and pulse, although an increase in BP was not seen in sibutramine-treated patients who lost ≥ 5% of their weight. Conclusions: Sibutramine produced statistically and clinically significant weight loss when used in combination with recommendations for moderate caloric restriction. This weight loss was associated with improvements in metabolic control and quality of life, and sibutramine was generally well tolerated in obese patients with type 2 diabetes.

Physiology of glucose homeostasis.

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Sibutramine is effective for weight loss and diabetic control in obesity with type 2 diabetes: a randomised, double‐blind, placebo‐controlled study

Abstract: Summary Aims: To assess the efficacy and tolerability of sibutramine 15 mg once daily as a weight reduction agent in overweight and obese patients (body mass index (b.m.i.) > 26 kg/m2) with type 2 diabetes when given with a customised, reduced-calorie diet, and to evaluate the influence of weight loss on diabetic control. Methods: Randomised, placebo-controlled, double-blind, parallel-group, 12-week study conducted at two hospital-based obesity/diabetes clinics. Patients were men and women aged 30–65 years, with b.m.i. > 26 kg/m2 and ≤ 35 kg/m2 and treated or untreated type 2 diabetes diagnosed ≥ 6 months previously. Each patient was given sibutramine 15 mg or placebo once daily and advised to follow a customised diet of 500 kcal/day less than the individual's energy needs. The principal measure of efficacy was change in body weight (b.w.). Additional efficacy measurements were changes in b.m.i., body composition as measured by dual-energy X-ray absorptiometry, and change in waist and hip measurements. Changes in diabetic control were assessed by blood glucose levels fasting and after a standard test meal, fasting insulin level, and glycosylated haemoglobin level. Adverse events (AEs) were monitored at each visit, and routine laboratory safety tests were done at 4-week intervals. Results: Ninety-one patients were randomised into the study, 44 to placebo and 47 to sibutramine 15 mg once daily. Eighty-three patients (91%) completed the study, 40 (91%) on placebo and 43 (91%) on sibutramine. Mean weight reduction from baseline was statistically significantly greater with sibutramine than with placebo at every measurement and at the end of the study (2.4 vs. 0.1 kg at week 12; p 5% of their baseline b.w. was 19% in the sibutramine group and 0% in the placebo group (p < 0.001; 95% confidence interval: 9, 30). Patients receiving sibutramine lost significantly more fat mass compared with those receiving placebo, as a percentage (1.0% vs. 0.1%; p < 0.05) and in absolute terms (1.8 vs. 0.2 kg, p < 0.001). Loss of lean mass was not significantly different between the groups. Mean peak blood glucose concentration after a standard test meal decreased by 1.1 mmol/l in the sibutramine treatment group but increased by 0.5 mmol/l in the placebo group (p = 0.04; difference in means, 1.6, 95% confidence interval: −3.3, −0.1). Mean fasting blood glucose decreased by 0.3 mmol/l with sibutramine and increased by 1.4 mmol/l with placebo. Mean glycosylated haemoglobin levels decreased by 0.3% units with sibutramine treatment, and were unchanged with placebo. However, more sibutramine-treated patients (33%) than placebo-treated patients (5%) achieved decreases in glycosylated haemoglobin of 1% unit or more (p < 0.05). Sibutramine 15 mg was safe and well tolerated, and AEs were mostly mild or moderate in severity. No significant differences were found between treatment groups in blood pressure. No clinically significant conduction or rhythm abnormalities were observed on ECG. Conclusions: Sibutramine 15 mg once daily with a customised, reduced-calorie diet significantly reduced weight compared with placebo in overweight and obese patients (b.m.i. > 26 kg/m2) with type 2 diabetes. Sibutramine was well tolerated, and significant improvement in diabetic control was seen in conjunction with weight reduction on sibutramine treatment.

Disturbed release of gastrointestinal peptides in anorexia nervosa and in obesity.

Abstract: AIM It is commonly accepted that some neuropeptides play an important role in the control of appetite and hormonal secretion. Several gastrointestinal peptides may affect on central control of appetite via vagal and spinal nerves. The aim of this study was to evaluate the release of gastrointestinal peptides in anorexia nervosa and in obesity, because in these diseases the disturbances in the control of appetite and hormonal secretion were found. Material consisted of 30 women with anorexia nervosa aged 16-29 years (mean 22 years) and 23 women with obesity aged 19-33 years (mean 29 years) and 25 lean women of control group. METHODS In women with anorexia nervosa as compared with control group we observed a significant increase of plasma vasoactive intestinal peptide (VIP) levels (p < 0.01) and a significant decrease of leptin (p < 0.001), beta-endorphin (p < 0.01), gastrin (p < 0.05), cholecystokinin (CCK; p < 0.05) and somatostatin (S-S; p < 0.01). In obese women we found a significant increase of neuropeptide Y (NPY; p < 0.001), leptin (p < 0.01), galanin (p < 0.001), beta-endorphin (p < 0.001), gastrin (p < 0.01), CCK (p < 0.001) and S-S (p < 0.01) and a significant decrease of VIP concentrations (p < 0.001) as compared with control group. CONCLUSION Our results indicate that the release of gastrointestinal peptides is disturbed in obesity and in anorexia nervosa. These findings suggests that dysfunction of brain-gut axis may be also an important factor in the abnormal control of appetite axcept of hypothalamic dysfunction.

Effect of four-week metformin treatment on plasma and erythrocyte antioxidative defense enzymes in newly diagnosed obese patients with type 2 diabetes.

Abstract: The principal metabolic effect of metformin-an oral antihyperglycaemic agent-is the improvement in the sensitivity of peripheral tissues and liver to insulin. This study examined the effect of metformin monotherapy on antioxidative defence system activity in erythrocytes and plasma in diabetic patients. We studied the effect of metformin treatment on the activities of Cu, Zn-superoxide dismutase (EC 1. 15. 1. 1.), catalase (EC 1. 11. 1. 6.) and glutathione peroxidase (EC 1. 11. 1. 9.) in relation to lipid peroxidation products and reduced glutathione level in plasma and erythrocytes. In this study we also examined erythrocytes' susceptibility to H2O2-induced oxidative stress during metformin therapy. Although metformin monotherapy ameliorated the imbalance between free radical-induced increase in lipid peroxidation (by reducing the MDA level in both erythrocytes and plasma) and decreased plasma and cellular antioxidant defences (by increasing the erythrocyte activities of Cu, Zn, SOD, catalase and GSH level) and decreased erythrocyte susceptibility to oxidative stress, it had negligible effect to scavenge Fe ion-induced free radical generation in a phospholipid-liposome system.

Rosiglitazone prevents the onset of hyperglycaemia and proteinuria in the Zucker diabetic fatty rat.

Abstract: Summary Aim To investigate the potential of rosiglitazone, a highly potent agonist at the nuclear peroxisome proliferator activated receptor-γ (PPAR-γ), to prevent the development of diabetes in the Zucker diabetic fatty (ZDF) rat or to ameliorate the condition at a later stage of the disease. Methods Rosiglitazone (10 μmol/kg body weight daily) was given via the diet to ZDF rats from aged 6 weeks, before the onset of hyperglycaemia (Prevention group), or from aged 21 weeks after hyperglycaemia and proteinuria were established (Intervention group). Untreated ZDF rats and age-matched Zucker lean rats (ZL) served as controls and the experiment was terminated when the animals were aged 28 weeks. Results Whilst the combined ZDF control and Intervention groups were already hyperglycaemic (14.6 ± 1.6 vs. ZL 5.7 ± 0.1 mmol/l, mean ± s.e.m.; p < 0.05), glycosuric and polydipsic at aged 11 weeks, and thereafter had a declining plasma insulin concentration, rosiglitazone Prevention treatment maintained normoglycaemia even at aged 27 weeks (3.7 ± 0.3 mmol/l vs. ZL 3.0 ± 0.3 mmol/l; NS). Intervention treatment at aged 21 weeks, however, failed to ameliorate the diabetes. These functional data were supported by determinations of pancreatic insulin content (μg/mg tissue as follows: ZL, 43.1 ± 3.9; ZDF control (28 weeks) + ZDF Intervention control (21 weeks), 6.0 ± 0.8; Prevention, 63.6 ± 15.8; Intervention, 6.2 ± 0.9) and by morphological, immunohistochemical and electron microscopical examination of pancreata at the end of the study. Thus, islets from rosiglitazone Prevention rats were similar to ZL rats, whereas ZDF controls and Intervention rats exhibited islets depleted of insulin, with a disorganized architecture and an ultrastructure indicative of work hypertrophy. ZDF control rats and Intervention rats, though not rosiglitazone Prevention rats, also exhibited marked proteinuria, indicative of renal glomerular damage. Conclusions Our results demonstrate that in ZDF rats, rosiglitazone prevents the progression from insulin resistance to overt diabetes. These data provide a rationale for investigating whether treatment with rosiglitazone of patients with early signs of perturbed glucose metabolism (e.g. impaired fasting glucose (IGT)) may prevent the progression to type 2 diabetes and its associated complications.

Variations in plasma soluble tumour necrosis factor receptors after diet-induced weight loss in obesity.

Abstract: Summary The aim of this study was to investigate the variations in the plasma levels of the soluble tumour necrosis factor receptor type-I (sTNFR-I) and type-II (sTNFR-II) during weight loss which was induced by 3 weeks on a very low calorie diet (3.9 ± 0.1 MJ/day), in 17 non-diabetic obese women. Plasma sTNFR-I concentrations decreased significantly after weight loss (p < 0.05), but there was no significant change in plasma sTNFR-II. As the diet was associated with a significant decrease in body fat mass (≈2.5 kg), this result supports the emerging concept that adipose tissue can produce significant amounts of sTNFR-I and that this production can be modified by weight loss in human obesity

Diabetes and vascular disease.

Abstract: Cardiovascular and cerebrovascular disease are two of the most important causes of morbidity and mortality in the USA and worldwide. The impact of these conditions is even more profound in patients with diabetes. The aims of the Vascular Disease Working Group in the articles that follow are to review the impact of cerebrovascular and cardiovascular disease in the general population, and, specifically, in the patient with diabetes, and to suggest appropriate treatment. Important steps to decreasing the risk of these diseases in diabetic patients are strict glycaemic control, control of hypertension, and modification of dyslipidaemia.

Comparative efficacy study of atorvastatin vs simvastatin, pravastatin, lovastatin and placebo in type 2 diabetic patients with hypercholesterolaemia.

Abstract: Although there is little information from primary or secondary prevention trials on cholesterol-lowering medication in diabetic patients, the reduction of elevated cholesterol is widely recommended for this group. The American Diabetes Association (ADA) recommends drug therapy in diabetic patients if low density lipoprotein (LDL)-cholesterol remains at > 130 mg/dl, or > 100 mg/dl in patients with macroangiopathy, after dietary intervention. When cholesterollowering medication is indicated, the choice of the drug must take into account the other lipid abnormalities that are often present and the need to maintain optimal glycaemic control. In the present study we compared the efficacy and safety of the novel HMG-CoA reductase inhibitor atorvastatin at the dose of 10 mg/day with simvastatin , lovastatin and pravastatin at doses of 10, 20 and 20 mg/day, respectively, and placebo, in type 2 diabetic patients with moderate elevation of LDL-cholesterol with or without elevation of triglycerides. All the quoted agents are enzyme inhibitors effective in lowering LDL-cholesterol in humans. The efficacy endpoints were the mean per cent changes in plasma LDL-cholesterol (primary), total cholesterol, triglycerides, and high-density lipoprotein (HDL)-cholesterol concentrations from baseline to the end of treatment (24 weeks). Atorvastatin at a dose of 10 mg/day produced: (1) a significant reduction in LDL-cholesterol (-37%) in comparison with equivalent doses of simvastatin (-26%), pravastatin (-23%), lovastatin (-21%), and placebo (-1%); (2) HDL-cholesterol increases (7.4%) comparable to or greater than those obtained with simvastatin (7.1%), pravastatin (3.2%), lovastatin (7.21%), and placebo (-0.5%); (3) a significantly greater reduction in total cholesterol (- 29%) than that obtained with simvastatin (-21%), pravastain (-16%), lovastatin (-18%), and placebo (1%); and (4) a significantly greater reduction in triglycerides than that obtained with all the other drugs and placebo. In all treatment groups no significant variation in fibrinogen concentration was observed. All reductase inhibitors studied had similar levels of tolerance. There were no incidents of persistent elevations of serum aminotransferases or myositis.

Diabetes‐induced biochemical changes in rat lens: attenuation of cataractogenesis by pyruvate

Abstract: Summary Aim: Studies have been conducted to determine the effect of pyruvate administration on the biochemistry of rat lens and the status of its transparency as affected by diabetic conditions. Methods: Sprague-Dawley rats were rendered diabetic by intravenous (i.v.) injection of streptozotocin (55 mg/kg body weight (b.w.)) and treated with sodium pyruvate (2%) in drinking water. The levels of glucose, fructose, sorbitol, ATP, GSH, MDA as well as glycated proteins in the lenses were determined at various intervals after the onset of diabetes and the values compared with untreated diabetic controls. The progress of cataract formation and associated histological changes in the tissue were also monitored. Results: Studies show that the pyruvate treatment decreased the extent of several biochemical changes known to be associated with cataract formation, such as the elevation in the levels of glycated proteins, sorbitol, lipid peroxidation (MDA) and inhibition of the cation pump. The progress of cataract was also significantly delayed. Conclusion: Exogenous administration of this compound hence was found to exert an overall protective effect against cataract formation induced by the diabetic conditions.

Troglitazone reduces plasma levels of tumour necrosis factor-alpha in obese patients with type 2 diabetes.

Abstract: We evaluated the effect of troglitazone (given orally 400 mg/day) on glucose intolerance and on the plasma levels of tumour necrosis factor-alpha (TNF-alpha) in 12 obese patients with type 2 diabetes for 12 weeks. Troglitazone significantly decreased fasting plasma glucose, serum C-peptide, serum insulin and HbA1c levels. Plasma levels of TNF-alpha were significantly reduced by troglitazone administered for 8 and 12 weeks. Troglitazone administration significantly improved insulin resistance, but did not affect pancreatic beta-cell function as evaluated by the homeostasis model assessment (HOMA). In the present study, we reported for the first time that troglitazone administration significantly reduces plasma levels of TNF-alpha in obese patients with type 2 diabetes.

Cosegregation of obesity with familial aggregation of type 2 diabetes mellitus

Abstract: Summary Objective: We have shown that a positive family history of diabetes, and the variables of general and central obesity are independent risk factors for type 2 diabetes in our population. This study was done to evaluate whether a familial predisposition to diabetes resulted in a tendency for adverse anthropometric and haemodynamic profiles in south Indian non-diabetic subjects. Methods: The analysis was carried out on 2463 subjects (M: F, 1196 : 1267) with normal glucose tolerance (NGT). The study subjects were selected from population surveys for diabetes. Details of age, sex, family history of diabetes, body mass index (b.m.i.), waist-to-hip ratio (WHR) and blood pressure were recorded. Serum cholesterol and triglycerides were estimated. Results: A positive family history of diabetes was present in 24.7% of our subjects. Mean b.m.i. and percentage of obesity were significantly higher in families with a positive family history (group 2) vs. families with no family history (group 1). Subjects in group 2 had a higher 2-h plasma glucose (p < 0.001) and higher prevalence of hypertension (χ2 = 6.91, p = 0.0086). Factor analysis with principle components analysis (PCA) showed that a family history of diabetes clustered with WHR in men, and with b.m.i. and WHR in women. The b.m.i. formed a different domain with blood pressure in both sexes. WHR and b.m.i. clustered with cholesterol and triglycerides in another domain. Conclusions: In this population, general and central obesity are associated with a family history of diabetes. A family history of diabetes may increase the risk of hypertension and hyperlipidaemia indirectly through its connection with b.m.i.

Optimizing insulin delivery: assessment of three strategies in intensive diabetes management

Abstract: SUMMARY Objective To compare three intensive management strategies with respect to metabolic control (glycated haemoglobin, preprandial blood glucose, lipid profile, body weight, hypoglycaemic episodes) and psycho-social adaptation (quality of life, self-efficacy, stress and perceived complexity). Research Design and Methods: Fifteen adults with type 1 diabetes completed this 1-year, randomized, prospective, cross-over study. The three treatment strategies were categorized according to flexibility with insulin self-adjustments as follows: Simplified (SIMP) = meal plan based on food exchanges with no self-adjustments of insulin for food, exercise and stress; Qualitative (QUAL) = meal plan based on food exchanges with qualitative adjustment of insulin for food, exercise and stress; Quantitative (QUANT) = meal plan using carbohydrate counting with quantitative adjustment of insulin for food and qualitative adjustment for exercise and stress. All three strategies allowed for adjustments of insulin for preprandial blood glucose and the option of adjusting diet for exercise. All subjects followed each strategy for 3.5 months. Subjects kept detailed log sheets where they recorded preprandial blood glucose, insulin dosages, food intake, activity and stress level at least four times/day. The psycho-social aspects were determined with validated questionnaires that were completed before and after each strategy. Results There were no statistically significant differences in metabolic control, quality of life and self-efficacy between the three strategies. The mean (± s.e.) for HbA1 levels (normal < 8.5%) were: Baseline: 10.9 ± 0.06 and End of SIMP = 9.7 ± 0.03; QUAL = 9.5 ± 0.04; QUANT = 10.2 ± 0.04. Body weight and serum lipid levels did not change significantly. The frequency of severe hypoglycaemic episodes for the entire study was 20 episodes/100 patient-years. Perceived complexity of treatment strategy increased (p < 0.0001) from SIMP to QUANT (least to most flexible). Although the majority of subjects (n = 11) were following a strategy similar to SIMP prior to entering the study, 12 subjects chose to continue with QUAL, three with QUANT and none with SIMP at the end of the study. Conclusions These results indicate that a strategy that allows for flexibility of self-adjustments of insulin and is not very complex (such as QUAL) may be the strategy of choice for intensive management programmes.

Effects of inhibition of the renin‐angiotensin system on the cardiovascular actions of insulin

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Ethnicity and risk factors for coronary heart disease in diabetes mellitus.

Abstract: Summary Introduction: The Framingham equation can be used to predict the risk of coronary heart disease (CHD) and so to target risk factor intervention. Reservations have been applied to its use in south Asian populations since the high CHD mortality in this group may not be accounted for by traditional risk factors. Methods: We applied the Framingham equation to 1826 patients with diabetes of whom 1215 were of white Caucasian and 611 south Asian origin. Having calculated the 10-year CHD risks the contribution of risk factors were compared between ethnic groups. Results: Mean 10-year CHD risk was the same in the two ethnic groups (20.7 vs. 21.5%, white Caucasian vs. south Asian men and 16.5 vs. 15.9%, white Caucasian vs. south Asian women). However, the risk factor profile was different between the two groups. Mean total cholesterol was lower in south Asians (5.23 vs. 5.41 mmol/l, south Asian vs. white Caucasian men (p = 0.01) and 5.38 vs. 5.68 mmol/l, south Asian vs. white Caucasian women (p < 0.001)). HDL cholesterol levels were also lower (median HDL cholesterol 0.94 vs. 1.11 mmol/l, south Asian vs. white Caucasian men (p < 0.001) and 1.07 vs. 1.3 mmol/l, south Asian vs. white Caucasian women (p < 0.0001)) leading to higher total : HDL cholesterol ratios (5.48 vs. 4.78, south Asian vs. white Caucasian men (p = 0.032) and 4.91 vs. 4.26, south Asian vs. white Caucasian women (p < 0.001). Conclusion: Calculated 10-year CHD risks are the same in south Asian and white Caucasian diabetic patients but the factors contributing to this risk differ. Different management of these risk factors may account for the higher mortality from CHD in those of south Asian origin.

Time-course changes in plasma endothelin-1 and its effects on the mesenteric arterial bed in streptozotocin-induced diabetic rats.

Abstract: Summary Aim: To examine the mechanisms underlying the elevated plasma endothelin-1 (ET-1) in diabetes and its vascular effects. Results: Relationships between the plasma ET-1 level and the levels of other plasma constituents (glucose, cholesterol, and triglyceride) were found in 10-week streptozotocin (STZ)-induced diabetic rats. In contrast, at 1 week after the STZ injection only plasma ET-1 and glucose levels were elevated, suggesting that the hyperglycaemia might trigger the excess production of ET-1. Incubation with high glucose promoted the release of ET-1 from the isolated mesenteric arterial bed. In STZ-induced diabetic rats, the maximum contractile response of the mesenteric arterial bed to ET-1 was significantly reduced, and the vasoconstriction and vasodilation induced by the ETB-receptor agonist IRL-1620 in this bed were significantly impaired. The vascular responses induced by these ET receptor agonists were restored to normal by chronic treatment of diabetic rats with insulin for 7 or 4 weeks. Conclusions: These results suggest: (1) that the marked increase in plasma glucose in STZ-induced diabetic rats elevates the plasma ET-1; and (2) that the decreased contractile and vasodilator responses of the mesenteric arterial bed to ET-1 receptor agonists may be due to desensitization of not only ETA, but also ETB receptors, an effect secondary to the elevation of plasma ET-1.

Factors associated with nocturnal hypoglycaemia among patients with type 2 diabetes new to insulin therapy: experience with insulin lispro.

Abstract: Summary Aim: To identify factors associated with nocturnal hypoglycaemia in patients with type 2 diabetes who were new (< 2 months therapy) to insulin therapy. Methods: A randomised, multicentre, 12-month parallel open-label study compared the clinical safety and efficacy of insulin lispro with regular human insulin. A cohort of North American patients completed a health-related quality of life (HRQOL) questionnaire which included questions related to the Health Beliefs Model (HBM). Measurements of hypoglycaemia rate and short-and long-term glucose control assessed clinical safety and efficacy. Three hundred and sixty-five type 2 diabetic patients were enrolled in the study, and 195 North American patients completed the HRQOL questionnaire. Results: After adjustment for demographic and psychological factors, the study population demonstrated lower nocturnal hypoglycaemia risk with insulin lispro. Higher nocturnal hypoglycaemia risk was associated with reduced body mass index (b.m.i.), lower age, and basal ultralente insulin therapy. The associated hypoglycaemia risk was lower with increased alcohol consumption. Patients who completed the HRQOL survey demonstrated higher risk for nocturnal hypoglycaemia if they: (1) had more troublesome hyperglycaemia symptoms in the week before starting insulin; (2) were more confident in their ability to control their diabetes; or (3) thought that diabetes control did not offer a clear health benefit. Nocturnal hypoglycaemia risk was inversely associated with fear of hypoglycaemia. Conclusions: Type 2 diabetic patients new to insulin therapy demonstrated lower risk of nocturnal hypoglycaemia with insulin lispro. Practitioners should consider patient characteristics and psychological factors that may predispose type 2 diabetes patients to nocturnal hypoglycaemia when initiating insulin therapy.

Preliminary study of oral polylactide microcapsulated insulin in vitro and in vivo.

Abstract: Summary Aim: Although the oral route for insulin delivery is the most convenient, directly administered oral insulin is degraded by proteolytic enzymes in the gastrointestinal (GI) tract. Polylactide was prepared in order to microcapsulate the insulin to avoid the enzymes in the GI. The physical characteristics and therapeutic possibilities of polylactide microcapsulated insulin (PLA-MCI) were studied in vivo and in vitro. Methods: PLA-MCI was prepared by the two-step method of emulsion and solvent extraction. Its morphologic character was observed by scanning electron microscopy (SEM). The insulin release profile was determined in vitro by insulin measurement and in vivo by blood glucose measurement after the force-feeding of 66 diabetic rats. Results: When the microcapsule was spherical in shape (diameter 1.5–2.0μm) the entrapment efficiency of insulin was 90% and the loading rate was 10% (W/W). The PLA-MCI (which contained 3.0 units of insulin/mg of PLA) had peak release rates of 65–74% over 6–8 h in phosphate buffer. The same dose of PLA-MCI (insulin 2.5 mg) led to decreased responses (from 28% to 68% of control blood glucose levels) in the level of blood glucose in 32 rats which had not fasted after they had been force-fed. When 1.2, 1.8, 2.2 and 3.0 mg of insulin + PLA-MCI was administered to eight diabetic rats, their blood glucose levels decreased by 28%, 36%, 54% and 78%, respectively. Conclusions: PLA microcapsules are capable of protecting insulin from degradation by the proteolytic enzymes in the GI and of alleviating hyperglycaemia for a prolonged period of time in diabetic rats. It may therefore be considered as a new carrier for oral insulin.

Physiological responses during hypoglycaemia induced by regular human insulin or a novel human analogue, insulin glargine.

Abstract: SUMMARY Aim Glargine, a product of recombinant technology, has different structural and physico-chemical properties compared with native human insulin. We determined whether such differences are associated with alterations in the responses to hypoglycaemia induced by glargine. Methods Nineteen adults (six healthy and 13 with type 1 diabetes) underwent a 5-h hyperinsulinaemic (2 mU/kg/min−1) stepped hypoglycaemic clamps (hourly targets of 4.7, 4.2, 3.6, 3.1 and 2.5 mmol/l, respectively) on two occasions using intravenous infusion of regular human insulin or glargine, in random sequence. Hypoglycaemic symptoms, counter-regulatory hormones and glucose disposal rates were assessed at intervals throughout the clamps. A 1-week ‘wash out’ period was observed between studies. Results The peak total symptoms scores (mean ± s.e.m.) at nadir blood glucose (2.5 mmol/l) were 18.83 ± 2.68 (healthy) and 17.46 ± 3.62 (diabetic) during regular insulin, and 18.50 ± 3.20 (healthy) and 19.08 ± 3.83 (diabetic) during glargine infusion. The peak epinephrine levels during hypoglycaemia were 767.8 ± 140.4 pg/ml (regular insulin) and 608.8 ± 129.9 pg/ml (glargine) among healthy subjects, and 332.5 ± 54.8 pg/ml (regular insulin) and 321.8 ± 67.4 pg/ml (glargine) in diabetic patients. Diabetic patients had blunted glucagon responses during hypoglycaemia with either insulin. Both insulins also elicited similar rates of glucose disposal. Conclusions We conclude that insulin glargine and regular human insulin elicit comparable symptomatic and counter-regulatory hormonal responses during hypoglycaemia in healthy or diabetic subjects, and induce similar rates of glucose disposal. Since glargine is designed for subcutaneous (s.c.) use, it is possible (though unlikely) that our findings obtained using an intravenous protocol could differ from responses to hypoglycaemia induced by the s.c. route.

What are the barriers to medical care for patients with newly diagnosed diabetes mellitus

Abstract: Summary Context: Few data are available describing factors that prevent patients with newly diagnosed diabetes from seeking medical care. Objective To identify socioeconomic factors that act as barriers to healthcare among such patients. Setting A community-wide diabetes screening programme. Participants One hundred and eighteen patients with newly identified diabetes mellitus out of 1824 total screenings. Interventions Each newly identified person with diabetes was instructed to contact a physician for follow-up care. Design A follow-up survey was obtained from 89 (75%) subjects 9 ± 7 months after diagnosis. Main outcome measure: Whether or not subjects had obtained follow-up care for their diabetes. Results Of seven variables examined, only lack of health insurance correctly predicted those patients who failed to seek medical care for their diabetes by multivariate analysis. Conclusions Lack of health insurance coverage is the primary reason that patients with newly diagnosed diabetes fail to seek medical care.

Hypoglycaemia and associated hypokalaemia in diabetes: mechanisms, clinical implications and prevention

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Impact of insulin lispro on HbA1c values in insulin pump users.

Abstract: SUMMARY Aim To compare the therapeutic efficacy of the short-acting insulin analogue insulin lispro (Humalog®) with that of buffered regular human insulin (Velosulin®) in patients on insulin pump therapy. Patients and Methods Sixty-two (45 women and 17 men) young patients with type 1 diabetes using insulin pump therapy were compared while using buffered regular human insulin for a mean ± s.e.m. of 20.1 ± 1.2 months or insulin lispro for a mean ± s.e.m. of 19.7 ± 0.5 months. The initial mean ± s.e.m. age and duration of diabetes were 29.1 ± 0.9 and 17.7 ± 0.9 years, respectively. The mean HbA1c values, basal insulin dosages, premeal insulin dosages and number of low blood sugars were recorded during treatment with both insulins. Results Mean ± s.e.m. HbA1c values were significantly lower (p < 0.001; paired Wilcoxon t-test) during insulin lispro treatment (7.4 ± 0.1%) as compared to treatment with buffered regular human insulin (7.9 ± 0.1%). Total units of insulin (mean ± s.e.m.)/kg/day was significantly (p = 0.03) lower (0.61 ± 0.02) during the insulin lispro treatment period as compared to the buffered regular human insulin treated period (0.65 ± 0.03). Total mean ± s.e.m. (U/kg/day) of basal insulin administered per day was higher when patients received insulin lispro treatment (0.44 ± 0.02 vs. 0.42 ± 0.01 for buffered regular human insulin treated period; p = 0.002). The pre-meal insulin boluses (mean ± s.e.m.) for the two treatment groups were significantly different with less insulin required for the insulin lispro treatment period for all three meals (p < 0.001, t-test). The number of mild/moderate and severe hypoglycaemic episodes were similar in the two groups. Conclusion We conclude that use of insulin lispro in pump therapy significantly lowers HbA1c values in comparison to therapy with buffered regular human insulin insulin without increasing hypoglycaemic episodes.

Pathogenesis of vascular disease

Abstract: Summary Only recently are we beginning to understand the complex interplay of factors involved in vascular disease and diabetes. Insulin resistance provides a starting point to explain the many factors that lead to the more severe vascular disease characteristic of diabetes. Insulin resistance syndrome comprises insulin resistance and compensatory hyperinsulinaemia as well as hypertension, dyslipidaemia, macrovascular disease, and increased plasminogen activator inhibitor-1 activity. The development of type 2 diabetes may be viewed as the inability of the pancreas to continue to overcome insulin resistance, even with excessive insulin production.