Does insulin therapy have a hypertensive effect in type 2 diabetes?

In this prospective study, the 24-h blood-pressure profile of 12 patients with type 2 diabetes was monitored before, at 6, and at 12 weeks after initiation of insulin therapy, to determine whether commencement of insulin therapy increases blood pressure in these patients. Insulin dosage adjustment was carried out by using a predetermined algorithm according to body weight and degree of hyperglycemia. The mean insulin dosage at 12 weeks was 72.9 +/- 3.9 units/day. This was associated with an increase in systolic blood pressure from 134.6 +/- 4.3 mm Hg to 144.8 +/- 4.5 mm Hg (p = 0.0001), diastolic blood pressure from 71.9 +/- 2.6 mm Hg to 74.9 +/- 2.2 mm Hg (p = 0.0001), and body mass index (BMI) from 27.2 +/- 0.8 kg/m2 to 29.6 +/- 0.8 kg/m2 (p = 0.0001). Multiple regression analysis showed insulin dosage to be a significant independent factor (p = 0.0003) accounting for 63% of the variance in blood pressure change after adjusting for age, diastolic blood pressure, and base HbA1c. We conclude that insulin therapy may have a deleterious effect on blood pressure in patients with type 2 diabetes. However, in the clinical setting, it is difficult to isolate this from the confounding effect of weight gain.

Indapamide is as effective as captopril in the control of microalbuminuria in diabetes.

Microalbuminuria is a predictor of overt diabetic nephropathy and macrovascular disease. Thirty-one diabetic patients with persistent urinary albumin excretion rate (AER) of 20-200 mu g min-1 were randomised to receive indapamide 2.5 mg or captopril 37.5 mg daily for 12 weeks. After a 4-week washout, patients received the alternate agent for 12 weeks. Resting blood pressure (BP), AER, cholesterol, triglycerides, and HbA1c were measured at baseline, after 6 and 12 weeks of each treatment, and after a 4-week washout period following each treatment arm. Results from patients who completed at least one treatment arm were analysed by repeated-measures analysis of variance (ANOVA). AER (median value and interquartile range) decreased significantly from baseline after treatment with indapamide and captopril [60(27-106) vs. 40(14-112) and 33(17-100); p < 0.005], but there was no difference between the effects of the two agents. Mean systolic BP (SBP) was also significantly reduced with treatment, and no difference was noted between the effects of the two agents. No correlation between changes in AER and SBP was noted with either agent. Diastolic blood pressure (DBP), cholesterol, triglycerides, and HbA1c did not change during the study. These results suggest that indapamide is an effective alternative to angiotensin-converting enzyme (ACE) inhibitors in the treatment of diabetic patients with microalbuminuria.

Comparative effects of indapamide and captopril on blood pressure and albumin excretion rate in diabetic microalbuminuria.

Nephropathy affects about one third of diabetic patients and its onset can be predicted almost a decade in advance by detecting small quantities of albumin in the urine (microalbuminuria). Thus, detection of proteinuria or microalbuminuria in diabetic patients carries important implications and merits intervention. Strategies for delaying the relentless progression of microalbuminuria to diabetic nephropathy and ultimately end-stage renal failure are focused on improving glycemic control and reducing blood pressure. Studies with beta-blockers, calcium antagonists, diuretics, and angiotensin-converting enzyme (ACE) inhibitors in hypertensive diabetics with microalbuminuria have shown a significant reduction in urinary albumin excretion rates (AER), with effective lowering of blood pressure. In a crossover study, we compared the effects of captopril versus indapamide as monotherapy for 12 weeks on AER and blood pressure in 31 diabetic patients with established microalbuminuria. The 2 drugs were equally effective in reducing AER (average reduction 30-40%) and had comparable antihypertensive effects.

Obese patients with type 2 diabetes poorly controlled by insulin and metformin: effects of adjunctive dexfenfluramine therapy on glycaemic control.

Dexfenfluramine is well known for its weight reducing action and has been reported to improve glycaemic control in obese Type 2 diabetic patients not adequately controlled on conventional oral hypoglycaemic therapy. In this double-blind placebo-controlled study, 20 obese Type 2 diabetic patients with mean HbA1c of 8.8 +/- 0.5% (normal range 3.5-6.0%), and mean body mass index (BMI) of 34.4 +/- 1.0 kg m-2, who were poorly controlled on insulin (mean dosage 58.0 +/- 6.1 units day-1) were randomized to receive either additional dexfenfluramine or placebo for 12 weeks. Seventeen of these patients were already taking maximum tolerated metformin therapy (mean dosage 1.6 +/- 0.2 g day-1) and the other three were unable to tolerate any at all. At baseline, the dexfenfluramine and placebo groups were similar in all parameters studied. After the 12-week treatment period, median HbA1c had fallen in dexfenfluramine treated patients from 8.5 (interquartile range (IR): 7.5-10.3) to 7.1% (IR: 6.7-7.5; p < 0.02). The fall in HbA1c in individual patients after treatment with dexfenfluramine was strongly associated with weight loss (r = 0.69; p < 0.04), although as a group the changes in weight and BMI were not statistically significant. Placebo was without effect. These results show that in the obese patient with Type 2 diabetes who is poorly controlled despite large daily doses of insulin and metformin, adjunctive dexfenfluramine can improve glycaemic control without exacerbating weight gain.

The effects of dexfenfluramine on blood glucose control in patients with type 2 diabetes.

Dexfenfluramine has been shown to promote weight loss in overweight people. The present double-blind study was designed to test whether the addition of dexfenfluramine to conventional oral hypoglycaemic treatment would promote weight loss and improve blood glucose control in overweight patients with Type 2 diabetes. The 34 patients studied were randomly assigned to dexfenfluramine or placebo therapy which was added for 12 weeks to their existing treatment regimens of metformin with or without a sulphonylurea. Dexfenfluramine treatment was associated with a significant reduction in weight (98.7 +/- 5.0 (+/- SE) vs 94.9 +/- 5.2 kg; p less than 0.001), BMI (35.0 +/- 1.2 vs 33.6 +/- 1.9 kg m-2; p less than 0.001), HbA1c (7.5 +/- 0.3 vs 6.3 +/- 0.2%; p less than 0.001), fructosamine (313.9 +/- 17.6 vs 274.3 +/- 10.4 mumol l-1; p less than 0.01), systolic (137 +/- 5 vs 128 +/- 6 mmHg; p less than 0.05), and diastolic blood pressure (85 +/- 2 vs 73 +/- 3 mmHg; p less than 0.001). At the end of the study period, the dexfenfluramine treated group had a significantly lower HbA1c (6.3 +/- 0.2 vs 7.2 +/- 0.4; p less than 0.05), fructosamine level (274.3 +/- 10.4 vs 313.3 +/- 16.1 mumol l-1; p less than 0.05) and diastolic blood pressure (73 +/- 3 vs 81 +/- 3 mmHg; p less than 0.03) when compared with the placebo group. In those patients treated with dexfenfluramine, the reduction in HbA1c and blood pressure did not correlate with the decrease in BMI (r = 0.44 and 0.12, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

High-performance liquid chromatographic preparation of single-site carrier-free pancreatic polypeptide hormone radiotracers.

The preferred radiotracer for use in radioimmuno- and receptor assays is one which is as similar as possible to the native hormone in both physicochemical and biological properties. Until recently, rapid detailed evaluation of iodination methodology as well as separation of site-specific tracers and their evaluation relative to the native protein has not been possible. Using reversed-phase high-performance liquid chromatographic methodology (C8 or C18 columns) we have evaluated a variety of iodination techniques and conditions. Procedures were found that allow the isolation of site-specific radiolabelled protein hormones in a rapid, reproducible and quantitative manner. The radiotracers are of the highest possible specific activity, have very low levels of damage and are more stable than tracers prepared by conventional techniques. This methodology has been applied to preparing tracers of beef, pork and human insulins, proinsulins and C-peptides as well as analogues of these proteins. In addition, the methodology has been applied to somatostatin, glucagon, pancreatic polypeptide, vasoactive intestinal peptide and luteinizing hormone-releasing hormone. The use of these tracers yielded increased sensitivity and reproducibility in a number of radioimmunoassays (e.g. C-peptide and glucagon), more reproducible results in radioreceptor assays (e.g. insulin receptors) and more defined studies on drug absorption and degradation. Finally, scale-up of our isolation procedures has yielded the 127I-analogue for homologous binding and displacement studies.