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Aims: To establish the safety in terms of insulin sensitivity of a low dose thiazide/ACE inhibitor combination., Methods: We examined the effects on insulin sensitivity of captopril either alone or in combination with low-dose bendroflumethiazide (1.25 mg) in 15 hypertensive Type 2 diabetic patients. Insulin action was assessed using an isoglycaemic hyperinsulinaemic clamp in a double-blind, randomised, crossover study after a 6-week placebo run-in and following two 12-week treatment periods with captopril (C) (100 mg) alone or in combination with bendroflumethiazide (CB) (1.25 mg)., Results: Blood pressure was lower following CB compare to C (138/83 vs. 144/85 mmHg; P < 0.05) and both were lower than baseline (153/92 mmHg; P < 0.01). CB resulted in a significant increase in fasting plasma glucose compared to C (9.6 +/- 2.6 vs. 8.5 +/- 1.6 mmol/l; P < 0.05). Exogenous glucose infusion rates required to maintain isoglycaemia during hyperinsulinaemia were lower after CB compared to C (25.1 +/- 13.3 vs. 34.2 +/- 16.8 micromol/kg/min; P < 0.01) as were isotopically determined glucose utilisation rates (29.0 +/- 12.4 vs. 36.6 +/- 17.3 micromol/kg/min; P < 0.05). There was no significant difference in fasting endogenous glucose production between treatments (CB 9.3 +/- 3.3 vs. C 8.6 +/- 1.6 micromol/kg/min), nor between suppression following insulin (CB 4.0 +/- 2.1 vs. C 4.3 +/- 3.1 micromol/kg/min)., Conclusions: Combination of low-dose bendroflumethiazide with captopril lowered blood pressure but resulted in deleterious effects on insulin action compared to captopril alone.

Aim: Disordered insulin pulsatility is associated with insulin resistant states including Type 2 diabetes. However, whether abnormal basal insulin pulses play a role in the pathogenesis of insulin resistance or are simply an associated feature remains undetermined. We investigated this relationship further by studying the effect of overnight (10 h) pulsatile insulin infusion on subsequent insulin sensitivity., Methods: We studied 17 Type 2 diabetic patients who underwent one of two protocols. In protocol A (10 patients) on two separate nights we infused insulin 0.1 mU/kg/min either in a constant infusion or in pulses every 13 min. Octreotide (0.43 microg/kg/h) was given to suppress endogenous insulin secretion and physiological replacement of glucagon (30 ng/kg/h) administered. Insulin sensitivity was measured using a hyperinsulinaemic euglycaemic clamp (2 mU/kg/min) next morning. In protocol B (seven patients), we employed the same experimental procedure but used a basal insulin infusion rate of 0.09 mU/kg/min in 7-min or 13-min pulses., Results: Appropriate pulse patterns were confirmed in each protocol. In protocol A, after overnight infusions, glucose infusion rates required to maintain euglycaemia at steady state hyperinsulinaemia were similar (33.9 +/- 5.2 vs. 31.2 +/- 4.1 micromol/kg/min; P = NS). In protocol B, after overnight infusions the glucose infusion rates required during hyperinsulinaemia were significantly lower during 7-min pulses (39.9 +/- 5.7 vs. 44.7 +/- 5.6 micromol/kg/min; P < 0.05)., Conclusion: There was no demonstrable priming effect derived from overnight pulsatile insulin compared with constant insulin infusion on subsequent insulin sensitivity in Type 2 diabetic subjects. The failure of 7-min pulses to exhibit an advantageous effect over 13-min pulses raises questions about the natural frequency of basal insulin pulses and their biological effect.

Background and Aims: Endothelial dysfunction, insulin resistance and oxidative stress are believed to be central and associated mechanisms in atherogenesis. We aimed to determine the effect of the antioxidant vitamin E on endothelial function, insulin action and cardiovascular risk markers in young healthy adult offspring of parents with Type 2 diabetes., Methods: Healthy, glucose-tolerant adults (18-38 years), 14 (12 male/2 female) with at least one parent with Type 2 diabetes, and 14 (12 male/2 female) subjects with no family history of diabetes (controls) were studied. Insulin action was assessed by euglycaemic hyperinsulinaemic clamp (1 mU/kg/min). Endothelial function was assessed by forearm blood flow (FBF) responses to intra-brachial artery infusions of acetylcholine (ACh) (endothelium-dependent vasodilation), sodium nitroprusside (SNP) (endothelium-independent vasodilation) and N(G)-monomethyl L-arginine (LNMMA) (nitric oxide synthase inhibition). Thirteen offspring (18-38 years, 11 male/2 female, BMI < 30 kg/m2) completed a randomized, double-blind, crossover trial (12 weeks vitamin E 800 IU/day or placebo, 6-week washout)., Results: Exogenous glucose infusion rates to maintain euglycaemia were positively associated with response to acetylcholine in offspring (r = 0.61, P < 0.05), and were linked with triglycerides. Vitamin E had no effect on endothelial function, insulin action or cardiovascular risk markers in healthy adult offspring of parents with Type 2 diabetes., Conclusions: Our results support a positive association between insulin action and endothelial-dependent vasodilation in young healthy adult offspring of parents with Type 2 diabetes, but indicate no effect of vitamin E on these parameters.

Aims: It has been suggested that the adverse metabolic effects of antihypertensive therapy offset some of the benefits of blood pressure reduction. It has also been suggested that angiotensin converting enzyme (ACE) inhibitors reduce insulin resistance and that, if used together with thiazide diuretics, the adverse effects of thiazides on insulin sensitivity may be eliminated. We examined the effects on insulin sensitivity of captopril either alone or in combination with bendrofluazide in 11 hypertensive Type 2 diabetic patients., Methods: Insulin action was assessed using an isoglycaemic hyperinsulinaemic clamp in a double-blind, randomized, crossover study after a 6-week placebo run-in and following two 12-week treatment periods with captopril (C) (100 mg) alone or in combination with bendrofluazide (CB) (2.5 mg)., Results: Blood pressure was lower following CB compared to C (128/82 vs. 144/ 88 mmHg; P<0.005) and both were lower than baseline (162/101 mmHg; P < 0.001). CB resulted in a significant increase in fasting plasma glucose compared to C (9.7+/-0.8 vs. 8.5+/-0.6 mmol/; P < 0.05). Exogenous glucose infusion rates required to maintain isoglycaemia during hyperinsulinaemia were lower after CB compared to C (22.3+/-2.4 vs. 27.4+/-4.2 mol x kg(-1) x min(-1); P < 0.05). Suppression of endogenous glucose production was reduced after CB compared to baseline (4.0+/-0.6 vs. 2.4+/-0.5 mol x kg(-1) x min(-1); P< 0.05)., Conclusions: Combination of bendrofluazide with captopril lowered blood pressure but resulted in deleterious effects on insulin action compared to captopril alone.

Aims: Familial aggregation of diabetes and nephropathy has been observed in several populations. Various interpretations have included underlying genetic mechanisms possibly mediated by a predisposition to hypertension. Endothelial dysfunction is now recognized as central to these conditions and offers a unifying mechanism to explain the disease aggregation. To test this hypothesis, we have examined endothelial function in healthy subjects at differing risks for diabetic nephropathy., Methods: Endothelial function was assessed in 12 healthy offspring (nine male (M)/three female (F); age 25.8+/-1.2 years, mean +/- SEM) of parents with Type 1 diabetes mellitus (DM) and end-stage renal disease compared with 12 control offspring (9 M/3 F; age 26.3+/-1.3 years) of parents with long duration (>20 years) Type 1 DM but without evidence of nephropathy. Forearm blood flow responses to brachial artery infusion of acetylcholine (endothelium-dependent), sodium nitroprusside (endothelium-independent), noradrenaline and the competitive inhibitor of basal nitric oxide release N(G)-monomethyl-L-arginine were assessed using venous occlusion plethysmography., Results: There were no significant differences between the groups in von Willebrand factor, fasting plasma glucose (4.2+/-0.1 vs. 4.0+/-0.2 mmol/l) or in 24-h ambulatory blood pressure. Similarly, the groups did not differ in vasodilation to acetylcholine (P = 0.75) and sodium nitroprusside (P = 0.79) or in vasoconstriction to noradrenaline (P = 0.45) and N(G)-monomethyl-L-arginine (P = 0.30)., Conclusion: These data do not support a role for endothelial dysfunction in the familial aggregation of diabetic nephropathy.

Secondary failure of plasma glucose control following initial successful response to diet therapy may be due to dietary indiscretion, or to progression of the intrinsic diabetic condition. We report a 10-year prospective natural history study of 432 newly diagnosed diabetic patients aged 40-69 years undertaken to assess the effect of intensive dietary management, where patients were transferred to insulin, or oral hypoglycaemic therapy (tolbutamide, metformin) by predetermined criteria of weight and plasma glucose. Secondary failure to diet therapy occurred in 41 patients in years 2-4, 67 patients in years 5-7, and 51 patients in years 8-10; 173 patients remained on diet alone until death or the end of the study. Continuation on diet alone was associated with a lower ongoing fasting plasma glucose, greater beta-cell function assessed by an oral glucose tolerance test at 6 months, and increasing age. The rate of rise of fasting plasma glucose was inversely related to the duration of successful dietary therapy, but mean weight remained constant in all groups while on diet alone. The ongoing fall in beta-cell function assessed by HOMA modelling closely mirrored the progressive rise in fasting plasma glucose: there was no change in mean insulin sensitivity in any of the groups.

The relationship between macrovascular disease and blood glucose control in long-term follow-up of Type 2 (non-insulin-dependent) diabetes mellitus is difficult to study because of the gradual rise in fasting plasma glucose due to ongoing beta-cell failure. We used time-dependent covariates in Cox's proportional hazards model to allow variables measured annually during a 10-year prospective follow-up to be related to risk of myocardial infarction or cerebrovascular accident. Data for 432 newly diagnosed diabetic patients were available, 112 of whom suffered myocardial infarction (fatal or non-fatal). Analysis of baseline measurements only gave relative hazards (95% CL) of 1.04 (0.99, 1.09) per mmol l(-1) increase in fasting plasma glucose, 1.43 (1.12, 1.83) per decade increase in age and 1.07 (0.98, 1.17) per 10 % increase in percentage of ideal weight. Analysis incorporating ongoing measurements gave corresponding figures of 1.07 (1.02, 1.12) for fasting plasma glucose, 1.64 (1.23, 2.20) for age and 1.06 (0.95, 1.18) for percentage of ideal weight. The risk of myocardial infarction while on insulin treatment 1.09 (0.58, 2.06) or oral agents 1.41 (0.86, 2.31) was not significantly elevated relative to dietary treatment. Baseline smoking status, systolic blood pressure, and previous myocardial infarction were also significant predictors of myocardial infarction. Similar relationships were found for cerebrovascular accident and total mortality. Increasing fasting plasma glucose is a significant independent predictor of macrovascular disease in diabetes.

This study followed up a cohort of patients with microalbuminuria identified on a spot morning urine sample 8 years earlier and aimed to determine if a spot morning urinary albumin concentration was able to identify patients with non-insulin treated diabetes at increased risk of mortality and progression to nephropathy. In 1984, 47 of 216 patients chosen by random selection from our teaching hospital-based diabetes clinic were identified as having microalbuminuria (urinary albumin concentration 35-300 micrograms ml-1). Subjects were compared with an age-matched control group from the 1984 cohort who did not have microalbuminuria. Eight years later, 22 of 47 (46.8%) patients with microalbuminuria had died compared to 10 of 47 (21.3%) patients without albuminuria (p < 0.05). The majority of deaths were from cardiovascular disease (53.1%). Logistic regression showed microalbuminuria to be an independent predictor of mortality, not influenced by age, duration of diabetes, blood pressure, glycosylated haemoglobin or creatinine at the initial examination. Eight years later, in the group with initial microalbuminuria, eight still had microalbuminuria and five patients had developed nephropathy. In the group without albuminuria in 1984, only one patient had progressed to microalbuminuria and no patients to nephropathy. In conclusion, a spot urinary albumin concentration is of value in identifying patients with an increased risk of mortality or progression to nephropathy, and is simple to obtain at a clinic.

Hypertension is linked to the development of nephropathy in Type 1 diabetes. Total exchangeable sodium is elevated in patients with Type 1 diabetes in good metabolic control, and correlates with blood pressure. Atrial natriuretic factor has been shown to have effects on sodium and blood pressure homeostasis in man. Basal and NaCl-stimulated plasma atrial natriuretic factor was therefore studied in 33 patients with Type 1 diabetes. Seventeen had no evidence of nephropathy, 11 had incipient nephropathy (albumin excretion rate 20-199 micrograms min-1) and five had overt nephropathy. Seventeen age- and sex-matched normal control subjects were also studied. Subjects fasted from 2200 h, rose at 0745 h and remained ambulant until 0945 h. After 15 min supine, 2 l 0.15 mmol l-1 NaCl was infused over 4 h. Basal erect (0945 h) plasma atrial natriuretic factor was 4.2 +/- 0.5, 3.5 +/- 0.4, 2.5 +/- 0.2, and 2.5 +/- 0.3 pmol l-1 in the control, non-nephropathic, incipient-nephropathic, and overt nephropathic diabetic groups, respectively (all NS). Levels in all groups increased in response to NaCl infusion, and the responses were not different between groups. Urinary sodium excretion for 12 h before NaCl infusion was not different between groups, but during the 12 h after the start of the infusion was significantly (p less than 0.05) less in the Type 1 diabetic group without nephropathy than in the control group. These results suggest that atrial natriuretic factor does not play a major role in the development of changes in sodium balance which are associated with Type 1 diabetes and nephropathy.

A six-year prospective study of 144 newly diagnosed, symptomatic diabetic patients aged 40-69 years showed that 21 (15%) required insulin therapy, commencing 1-61 months after diagnosis. The plasma insulin response to oral glucose was assessed at the time of diagnosis. All 12 patients with very low peak insulin response (less than or equal to 6 mU/l) required insulin therapy. Thirty-six patients had an intermediate insulin response (greater than 6 less than or equal to 18 mU/l); of these, 7 with a mean weight 88% (range 73-96%) of average body weight required insulin, while 29 with a mean weight 117% (range 98-158%) of average body weight, did not. Ninety-six patients had a peak insulin response (greater than 18 mU/l); 2 patients whose weights were 96% and 100% of average body weight, required insulin, while the remainder did not. Consideration of initial body weight and peak insulin response provides a useful prediction of the eventual need for insulin.

Islet B-cell function and insulin sensitivity were estimated with the aid of a mathematical model from repeated fasting plasma glucose and insulin measurements over a 6 year period in 131 patients with type 2 diabetes mellitus who could be managed satisfactorily on dietary therapy alone. They presented between the ages of 40 and 69 years, and were studied before and after one year of treatment, and then at regular intervals from 12 until 72 months later. A method of averaging the individual trends by means of a linear model regression technique was used to assess the progression of their diabetes. Dietary management over the first 12 months resulted in weight loss from 118% to 106% average body weight, and improved insulin sensitivity from 26% to 40% of normal (p less than 0.001). From 12 to 72 months, the fasting plasma glucose rose at a mean rate of 0.23 mmol/l per year (p less than 0.001) despite a rate of weight loss of 0.2% average body weight per year (p less than 0.01). The estimated islet B-cell function, expressed as a percentage of normal, decreased significantly (p less than 0.05) at a rate of 1.5% per year, with no statistically significant change in insulin sensitivity. Extrapolation suggests the reduction in B-cell function predated the departure of fasting plasma glucose from the normal range.

The prevalence of secondary forms of hypertension in diabetes is unknown. One hundred and five of 465 patients randomly selected from a diabetic clinic population were found to be hypertensive. Hypertensive patients aged less than 70 years were screened for renal artery stenosis using intravenous digital subtraction angiography. Two angiograms were technically unsatisfactory. All 18 insulin-dependent patients successfully screened had normal renal arteriograms. Five of 24 non-insulin-dependent patients had unilateral renal artery stenosis but functional tests did not clearly suggest that renal artery stenosis was causing the hypertension in these cases. No patient was referred for surgery or angioplasty. We conclude that renal artery stenosis is common in hypertensive non-insulin-dependent diabetics but may not, in many cases, be the cause of the hypertension. The criteria for investigating diabetic hypertensives for renal artery stenosis should be no different from those used in the general hypertensive population.