The aim of this randomized double-blind study was to compare the within-subject variability of the glucoselowering effect of a novel insulin analog, insulin detemir, with that of insulin glargine and NPH insulin in people with type 1 diabetes. Fifty-four subjects (32 males and 22 females, age 38 ؎ 10 years [ D aily clinical experience indicates that subcutaneous administration of insulin often does not result in a reproducible metabolic effect even when injected at the same dose under comparable conditions. Nonetheless, only few studies have assessed the variability of insulin absorption after subcutaneous administration (1-7), and even fewer have assessed the variability in the glucose-lowering effect of insulin. Thus, even though variability of the glucoselowering effect is regarded as a major obstacle to achieving optimal metabolic control (8 -10), our knowledge of the variability of insulin preparations is surprisingly scarce (11,12). This is particularly true for basal insulin preparations. The few studies available report coefficients of variation (CVs) for within-and between-subject variability in the pharmacodynamic action of long-acting zinc insulin preparations to be between 35 and 55% (9) and even greater for NPH insulin (13). Compared with these findings, the variability (CV) of short-acting insulin preparations, which are reported in the range of "only" 20 -30% (10,11), are less of a concern. The development of the new long-acting insulin analogs such as insulin detemir and insulin glargine has raised the hope of concurrent lower within-subject variability. However, insulin glargine does not appear to provide any improvement in the within-subject variability compared with NPH insulin (8).The aim of this study was to compare the within-subject variability in the glucose-lowering effect of the novel long-acting insulin analog insulin detemir with that of NPH insulin and insulin glargine. Insulin detemir [Lys B29 (N ε -tetradecanoyl) des(B30) human insulin] is the first of a new class of long-acting soluble insulin analogs. Its prolonged duration of action is attributable to a combination of increased self-association (hexamer stabilization and hexamer-hexamer interaction) and albumin binding due to acylation of the amino acid lysine in position B29 with a 14 C fatty acid (myristic acid). Insulin detemir is highly albumin bound in the interstitial fluid and in plasma (14) and has been shown to elicit a protracted metabolic action, with a slow onset of action and a less pronounced peak of action compared with that observed for NPH insulin (15,16).

OBJECTIVE: To study the effect on weight loss in obese subjects by replacement of carbohydrate by protein in ad libitum consumed fat-reduced diets. DESIGN: Randomized dietary intervention study over six months comparing two ad libitum fat reduced diets (30% of total energy) strictly controlled in composition: High-carbohydrate (HC, protein 12% of total energy) or high-protein (HP, protein 25% of total energy). SETTING AND PARTICIPANTS: Subjects were 65 healthy, overweight and obese subjects (50 women, 15 men, aged 18 ± 55 y) randomly assigned to HC (n 25), HP (n 25) or a control group (C, n 15). All food was provided by selfselection in a shop at the department, and compliance to the diet composition was evaluated by urinary nitrogen excretion. MAIN OUTCOME MEASURE: Change in body weight, body composition and blood lipids. RESULTS: More than 90% completed the trial. Weight loss after six months was 5.1 kg in the HC group and 8.9 kg in the HP group (difference 3.7 kg, 95% con®dence interval (CI)(1.3 ± 6.2 kg) P`0.001), and fat loss was 4.3 kg and 7.6 kg, respectively (difference 3.3 kg (1.1 ± 5.5 kg) P`0.0001), whereas no changes occurred in the control group. More subjects lost b10 kg in the HP group (35 %) than in the HC group (9 %). The HP diet only decreased fasting plasma triglycerides and free fatty acids signi®cantly. CONCLUSIONS: Replacement of some dietary carbohydrate by protein in an ad libitum fat-reduced diet, improves weight loss and increases the proportion of subjects achieving a clinically relevant weight loss. More freedom to choose between protein-rich and complex carbohydrate-rich foods may allow obese subjects to choose more lean meat and dairy products, and hence improve adherence to low-fat diets in weight reduction programs.

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Progression of microalbuminuria (defined as urinary albumin excretion rate (AER) of 30±300 mg/24h [1]) to overt diabetic nephropathy in patients with Type I (insulin-dependent) diabetes mellitus is retarded by treatment with inhibitors of angiotensin converting enzyme (ACE). Even at the microalbuminuric stage, pathologic changes are present in the kidney [2] together with widespread endothelial dysfunction [3] [4]. Microalbuminuria is associated with excess cardiac morbidity [5]. It may therefore be worthwile to identify diabetic patients at risk before the stage of microalbuminuria, to start preventive treatment. Several risk factors for progression to microalbuminuria have been proposed [6,7], such as poor metabolic control, hypertension and high-normal AER.The most attractive factors for identifying risk are those involved in the pathogenesis of the disease. The favourable response to ACE inhibitors [8,9] suggests that the renin angiotensin system is one which is supported by experimental evidence that angiotensin II (AngII) is an important factor in the pathogenesis Diabetologia (1999) Abstract Aims/hypothesis. The renin-angiotensin system is possibly involved in the pathogenesis of diabetic nephropathy. The most striking change in renin-angiotensin system components in blood of patients with diabetic nephropathy is an increased prorenin concentration. We investigated prospectively serum concentrations of renin-angiotensin system components and the time course of prorenin increase in normoalbuminuric diabetic patients developing microalbuminuria. Methods. Patients (n = 199) with Type I (insulin-dependent) diabetes mellitus and normoalbuminuria at baseline were prospectively followed for 10 years. The prorenin concentrations and other variables possibly associated with the occurrence of microalbuminuria, were investigated by Cox-regression analysis. Results. Of the patients 29 developed microalbuminuria. Glycated haemoglobin values were higher at baseline in these patients. Serum prorenin was similar at baseline but rose in the 29 patients before the development of microalbuminuria and was stable in patients with stable albumin excretion. Renin, angiotensinogen and angiotensin converting enzyme serum concentrations were stable in both groups. Prorenin and glycated haemoglobin were independent prognostic factors for the development of microalbuminuria. A prognostic index, based on these variables, was constructed to estimate the relative risk of developing microalbuminuria. Conclusions/interpretation. Increase in serum prorenin precedes onset of microalbuminuria in normotensive patients with insulin-dependent diabetes mellitus. High concentrations of prorenin in combination with high values of glycated haemoglobin can be used as a predictor of development of microalbuminuria. [Diabetologia (1999

The purpose of this study was to describe the clinical course in patients followed right from the onset of microalbuminuria to the development of diabetic nephropathy. A 10-year prospective follow-up of 209 consecutive normotensive insulin-dependent diabetic patients with normal urinary albumin excretion (UAE < 30 mg 24 h-1), age 34 (18-50) years and duration of diabetes 17 (10-30) years was performed. Twenty-four-hour urinary albumin excretion was measured every 4 months, glycated haemoglobin and supine blood pressure was measured annually. Two-hundred (96%) patients completed 10 (range 5-10) years follow-up. Twenty-nine (15%) patients developed persistent microalbuminuria (UAE 30-300 mg 24 h-1). Eight of these have progressed to nephropathy and one had died of diabetic nephropathy. Multiple stepwise logistic regression analysis demonstrated baseline urinary albumin excretion (p = 0.0016) and glycated haemoglobin (p = 0.0014) but not blood pressure as predictors of development of microalbuminuria within the following 10 years. The median annual increase in urinary albumin excretion was 27 (range 17-65) % in the 29 patients developing microalbuminuria. The median duration from onset of microalbuminuria to development of nephropathy was 7 years. The prevalence of patients receiving antihypertensive treatment (BP > 140/90 mmHg) increased from 10% at onset of microalbuminuria to 45% 4 years after onset of microalbuminuria. The prevalence of patients with proliferative retinopathy increased from 7% at onset of microalbuminuria to 28% 4 years after onset of microalbuminuria.(ABSTRACT TRUNCATED AT 250 WORDS)