Atrial natriuretic peptide increases urinary albumin excretion in men with Type 1 diabetes mellitus and established microalbuminuria

Raised plasma concentrations of atrial natriuretic peptide (ANP) have been reported in patients with Type 1 (insulin dependent) diabetes mellitus (DM) who have poor glycaemic control and are associated with the presence of microalbuminuria. To test the hypothesis that elevations in plasma ANP concentration increase urinary albumin excretion in Type 1 DM, we have studied the effects of intravenous infusions of ANP in eight such subjects with established microalbuminuria. Blood glucose was maintained between 4 and 7 mmol l⁻¹ in all subjects for the duration of studies; after euglycaemia had been established, a standard oral water load (20 ml kg⁻¹ plus replacement of urinary losses) was given. Once steady state diuresis was attained, subjects received intravenous infusion of either placebo (0.9 % saline), low dose (2.5 pmol kg⁻¹ min⁻¹) or high dose (5.0 pmol kg⁻¹ kg min⁻¹) ANP solution in a randomized, double-blind protocol. Infusion of ANP caused a dose-dependent increase in urinary albumin excretion rate (placebo, 11.3 (SD 8.9) to 8.7 (SD 6.8) μg min⁻¹; low dose ANP, 12.4 (SD 9.9) to 26.5 (SD 27.5) μg min⁻¹, p < 0.01; high dose ANP 10.3 (SD 7.3) to 36.6 (SD 28.5) μg min⁻¹, p < 0.001, ANOVA). Only high dose ANP caused an increase in urine flow. Blood glucose remained unchanged in all studies. We conclude that intravenous infusions of ANP cause a dose-dependent increase in urinary albumin excretion rate in Type 1 DM subjects with microalbuminuria. These data support the hypothesis that ANP has albuminuric actions which may contribute to microalbuminuria in Type 1 DM. © 1998 John Wiley & Sons, Ltd.     

Immunochemical quantification of crossline as a fluorescent advanced glycation endproduct in erythrocyte membrane proteins from diabetic patients with or without retinopathy

Crossline is a novel advanced glycation endproduct (AGE) which has both a crosslink and fluorescence similar to AGE-protein in vivo. To assess the association of AGEs to the development of diabetic retinopathy we developed a sensitive and specific enzyme-linked immunosorbent assay (ELISA) for crossline in blood samples and investigated the association of the development of retinopathy and erythrocyte membrane protein (EMP)-crossline concentrations in patients with Type 2 diabetes mellitus (Type 2 DM). Crossline formation in EMP exceeded that in haemoglobin and was detectable in normal EMP samples without pretreatment by this ELISA system. Mean (±SE) EMP crossline levels were elevated 1.6-fold in diabetic patients without retinopathy (7.6 ± 0.5 pmol mg⁻¹, p < 0.005), 2.2-fold in diabetic patients with non-proliferative retinopathy (10.5 ± 0.6 pmol mg⁻¹, p < 0.001) and 2.6-fold in diabetic patients with proliferative retinopathy (12.0 ± 0.6 pmol mg⁻¹, p < 0.001) compared with healthy control subjects (4.7 ± 0.5 pmol mg⁻¹). Type 2 DM patients with retinopathy had significantly higher EMP-crossline levels than those without retinopathy (p < 0.005). Our data suggest that elevated EMP-crossline concentrations are associated with the presence of retinopathy in patients with Type 2 DM and EMP-crossline measured by our ELISA may provide a useful marker for assessing the role of glycation in the development of diabetic retinopathy. © 1998 John Wiley & Sons, Ltd.     

Oral magnesium supplementation in insulin-requiring Type 2 diabetic patients

Oral magnesium (Mg) supplementation can improve insulin sensitivity and secretion in patients with Type 2 diabetes mellitus (DM). We studied the effect of Mg supplementation on glycaemic control, blood pressure, and plasma lipids in insulin-requiring patients with Type 2 DM. Fifty moderately controlled patients were randomized to 15 mmol Mg or placebo daily for 3 months. Plasma Mg, glucose, HbA_1c, lipids, erythrocyte Mg, Mg and glucose concentrations in 24-h urine, and systolic and diastolic pressure were measured before and after 3 months treatment. Plasma Mg concentration was higher after supplementation than after placebo (0.82 ± 0.07 vs 0.78 ± 0.08 mmol l⁻¹, p<0.05), as was Mg excretion (5.5 ± 1.9 vs 3.7 ± 1.4 mmol 24 h⁻¹, p = 0.004) but erythrocyte Mg concentrations were similar. No significant differences were found in glycaemic control (glucose: 10.7 ± 3.8 vs 11.6 ± 6.2 mmol l⁻¹, p = 0.8; HbA_1c: 8.9 ± 1.6 vs 9.1 ± 1.2%, p = 0.8), lipids or blood pressure. On-treatment analysis (34 patients: 18 on Mg, 16 on placebo) yielded similar results. An increase in plasma Mg concentration irrespective of medication was associated with a tendency to a decrease in diastolic pressure (increased plasma Mg vs no increase: −4.0 ± 10.1 vs +2.5 ± 12.0 mmHg, p = 0.059). Three months’ oral Mg supplementation of insulin-requiring patients with Type 2 DM increased plasma Mg concentration and urinary Mg excretion but had no effect on glycaemic control or plasma lipid concentrations. © 1998 John Wiley & Sons, Ltd.     

Prandial Glycaemia After a Carbohydrate-rich Meal in Type I Diabetic Patients: Using the Rapid Acting Insulin Analogue [Lys(B28), Pro(B29)] Human Insulin

The time–action profile of the insulin analogue insulin lispro ([Lys(B28), Pro(B29)] human insulin) with its rapid onset and short duration of action might be more suitable to limit hyperglycaemic excursions after a meal rich in rapidly absorbable carbohydrates in comparison to regular human insulin. A randomized, double-blind study was performed in 10 Type I diabetic patients with good metabolic control (HbA_1c 7.0 ± 0.5 %). After a baseline period of 3 h (blood glucose clamped at 6.7 mmol l⁻¹, i.v. insulin infusion of 0.2 mU kg⁻¹ min⁻¹ throughout the study), the patients ate a pizza, drank a cola and had a carbohydrate-rich dessert (total carbohydrate content 140 g). Immediately before the meal 15.4 ± 3.5 U of either insulin preparation were injected subcutaneously. Blood glucose concentrations were monitored continuously thereafter. Following the injection of insulin lispro the area under the blood glucose curve after the meal was 78 % of that of regular insulin (1.76 ± 0.34 vs 2.26 ± 0.68 mol l⁻¹ *240 min⁻¹; p < 0.01). Maximal blood glucose excursions were higher and were reached later after regular insulin as compared to insulin lispro (11.9 ± 2.8 vs 9.9 ± 1.4 mmol l⁻¹; p < 0.05; 66 ± 37 vs 41 ± 7 min; p < 0.05). Maximal individual differences in the blood glucose excursions (regular human insulin minus insulin lispro) were 4.8 ± 2.2 mmol l⁻¹ (p < 0.0001 against zero) after 110 ± 37 min. In Type I diabetic patients prandial blood glucose excursions after a carbohydrate rich meal were reduced after preprandial injection of insulin lispro in comparison to human regular insulin.     

Normalization of fasting glycaemia by intravenous GLP-1 ([7-36 amide] or [7-37]) in Type 2 diabetic patients

Intravenous GLP-1 [7-36 amide] can normalize fasting hyperglycaemia in Type 2 diabetic patients. Whether GLP-1 [7-37] has similar effects and how quickly plasma glucose concentrations revert to hyperglycaemia after stopping GLP-1 is not known. Therefore, 8 patients with Type 2 diabetes (5 female, 3 male; 65 ± 6 years; BMI 34.3 ± 7.9 kg m⁻²; HbA_1c 9.6 ± 1.2 %; treatment with diet alone (n = 2), sulphonylurea (n = 5), metformin (n = 1)) were examined twice in randomized order. GLP-1 [7-36 amide] or [7-37] (1 pmol kg⁻¹min⁻¹) were infused intravenously over 4 h in fasted subjects. Plasma glucose (glucose-oxidase), insulin and C-peptide (ELISA) was measured during infusion and for 4 h thereafter. Indirect calorimetry was performed. Fasting hyperglycaemia was 11.7 ± 0.9 [7-36 amide] and 11.3 ± 0.9 mmol l⁻¹ [7-37]. GLP-1 infusions stimulated insulin secretion approximately 3-fold (insulin peak 168 ± 32 and 156 ± 47 pmol l⁻¹, p < 0.0001 vs basal; C-peptide peak 2.32 ± 0.28 and 2.34 ± 0.43 nmol l⁻¹, p < 0.0001, respectively, with GLP-1 [7-36 amide] and [7-37]). Four hours of GLP-1 infusion reduced plasma glucose (4.8 ± 0.4 and 4.6 ± 0.3 mmol l⁻¹, p < 0.0001 vs basal values), and it remained in the non-diabetic fasting range after a further 4 h (5.1 ± 0.4 and 5.3 ± 0.4 mmol l⁻¹, for GLP [7-36 amide] and [7-37], respectively). There were no significant differences between GLP-1 [7-36 amide] and [7-37] (glucose, p = 0.99; insulin, p = 0.99; C-peptide, p = 0.99). Neither glucose oxidation nor lipid oxidation (or any other parameters determined by indirect calorimetry) changed during or after the administration of exogenous GLP-1. In conclusion, GLP-1 [7-36 amide] and [7-37] normalize fasting hyperglycaemia in Type 2 diabetic patients. Diabetes therapy (diet, sulphonyl ureas or metformin) does not appear to influence this effect. In fasting and resting patients, the effect persists during administration of GLP-1 and for at least 4 h thereafter, without rebound. Significant changes in circulating substrate concentrations (e.g. glucose) are not accompanied by changes in intracellular substrate metabolism. © 1998 John Wiley & Sons, Ltd.     

Effect of insulin on blood rheology in non-diabetic subjects and in patients with type 2 diabetes mellitus

We evaluated the effect of insulin on platelet function, blood viscosity, and filterability in healthy subjects and in patients with Type 2 (non-insulin-dependent) diabetes mellitus. Fifteen diabetic patients were free from cardiovascular complications (group A), while the other 15 patients had both clinical and measured evidence of coronary or peripheral vascular disease (group B); 15 non-diabetic subjects served as controls. On blood samples taken without stasis, maximal platelet aggregation to 1.25 μmol l⁻¹ ADP, blood and plasma viscosity, and blood filterability were measured in basal conditions, and after incubation of blood, plasma or platelet-rich plasma with insulin at two physiological concentrations (120 and 480 pmol l⁻¹). Compared with healthy subjects, the diabetic patients of group B had higher values of blood (p < 0.01) and plasma (p < 0.05) viscosity, and platelet aggregation response to ADP (p < 0.01), as well as lower values of blood filterability (p < 0.01). The diabetic patients of group A had values intermediate between normal subjects and the patients of group B. In non-diabetic subjects, insulin significantly decreased platelet aggregation and blood viscosity at low shear rates (22.5 s⁻¹) (p < 0.01 for both), and had no significant effects on other parameters. In the diabetic patients of group A, insulin decreased blood viscosity at high (225 s⁻¹) rates of shear (p < 0.01) and increased blood filterability (p < 0.01). The effects of insulin were not dose-related. In the diabetic patients of group B, none of the parameters evaluated was significantly influenced by insulin. Type 2 diabetic patients present many abnormalities of the rheologic properties of blood. The beneficial effects of insulin on platelet aggregation and blood viscosity are not evident in Type 2 diabetic patients, especially those with vascular complications and this may be relevant to the development of those complications. © 1997 John Wiley & Sons, Ltd.     

Adding metformin versus insulin dose increase in insulin-treated but poorly controlled Type 2 diabetes mellitus: an open-label randomized trial

To compare the effect of adding metformin to insulin therapy with a moderate increase in insulin dose alone in insulin-treated, poorly controlled Type 2 diabetic patients, 47 consecutive such patients (baseline daily dose >0.5 IU kg⁻¹ and HbA_1c >8 %) were openly randomized either to a combination of their previous insulin schedule plus metformin (2.55 g daily in three divided doses, n = 24) or to a moderate insulin dose increase (20 % of baseline, n = 23). The patient status/biochemical profile was assessed at entry and at 4 months. Among those assigned to insulin + metformin, 18 took the drug. Upon an intention-to-treat basis, patients assigned to insulin dose increase had a statistically significant weight gain (1.16 + 1.9 vs 0.3 ± 4.5 kg, p < 0.05). Patients assigned to the insulin + metformin regimen experienced a significantly greater fall in HbA_1c (−1.87 ± 2.16 vs 0.03 ± 1.68 %, p < 0.01), total cholesterol (−0.56 ± 0.89 vs 0.14 ± 0.72 mmol l⁻¹, p < 0.05) and LDL-cholesterol (−0.51 ± 0.73 vs 0.19 ± 0.6 mmol l⁻¹, p < 0.01). These data suggest that adding metformin to insulin in poorly controlled Type 2 DM patients offers an advantage in terms of glycaemic control and lipid plasma profile. Copyright © 1998 John Wiley & Sons, Ltd.     

Metabolic Abnormalities in Offspring of NIDDM Patients with a Family History of Diabetes Mellitus

NIDDM appears to be an inherited condition. Our aim was to identify early metabolic abnormalities in non-diabetic offspring with one NIDDM parent and with a strongly positive (n = 58, age 27.8 ± 7.0 years) or a negative family history (n = 38, age 27.4 ± 6.7 years) of diabetes. These were compared with 31 offspring of non-diabetic parents (age 26.9 ± 5.5 years). After an overnight fast, blood was taken for glucose, insulin, C-peptide, insulin receptors, and lipids. All the subjects underwent a 75 g oral glucose tolerance test. The positive family history group had significantly higher fasting levels of triglycerides (1.09 ± 0.24 vs control subjects: CS: 0.93 ± 0.16 mmol l⁻¹, p < 0.001), insulin (102.8 ± 46.4 vs CS: 77.5 ± 32.4 pmol l⁻¹, p < 0.01) and C-peptide (0.69 ± 0.22 vs CS: 0.61 ± 0.19 nmol l⁻¹, p < 0.05) and lower numbers of insulin receptors per red cell (9.1 × 10³ (4.5–18.1, 95 % confidence intervals) vs CS: (11.2 × 10³ (6.3–19.9)), p < 0.01, despite similar blood glucose levels. After a glucose challenge (120 min), the increases in both insulin and C-peptide concentrations were significantly greater in the positive family history group (289.2 ± 214.1 pmol l⁻¹, 2.23 ± 1.48 nmol l⁻¹), respectively, than in CS (192.4 ± 170.3 pmol l⁻¹, p < 0.05) (1.54 ± 0.99 nmol l⁻¹ p < 0.01), respectively. No significant differences were found in fasting and post-challenge glucose levels. The negative family history group had significantly lower numbers of insulin receptors 9.4 × 10³ (4.1–15.2) compared with CS (p < 0.05). Insulin sensitivity was significantly reduced in the positive family history group (41.6 %) compared with control subjects (51.9 %), p < 0.01. The results strongly support the familial basis of the disease.     

The Role of Plasma Non-esterified Fatty Acids During Exercise in Type 2 Diabetes Mellitus

Elevated fasting plasma non-esterified fatty acid (NEFA) levels have been reported in Type 2 diabetes. We examined whether such changes persist during low-grade exercise and influence carbohydrate metabolism. Eight Type 2 diabetic patients with moderate glycaemic control and eight healthy controls received the anti-lipolytic agent, acipimox, or placebo on separate occasions before exercising for 45 min at 35 % pre-determined V_o2max. Fasting plasma NEFA levels were similar (0.40 ± 0.06 (SEM) and 0.45 ± 0.05 mmol l^?1; healthy and Type 2 diabetic subjects) following placebo, and increased to comparable levels with exercise (0.73 ± 0.07 and 0.73 ± 0.10 mmol l^?1). Acipimox lowered basal NEFA levels (0.14 ± 0.03 and 0.28 ± 0.04 mmol I^?1; both p < 0.05 vs placebo), and prevented the rise with exercise. Blood glucose (p < 0.001) and serum insulin (p < 0.01) levels were higher in the Type 2 diabetic patients (vs controls) for both treatments. Whole body lipid oxidation increased from baseline to a comparable degree with exercise following placebo (3.2 ± 0.3 and 2.8 ± 0.3 mg kg^?1 min^?1; healthy and Type 2 diabetic subjects, both p < 0.02). Although less marked, the same was also observed following acipimox (2.0 ± 0.4 and 2.1 ± 0.5 mg kg^?1 min^?1; both p < 0.05). Carbohydrate oxidation increased with exercise in both subject groups, but with no significant difference between the treatments. Thus, the metabolic response to low-grade exercise was normal in Type 2 diabetic patients with moderate glycaemic control, but occurred against a background of hyperinsulinaemia. Plasma NEFA do not exert a major regulatory effect on carbohydrate metabolism during low-grade exercise.     

Spontaneous hypoglycaemia after pancreas transplantation in Type 1 diabetes mellitus

Hypoglycaemia is an important complication of insulin treatment in Type 1 diabetes mellitus (DM). Pancreas transplantation couples glucose sensing and insulin secretion, attaining a distinctive advantage over insulin treatment. We tested whether successful transplantation can avoid hypoglycaemia in Type 1 DM. Combined kidney and pancreas transplanted Type 1 DM who complied with good function criteria (KP-Tx, n = 55), and isolated kidney or liver transplanted non-diabetic subjects on the same immunosuppressive regimen (CON-Tx, n = 14), underwent 1-day metabolic profiles in the first 3 years after transplantation, sampling plasma glucose (PG) and pancreatic hormones every 2 hours. KP-Tx had lower PG than CON-Tx in the night and in the morning and higher insulin concentrations throughout the day. KP-Tx had lower PG nadirs than CON-Tx (4.40 ± 0.05 vs 4.96 ± 0.16 mmol l⁻¹, ANOVA p = 0.001). Nine per cent of KP-Tx had hypoglycaemic values (PG ≤3.0 mmol l⁻¹) in the profiles, both postprandial and postabsorptive, whereas none of CON-Tx did (p < 0.02). In conclusion, after pancreas transplantation, mild hypoglycaemia is frequent, although its clinical impact is limited. Compared to insulin treatment in Type 1 DM, pancreas transplantation improves but cannot eliminate hypoglycaemia. Copyright © 1998 John Wiley & Sons, Ltd.     

Nutritional Antioxidants,Red Cell Membrane Fluidity and Blood Viscosity in Type 1 (insulin dependent) Diabetes Mellitus

The study was designed to evaluate whether the antioxidant nutrients selenium, vitamin A, and vitamin E are associated with alterations of blood viscosity in patients with insulin-dependent (Type 1) diabetes mellitus (IDDM). We assessed selenium concentrations in plasma and red blood cells (RBC), glutathione peroxidase activity in RBC, vitamin A and vitamin E, and the viscosity of whole blood and plasma in 20 patients with IDDM and 20 sex, age and body mass index-matched healthy controls. While selenium was not altered in plasma in IDDM, it was markedly decreased in RBC of IDDM (1.24 ± 0.32 vs 0.92 ± 0.38 μmol l⁻¹, p = 0.006) correlating negatively with the elastic and viscous component of whole blood viscosity. Plasma viscosity increased with stage of retinopathy. Mean glutathione peroxidase activity in RBC was reduced in IDDM (5.78 ± 0.77 vs 5.13 ± 1.03 U gHb⁻¹, p = 0.029). In IDDM with normal renal function (creatinine ≤ 97.2 μmol l⁻¹, no albuminuria) vitamin A was significantly reduced (1.26 ± 0.62 vs 1.89 ± 0.56 μmol l⁻¹, p = 0.005). Vitamin A levels increased with impaired renal function. They strongly correlated with plasma creatinine (r = 0.86, p < 0.001) and plasma viscosity (r = 0.71, p = 0.001). However, in vitro experiments with different vitamin A plasma concentrations indicated that this particular correlation may not represent a causal one. No changes in vitamin E were found in IDDM. We conclude that reduced selenium concentrations in RBC contribute to impaired haemorheology in IDDM patients. Plasma visocisty was not affected by the plasma concentrations of vitamins A and E.     

NEFA elevation during a hyperglycaemic clamp enhances insulin secretion

Elevated non-esterified fatty acid (NEFA) levels may influence insulin secretion and contribute to the development of Type 2 DM. We investigated the effects of acute NEFA elevation in controls (n = 6) and subjects predisposed to Type 2 DM (n = 6) on basal insulin levels, and following glucose and arginine stimulation. Each subject had one study with a triglyceride (TG) plus heparin infusion (elevated NEFA levels) and another with normal saline. Twenty minutes after the TG or saline infusion began a glucose bolus was given and 10 min later a 90-min hyperglycaemic clamp (∼ 9 mmol l⁻¹) was started. Intravenous arginine was given at 110 min. Elevated NEFA levels (∼ 4000 μmol l⁻¹) did not enhance basal or first phase glucose stimulated insulin levels. During hyperglycaemia, NEFA elevation further increased insulin levels in both groups by 20–44 % (p < 0.05) and C-peptide levels by 17–25 % (p < 0.05). The post-arginine insulin levels during hyperglycaemia were increased by 45 % in the Type 2 DM-risk group (p < 0.02). The glucose infusion rate maintaining matched hyperglycaemia was similar during NEFA elevation and for saline control for both groups. We conclude that acute elevation of NEFA levels enhances glucose and non-glucose-induced insulin secretion. © 1998 John Wiley & Sons, Ltd.     

Plasminogen Activator Inhibitor (PAI-1) Activity is Elevated in Asian and Caucasian Subjects with Non-insulin-dependent (Type 2) Diabetes but not in Those with Impaired Glucose Tolerance (IGT) or Non-diabetic Asians

In order to study the plasminogen activator inhibitor activity (PAI-1) in subjects at different risk of non-insulin-dependent diabetes and ischaemic heart disease we examined 89 subjects with diet controlled NIDDM (49 Caucasian, 40 Asian), 29 with impaired glucose tolerance (IGT) (13 Caucasian, 16 Asian), and 149 with normal glucose tolerance (67 Caucasian, 82 Asian). Diabetes was diagnosed by WHO criteria and highly specific, monoclonal antibody-based assays were used to measure insulin, intact proinsulin, and des 31,32 proinsulin. Subjects with NIDDM were significantly more obese, had more central distribution of obesity, higher fasting plasma specific insulin concentrations (NIDDM median 74 pmol l⁻¹ vs IGT 41 pmol l⁻¹, p < 0.01 and vs normals 34 pmol l⁻¹, p < 0.001) and higher PAI-1 activity than normals and those with IGT (NIDDM 23.0 ± 6.9 vs IGT 16.8 ± 5.0, p < 0.001 and vs normals 17.1 ± 6.9 AU ml⁻¹, p < 0.001). However, PAI-1 activity was not significantly different between Asian and Caucasian normals (17.5 ± 7.3 vs 16.5 ± 6.4 AU ml⁻¹, p = ns) and diabetic (22.8 ± 7.3 vs 23.1 ± 6.6 AU ml⁻¹, p = ns) subjects. In addition to relationships with obesity and plasma triglyceride, PAI-1 activity, after controlling for age, sex, body mass index, and waist–hip ratio, was related to fasting insulin (partial r = 0.22, p < 0.001), intact proinsulin (partial r = 0.36, p < 0.001), and des 31,32 proinsulin concentrations (partial r = 0.33, p < 0.001) as measured by highly specific assays. The association of PAI-1 with diabetes was weakened but remained statistically significant (p = 0.042) after controlling for age, sex, ethnicity, obesity, plasma triglyceride, and all insulin-like molecules. We conclude that, although PAI-1 activity is raised in subjects with diet-treated NIDDM, it is normal in subjects with IGT and non-diabetic Asians, populations at high risk of NIDDM and ischaemic heart disease. Raised PAI-1 activity may play an important role in the pathogenesis of macrovascular disease in subjects with NIDDM, but is unlikely to explain excess risk of ischaemic heart disease in Asians and those with impaired glucose tolerance.     

No deterioration in insulin sensitivity,but impairment of both pancreatic β-cell function and glucose sensitivity,in Japanese women with former gestational diabetes mellitus

To identify the primary pathogenic factors involved in the development of Type 2 diabetes mellitus (DM), we studied Japanese women with former gestational diabetes mellitus (GDM) who are at risk for the later development of Type 2 DM. We used the minimal model analysis derived from frequently sampled intravenous glucose tolerance test (FSIGT). The subjects consisted of eight non-obese women with a history of GDM and eight non-obese normal women as control subjects. The 75 g oral glucose tolerance test (75 g OGTT) performed within 6 months of delivery confirmed that all the subjects with former GDM had a normal glucose tolerance. Insulin sensitivity (SI) derived from the minimal model analysis was not different between the two groups. Glucose effectiveness at zero insulin (GEZI), reflecting tissue glucose sensitivity, was significantly lower in former GDM patients than in control subjects (1.18 ± 0.34 vs 2.26 ± 0.29 × 10⁻² min⁻¹, p < 0.05). The early phase insulin secretion found in FSIGT was markedly reduced to 56 % of that observed in control subjects (1250 ± 187.4 vs 2223 ± 304.3 pmol l⁻¹ min, p < 0.01). Our results indicate that in former GDM patients, who are Japanese and non-obese, impairment of the acute insulin response to glucose and a decrease in tissue glucose sensitivity rather than insulin sensitivity are the primary pathogenic factors involved. Copyright © 1998 John Wiley & Sons, Ltd.     

UKPDS 26: sulphonylurea failure in non-insulin-dependent diabetic patients over six years

Patients with Type 2 (non-insulin-dependent) diabetes mellitus (DM) on sulphonylurea therapy convert to insulin progressively as the sulphonylureas ‘fail’. The rate of failure and the features of those who fail have been poorly described. To assess secondary failure rates of sulphonylureas, we report on the responses in 1305 patients with newly diagnosed Type 2 DM randomly allocated to therapy with either chlorpropamide or glibenclamide in the UK Prospective Diabetes Study (UKPDS). These patients were initially treated by diet for 3 months and had a fasting plasma glucose >6 mmol l⁻¹; mean age 53 (SD 9) years; BMI 26.8 (SD 5.0) kg m⁻²; and median fasting plasma glucose 9.1 (7.6–12.5 quartiles) mmol l⁻¹. If their fasting plasma glucose subsequently rose above 15.0 mmol l⁻¹, or they developed hyperglycaemic symptoms, additional hypoglycaemic therapy was given: metformin, ultratard insulin, and soluble insulin as required. By 6 years, 44 % had required additional therapy. Of those randomized to glibenclamide, 48 % required additional therapy by 6 years, compared with 40 % of those allocated to chlorpropamide (p < 0.01). 61 %, 39 %, and 23 %, respectively, of patients with fasting plasma glucose ≥10.0 mmol l⁻¹, ≥7.8 mmol l⁻¹ to <10.0 mmol l⁻¹ and <7.8 mmol l⁻¹ at randomization required additional therapy (p < 0.001). In the initial 3 years, non-obese subjects (BMI <30 kg m⁻²) were more likely to require additional therapy than obese patients (BMI ≥30 kg m⁻²) (43 % vs 53 % at 6 years; p < 0.001). Modelled beta-cell function showed that those with lower function were more likely to fail (p < 0.0001). Thus sulphonylureas fail as a therapeutic agent at rates which are dependent both on the phenotype at presentation and perhaps on the agent used initially. Higher failure rates were found in those with higher glucose concentrations, those who were younger, those with lower beta-cell reserve and those randomized to glibenclamide compared with chlorpropamide. © 1998 John Wiley & Sons, Ltd.     

Effect of Metformin on Intact Proinsulin and des 31,32 Proinsulin Concentrations in Subjects with Non-insulin-dependent (Type 2) Diabetes Mellitus

We have investigated the effects of metformin treatment on concentrations of proinsulin-like molecules in subjects with Type 2 (non-insulin-dependent) diabetes mellitus. Metformin was given for 12 weeks in an increasing dose up to 850 mg three times daily in a double-blind placebo-controlled cross-over design to 27 subjects (age 53.0 ± 9.9 years; 19 male, 8 female). Concentrations of insulin and proinsulin-like molecules were measured by highly specific enzymoimmunometric assays. The end of metformin treatment was compared with end of placebo treatment. Metformin lowered fasting plasma glucose concentrations (at 12 weeks, metformin: 8.0 ± 2.5 vs placebo: 12.0 ± 2.3 mmol l⁻¹, p r2 0.001;). Concentrations of intact (median change −2.9 (range −28.4 to +2.5 pmol l⁻¹), p =0.02) and des 31,32 proinsulin (median change −1.6 (range −14.1 to +5.4 pmol l⁻¹), p = 0.07) and percentage of proinsulin-like molecules were reduced by metformin treatment (median change −6 % (range −16 % to +6 %), p = 0.02). Changes in the ratio of proinsulin-like molecules were significantly related with those in fasting plasma glucose (r_s = 0.69, p < 0.001). Changes in concentrations of intact and des 31,32 proinsulin on metformin were not related to changes in body mass index or fasting glucose concentration or changes in concentrations of total triglyceride, cholesterol, and plasminogen activator inhibitor-1. Therefore, metformin treatment in subjects with Type 2 diabetes mellitus significantly reduced concentrations of proinsulin-like molecules over a 12-week period. However, these changes were not related to changes in cardiovascular risk factors seen during metformin treatment. We conclude that short-term effects of metformin treatment on proinsulin-like molecules are similar to those previously observed with dietary treatment in subjects with Type 2 diabetes but opposite to those of sulphonylurea treatment. The effect of long-term treatment with metformin on proinsulin-like molecules needs to be assessed.     

Effects of different glycaemic index foods and dietary fibre intake on glycaemic control in Type 1 diabetic patients on intensive insulin therapy

To evaluate the influence of a low glycaemic index (GI), high GI and high fibre diet on glycaemic control and insulin requirement in Type 1 diabetic patients on intensive insulin therapy, nine well-controlled, highly-motivated Type 1 diabetic patients were put on a control diet for 12 days and then randomized in a consecutive manner to 12 days of each diet, in a crossover design. During each experimental diet, the study subjects adjusted their premeal insulin (soluble) dose to maintain their 1-h postprandial capillary glucose at or below 10 mmol l⁻¹. At the end of each experimental diet, they were submitted to a standardized breakfast of the diet under study, using the same premeal insulin dose as that required for the control diet. The control diet contained 16.0 ± 3.0 g of fibre day⁻¹ with a GI of 77.4 ± 2.7 compared to 15.3 ± 6.3 and 66.2 ± 1.2 for the low GI diet, 17.1 ± 7.2 and 92.9 ± 3.6 for the high GI diet, and 56.1 ± 3.6 (including 15 g of guar) and 73.5 ± 2.1 for the high fibre diet. Prebreakfast capillary blood glucose (6.2 ± 1.2 mmol l⁻¹) on the low GI diet and postbreakfast capillary blood glucose (8.7 ± 1.8 mmol l⁻¹) on the high fibre diet were significantly lower than the values obtained with the control diet (8.0 ± 1.8 and 10.6 ± 2.4, respectively; p <0.05). No change in premeal or basal insulin dose was required. During the standardized breakfasts, the incremental area under the curve was 1.6 ± 1.5 mmol l⁻¹ min⁻¹ for the control diet compared to 1.1 ± 1.8 for the low GI diet, 3.2 ± 1.4 for the high GI diet (p <0.05 versus low GI and high fibre; p = 0.08 versus control), and 1.0 ± 0.9 for the high fibre diet. These observations indicate that in well-controlled Type 1 diabetic subjects on intensive insulin therapy, major alterations in the GI and fibre content of meals induce small but significant changes in glucose profile. In everyday life, however, these differences are blunted, and plasma glucose remains within the target range for optimal metabolic control. © 1998 John Wiley & Sons, Ltd.     

The Effects of Lipid Lowering Drugs on Metabolic Control and Lipoprotein Composition in Type 2 Diabetic Patients with Mild Hyperlipidaemia

Patients with Type 2 diabetes are at increased risk from macrovascular disease whether or not they are hyperlipidaemic. Several factors may contribute to this increased risk including abnormalities of lipoprotein composition. The aim of our study was to determine the effects of lipid lowering drugs on lipoprotein composition (lipoprotein fractions were separated by sequential flotation ultracentrifugation) and insulin sensitivity (measured by a modified Harano technique) in 44 patients with mild hyperlipidaemia. All patients had total cholesterol concentrations between 5.2 and 6.5 mmol l^?1 and total triglyceride concentrations < 3.0 mmol l^?1, and were randomized by minimization to receive treatment for 12 weeks with bezafibrate, acipimox, simvastatin or placebo. Total cholesterol concentrations were decreased by simvastatin, 5.7 ± 0.4 to 3.7 ± 0.6 mmol l^?1 (p < 0.05), due mainly to reduced LDL-cholesterol levels (?1.25 mmol l^?1; p < 0.05), and bezafibrate 5.7 ± 0.6 to 4.6 ± 0.4 mmol l^?1 (p < 0.05). The LDL:HDL-cholesterol ratio was reduced in the simvastatin group 2.0 ± 0.5 to 1.2 ± 0.3 (p < 0.005). There was no effect of the drugs on glycated haemoglobin or insulin sensitivity. In conclusion bezafibrate and simvastatin improve the lipid profile in Type 2 diabetic patients without adversely affecting diabetic control.     

Preservation of Renal Haemodynamic Response to an Oral Protein Load in Non-insulin-dependent Diabetes Mellitus

Glomerular Filtration Rate (GFR) and Effective Renal Plasma Flow (ERPF) were determined, for 2h prior to and 3h following the ingestion of a 1.2 g kg^?1 meat meal, in seven normotensive normoalbuminuric Type 2 diabetic patients exhibiting good glycaemic control (fasting plasma glucose (mean ± SD): 7.2 ± 2.0 mmol l^?1; glycosylated haemoglobin: 8.1 ± 1.7%) and in nine normal subjects selected for similar basal GFR values. Baseline GFR and ERPF (corrected to 1.73 m² surface area) were 83 ± 10 and 410 ± 76 ml min^?1 for the Type 2 diabetic patients and 86 ± 11 and 405 ± 113 ml min^?1 for the normals. GFR increased by 38 ± 8 and 32 ± 15% in the diabetic patients and normals, to 108 ± 25 and 105 ± 26 ml min^?1 (p < 0.01 vs baseline). Peak ERPF was 501 ± 127 and 476 ± 119 ml min^?1 for the two respective groups (p < 0.01 vs baseline). Filtration fractions at peak GFR and EPRF values were unchanged from baseline for either groups. Fractional clearance of albumin for the Type 2 diabetic patients was unaltered by protein ingestion. Therefore, protein ingestion in Type 2 diabetes, as in normals, results in an acute elevation of GFR. Absolute and incremental changes in GFR were identical for the two groups. These data demonstrate a preserved capacity for renal vasodilatation in Type 2 diabetic patients despite their greater chronological age.     

Atropine Inhibits Meal-Stimulated Release of Cholecystokinin

To examine the effect of atropine on cholecystokinin (CCK) release, we studied CCK concentrations after a liquid fat meal in five volunteers both with and without pretreatment with atropine. In control studies peak plasma CCK 8 concentrations were 15.0 ± 6.2 pmol l^-1, and the integrated plasma CCK 8 response was 415 ± 216 pmol l^-1 2 h^-1. Peak plasma CCK 33/39 concentrations were 16.5 ± 4.6 pmol l^-1, and integrated CCK 33/9 response was 469 ± 200 pmol l^-1 2h^-1. After pretreatment with atropine postprandial CCKs were undetectable (p < 0.05 versus control studies). The abolition of measurable CCK release by atropine may entirely account for its inhibitory effects on biliary secretion and in part for its effect on the pancreas.