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 HbA_1c 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 HbA_1c 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 HbA_1c 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 course and determinants of insulin action in Type 1 (insulin-dependent) diabetes mellitus

Summary The course and determinants of insulin action were investigated in 8 newly diagnosed Type 1 (insulin-dependent) diabetic patients, who were studied every 3 months for one year, and in three groups of 8 patients each with 5, 10 and 20 years diabetes, studied once. Fifteen healthy subjects matched for age, sex and body weight served as control subjects. Dose-response curves were constructed using sequential euglycaemic (5.0 mmol/l) clamps (insulin infusion rates: 0.5, 1.0, 2.0 and 5.0 mU·kg^–1·min^–1 in periods of 2h). After 1/2 month of insulin treatment, insulin responsiveness was normal, but sensitivity was decreased (ED₅₀ 70±7 mU/l (SEM) vs 54±4mU/l in control subjects, p<0.05). After 6 months, insulin sensitivity was improved (ED₅₀ 57±4 mU/l, p<0.01 vs 1/2 month and not significant (NS) vs control subjects); but after 9 and 12 months, it was reduced again, similarly to 0.5 month. Insulin responsiveness remained normal at all time-points. In the three groups of patients with longstanding diabetes, impaired insulin sensitivity with normal responsiveness was noted also (ED₅₀ 73±9 mU/l, p<0.02 vs control subjects). At 6, 9 and 12 months, glycaemic control (HbA₁) and insulin dose were inverse correlates for insulin action; in patients with longstanding disease, this was noted for HbA₁ and body weight, in control subjects for body weight. In conclusion, decreased insulin sensitivity re-develops in Type 1 diabetes within the first year following an initial improvement. Presumably, hyperglycaemia plays a role in the pathogenesis of this recurrence.     

Influences on Weight Loss in Type 2 Diabetic Patients: Little Long-term Benefit from Group Behaviour Therapy and Exercise Training

The aim of our study was to assess the long-term (24 months) efficacy of a comprehensive weight reduction programme as compared to that of a conventional programme. The Comprehensive Programme comprised, besides the Conventional Programme (diet counselling), behavioural modification and exercise training. The 2-year follow-up period was completed by 53 patients (19M/34F; 88.3%). The differences (95% confidence intervals; CI) between the change in body weight of patients in the Comprehensive Programme compared to the Conventional Programme after 6 and 24 months of treatment were ?2.2 (-4.0, ?0.3) kg, p = 0.03 and ?1.3 (-3.3, 0.7) kg, p = 0.21, respectively. In comparison to the Conventional Programme, the Comprehensive Programme resulted in a greater decrease (95% CI) of HbA_1c after 6 months: ?0.8 (-1.2, ?0.2)%, p = 0.01, but not after 2 years: ?0.4 (-1.0, 0.1)%, p = 0.12. The effects on blood pressure and serum lipids of the Comprehensive Programme and the Conventional Programme were comparable. Changes in body weight at 6 months correlated well with changes in HbA_1c, fasting plasma insulin, and blood pressure, whereas at 24 months no such correlation was found with HbA_1c. Pretreatment variates that were associated with the greatest 2-year weight loss were a high HbA_1c value, a low energy per cent carbohydrate intake and a low percentage of obese subjects within the family. In conclusion, the long-term outcome of the Comprehensive Programme was not different from that of the Conventional Programme. The achieved body weight reduction was associated with a sustained fall in blood pressure, but with only a transient beneficial effect on the glycaemic control in the Type 2 diabetic patient.     

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.     

Glycaemic control and cardiovascular risk factors in Type 2 diabetes: a population-based study

The objective of this study was to estimate the prevalence of poor glycaemic control and cardiovascular risk factors in an Italian population-based cohort of subjects with Type 2 diabetes mellitus (DM). Out of a cohort of 1967 subjects (estimated completeness of ascertainment 80 %), 1574 (80 %) were investigated, and adherence to targets for control of the European NIDDM Policy Group assessed. Prevalence of poor glycemic control (HbA_1c > = 8) was 47.7 %. Obesity was present in 23.4 % of the cohort, hypertension in 83.4 %, hypertriglyceridaemia (>2.26 mM) in 19.3 %, hypercholesterolaemia (>6.46 mM) in 25.5 %, and low HDL-cholesterol (<0.90 mM in men and <1.03 mM in women) in 13.7 %. Only 153 (9.7 %) subjects were free from other disorders. Subjects were treated as follows: 26.2 % exclusively by general practitioners; 13.3 %, 69.9 %, 10.9 %, and 5.9 % with diet, oral hypoglycaemic drugs, insulin, and both, respectively. Multiple linear regression analysis showed associations between HbA_1c and fibrinogen (p < 0.001), total cholesterol (p = 0.006), and triglycerides (p = 0.04), independent of age, sex, duration of diabetes, and antidiabetic treatment. Neither BMI nor blood pressure were associated with HbA_1c. In conclusion, this Italian population-based cohort of subjects with Type 2 DM showed a high prevalence of poor glycaemic control, high consumption of oral hypoglycaemic drugs, and an independent association between glycaemic control and cardiovascular risk factors (fibrinogen, total cholesterol, and triglycerides). The presence of obesity or hypertension was not significantly associated with glycaemic control. © 1998 John Wiley & Sons, Ltd.     

The postprandial state does not impair endothelial function in women with Type 2 diabetes irrespective of glycaemic control

Aims/hypothesis The postprandial state has been shown to be associated with endothelial dysfunction, a predictor of cardiovascular morbidity. In Type 2 diabetes, postprandial metabolic excursions are prolonged and exaggerated, but less pronounced if glycaemic control is optimised. We investigated the impact of improved glycaemic control on endothelial function in the postprandial state.Methods We studied 19 postmenopausal women with Type 2 diabetes and ten non-diabetic subjects. Participants with diabetes were re-studied 3 months after intensive glucose regulation. We measured forearm blood flow by strain gauge plethysmography during rest, during acetylcholine infusion and post ischaemia in the fasting state, and again 3 hours after a mixed meal (660 kcal, 55% fat).Results Endothelium-dependent vasodilation was impaired in the diabetic group (p<0.005) and improved following an HbA₁c reduction of 0.96% (p<0.05 for high-dose acetylcholine infusion). Postprandial metabolic excursions were higher in the diabetic group (p<0.001, p<0.01 and p<0.05 for glucose, insulin and triglycerides respectively). Resting forearm blood flow increased in all groups after the meal (p<0.005). There was no difference in fasting and postprandial endothelium-dependent vasodilation before and after improved glucose regulation in either group.Conclusions/interpretation The postprandial state does not impair endothelial function in non-diabetic women and does not make pre-existing endothelial dysfunction worse in women with Type 2 diabetes, irrespective of glycaemic control.     

Diet Treatment of Newly Presenting Type 2 Diabetes Improves Insulin Secretory Capacity,but Has No Effect on Insulin Sensitivity

Fifteen newly diagnosed obese Type 2 diabetic subjects were treated with diet alone for 3 months with a median 1.5 kg weight loss. Each had a Continuous Infusion of Glucose with Model Assessment (CIGMA) test, at diagnosis and at 3 months, measuring insulin and C-peptide responses, and deriving mathematically modelled measures of beta-cell function and insulin sensitivity. Median fasting glucoses were 9.6 mmol l^?1 at diagnosis and 8.5 mmol l^?1 at 3 months (NS). Median fasting insulin was 9.3 mU l^?1 at diagnosis and 11.7 mU l^?1 at 3 months (NS). Median fasting C-peptide was 0.58 nmol l^?1 at diagnosis and 0.64 nmol l^?1 at 3 months (p < 0.05). Median achieved plasma insulin increased from 13.8 mU l^?1 at diagnosis to 17 mU l^?1 at 3 months (p < 0.02); median achieved plasma C-peptide increased from 0.72 nmol l^?1 at diagnosis to 0.81 nmol l^?1 at 3 months (p < 0.002). Modelled beta-cell function rose from median 26 % at diagnosis to 37 % at 3 months (p < 0.02). Modelled insulin sensitivity showed no significant change (median 0.31 at diagnosis, 0.27 at 3 months, NS). Elevation of achieved C-peptide was positively correlated with weight loss (R_s = 0.53, p < 0.05), but not with change in fasting glucose. Diet treatment of newly diagnosed Type 2 diabetes, with modest weight loss, results primarily in improvement of insulin secretory capacity, rather than insulin sensitivity.     

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.     

Orlistat 120 mg improves glycaemic control in type 2 diabetic patients with or without concurrent weight loss

Background: Both obesity and type 2 diabetes are associated with increased morbidity and mortality. Published data suggest that orlistat 120 mg, a lipase inhibitor used to treat obesity, may improve glycaemic parameters through weight loss–independent effects. Aim: To investigate the effect of orlistat 120 mg on weight loss, and assess whether changes in glycaemic parameters [fasting plasma glucose (FPG) and haemoglobin A_1c (HbA_1c)] are independent of weight loss. Methods: This retrospective analysis of pooled data from seven multicentre, double‐blind, placebo‐controlled studies involved overweight or obese patients with type 2 diabetes (aged 18–70 years). Patients were required to have a body mass index of 27–43 kg/m², HbA_1c of 6.5 to <13%, and stable weight for ≥3 months. Subjects received orlistat 120 mg tid or placebo for 6 or 12 months. Results: A total of 2550 overweight or obese patients with type 2 diabetes were enrolled and randomized to treatment with orlistat 120 mg tid (n = 1279) or placebo (n = 1271). For the whole population, patients treated with orlistat 120 mg had significantly greater mean decreases in FPG compared with placebo‐treated patients (?1.39 mmol/l vs. ?0.47 mmol/l; p < 0.0001). In addition, orlistat 120 mg provided significantly larger mean decreases in HbA_1c compared with placebo (?0.74% vs. ?0.31%; p < 0.0001). For patients with minimal weight loss (≤1% of baseline body weight), orlistat 120 mg still provided a significantly greater decrease in the least squares mean value for both FPG (?0.83 mmol/l vs. ±0.02 mmol/l; p = 0.0052) and HbA_1c?0.29% vs. ±0.14%; p = 0.0008). This suggested that the improvement of glycaemic control with orlistat 120 mg was independent of weight loss. Using linear regression analysis, improvement in glycaemic control (FPG and HbA_1c) with orlistat 120 mg was less strongly correlated with weight loss than for placebo. Conclusion: Orlistat 120 mg appears to improve glycaemic control more than would be predicted by weight loss alone in overweight or obese patients with type 2 diabetes. Postulated mechanisms underlying this effect include an improvement of insulin sensitivity, a slower and incomplete digestion of dietary fat, reduction of postprandial plasma non‐esterified fatty acids, decreased visceral adipose tissue, and stimulation of glucagon‐like peptide‐1 secretion in the lower small intestine.     

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.     

Fluoxetine in the Treatment of Obese Type 2 Diabetic Patients

In a 12-month randomly allocated double-blind trial in 19 obese Type 2 diabetic patients, fluoxetine 60 mg daily compared to placebo produced a significant fall in median body weight after 3 months (3.8 kg), 6 months (6.5 kg), 9 months (7.1 kg), and at 1 year (5.8 kg). Median fasting blood glucose and HbA_1c levels fell significantly after 3 months (1.9 mmol l^?1 and 1.7 %, respectively) and 6 months (1.8 mmol l^?1 and 1.7%) but neither showed a significant difference to placebo after 9 or 12 months therapy with fluoxetine. There were no significant changes in serum cholesterol levels in the year but patients on fluoxetine showed a significant fall in serum triglyceride level (0.5 mmol l^?1 after 3 months therapy but not thereafter. Compared to placebo there was a significant fall in median energy intake on fluoxetine after 3 months (257 kcal day^?1) and 6 months (199 kcal day^?1) but this difference was not significant at 9 or 12 months. There was also a significant fall in carbohydrate intake after 3 months (30 g day^?1) and 6 months (23 g day^?1) on fluoxetine as well as a significant fall in carbohydrate intake expressed as a percentage of the total daily energy intake; 5.9% at 3 months, 6.1% at 6 months, and 4.0% at 9 months. There were no significant effects on protein or fat intake except a significant increase in the intake of fat expressed as a percentage of daily energy intake, 5.9% after 6 months. Two of the nine patients on fluoxetine dropped out of the study due to gastrointestinal side-effects. Fluoxetine might prove to be a useful adjunct therapy in obese Type 2 diabetic patients where short-term weight loss and fall in carbohydrate intake and an improvement in glycaemia are indicated.     

Change in patients’ body weight after 12 months of treatment with glimepiride or glibenclamide in Type 2 diabetes: a multicentre retrolective cohort study

Aims/hypothesis Our study compared the effects of glimepiride or glibenclamide treatment on body weight over 12 months of treatment in patients with Type 2 diabetes in routine outpatient practice.Methods This new retrospective study design used data from physicians in a restricted manner (retrolective). Data from case report forms from 520 patients from 91 randomly selected centres were assessed and covariance analysis performed.Results The influence of practice and patient characteristics on treatment assignment was low, reflecting the design of randomised controlled trials. Mean weight loss and reduction in body mass index from baseline to study endpoint were greater with glimepiride than with glibenclamide (–2.04±3.99 kg vs –0.58±3.65 kg, p<0.001; –0.71±1.38 kg/m² vs –0.20±1.28 kg/m², p<0.001). Duration of treatment at baseline influenced treatment outcome, but propensity score, sex, age and fasting blood glucose at baseline did not. Both glimepiride and glibenclamide led to decreases in fasting blood glucose (–2.43±0.24 mmol/l vs –3.03±0.24 mmol/l; p<0.001 vs baseline) and HbA_1c (–1.23±0.09% vs –1.26±0.09%; p<0.001 vs baseline). Both treatments were associated with a decrease in serum total cholesterol and low density lipoprotein cholesterol. Triglycerides were lower in the glibenclamide group and high density lipoprotein cholesterol was higher in the glimepiride group only.Conclusions/interpretation Initial treatment of Type 2 diabetes with glimepiride was associated with a significantly greater decrease in body weight and body mass index than treatment with glibenclamide, while providing equivalent glycaemic control.Abbreviations FBG Fasting blood glucose - SU sulphonylurea - UKPDS United Kingdom Prospective Diabetes Study     

Glycaemic control and development of retinopathy in Type 2 diabetes mellitus: a longitudinal study

Relationships between glycaemic control, hypertension, and development of microangiopathy have been well documented in Type 1 (insulin-dependent) but not in Type 2 (non-insulin-dependent) diabetes mellitus. Therefore, we have investigated these relationships in a cohort of 64 Type 2 patients free of retinopathy (by angiofluorography), who were regularly followed until development of retinopathy or for at least 7 years as outpatients. Glycaemic control was assessed by 1 to 4 HbA₁ determinations per year. Retinal status was monitored by annual angiofluorography. Nonproliferative retinopathy developed in 14 patients (cumulative incidence at 13 years: 29.8 %) after a mean diabetes duration of 14.3 ± 8.9 years (range 2–27). In multivariate analysis (Cox model), mean HbA₁ during follow-up (p < 0.001), and hypertension at first examination (p = 0.09) were associated with the development of retinopathy, but age, sex, BMI, diabetes duration, smoking, and fasting blood glucose were not. The relative risk for developing retinopathy (RR) was 7.2 (IC 95 %: 1.61–32.4) in patients with a mean HbA₁ during follow-up above the median value of the cohort (8.3 %) compared with patients with HbA₁ during follow-up below this value. RR was 2.5 (IC 0.8–8) in patients with HbA₁ at first examination above compared to below the median value (8.4 %). RR was 3.0 (IC 0.9–10) in patients treated for hypertension at baseline compared to those without treatment. A sixfold increase in retinopathy prevalence was observed between patients with mean HbA₁ in the highest or lowest quartile of mean HbA₁ distribution during follow-up. This longitudinal study indicates a strong association between long-term glycaemic control and the development of diabetic retinopathy in Type 2 diabetes. © 1998 John Wiley & Sons, Ltd.     

NIDDM: a rapid progressive disease Results from a long-term,randomised, comparative study of insulin or sulphonylurea treatment

Summary The objective of the present study was to assess the relative efficacy of insulin or glibenclamide treatment for non-insulin-dependent diabetes mellitus (NIDDM) over 42 months. We performed a randomised, controlled trial allocating patients treated with diet and oral antihyperglycaemic agents to treatment with glibenclamide or insulin to achieve HbA_1c levels under 7.5 %. We included 36 subjects with established NIDDM of more than 2 years' duration. Mean HbA_1c levels were significantly reduced in patients allocated to insulin treatment from 9.1 ± 1.4 % before the start to 7.8 ± 1.3 % (p< 0.05) after 1 year, and did not change significantly thereafter throughout the study period. Mean HbA_1c levels increased during the study in the patients allocated to glibenclamide treatment, and 11 of 18 patients had to be switched to insulin treatment due to increasing hyperglycaemia (HbA_1c > 10 %). Mean body weight increased in the subjects allocated to insulin by 7.2 ± 4.1 kg during the study period. In conclusion, insulin was more effective than glibenclamide treatment in obtaining control over hyperglycaemia in these patients, and once improved, glycaemic control did not deteriorate over 42 months in the insulin-treated group. Two thirds of the patients allocated to glibenclamide treatment had to be given insulin due to inadequate glycaemic control. [Diabetologia (1996) 39: 1629–1633]     

Menstrual Irregularities are more Common in Adolescents with Type 1 Diabetes: Association with Poor Glycaemic Control and Weight Gain

Ovarian function in post-menarchal girls with Type 1 diabetes was evaluated. Menstrual histories from 24 adolescents with Type 1 diabetes were compared with those from 24 age and sex matched controls. A fasting blood sample was obtained from subjects with Type 1 diabetes for the measurement of ovarian and adrenal sex hormones, LH and FSH, glucose and insulin, insulin-like growth factor-l (IGF-I), and insulin-like growth factor binding protein-1 (IGFBP-1); and an ovarian ultrasound scan was performed. Menstrual irregularity was more prevalent in patients with Type 1 diabetes than controls (54% vs 21%, p < 0.01) and their mean body mass index (BMI) was greater (22.3 ± 0.5 (± SEM) vs 20.7 ± 0.6 kg m^?2, p < 0.05). Subjects with Type 1 diabetes with irregular menses (when compared with diabetic subjects with a regular cycle) had a significantly higher HbA_***1 (12.8 ± 0.4 vs 10.5 ± 0.5%, p < 0.01) and BMI (23.2 ± 0.6 vs 21.4 ± 0.6 kg m^?2, p < 0.05) associated with a lower sex hormone binding globulin (SHBG) (37.2 ± 4.0 vs 52.6 ± 4.0 nmol I^?1, p < 0.025) and IGF-I (1.4 ± 0.2 vs 2.2 ± 0.2 ***mUI^?1, p < 0.025) and a higher LH:FSH ratio (2.6 ± 0.5 vs 1.4 ± 0.2, p < 0.05). Polycystic ovarian changes were identified in 10/13 (77%) of these patients with an irregular cycle. Menstrual irregularity is common in post-menarchal girls with Type 1 diabetes and is associated with poor glycaemic control and weight gain. The apparent high incidence of polycystic ovarian change requires further investigation.     

A placebo-controlled trial of exenatide twice-daily added to thiazolidinediones alone or in combination with metformin

Aim: To test the hypothesis that glycaemic control with exenatide added to thiazolidinediones (TZDs) with or without metformin was superior to placebo. Methods: A 26‐week, multi‐country (Canada, Mexico, Romania, South Africa and the USA), randomized, double‐blind, placebo‐controlled study compared exenatide twice‐daily vs. placebo in 165 subjects suboptimally controlled with TZDs with or without metformin [HbA_1c 8.2% (s.d. 0.9), fasting serum glucose 9.1 (2.6) mmol/l, body weight 93.9 (17.8) kg, diabetes duration 6.4 (4.3) years]. After a 2‐week, single‐blind, lead‐in period, subjects were randomly assigned (2 : 1) to add exenatide or placebo to current regimens. The primary endpoint was HbA_1c change at endpoint (Week 26 or last‐observation‐carried‐forward). Results: Only 8 subjects were treated with concomitant TZD alone. Exenatide reduced HbA_1c significantly more than placebo [?0.84% (s.e. 0.20) vs. ?0.10% (0.23), treatment difference ?0.74% (0.16), p < 0.001)]. Mean reductions in body weight were similar in both treatments at endpoint [exenatide, ?1.4 (s.e. 0.6) kg vs. placebo, ?0.8 (0.7) kg, p = 0.176)]. Nearly 71% of subjects had both a reduction in HbA_1c and body weight with exenatide compared with 54% with placebo. The most common adverse events (exenatide vs. placebo) were nausea (12% vs. 2%, p = 0.037), vomiting (8% vs. 0%, p = 0.031) and headache (4% vs. 4%). Confirmed (blood glucose <3.0 mmol/l) minor hypoglycaemia was experienced by 4 and 2% of subjects treated with exenatide and placebo, respectively. Incidence of hypoglycaemia was not significantly different between groups. Conclusions: Exenatide added to TZDs alone or in combination with metformin significantly improved glycaemic control as determined by significant improvement in HbA_1c without associated hypoglycaemia.     

Psychological and Demographic Correlates of Glycaemic Control in Adult Patients with Type 1 Diabetes

The relationship between an objective measure of glycaemic control (glycated haemoglobin (HbA₁)) and personality variables was examined in two separate groups of adult Type 1 (insulin-dependent) diabetic patients. Study 1 included 121 patients, all of whom also had subjective self-reporting of treatment compliance assessed, while the first 57 patients had individual differences in intelligence, major dimensions of personality and forgetfulness documented. Study 2 examined 303 patients, all of whom had their major dimensions of personality assessed using a shortened and updated version of the original personality questionnaire. Demographic indices (age, onset-age, duration of diabetes) were assessed in both groups. No significant correlation was found between HbA₁ and self-report compliance suggesting that self-reporting may be invalid as a measure of glycaemic control. In study 1 personality and intelligence variables did not correlate significantly with HbA₁ values. Older patients with shorter duration of diabetes had significantly better glycaemic control (p<0.05). A significant correlation was observed between HbA₁ concentration and onset-age of diabetes (p<0.001); the patients who had developed diabetes later in life were achieving better control of their blood glucose. In the larger number of subjects in study 2 no significant correlations were evident between HbA₁ and personality variables. It is concluded that the predictors of glycaemic control indexed by HbA₁ may be distinct from predictors of self-report compliance and that the latter have limited or no value in providing an assessment of quality of glycaemic control. There is no evidence of an effect of personality on glycaemic control as measured by HbA₁.     

Unchanged incidence of severe retinopathy in a population of Type 1 diabetic patients with marked reduction of nephropathy

The incidence of nephropathy in Type 1 diabetes mellitus has declined during the past decade, probably as a result of improved glycaemic control. We wanted to investigate whether the incidence of severe retinopathy has changed during the same time period and to evaluate the importance of glycaemic control in relation to the development of severe retinopathy and nephropathy. All 213 patients in whom Type 1 diabetes mellitus was diagnosed before the age of 15 years between 1961 and 1980 in a district in south-eastern Sweden were studied. Ninety-two per cent of the patients were followed from the onset of diabetes to 1991 or to death. The cumulative incidence of severe retinopathy was not significantly different between the patients with diabetes onset 1961–65, 1966–70, 1971–75, and 1976–80. The risk of developing severe retinopathy or nephropathy was higher in patients with very poor glycaemic control (HbA_1c ≥ 8.4 %) vs patients with poor control (HbA_1c ≥ 7.2 < 8.4 %; p < 0.001). Patients with poor control had an increased risk of developing severe retinopathy vs patients with good control (HbA_1c < 7.2 %; p < 0.008) but there was no difference in the risk of nephropathy. No patients with good control developed nephropathy and only one patient developed severe retinopathy during 25 years of diabetes. © 1998 John Wiley & Sons, Ltd.     

Serum Immunoglobulin Concentrations in Diabetic Patients

The relationship between glycated haemoglobin (an index of long-term diabetic control), fructosamine (an index of intermediate-term diabetic control), and serum IgA, IgG, and IgM was studied in 110 diabetic patients (41 Type 1 and 69 Type 2) and compared with 111 healthy non-diabetic subjects. Significant increases in serum IgA (by 82.7%, p < 0.001) and IgG (by 35.2%, p< 0.001) concentrations were observed whereas the concentration of IgM was significantly decreased (by 46.7%, p < 0.001) in diabetic patients compared with non-diabetic subjects. Using Spearman's rank correlations, IgA correlated with fructosamine (r = 0.77, p < 0.001), HbA₁ (r = 0.76, p < 0.001), and albumin (r = ?0.58, p < 0.001) for the entire population sample but only fructosamine (r = 0.19, p < 0.05) and HbA₁ (r = 0.28, p < 0.001) correlated with IgA in diabetic patients, respectively. It is concluded that abnormal levels of IgA, IgG, and IgM are very common in diabetic patients in whom serum IgA concentrations are influenced by the degree of glycaemic control. Whether changes in IgA and other immunoglobulins are implicated in the pathogenesis of diabetic complications (such as susceptibility to infection) deserve further study.     

Are European standard deviation targets for haemoglobin A1c too strict?

The Diabetes Control and Complications Trial (DCCT) has provided objective evidence for desirable glycaemic control in Type 1 patients and defines the benefits of good glycaemic control in terms of haemoglobin A_1c (HbA_1c) values. However, HbA_1c assays vary, leading to suggestions that glycaemic control be classified according to numbers of standard deviations (SD) from a local non-diabetic population mean. We have classified the glycaemic control of 339 UK Type 1 diabetic patients (182 male, 157 female, median age 36 (range 15–74) years) using the DCCT to set HbA_1c targets and compared this with the SD method. Using age matched controls (mean HbA_1c 4.02 %, SD 0.28 %, n = 106), SD guidelines classified 1 % of patients into good (HbA_1c <3sd from reference mean), 4 % into borderline (3–5SD) and 95 % into poor (>5SD) glycaemic control. When calibrating the same instrument to the DCCT analyser (r = 0.996), 37 % of patients had HbA_1c results lower than the 7 % median value found in the intensively treated DCCT group, while only 12 % of patients had values greater than the 9 % conventionally treated median HbA_1c. DCCT subjects with HbA_1c values of less than 8 % belonged predominantly to the intensively treated group. In this study, 71 % of patients fell into this category. Thus, guidelines based on numbers of SD away from a non-diabetic mean may overestimate the glycaemic control required to reduce microvascular complications in Type 1 patients. Standardizing to DCCT targets is more appropriate. © 1998 John Wiley & Sons, Ltd.