Prospective study of risk factors for development of non-insulin dependent diabetes in middle aged British men.

OBJECTIVE--To determine the risk factors for noninsulin dependent diabetes in a cohort representative of middle aged British men. DESIGN--Prospective study. SUBJECTS AND SETTINGS--7735 men aged 40-59, drawn from one group practice in each of 24 towns in Britain. Known and probable cases of diabetes at screening (n = 158) were excluded. MAIN OUTCOME MEASURES--Non-insulin dependent diabetes (doctor diagnosed) over a mean follow up period of 12.8 years. RESULTS--There were 194 new cases of non-insulin dependent diabetes. Body mass index was the dominant risk factor for diabetes, with an age adjusted relative risk (upper fifth to lower fifth) of 11.6; 95% confidence interval 5.4 to 16.8. Men engaged in moderate levels of physical activity had a substantially reduced risk of diabetes, relative to the physically inactive men, after adjustment for age and body mass index (0.4; 0.2 to 0.7), an association which persisted in full multivariate analysis. A nonlinear relation between alcohol intake and diabetes was observed, with the lowest risk among moderate drinkers (16-42 units/week) relative to the baseline group of occasional drinkers (0.6; 0.4 to 1.0). Additional significant predictors of diabetes in multivariate analysis included serum triglyceride concentration, high density lipoprotein cholesterol concentration (inverse association), heart rate, uric acid concentration, and prevalent coronary heart disease. CONCLUSION--These findings emphasise the interrelations between risk factors for non-insulin dependent diabetes and coronary heart disease and the potential value of an integrated approach to the prevention of these conditions based on the prevention of obesity and the promotion of physical activity.     

Relation of coronary heart disease and apolipoprotein E phenotype in patients with non-insulin dependent diabetes.

OBJECTIVES--To examine the relation between coronary heart disease and the apolipoprotein E phenotypes in patients with non-insulin dependent diabetes mellitus. DESIGN--Cross sectional study. SETTING--District around Kuopio University Central Hospital, East Finland. SUBJECTS--138 men with non-insulin dependent diabetes and 64 men without diabetes as controls. MAIN OUTCOME MEASURE--Apolipoprotein E phenotype, electrocardiographic abnormalities, other signs of coronary heart disease. RESULTS--The prevalences of definite myocardial infarction and ischaemic electrocardiographic changes were highest in the diabetic men with the phenotypes E4/4 or E4/3 (25% (95% confidence interval 18% to 32%) and 50% (42% to 58%) respectively), although the difference between the phenotype groups was not significant. The prevalence of angina pectoris was 69% (61% to 77%) in men with the phenotypes E4/4 or E4/3 (p = 0.005 compared with other phenotypes), 41% (33% to 49%) in men with phenotype E3/3, and 47% (39% to 55%) in those with phenotypes E2/2 or E2/3. Similarly, the simultaneous presence of angina pectoris and ischaemic electrocardiographic changes was highest in the diabetic men with the phenotypes E4/4 or E4/3 (42% v 22% in those with E3/3 and 29% in those with E2/2, E2/3; p = 0.038). Overall, the prevalence of any evidence of coronary heart disease among the diabetic subjects with the phenotypes E4/4 or E4/3 was 81% (p = 0.011 compared with other phenotypes), 58% in those with phenotype E3/3, and 53% in those with phenotypes E2/2 or E3/3. CONCLUSION--Apolipoprotein E phenotypes E4/4 and E4/3 modulate the risk of coronary heart disease in men with non-insulin dependent diabetes.     

Risk factors for early death in non-insulin dependent diabetes and men with known glucose tolerance status.

OBJECTIVE--To identify risk factors for all cause mortality according to glucose tolerance status. DESIGN--Cohort study with an average 15.6 years'' follow up. SETTING--Paris, France. SUBJECTS--7166 working men aged 44-55 in 1968-72 in the Paris prospective study cohort, with non-insulin dependent diabetes or known result of two hour 75 g oral glucose tolerance test. MAIN OUTCOME MEASURES--Risk factors for death from all causes. RESULTS--128 men were known to be diabetic, 180 had diabetes diagnosed, and 697 had impaired glucose tolerance diagnosed. Compared with normoglycaemic men the relative risks of death in these groups were 2.0 (95% confidence interval 1.4 to 3.0), 2.7 (2.0 to 3.6), and 1.6 (1.3 to 2.0) respectively. Obesity, smoking, high blood pressure, and high non-esterified fatty acid concentration were risk factors for death in all subjects and were unaffected by glucose tolerance. The risks for fasting and two hour insulin concentrations and mean corpuscular volume were two times higher in known diabetic men than in men not known to be diabetic. Central obesity was significant only in men not known to be diabetic (1.6 (1.4 to 1.9)). In known diabetic men a two hour glucose concentration higher than 11.1 mmol/l carried a relative risk of death of 3.8 (1.4 to 9.4). CONCLUSIONS--Diabetic men have similar risk factors for early mortality to other men but are at higher risk from hyperinsulinaemia, hyperglycaemia, and high mean corpuscular volume.     

The combined use of insulin and sulfonylurea therapy in patients with non-insulin dependent diabetes mellitus

This study was initiated in order to evaluate the clinical efficacy of glipizide treatment in 18 patients with non-insulin dependent diabetes mellitus in poor glycemic control with insulin. Insulin dose was kept constant, and various facets of carbohydrate and lipid metabolism were evaluated before and from 4-6 months after the addition of glipizide. The results indicated that fasting and post-prandial glucose concentration were significantly (P less than 0.001) reduced following glipizide treatment, associated with a commensurate fall in glycosylated hemoglobin concentration. The average fall in fasting plasma glucose concentration in the total patient group approximated 60 mg/dl, and the mean decrement in 8 of the 18 patients who had a fall of more than 70 mg/dl in fasting glucose was 93 mg/dl. These results demonstrate that the addition of glipizide to the treatment program of patients with non-insulin dependent diabetes mellitus poorly controlled on insulin can lead to substantial clinical benefit.     

Characterization of the insulin resistance in liver cirrhosis: a comparison with non-insulin dependent diabetes mellitus.

To characterize the mechanisms of insulin resistance in liver cirrhosis (LC), we estimated the peripheral tissue sensitivity and responsiveness to insulin using the euglycemic clamp technique and determined the insulin binding to erythrocytes in patients with compensated LC as well as in patients with non-insulin dependent diabetes mellitus (NIDDM). The insulin dose-response curves of the glucose metabolic clearance rates (MCR) were shifted to the right and downward both in patients with LC and NIDDM, indicating a reduced sensitivity and responsiveness to insulin. In the cirrhotics, MCR at the maximally effective insulin level, an index of insulin responsiveness, was correlated with fasting insulin levels (r = -0.57, P < 0.01) and sigma BG in 75 gOGTT (r = -0.43, P < 0.05), but no correlations were found between them and the diabetics. Although specific insulin bindings to erythrocytes were significantly lower in patients both with LC and NIDDM, Scatchard analysis revealed a significant decrease in the number of insulin receptors in the cirrhotics, and a decrease in the empty-site affinity in the diabetics. These findings suggest that insulin resistance in LC consists of a combination of binding and postbinding defects. The latter defect may be caused by basal hyperinsulinemia and contribute to the development of glucose intolerance. Although binding and postbinding abnormalities are also found in NIDDM, the mechanisms of insulin resistance in LC and NIDDM may be different.     

Risk factors for developing non-insulin dependent diabetes: a 10 year follow up of men in Uppsala.

OBJECTIVE--To analyse anthropometric and metabolic characteristics as risk factors for development of non-insulin dependent diabetes mellitus in middle aged normoglycaemic men. DESIGN--Prospective population study based on data collected in a health survey and follow up 10 years later. SETTING--Uppsala, a middle sized city in Sweden. SUBJECTS--2322 men aged 47-53, of whom 1860 attended the follow up 7-14 years later, at which time they were aged 56-64. MAIN OUTCOME MEASURES--Incidence of non-insulin dependent diabetes. RESULTS--In a multivariate logistic regression analysis, variations of 1 SD from the mean of the group that remained euglycaemic were used to calculate odds ratios and 95% confidence intervals. Blood glucose concentration 60 minutes after the start of an intravenous glucose tolerance test (odds ratio = 5.93, 95% confidence interval 3.05 to 11.5), fasting serum insulin concentration (2.12, 1.54 to 2.93), acute insulin increment at an intravenous glucose tolerance test (1.71, 1.21 to 2.43), body mass index (1.41, 1.01 to 1.97), and systolic blood pressure (1.23, 0.97 to 1.56) were independent predictors of diabetes. In addition, the use of antihypertensive drugs at follow up (selective or unselective beta blocking agents, thiazides, or hydralazine) was an independent risk factor (1.70, 1.11 to 2.60). CONCLUSIONS--Metabolic and anthropometric characteristics associated with or reflecting insulin resistance as well as a poor acute insulin response to glucose challenge were important predictors of future diabetes in middle aged men. Antihypertensive drugs were found to constitute a further, iatrogenic risk factor.     

Clustering of hemodynamic and metabolic abnormalities and of anthropometric characteristics in men and women, aged 21-60 years.

The associations between fat pattern and metabolic profile were evaluated, using cluster analysis, in 214 males and 244 females (aged 21-60 years). The subjects were randomly selected from the patients of one general practice in Castel D'Azzano (Italy). The metabolic status was indexed by blood pressure, blood glucose, uric acid, serum triglycerides, total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol (both total and percentage). Fat pattern was evaluated using six skinfolds and three circumferences. The analyses were performed separately on anthropometric and metabolic variables for each sex. The analyses were repeated five times to evaluate the stability of the cluster solution. Anthropometric rather than metabolic variables provided a more stable solution for cluster analysis. Anthropometric clusters showed significantly different metabolic patterns. Most of the differences disappeared when a body mass index (BMI) effect was taken into account but not when an adjustment for waist to hip ratio (WHR) was made. On the other hand, neither BMI nor WHR was able to fully account for the differences in metabolic profiles of metabolic clusters. Cross-classification results of anthropometric and metabolic cluster membership showed a significant, although moderate, degree of association between the two classification sets. These results indicate that in both sexes anthropometric characteristics contribute to a limited degree to the metabolic profile and that the associations probably reflect a complex mechanism.     

Blood and liver lipid concentrations in EDS shrews exhibiting spontaneous non-insulin dependent diabetes mellitus (NIDDM).

The EDS (early-onset diabetes in suncus) colony was developed as a new laboratory colony of the musk shrew and is characterized by a high incidence of early-onset spontaneous non-insulin dependent diabetes mellitus (NIDDM). We examined blood lipid (triglyceride [TG], total cholesterol [TC], phospholipid [PL], free fatty acid [FFA]) and liver lipid (TG, TC, PL) concentrations to investigate the features of lipid metabolism in these animals. All lipid concentrations examined both in blood and liver of the diabetic shrews had a tendency toward higher values than those in non-diabetic shrews. The PL concentration was the only parameter that barely showed a significant difference. Values for all blood lipid concentrations in diabetic shrews at 7-9 months tended to be higher than those of 2-month-old diabetic shrews, although the difference was not significant. These findings indicate that diabetic EDS shrews exhibit a much milder defect of lipid metabolism induced by NIDDM than other rodent models.     

Low plasma C4 concentrations: association with microangiopathy in insulin dependent diabetes.

Plasma C4 concentrations were measured in insulin dependent diabetics with and without microangiopathy and in controls. The diabetics had significantly lower C4 values than controls (p less than 0.001), and patients with insulin dependent diabetes and microangiopathy had lower values than those without this complication (p less than 0.001). There was a 7.1-fold increase in the prevalence of complications in the diabetics with low C4 values. Of 41 diabetics whose rate of albumin excretion was measured, 13 had increased rates and 11 of these had low C4 concentrations. Low plasma C4 concentration in insulin dependent diabetes is strongly associated with microvascular disease and may identify diabetics with a particular propensity to develop this complication.     

Genetic susceptibility to non-insulin dependent diabetes mellitus and glucose intolerance are located in HLA region.

OBJECTIVES--To test the hypothesis that the genetic susceptibility to non-insulin dependent diabetes mellitus is the same as that to insulin dependent disease and to see whether glucose intolerance is associated with specific HLA haplotypes. DESIGN--Population based study of men in 1989 first tested for glucose tolerance in 1984. HLA haplotypes, including HLA-A, C, B, DR, and DQ, were defined serologically. HLA haplotype data from a population based Finnish study of childhood diabetes were used for predicting non-insulin dependent diabetes and impaired glucose tolerance. SETTING--Two communities in Finland. SUBJECTS--Representative cohort of Finnish men aged 70-89, comprising 98 men with non-insulin dependent diabetes mellitus and a randomly selected group of 74 men, who served as controls, who were tested for glucose tolerance twice within five years. MAIN OUTCOME MEASURES--Non-insulin dependent diabetes, impaired glucose tolerance, blood glucose concentration. RESULTS--Diabetes associated HLA haplotypes were present in 94% (85/90) of diabetic subjects, 79% (27/34) of subjects with impaired glucose tolerance, and only 13% (3/23) of non-diabetic subjects. In this group of elderly men sensitivity of the diabetes associated HLA haplotypes for non-insulin dependent diabetes and impaired glucose tolerance was 90%, specificity 87%, and predictive power 97%. Mean fasting blood glucose concentration was only just significantly higher in men with diabetes associated haplotypes than in men with no such haplotypes, but there was a substantial difference in blood glucose values two hours after glucose loading (10.4 and 6.4 mmol/l in men with diabetes associated HLA haplotypes and men with no such haplotypes, respectively (p < 0.0001)). CONCLUSIONS--These findings support the hypothesis that specific HLA haplotypes exhibit a common genetic determinant for insulin dependent and non-insulin dependent diabetes. Furthermore, HLA is a major genetic determinant of glucose intolerance in elderly Finnish men. The belief that the HLA predisposition to diabetes is specific for insulin dependent diabetes mellitus is largely incorrect.     

Rising incidence of insulin dependent diabetes in children aged under 5 years in the Oxford region: time trend analysis. The Bart's-Oxford Study Group.

OBJECTIVES: To monitor incidence of insulin dependent diabetes in children in Oxford health region since 1985, and to look for any evidence of disproportionate increase in children aged under 5. DESIGN: Primary ascertainment of cases of childhood diabetes was by prospective registration of all patients with insulin dependent diabetes diagnosed before age 15 years between 1985 and 1996 and resident in Oxford region at time of diagnosis. This was supplemented by examination of centralised hospital discharge records and death certificates. Secondary case ascertainment was by postal surveys of general practitioners in 1987 and 1996. SETTING: Area formerly administered by Oxford Regional Health Authority. SUBJECTS: 1037 children presenting with insulin dependent diabetes under age of 15 years. MAIN OUTCOME MEASURES: Incidence of insulin dependent diabetes in children aged 0-4, 5-9, and 10-14 years during 1985-95. RESULTS: Overall incidence of diabetes in children aged 0-15 was 18.6 cases/100000/year and showed an annual increase of 4% from 1985 to 1996. This was mainly due to a rapid increase in children aged 0-4 years, in whom there was an annual increase of 11% (95% confidence interval 6% to 15%, P < 0.0001), while the annual increase in those aged 5-9 was 4% (0 to 7%, P = 0.05) and in those aged 10-14 was 1% (-2% to 4%, P = 0.55). CONCLUSIONS: Incidence of insulin dependent diabetes in children aged under 5 years has risen markedly in the Oxford region over the past decade. The cause of the increase is unknown, but environmental influences encountered before birth or in early postnatal life are likely to be responsible.