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Aims: To determine if the presence of diabetes autoantibodies predicts the development of diabetes among participants in the Diabetes Prevention Program., Methods: A total of 3050 participants were randomized into three treatment groups: intensive lifestyle intervention, metformin and placebo. Glutamic acid decarboxylase (GAD) 65 autoantibodies and insulinoma-associated-2 autoantibodies were measured at baseline and participants were followed for 3.2 years for the development of diabetes., Results: The overall prevalence of GAD autoantibodies was 4.0%, and it varied across racial/ethnic groups from 2.4% among Asian-Pacific Islanders to 7.0% among non-Hispanic black people. There were no significant differences in BMI or metabolic variables (glucose, insulin, HbA(1c), estimated insulin resistance, corrected insulin response) stratified by baseline GAD antibody status. GAD autoantibody positivity did not predict diabetes overall (adjusted hazard ratio 0.98; 95% CI 0.56-1.73) or in any of the three treatment groups. Insulinoma-associated-2 autoantibodies were positive in only one participant (0.033%)., Conclusions: These data suggest that 'diabetes autoimmunity', as reflected by GAD antibodies and insulinoma-associated-2 autoantibodies, in middle-aged individuals at risk for diabetes is not a clinically relevant risk factor for progression to diabetes., (© 2014 The Authors. Diabetic Medicine © 2014 Diabetes UK.)

Aims: Whether long-term cardiovascular risk is reduced by the Diabetes Prevention Program interventions is unknown. The aim of this study was to determine the long-term differences in cardiovascular disease risk factors and the use of lipid and blood pressure medications by the original Diabetes Prevention Program intervention group., Methods: This long-term follow-up (median 10 years, interquartile range 9.0-10.5) of the three-arm Diabetes Prevention Program randomized controlled clinical trial (metformin, intensive lifestyle and placebo), performed on 2766 (88%) of the Diabetes Prevention Program participants (who originally had impaired glucose tolerance), comprised a mean of 3.2 years of randomized treatment, approximately 1-year transition (during which all participants were offered intensive lifestyle intervention) and 5 years follow-up (Diabetes Prevention Program Outcomes Study). During the study, participants were followed in their original groups with their clinical care being provided by practitioners outside the research setting. The study determined lipoprotein profiles and blood pressure and medication use annually., Results: After 10 years' follow-up from Diabetes Prevention Program baseline, major reductions were seen for systolic (-2 to -3) and diastolic (-6 to -6.5 mmHg) blood pressure, and for LDL cholesterol (-0.51 to -0.6 mmol/l) and triglycerides (-0.23 to -0.25 mmol/l) in all groups, with no between-group differences. HDL cholesterol also rose significantly (0.14 to 0.15 mmol/l) in all groups. Lipid (P = 0.01) and blood pressure (P = 0.09) medication use, however, were lower for the lifestyle group during the Diabetes Prevention Program Outcomes Study., Conclusion: Overall, intensive lifestyle intervention achieved, with less medication, a comparable long-term effect on cardiovascular disease risk factors, to that seen in the metformin and placebo groups., (© 2012 The Authors. Diabetic Medicine © 2012 Diabetes UK.)

Objective: The Diabetes Prevention Program demonstrated the ability to delay or prevent type 2 diabetes in participants with impaired glucose tolerance (IGT). Participants with IGT are at high risk for cardiovascular disease (CVD), with a marked increase in the number and severity of CVD risk factors. We prospectively assessed the impact of our interventions on hypertension, dyslipidemia, and CVD events., Research Design and Methods: The study group consisted of 3,234 individuals with IGT randomly assigned to receive intensive lifestyle intervention, metformin, or placebo. Annual assessment of blood pressure, lipids, electrocardiogram, and CVD events was undertaken., Results: Hypertension was present in 30% of participants at study entry and then increased in the placebo and metformin groups, although it significantly decreased with intensive lifestyle intervention. Triglyceride levels fell in all treatment groups, but fell significantly more with intensive lifestyle intervention. Total cholesterol and LDL cholesterol levels were similar among treatment groups. Intensive lifestyle intervention significantly increased the HDL cholesterol level and reduced the cumulative incidence of the proatherogenic LDL phenotype B. At 3 years of follow-up, the use for pharmacologic therapy to achieve established goals in the intensive lifestyle group was 27-28% less for hypertension and 25% less for hyperlipidemia compared with placebo and metformin groups. Over an average of 3 years, 89 CVD events from 64 participants were positively adjudicated studywide, with no differences among treatment groups., Conclusions: Lifestyle intervention improves CVD risk factor status compared with placebo and metformin therapy. Although no differences in CVD events were noted after 3 years, achieved risk factor modifications suggest that longer intervention may reduce CVD event rates.

Objective: Clinical cardiovascular disease (CVD) is highly prevalent among people with diabetes. However, there is little information regarding the prevalence of subclinical CVD and its relation to clinical CVD in diabetes and in the glucose disorders that precede diabetes., Research Design and Methods: Participants in the Cardiovascular Health Study, aged > or = 65 years (n = 5,888), underwent vascular and metabolic testing. Individuals with known disease in the coronary, cerebral, or peripheral circulations were considered to have clinical disease. Those without any clinical disease in whom CVD was detected by ultrasonography, electrocardiography, or ankle arm index in any of the three vascular beds were considered to have isolated subclinical disease., Results: Approximately 30% of the cohort had clinical disease, and approximately 60% of the remainder had isolated subclinical disease. In those with normal glucose status, isolated subclinical disease made up most of the total CVD. With increasing glucose severity, the proportion of total CVD that was clinical disease increased; 75% of men and 66% of women with normal fasting glucose status had either clinical or subclinical CVD. Among those with known diabetes, the prevalence was approximately 88% (odds ratio [OR] 2.46 for men and 4.22 for women, P < 0.0001). There were intermediate prevalences and ORs for those with impaired fasting glucose status and newly diagnosed diabetes., Conclusions: Isolated subclinical CVD is common among older adults. Glucose disorders are associated with an increased prevalence of total CVD and an increased proportion of clinical disease relative to subclinical disease.

Objective: To assess the prevalence and incidence of being overweight in type 1 diabetes, to identify factors associated with weight gain and improved glycemic control, and to examine relationships among weight gain, glycemic control, and cardiovascular risk factors., Research Design and Methods: The prevalence and incidence of being overweight in the Pittsburgh Epidemiology of Diabetes Complications (EDC) cohort (n = 441) were compared with the general population (National Health and Nutrition Examination Survey [NHANES]). Factors associated with weight gain and improved glycemic control were identified, and relationships among weight gain, glycemic control, and cardiovascular risk factors were examined over a 6.9 +/- 2.2-year period., Results: At baseline, the prevalence of being overweight (BMI > 27.8 kg/m2 for men and > 27.3 kg/m2 for women) was 10.4 and 11.4%, respectively, and was lower than the age- and sex-specific estimate for the general population (P < 0.05). The incidence of being overweight was comparable in men (12.6%) and women (11.8%) and did not differ from the general population (P = 0.98). Weight gain correlated with improvements in HbA1c (r = -0.21, P < 0.001). Patients with the highest baseline HbA1c levels gained the most weight and had the greatest improvement in glycemic control. A lower baseline BMI was also associated with a greater improvement in glycemic control. Weight gain favorably influenced the lipid profile in the setting of improved glycemic control, but adversely influenced the lipid profile in the absence of improved glycemic control. Weight change was directly associated with blood pressure change, but the incidence of hypertension was more strongly influenced by the development of nephropathy., Conclusions: The prevalence of being overweight in type 1 diabetes remains lower than that in the general population. Moderate weight gain did not adversely affect the cardiovascular risk profile in the setting of improved glycemic control.

Background: We aimed to compare the prevalence of abnormal glucose tolerance identified by the 1985 WHO and the 1997 American Diabetes Association (ADA) diagnostic categories based on information collected in the Cardiovascular Health Study, an epidemiological study of elderly people., Methods: We measured glucose concentrations during fasting and 2 h after a 75 g oral glucose-tolerance test in participants aged 65-100 years in the Cardiovascular Health Study. From a 1989 cohort, we analysed the glucose measurements of 4515 individuals without a previous diagnosis of diabetes and of 262 additional measurements from an African-American cohort recruited in 1992-93., Findings: In the 1989 cohort, the prevalence of untreated diabetes with ADA diagnostic fasting criteria was 7.7% versus a prevalence of 14.8% by the WHO criteria. In the African-American cohort, the prevalence of untreated diabetes was 2.7% with ADA criteria and 11.8% with WHO criteria. 3509 (77.7%) of the 4515 participants in the 1989 cohort had normal glucose concentrations according to ADA fasting criteria, compared with 2401 (53.2%) according to WHO criteria. In the African-American cohort, the corresponding numbers were 239 (91.2%) versus 153 (58.4%). All differences in prevalence of abnormal glucose tolerance between ADA and WHO classifications were significant (p<0.0001)., Interpretation: Among elderly individuals, there was a significant difference in the prevalence of diabetes identified by the WHO diagnostic criteria based on oral glucose-tolerance test and the ADA fasting criteria. Consequently, many individuals currently classified as non-diabetic according to ADA criteria would previously have had a diagnosis of diabetes according to WHO criteria. Longitudinal studies are needed to assess the value of the criteria in the identification of individuals at increased risk of diabetes-associated chronic complications.

It is clearly recognized that patients with NIDDM have an increased risk for CHD. Recent data indicate that persons with glucose concentrations in the nondiabetic range also may be at higher risk for CHD. These associations may not represent cause and effect, however. Emerging data suggest that hyperglycemia and CHD may both arise from hyperinsulinemia/insulin resistance. In support of this hypothesis are studies showing that NIDDM and CHD have many risk factors in common, including age, elevated blood pressure, dyslipidemia, adiposity, and a central pattern of fat distribution. Moreover, these risk factors are frequent concomitants of hyperinsulinemia, itself a risk factor for CHD and perhaps for NIDDM. Although the duration of NIDDM has been infrequently related to risk of CHD, the authors hypothesize that duration of hyperinsulinemia/insulin resistance would be a more sensitive marker for risk of CHD. The relation of IDDM to CHD is a different situation. The etiological process leading to IDDM, namely the destruction of beta-cells in genetically predisposed persons, is not related to cardiovascular risk. However, IDDM patients still have an excess of CVD, the risk factors for which may vary according to the location of the diseases (e.g., LEAD vs. CHD). There is a strong relationship between proteinuria and CVD, which has led to a general theory of vascular complications in IDDM based on defective heparan sulfate metabolism (Steno hypothesis). Recent evidence challenges parts of this hypothesis, and the possibility is raised that a higher case-fatality rate in a subgroup of patients with both renal and CVD explains part of the renal connection, as does the general worsening of CVD risk factors.

Objective: This project evaluated the utility of quantitative sensory techniques in predicting the development of neuropathy for subjects participating in a prospective study., Research Design and Methods: Distal symmetric polyneuropathy was evaluated in 77 insulin-dependent diabetes mellitus individuals via quantitative sensory testing, nerve conduction studies, and clinical examination., Results: Although the specificity and positive predictive value were low for the quantitative sensory techniques as predictors of neuropathy diagnosed on clinical exam approximately 2 yr later, the sensitivity for vibratory thresholds was high (100%). Variability over the 2-yr interval was shown on follow-up testing for each of the objective assessment modalities and it was not explained by differences for potential risk factors measured at baseline., Conclusion: Despite a cross-sectional relationship between the assessment modalities and clinically overt neuropathy at baseline, these follow-up data suggest that the potential for the objective modalities as predictors of clinically diagnosed neuropathy may be limited.

The incidence of insulin dependent diabetes mellitus, as determined from the Pittsburgh Insulin Dependent Diabetes Mellitus Registry, was examined in relationship to social class. The registry consists of all Allegheny County, Pennsylvania, cases of insulin dependent diabetes diagnosed under age 20 years in 1965-1976. Analyses of the registry data revealed little relationship between incidence, age at onset and social class. The lack of a strong relationship to social class indicates that the epidemiology of insulin dependent diabetes is not similar to those of polio or Hodgkin's disease, in which social class is strongly related to incidence and age at onset.

The venous plasma glucose and insulin concentrations recorded during oral glucose tolerance testing of over 300 1st degree relatives (parents and siblings) of insulin dependent diabetics are presented. Men had higher glucose concentrations than women, the difference increasing with age, while insulin responses appeared greater in adolescent girls and young women than their male counterparts. The possible relationship between the different insulin responses in the two sexes and the sex difference in cardiovascular risk factors is discussed. It is suggested that the absence of a marked sex differential in heart disease mortality amongst diabetics may partly result from the loss by diabetic women of their greater insulin production relative to men in young adult life.

An insulin-dependent Diabetes Mellitus Registry has been developed in Allegheny County, Pennsylvania, through hospital record review and surveillance of pediatric practices. The yearly incidence ranged from 10/100,000 for nonwhite males to 16/100,000 for white males. There were no temporal trends in incidence for 1965-1976 nor major sex differences. Nonwhites had a slightly lower incidence, primarily in the younger age groups.

Family history data were collected in 1203 consecutive admissions of insulin-dependent diabetes mellitus cases to the Children's Hospital of Pittsburgh between Dec. 31, 1964 and Jan. 1, 1981. This report deals with two issues: the closeness in time of dates of onset of diabetes in multiple sibling case families and the similarity of ages of onset within these families. The age-specific incidence rates among siblings were 6-18 times higher than in the general population. Contrary to other reports, this study does not find an increased risk to siblings during the first year or two after the onset of the index diabetic case. The mean duration between cases is 6.1 years. Fitting a log-normal distribution to the periods between cases verified the long median incubation period (4.35 years) with a high degree of variability (dispersion factor = 3.38). However, the log-normal was not a good fit to the data (p less than 0.005). There is a significant correlation for age of onset for pairs of affected siblings within families (0.25). However, it is shown that the similarity in age of onset within families may be a function of the greater similarity to ages of siblings within a family. It is noted that secondary cases are more often younger children in the family, particularly so if the index child is of school age at the time of onset.

A number of current issues in diabetes research are reviewed from an epidemiologic viewpoint. Though many advances have been made in our understanding of the causes of insulin-dependent diabetes mellitus (IDDM), there are many unresolved issues which could benefit from epidemiologic research. These include study of the 36-fold geographic variation in IDDM incidence seen across the world, perhaps by the development of registries, and the placing into a population perspective recent genetic and autoimmune findings concerning IDDM etiology. Epidemiologic considerations should also be incorporated into future trials of immunotherapy for IDDM. Despite considerable research, very little is known about risk factors and genetic environmental interactions in non-insulin dependent diabetes. Large scale prospective epidemiologic studies are, therefore, needed to delineate the potential roles of factors such as diet and physical activity, and how these interact with genetic predisposition.