W. C. Knowler

Predisposition to Hypertension and Susceptibility to Renal Disease in Insulin-Dependent Diabetes Mellitus

Only one third of patients with juvenile-onset insulin-dependent diabetes seem to be susceptible to diabetic nephropathy. To test whether this susceptibility is related to a predisposition to hypertension, we investigated the association of nephropathy with markers of risk for hypertension. We randomly selected 89 patients with insulin-dependent diabetes from a roster of children and adolescents who were seen between 1968 and 1972 at about the time the diagnosis was made. These 89 patients were recalled for examination, as young adults, in 1986 and 1987. Patients with nephropathy (cases, n = 33) were compared with controls without nephropathy (n = 56). Having a parent with hypertension tripled the risk of nephropathy (odds ratio, 3.7; 95 percent confidence interval, 1.4 to 10.1). Moreover, cases had significantly higher values for maximal velocity of lithium-sodium countertransport in red cells than controls (mean maximal velocity +/- SE, 0.51 +/- 0.04 vs. 0.38 +/- 0.02 mmol per liter of cells per hour; P less than 0.05). The excess risk associated with both these indicators of a predisposition to hypertension was evident principally in patients with poor glycemic control during their first decade of diabetes; the odds ratios were 4.5 (95 percent confidence interval, 1.1 to 18.7) for patients with a parental history of hypertension and 7.7 (95 percent confidence interval, 1.8 to 33.8) for patients with a maximal velocity of lithium-sodium countertransport greater than or equal to 0.35 mmol per liter of cells per hour. We conclude that the risk of renal disease in patients with juvenile-onset insulin-dependent diabetes is associated with a genetic predisposition to hypertension. Predisposition to hypertension appears to increase susceptibility for renal disease principally in patients with poor glycemic control.

Comparison of tests for glycated haemoglobin and fasting and two hour plasma glucose concentrations as diagnostic methods for diabetes

Abstract Objective : To compare the ability of tests measuring two hour plasma glucose, fasting plasma glucose, and glycated haemoglobin concentrations in predicting the specific microvascular complications of non-insulin dependent diabetes mellitus. Design : Cross sectional and longitudinal analysis of the relation between complications and concomitant results of the three tests. Setting : Gila River Indian Community, Arizona. Subjects : Pima Indians (cross sectional, n=960),aged 25 years or above who were not receiving insulin or oral hypoglycaemic treatment at the baseline examination. Main outcome measures : Development of retinopathy and nephropathy. Results : Cross sectionally, frequency distributions of logarithms of the three sets of results were bimodal, with the prevalence of retinopathy and nephropathy being, respectively, 12.0-26.7 and 3.9-4.2 times as high above as below cut off points which minimised overlap (two hour plasma glucose concentration 12.6 mmol/l; fasting plasma glucose concentration 9.3mmol/l; glycated haemoglobin (HbA1c) concentration 7.8%). Longitudinally, each of the three measures of glycaemia significantly predicted the development of retinopathy (P<0.0001) and nephropathy (P<0.05). Receiver operating characteristic curves showed that two hour plasma glucose concentration was superior to fasting plasma glucose concentration (P<0.05) for prevalent cases of retinopathy, but otherwise no variable had a significant advantage for detecting incident or prevalent cases of either complication. Conclusions : These findings suggest that determination of glycated haemoglobin or fasting plasma glucose concentrations alone may be acceptable alternatives to measuring glucose concentration two hours after challenge with 75 g glucose for the diagnosis of diabetes.

Familial predisposition to renal disease in two generations of Pima Indians with Type 2 (non-insulin-dependent) diabetes mellitus

SummaryWe studied the occurrence of renal disease by measuring serum creatinine and urine protein concentrations in the diabetic members of 316 Pima Indian families with Type 2 (non-insulin-dependent) diabetes in two successive generations to determine if diabetic renal disease aggregates in families. After adjustment for sex and other risk factors, proteinuria occurred among 14.3% of the diabetic offspring if neither parent had proteinuria, 22.9% if at least one diabetic parent had proteinuria, and 45.9% if both parents had diabetes and proteinuria. Among male offspring, an elevated serum creatinine concentration (≥177 μmol/l) was present in 11.7% if the parent had an elevated creatinine and in 1.5% if the parent did not. Thus, proteinuria and high serum creatinine aggregated in diabetic families, suggesting that susceptibility to renal disease is inherited independently of diabetes.

Increasing prevalence of Type II diabetes in American Indian children

Summary Until recently, Type II diabetes was considered rare in children. The disease is, however, increasing among children in populations with high rates of Type II diabetes in adults. The prevalence of Type II diabetes was determined in 5274 Pima Indian children between 1967 and 1996 in three 10-year time periods, for age groups 5–9, 10–14 and 15–19 years. Diabetes was diagnosed using World Health Organisation criteria, based on an oral glucose tolerance test. The prevalence of diabetes increased over time in children aged 10 years and over: in boys from 0 % in 1967–1976 to 1.4 % in 1987–1996 in the 10–14 year old age group, and from 2.43 % to 3.78 % for age group 15–19 and in girls from 0.72 % in 1967–1976 to 2.88 % in 1987–1996 in the 10–14 year old age group, and from 2.73 % to 5.31 % for age group 15–19 years. Along with the increase in the prevalence of Type II diabetes (p < 0.0001), there was an increase in weight (calculated as percentage of relative weight, p < 0.0001), and in frequency of exposure to diabetes in utero (p < 0.0001). The increasing weight and increasing frequency of exposure to diabetes in utero accounted for most of the increase in diabetes prevalence in Pima Indian children over the past 30 years. Type II diabetes is now a common disease in American Indian children aged 10 or more years and has increased dramatically over time, along with increasing weight. A vicious cycle related to an increase in the frequency of exposure to diabetes in utero appears to be an important feature of this epidemic. [Diabetologia (1998) 41: 904–910]

Obesity in the Pima Indians: its magnitude and relationship with diabetes.

Members of the Pima Indian population are obese, on average, as estimated by the body mass index (BMI). Young adults have had the highest BMIs and there have been modest increases in age- and sex-specific mean BMIs for the past 25 y. These observations suggest that the older adults have had less exposure to factors leading to obesity than have the younger adults. Compared with children studied early in this century, present-day Pima children are much heavier for height, suggesting that the degree of obesity has increased since that time. Obesity in the Pimas is familial and has complex relationships with non-insulin-dependent diabetes mellitus, a common disease in this population. Obesity predicts the development of diabetes; once people have diabetes, however, they tend to lose weight. Thus, obesity should not be studied in this population without also considering diabetes, which tends to limit the degree of obesity.

SEQUENTIAL CHANGES IN SERUM INSULIN CONCENTRATION DURING DEVELOPMENT OF NON-INSULIN-DEPENDENT DIABETES

Changes in serum insulin concentrations during deterioration of glucose tolerance were studied in 81 Pima Indians who worsened from normal to impaired glucose tolerance (IGT); 44 who changed from IGT to non-insulin-dependent diabetes mellitus (NIDDM); 27 who were seen at diagnosis of NIDDM and 1.4-8.5 years later; and 11 subjects who were seen at each of these stages. When their glucose tolerance was normal, subjects who later developed NIDDM had higher fasting and post-load insulin concentrations than controls of similar age and body mass index who did not become diabetic. Onset of IGT or NIDDM was associated with a further increase in fasting insulin concentrations, although a deterioration from IGT to NIDDM was associated with little change in insulin responses to oral glucose in spite of increased blood glucose. After the onset of NIDDM, both fasting and post-load insulin concentrations diminished. These longitudinal data show that, as glucose tolerance worsens, insulin and glucose concentrations in individuals follow the inverted-U-shaped relation previously reported in cross-sectional population studies.

Gestational Diabetes: Infant and Maternal Complications of Pregnancy in Relation to Third-Trimester Glucose Tolerance in the Pima Indians

A modified oral glucose tolerance test was done during the third trimester in 811 pregnancies in Pima Indian women over a 13-yr period, and maternal and fetal complications were documented. Diabetes was known to be present in 51 pregnancies. Among those who were not previously known to have diabetes, rates of perinatal mortality, macrosomia, toxemia, and cesarean section varied directly with glucose concentration, but congenital malformation and prematurity rates did not. Rates of all of these complications were higher in known diabetic women than in the remainder of the population. In addition to glucose concentrations, maternal weight and age were predictive of macrosomia and toxemia. Third-trimester glucosuria was found to be of very limited value as a screening procedure for gestational diabetes. In 233 women followed for 4–8 yr, the third-trimester glucose concentration was highly predictive of the subsequent incidence of diabetes.

Medial arterial calcification and its association with mortality and complications of diabetes

SummaryMedial arterial calcification was studied among 4,553 subjects in a 20-year, longitudinal study of Pima Indians. The prevalence and incidence of medial arterial calcification were highest among men, the elderly, and patients with Type 2 (non-insulin-dependent) diabetes mellitus. Medial arterial calcification was most commonly observed in the feet and appeared to progress proximally. Proportional hazards analysis was used to evaluate risk factors for medial arterial calcification in the feet and to evaluate medial arterial calcification as a risk factor for death and for complications of diabetes. Among diabetic patients, risk factors for medial arterial calcification were impaired vibration perception, long duration of diabetes, and high plasma glucose concentration (p<0.01 for each). Among nondiabetic subjects, age, male gender (p<0.01 for each), and high serum cholesterol concentration (p=0.02) were risk factors for medial arterial calcification. Nondiabetic subjects with medial arterial calcification did not have higher mortality rates than subjects without medial arterial calcification (rate ratio = 0.95, 95% confidence interval = 0.7–1.3). Diabetic patients with medial arterial calcification, compared with diabetic patients without medial arterial calcification, had 1.5-fold the mortality rate (95% confidence interval = 1.0–2.1), 5.5-fold the rate of amputations (95% confidence interval = 2.1–14.1), 2.4-fold the rate of proteinuria (95% confidence interval = 1.3–4.5), 1.7-fold the rate of retinopathy (95% confidence interval = 0.98–2.8), and 1.6-fold the rate of coronary artery disease (95% confidence interval = 0.48–5.4).

The prevalence of retinopathy in impaired glucose tolerance and recent-onset diabetes in the diabetes prevention program

Aims  Retinopathy is considered the complication most closely associated with and characteristic of diabetes mellitus. Hyperglycaemia below levels diagnostic of diabetes, so called pre‐diabetes, is associated with a low prevalence of ‘diabetic’ retinopathy. However, few longitudinal studies of non‐diabetic populations have performed repeated measures of glycaemia and screened for retinopathy to determine its occurrence in the non‐diabetic population and the onset of retinopathy in new‐onset diabetic patients. We determined the prevalence of retinopathy characteristically seen in diabetes in persons with impaired glucose tolerance and in patients with new‐onset diabetes of known duration in the Diabetes Prevention Program (DPP) cohort.

Obesity in Offspring of Diabetic Pima Indian Women Despite Normal Birth Weight

The relationships of birth weight and maternal diabetes to the development of obesity were examined at 5–19 yr of age in the offspring of Pima Indian women. At each age, offspring of diabetic women, even those who were of normal birth weight, had a higher mean weight relative to height than offspring of nondiabetic and prediabetic women. Birth weight was predictive of relative weight in 5- to 9- and 10- to 14-yr-old offspring of nondiabetic women but not in the oldest group. In contrast, for offspring of prediabetic and diabetic women, birth weight was not predictive of subsequent obesity at any age studied. Offspring of diabetic women were heavier than offspring of nondiabetic and prediabetic women regardless of birth weight. Thus, maternal diabetes was important in predicting body size in the offspring even after accounting for the effects of the birth weight and maternal body size.