P. H. Bennett

Prevention of Diabetic Renal Disease with Special Reference to Microalbuminuria

In the past year six sets of recommendations on the prevention of diabetic nephropathy, with special reference to microalbuminuria, have been published [1–6]. The background to this activity was the large and increasing number of diabetic patients in whom end-stage renal failure (ESRD) develops and who therefore require dialysis or renal transplantation. Throughout the world about half a million patients are registered as being on renal replacement therapy, and diabetic nephropathy is the cause in nearly one-fifth of them [7]. These data are extrapolated from countries which have registries but in many areas, especially in the densely populated countries of the Far East, accurate information on numbers of patients with ESRD is not yet available. Moreover, the half-million figure probably underestimates the number of diabetic patients with ESRD because selection criteria for renal replacement therapies vary from country to country. Both insulin dependent (IDDM) and non-insulin-diependent (NIDDM) diabetic patients contribute to the increase in ESRD. Prevention of diabetic renal disease, or at least the postponement or slowing down of the disease process, has emerged as a key issue. Our strategy is to develop programmes for all patients with diabetes, focused on early detection of renal disease followed by intervention.

Congenital Susceptibility to NIDDM: Role of Intrauterine Environment

Non-insulin-dependent diabetes mellitus (NIDDM) during pregnancy in Pima Indian women results in offspring who have a higher prevalence of NIDDM (45%) at age 20–24 yr than in offspring of nondiabetic women (1.4%) or offspring of prediabetic women (8.6%), i.e., women who developed diabetes only after the pregnancy. These differences persist after taking into account paternal diabetes, age at onset of diabetes in the parents, and the offsprings weight relative to height. The findings suggest that the intrauterine environment is an important determinant of the development of diabetes and that its effect is in addition to effects of genetic factors.

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.

Podocyte number predicts long-term urinary albumin excretion in Pima Indians with Type II diabetes and microalbuminuria

Aims/hypothesis. The predictive value of glomerular structure on progression of renal disease was examined in patients with Type II (non-insulin-dependent) diabetes and microalbuminuria (urinary albumin-to-creatinine ratio = 30–299 mg/g). Methods. Kidney biopsy specimens were obtained from 16 diabetic Pima Indians (6 men, 10 women). Progression of renal disease was assessed by measuring urinary albumin excretion 4 years after the biopsy (UAE4 years) and by computing the change in urinary albumin excretion during the study (Δ UAE). Results. At baseline, the duration of diabetes averaged 13.3 years (range = 4.0–23.8 years) and the mean glomerular filtration rate was 159 ml · min–1· 1.73m–2 (range = 98 – 239 ml · min–1· 1.73m–2). Median urinary albumin excretion was 67 mg/g (range = 25–136 mg/g) and it increased to 625 mg/g (range = 9–13471 mg/g) after 4 years; 10 subjects (63 %; 4 men, 6 women) developed macroalbuminuria (urinary albumin-to-creatinine ratio ≥ 300 mg/g). Neither mean arterial pressure nor HbA1 c changed substantially during follow-up. Among the glomerular morphologic characteristics, the number of visceral epithelial cells, or podocytes, per glomerulus was the strongest predictor of renal disease progression (UAE4 years, r = –0.49, p = 0.05; ΔUAE, r = –0.57, p = 0.02), with fewer cells predicting more rapid progression. Glomerular basement membrane thickness did not predict progression (UAE4 years, r = 0.11, p = 0.67; ΔUAE, r = 0.09, p = 0.73) and mesangial volume fraction had only a modest effect (UAE4 years,r = 0.42, p = 0.11; ΔUAE, r = 0.48, p = 0.06). Conclusion/interpretation. Whether lower epithelial cell number per glomerulus among those that progressed was due to cellular destruction, a reduced complement of epithelial cells, or both is uncertain. Nevertheless, these findings suggest that podocytes play an important part in the development and progression of diabetic renal disease. [Diabetologia (1999) 42: 1341–1344]

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]

DIABETES MELLITUS IN AMERICAN (PIMA) INDIANS

Abstract The prevalence of diabetes mellitus among the Pima Indians, who live in a hot desert environment in Arizona, U.S.A., has been determined by means of systematic glucose-tolerance tests. Using conservative conventional criteria the prevalence was 50% among those aged 35 years and over. Frequency distributions of the two-hour postcarbohydrate-load plasma-glucose levels were clearly bimodal above 35 years of age. The findings indicate that the Pima Indians have the highest prevalence of diabetes mellitus yet recorded, and that in this population normal and hyperglycaemic groups may be logically separated on the basis of the bimodality of the frequency distributions of two-hour post-load glucose levels.

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.

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).