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We aimed to determine associations of regression to normal glucose tolerance (NGT), maintaining impaired glucose tolerance (IGT) or progression to diabetes with subsequent risks of CVD and microvascular disease among Chinese adults with IGT. We conducted an observational study among 540 participants in the Da Qing Diabetes Prevention Study, a 6 year lifestyle intervention trial in people with IGT, defined by 1985 WHO criteria as fasting plasma glucose

The global epidemic of type 2 diabetes has prompted numerous studies and public health efforts to reduce its development. A variety of interventions, including lifestyle modifications and pharmacological agents directed at ameliorating the major risk factors for type 2 diabetes, are of proven efficacy in reducing the development of type 2 diabetes in people with impaired glucose tolerance. While prevention of the hyperglycaemia characteristic of diabetes is arguably an important, clinically relevant outcome, a more compelling outcome with greater clinical significance is the prevention or reduction of the relatively diabetes-specific microvascular and less-specific cardiovascular disease (CVD) complications associated with diabetes. These complications cause the majority of morbidity and excess mortality associated with diabetes. Any reduction in diabetes should, logically, also reduce the occurrence of its long-term complications; however, most diabetes prevention trials have not been of sufficient duration to allow such an evaluation. The limited long-term data, largely from the Da Qing Diabetes Prevention Study (DQDPS) and the Diabetes Prevention Program (DPP) and their respective follow-up studies (DQDPOS and DPPOS), suggest a reduction in microvascular complications and amelioration of CVD risk factors. Only the DQDPOS and Study to Prevent Non-Insulin-Dependent Diabetes Mellitus (STOP-NIDDM) studies have shown a reduction in CVD events and only DQDPOS has demonstrated a decrease in CVD and overall mortality. While these limited data are promising, whether diabetes prevention directly reduces complication-related morbidity and mortality remains unclear. Longer follow-up of prevention studies is needed to supplement the limited current clinical trial data, to help differentiate the effects of diabetes prevention itself from the means used to reduce diabetes development and to understand the balance among benefits, risks and costs of prevention.

We aimed to examine risk factors for, and differences in, renal failure in diabetic patients from 10 centres. Risk factors for renal failure were examined in 3558 diabetic patients who did not have renal disease at baseline in the WHO Multinational Study of Vascular Disease in Diabetes (WHO MSVDD). In 959 subjects with Type I (insulin-dependent) diabetes mellitus and 2559 with Type II (non-insulin-dependent) diabetes mellitus, the average follow-up was 8.4 years ( ± 2.7). By the end of the follow-up period 53 patients in the Type I diabetic group and 134 patients in the Type II diabetic group had developed renal failure (incidence rate 6.3:1000 person years). Increasing age and duration of diabetes were associated with renal failure in Type II and Type I diabetes. In Type II diabetes duration of diabetes was a more important risk factor than age. In both Type I and Type II diabetic retinopathy and proteinuria were strongly associated with renal failure. Systolic blood pressure was associated with renal failure in Type I but not in Type II diabetic patients. ECG abnormalities at baseline, self-reported smoking and cholesterol were not associated with renal failure. Triglycerides were measured in a subset of centres. Among those with Type II, but not Type I diabetes, triglycerides were associated with renal failure independently of systolic blood pressure, proteinuria or retinopathy. In Type II diabetes fasting plasma glucose was associated with renal failure independently of other risk factors. We have confirmed the role of proteinuria and retinopathy as markers of renal failure and the importance of hyperglycaemia in renal failure in Type I and Type II diabetes. Plasma triglycerides seem to be an important predictor of renal failure in Type II diabetes. In Type I diabetes systolic blood pressure is an important predictor of renal failure. [Diabetologia (2001) 44 [Suppl 2]: S 46–S 53]

Incidence of severe visual impairment and the ultimate prevalence of all grades of impairment were estimated in the 10 centres of the WHO Multinational Study of Vascular Disease in Diabetes (WHO MSVDD) participating in the follow-up.Visual function was ascertained at follow-up in 2994 (77.9 %) of the 3845 eligible participating survivors of the 4709 originally recruited for the WHO MSVDD using the same baseline enquiry method. The associations between incident severe visual impairment, follow-up prevalence of all grades of impairment and baseline risk factors were examined by univariate and stepwise multiple logistic regression analysis.Overall, 8.4 year incidence of severe visual impairment was 1.94 % and showed statistically significant univariate correlations with age at diagnosis, diabetes duration, systolic blood pressure, fasting blood glucose and cholesterol, insulin treatment and strongly with baseline retinopathy. Baseline retinopathy, systolic pressure and cholesterol were statistically significant in multivariable analysis. Differences between centres (0.3% to 3.45%) were not significant. Ultimate prevalence of all grades of impairment differed between centres and within almost all of them was correlated in multivariable analysis with baseline retinopathy and proteinuria.Comparisons of incident severe visual impairment between centres are restricted by selective mortality, low incidence rates and relatively small numbers in each centre but before retinopathy, baseline systolic pressure and cholesterol predicted severe visual impairment. Follow-up prevalence of all degrees of impairment varied among centres and were associated with prior retinopathy and renal disease at baseline.

Glomerular filtration rate (iothalamate clearance) was measured serially for 48 months in 26 Pima Indians with impaired glucose tolerance and 27 with normal glucose tolerance. At baseline, the mean glomerular filtration rate (SEM) was 133 ± 8 ml/min in subjects with impaired glucose tolerance and 123 ± 5 ml/min in those with normal glucose tolerance (p = 0.12). In the 12 subjects with impaired glucose tolerance who progressed to Type II (non-insulin-dependent) diabetes during follow-up, mean glomerular filtration rate increased by 30 % (p = 0.011). Among the remaining 14 subjects with impaired glucose tolerance, 12 reverted to normoglycaemia. The glomerular filtration rate both at baseline and after 48 months in this subgroup exceeded the values of subjects with normal glucose tolerance by 20 % (p = 0.008) and 14 % (p = 0.013), respectively. A pronounced rise in the glomerular filtration rate occurs at the onset of Type II diabetes but a trend to hyperfiltration is also present in those with impaired glucose tolerance. [Diabetologia (1999) 42: 90–93]

To determine if parental hypertension is associated with proteinuria in offspring with non-insulin-dependent diabetes mellitus (NIDDM), 438 diabetic Pima Indians (172 men, 266 women) aged 20 years or more and both of their parents were examined. Hypertension was defined as a systolic blood pressure 140 mm Hg or more, diastolic blood pressure 90 mm Hg or more, or treatment with antihypertensive medicine. Sixty-three percent of the fathers and 80% of the mothers had diabetes at the time their blood pressure was measured. Families in which either parent had proteinuria, defined as a urine protein-to-creatinine ratioor = 0.5 g/g were excluded; 73 (16.7%) of the offspring had proteinuria. The prevalence rates of proteinuria in the offspring were similar if neither parent or only one parent had hypertension (8.9 and 9.4%, respectively), but was significantly higher if both parents had hypertension (18.8%), after adjustment for age, sex, duration of diabetes, and 2-h post-load plasma glucose concentration in the offspring and diabetes in the parents by logistic regression. The odds for proteinuria being present in the offspring if both parents had hypertension was 2.2 times (95% confidence interval, 1.2 to 4.2) that if only one parent had hypertension. When mean arterial pressure and blood pressure treatment in the offspring were added to the model the relationship remained (odds ratio = 2.2; 95% confidence interval, 1.1 to 4.3). Hypertension in both parents is associated with the development of proteinuria in offspring with NIDDM. This relationship was present even when controlled for the effects of blood pressure and its treatment in the offspring.

Metabolic abnormalities antedate the development of non-insulin-dependent diabetes mellitus (NIDDM) by some years. How these metabolic abnormalities relate to the genetic component of the disease and to the subsequent prediction of diabetes is unknown. The present study was designed to examine the association of parental diabetes with relative weight, fasting and 2-h plasma glucose and fasting and 2-h serum insulin in childhood, and to identify which of these variables were most predictive of subsequent NIDDM. Subjects comprised 1258 Pima Indians aged 5-19 years with normal glucose tolerance participating in a longitudinal population-based study. Age-sex-adjusted values of relative weight, fasting and 2-h glucose and fasting and 2-h insulin were positively associated with parental diabetes. Only one of 138 subjects with two non-diabetic parents developed diabetes. Among 1120 subjects with at least one diabetic parent, 101 (9.0%) developed diabetes during a mean follow up of 8.4 years. Fasting insulin was a significant predictor of diabetes, but did not add to the predictive value of relative weight. Relative weight and 2-h and fasting plasma glucose were the variables most predictive of NIDDM in childhood and adolescence. Against a background of parental diabetes, high fasting insulin concentrations predict diabetes, compatible with the hypothesis that insulin resistance is an early metabolic abnormality leading to NIDDM. In this study, however, its predictive power did not add significantly to that of relative weight, with which it was correlated.(ABSTRACT TRUNCATED AT 250 WORDS)

Blood pressure was measured in 490 non-proteinuric Pima Indians from the Gila River Indian Community in Arizona at least 1 year before the diagnosis of Type 2 (non-insulin-dependent) diabetes mellitus. Urine albumin concentration was measured in the same subjects 0-24 years (mean 5 years) after diabetes was diagnosed. Prevalence rates of abnormal albumin excretion (albumin-to-creatinine ratioor = 100 mg/g) after the onset of Type 2 diabetes were 9%, 16%, and 23%, respectively, for the lowest to highest tertiles of pre-diabetic mean blood pressure. When controlled for age, sex, duration of diabetes and pre-diabetic 2-h post-load plasma glucose concentration, higher pre-diabetic mean blood pressure predicted abnormal urinary excretion of albumin after the onset of diabetes. This finding suggests that the higher blood pressure seen in diabetic nephropathy is not entirely a result of the renal disease, but may precede and contribute to it.

To identify factors related to the development of end-stage renal disease after the onset of proteinuria, its incidence was determined in 364 Pima Indians aged 35 years or older with Type 2 (non-insulin-dependent) diabetes mellitus and proteinuria (protein-to-creatinine ratioor = 0.5 g/g). Of these 364 subjects, 95 (36 men, 59 women) developed end-stage renal disease. The cumulative incidence was 40% 10 years after and 61% 15 years after the onset of proteinuria. The incidence of end-stage renal disease was significantly related to the duration of diabetes, the duration of proteinuria, higher 2-h plasma glucose concentration, type of diabetes treatment, and the presence of retinopathy at the time of recognition of the proteinuria, but not to age, sex, or blood pressure. Duration of proteinuria influenced the risk of end-stage renal disease, contingent, however, upon the duration of diabetes at the onset of proteinuria. The higher cumulative incidence of end-stage renal disease 15 years after the onset of proteinuria in Pima Indians (61%) than in Caucasians from Rochester, Minnesota (17%) may be attributable, in part, to the younger age of onset of Type 2 diabetes in Pima Indians than in Caucasians, to ethnic differences in susceptibility to renal disease, or to lower death rates among the Pima Indians from competing causes of death, such as coronary heart disease.

Islet amyloid may have a pathological role in the development of Type 2 (non-insulin-dependent) diabetes mellitus. The prevalence of islet amyloid has been investigated on post-mortem pancreatic tissue from both diabetic and non-diabetic Pima Indian subjects who had previously been assessed by oral glucose tolerance tests. Islets were examined for amyloid deposits and for cellular immunoreactivity to pancreatic hormones and islet amyloid polypeptide, the constituent peptide of islet amyloid. Twenty of 26 diabetic subjects (77%) had islet amyloid, compared with one of 14 non-diabetic subjects (7%). Twelve of the diabetic subjects (46%) had amyloid in more than 10% of their islets, whereas only 4% of islets were affected in a single non-diabetic subject. Positive immunoreactivity for islet amyloid peptide was present in the islet amyloid and in islet cells in 54% of the diabetic and 50% of the non-diabetic subjects. Islet amyloid in diabetic Pima Indians may indicate a primary Beta-cell defect which interacts with insulin resistance to produce diabetes, or may develop as a result of Beta-cell dysfunction induced by insulin resistance and hyperglycaemia.

We aimed to determine variations in the prevalence of increased urinary albumin excretion, associated risk factors and complications in patients with diabetes participating in the WHO Multinational Study of Vascular Disease in Diabetes follow-up.Urinary albumin to urinary creatinine ratios were measured centrally in 2,033 of the 2,550 (79.7%) re-examined patients from eight centres in seven countries and the frequency of microalbuminuria and macroalbuminuria and their associations with risk factors and complications were examined.Macroalbuminuria prevalence (overall 15.6%) varied tenfold (3-37%) among centres, was higher in American Indian and Asian centres and not clearly related to type of diabetes. Microalbuminuria (overall 19.7 %) varied less (12-31%). Increased albumin excretion was related overall to baseline fasting plasma glucose in the pooled group in whom it was measured and to increased arterial pressure, insulin use, coronary heart disease, lower extremity amputation, retinopathy and stroke in most centres.Centres varied widely in the prevalence of increased albumin excretion but associations with risk factors and vascular complications were generally similar in most centres and in both major types of diabetes with ethnic and genetic differences probably contributing.

The incidence of retinal, renal and cardiovascular complications and their relation to baseline risk factors was documented in this follow-up study of 10 of the 14 original centres of the WHO Multinational Study of Vascular Disease in Diabetes (WHO MSVDD).The incidence of specified items of vascular disease and some associated risk factors was ascertained after 7 to 9 years (11-12 years in Oklahoma, USA) follow-up, re-using baseline examination methodology in 3165 patients (66.9 %) and, through secondary information in 717 (15.2%) of the 4729 original patients, of whom 540 (11.4%) had died and 307 (6.5 %) were untraceable.During follow-up, approximately one third of the patients developed hypertension and one third started insulin. Coronary heart disease incidence varied 10 to 20-fold among centres as did limb amputation rates. Inter-centre differences in incident retinopathy and severe visual impairment were smaller but incident clinical proteinuria and renal failure varied markedly. Vascular disease incidence of all categories was high in Native Americans though coronary heart disease incidence was relatively low in Pima Indians and absolutely low in Hong Kong and Tokyo patients. Specific vascular events and their relation with baseline risk factors are analysed in accompanying papers, summarised in the Epilogue.These 10 centres reported very different incidence rates of vascular complications. Observer variation, selection biases and competing causes of mortality contributed to these differences but their validity is supported by the more objective outcome indicators. The following papers also suggest that baseline factors such as raised arterial pressure, cholesterol and fasting glucose (in the centres where it was measured) were important and potentially reversible predictors of risk.

This study compared the incidence of vascular disease in subjects with younger-onset diabetes from different ethnic groups.The incidence of vascular disease endpoints has been studied in a sub-group (n = 994) of participants of the World Health Organization Multinational Study of Vascular Disease in Diabetes (WHO MSVDD) who had younger-onset diabetes (diagnosed before the age of 30 years). The study participants have been divided into European (n = 631), Asian (n = 84) and American Indian (n = 91) cohorts.For Type I (insulin-dependent) and Type II (non-insulin-dependent) diabetes mellitus, American Indian men had a higher incidence of lower-extremity amputation and renal failure than the other cohorts, whereas European women had a higher incidence of angina than other cohorts. American Indians also had a higher incidence of any retinopathy, clinical proteinuria and albuminuria than the European and Asian cohorts.This study confirms the high burden of large and small-vessel disease complications manifest in American Indian people with younger-onset diabetes.

Rates of vascular complications of diabetes in a cohort of mainland Chinese patients with diabetes, ascertained and examined by similar methodology, are compared with those of the WHO Multinational Study of Vascular Disease in Diabetes (WHO MSVDD). The standardised procedures carried out in the WHO MSVDD were followed in assembling and examining a Chinese cohort of 447 diabetic patients recruited in Beijing and Tianjin [2]. Compared with the WHO MSVDD centres, the Chinese cohort was slightly older, had a shorter duration of known diabetes and had fewer insulin-treated patients. Arterial pressure, total blood cholesterol and body mass index were substantially lower. Large vessel disease rate for age, sex and duration adjusted data (17.9 %) was about half that of the combined WHO MSVDD centres (33.5 % p < 0.001). However, retinopathy (47.4 % vs 35.8 % p < 0.001) and proteinuria (57.1 vs 24.9 % p < 0.001) rates were significantly higher. Relatively low arterial pressures and blood cholesterol are likely contributors to the notably low arterial disease rates in this Chinese diabetic cohort; they reflect low rates in the Chinese mainland general population and resemble the Tokyo and Hong Kong centres of the WHO MSVDD. The high rates of retinopathy and proteinuria could relate to later diagnosis, degree of hyperglycaemia and/or increased susceptibiltiy to microangiopathy. [Diabetologia (2001) 44 [Suppl 2]: S 82–S 86]

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]

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.

The current classification and diagnostic criteria for diabetes mellitus were introduced by the United States National Data Group in 1979 and endorsed by the World Health Organization in 1980, with modifications in 1985 and 1994. The criteria, chosen to reflect the risk of complications, were the synthesis of considerable thought and expertise and represented a consensus which, it was hoped, would prove helpful to all those involved with diabetes-practising clinician, research scientist and epidemiologist alike. The inconvenience, variability and non-physiological nature of the oral glucose tolerance test (OGTT) are well-recognised. In spite of these limitations the 2-h post-load plasma glucose has remained the standard against which all other tests have been evaluated. This article reviews the original justification for the OGTT, and in the light of more recent epidemiological research seeks to place the current diagnostic criteria for diabetes into a pathophysiological, diagnostic and prognostic perspective.

Risk factors predicting deterioration to diabetes mellitus were examined in 181 subjects with impaired glucose tolerance. Fifty-seven subjects had impaired glucose tolerance on one occasion followed by normal glucose tolerance at a repeat oral glucose tolerance test, and 124 subjects had impaired glucose tolerance on two successive oral glucose tolerance tests. Subjects were followed for a median period of 5.0 years (range 1.0–17.2). The age- and sex-adjusted cumulative incidence of diabetes at 10 years of follow-up was higher in subjects who had impaired glucose tolerance on both tests (70%) than in those whose glucose tolerance was normal at the repeat test (53%), [rate ratio (RR)=1.6, 95% confidence intervals (CI)=1.0–2.5]. Proportional hazards analyses were used to identify baseline risk factors (measured at the repeat oral glucose tolerance test) for subsequent diabetes, and incidence rate ratios were calculated for the 90th percentile compared with the 10th percentile of each continuous variable for the whole group. In all subjects, in separate models, higher body mass index [RR=2.0, 95% CI=2.2–9.9], high fasting serum insulin concentrations [RR=2.4, 95% CI=1.4–4.2], and low early insulin response [RR=0.5, 95% CI=0.3–0.8] 30 min after a glucose load were significant predictors for deterioration to diabetes. In a multivariate analysis which controlled for age and sex, 120-min post-load glucose, fasting insulin and late insulin response predicted diabetes. In subgroup analyses the predictors of diabetes were generally similar in subjects who had impaired glucose tolerance at only one test and those who had impaired glucose tolerance on both tests. These findings suggest that in those subjects with impaired glucose tolerance whose glucose tolerance has returned to normal, the risk of subsequent diabetes is high. Insulin resistance, impaired early insulin response, or both, are predictive of subsequent development of diabetes in Pima Indians with impaired glucose tolerance.

Both non-insulin-dependent diabetes mellitus and diabetic nephropathy show familial aggregation. If diabetes and renal disease have independent determinants (genetic or otherwise), offspring of parents with diabetic renal disease should have a similar risk of diabetes to those offspring of parents with diabetes alone. To test this hypothesis, the prevalence of diabetes was examined in a population-based pedigree study in Pima Indian offspring of three mutually exclusive parental types: 1) diabetic with renal disease, 2) diabetic, but without renal disease and 3) non-diabetic. Among offspring of one diabetic parent and one non-diabetic parent (n=320) the prevalence of diabetes at ages 15–24 years and 25–34 years was 0% and 11%, respectively if the diabetic parent did not have renal disease compared with 6% and 28% respectively if the diabetic parent did have renal disease. Corresponding rates for offspring of two diabetic parents (n=121) were 10% and 17%, respectively if neither parent had renal disease compared with 30% and 50%, respectively if one parent did have renal disease. The presence of renal disease in a parent with diabetes relative to diabetes alone was associated with 2.5 times the odds of diabetes (95% confidence interval 1.4–4.3) in the offspring controlled for age, age at onset of parental diabetes and diabetes in the other parent using logistic regression. These findings provide support for parental diabetic renal disease, independent of age at onset of parental diabetes, conferring an increased risk for diabetes in the offspring. The results are compatible with the hypothesis that the susceptibility to renal disease in the parents and to diabetes in the offspring are due to shared familial environmental factors or to the same gene or set of genes.

The relationships between physical activity, obesity, fat distribution and glucose tolerance were examined in the Pima Indians who have the highest documented incidence of non-insulin-dependent diabetes. Fasting and 2-h post-load plasma glucose concentrations, body mass index, and waist-to-thigh circumference ratios were determined in 1054 subjects aged 15–59 years. Current (during the most recent calendar year) and historical (over a lifetime) leisure and occupational physical activity were determined by questionnaire. Current physical activity was inversely correlated with fasting and 2-h plasma glucose concentrations, body mass index and waist-to-thigh ratios for most sex-age groups even when diabetic subjects were excluded. Controlled for age, obesity and fat distribution, activity remained significantly associated with 2-h plasma glucose concentrations in males. In subjects aged 37–59 years, individuals with diabetes compared to those without reported significantly less leisure physical activity during the teenage years (median hours per week of activity, 9.1 vs 13.2 for men; 1.0 vs 2.2 for women). Controlled for body mass index, sex, age and waist-to-thigh ratio, subjects who reported low levels of historical leisure physical activity had a higher rate of diabetes than those who were more active. In conclusion, current physical activity was inversely related to glucose intolerance, obesity and central distribution of fat, particularly in males. Subjects with diabetes were currently less active and reported less historical physical activity than non-diabetic subjects. These findings suggest that activity may protect against the development of non-insulin-dependent diabetes both directly and through an influence on obesity and fat distribution.

We 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 (greater than or equal to 177 mumol/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.

The prevalence of abnormal urinary albumin excretion, defined by a urine albumin to creatinine ratio greater than or equal to 30 mg/g (approximately equivalent to an albumin excretion rate of greater than or equal to 30 mg/24 h), was determined in 2728 Pima Indians aged greater than or equal to 15 years from the Gila River Indian Community in Arizona, a population with a high prevalence of Type 2 (non-insulin-dependent) diabetes mellitus. Excessive albumin excretion was present in 8% of subjects with normal glucose tolerance, 15% of those with impaired glucose tolerance, and 47% of subjects with diabetes. The intermediate prevalence of abnormal albuminuria in those with impaired glucose tolerance suggests that hyperglycaemia even at levels below those diagnostic of diabetes is associated with renal abnormalities in some subjects and that these abnormalities may precede the onset of diabetes. Abnormal albuminuria at levels not reliably detected by the usual dipstick methods was commonly observed in Pima Indians with diabetes, even those with diabetes of recent onset. Associations were found with age, duration of diabetes, level of glycaemia, blood pressure, and treatment with insulin.

The frequency distributions of both the fasting and two-hour post-load plasma glucose levels were bimodal in the Pima Indian population aged 25 years and over. The hyperglycaemic component of this distribution represents those with diabetes mellitus, as some 30 percent of this group had evidence of the specific vascular complications of the disease, whereas these abnormalities were virtually absent in those with lower glucose levels. The bimodal characteristics of the frequency distributions were utilized to define optimal criteria to separate those with and without diabetes. The sensitivity and specificity of these criteria for fasting and two-hour glucose levels were compared and were found to be similar. The fasting glucose determination, however, was more reproducible and stable, as well as being easier to obtain, indicating that it is the better measurement for diagnostic purposes. The optimal level for diagnosis of 7.5 mmol/l (136 mg/dl) for the fasting glucose and the equivalent two-hour value of 14 mmol/l (250 mg/dl), were higher than many previously recommended diagnostic levels. Nevertheless, there was no evidence that subjects with lower levels were at appreciable risk of developing the specific complications of diabetes. Subjects with impaired glucose tolerance (IGT), but without fasting hyperglycaemia, should not be diagnosed as having diabetes mellitus.

To determine whether sustained control of hyperglycaemia in Type 2 (non-insulin-dependent) diabetic patients would diminish proteinuria, the effect of hypocaloric diet therapy (500 kcal/day) on proteinuria was assessed in obese, Type 2 diabetic patients (n = 24) and compared with results obtained for obese subjects with normal glucose tolerance (n = 7) and impaired glucose tolerance (n = 6). Diet therapy of similar mean duration resulted in similar percentage weight loss (mean percentage of original weight +/- SEM) in diabetic (13.6 +/- 1.6%), glucose intolerant (16.4 +/- 3.3%) and obese non-diabetic (11.0 +/- 1.0%) subjects. Following therapy, plasma glucose concentrations 2h after an oral glucose load declined in the diabetic (18.34 +/- 0.81 to 10.67 +/- 0.50 mmol/l, mean +/- SEM; p less than 0.001) and in the glucose intolerant subjects (10.2 +/- 0.3 to 7.3 +/- 0.4 mmol/l, p less than 0.01) while remaining unchanged in the obese non-diabetic subjects (7.09 +/- 0.23 to 6.77 +/- 0.32 mmol/l, NS). Concentrations of total protein of plasma origin and albumin in 24-h urine collections were quantified by a sensitive immunonephelometric assay using specific antisera. Initially, 24-h excretion of total protein and albumin were elevated in the diabetic [mg protein/24 h; (median +/- 95% confidence limits): 63 (42-138), p less than 0.05; albumin: 26 (14-56), p less than 0.05] and glucose intolerant subjects [protein: 52 (13-92), NS; albumin: 24 (3-61), NS] compared with the non-diabetic subjects [protein: 20 (5-38); albumin: 6.2 (3.5-9.5)].(ABSTRACT TRUNCATED AT 250 WORDS)

Medical 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 less than 0.01 for each). Among nondiabetic subjects, age, male gender (p less than 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).

In Pima Indians with Type 2 (insulin independent) diabetes mellitus, HLA-A2 allele frequencies were inversely associated with age, (0.72, 0.59, and 0.52 in those less than 35, 35 to 54, and 55 years old and over, respectively). This suggests that there may be a gene closely linked with the HLA-A locus which plays a role in the expression of diabetes in the Pimas by contributing to an earlier age of onset. HLA-A2 was found in 65% non-diabetic and 81% of 191 diabetic subjects (relative risk = 2.2).

The study of different ethnic groups living in the same physical environment provides the opportunity to examine interaction of genetic and environmental factors in the aetiology of diabetes mellitus. In rural New Caledonia, the prevalence of diabetes was higher in part-Polynesians than in Melanesians: males — 6.6 versus 0.5%; females — 6.3 versus 3.5% respectively. The prevalence of abnormal glucose tolerance (impaired glucose tolerance and diabetes) was 11.5 and 15.7% in part-Polynesian males and females, respectively, and 4.7 and 9.2% in Melanesian males and females. Mean age and degree of obesity in these ethnic groups were sufficiently similar to suggest that these factors played no significant role in the difference in diabetes prevalence. Furthermore, adjustment of relative risk of impaired glucose tolerance and diabetes for age and obesity indicated that the modest differences between groups were not responsible for the observed variation in diabetes prevalence. The differences in prevalence of impaired glucose tolerance and diabetes between Melanesians and part-Polynesians may be genetically determined, although the role of certain environmental factors other than obesity, e.g. differences in physical activity or qualitative aspects of diet, cannot be excluded.

In a multinational study, fasting plasma glucose values in 3583 diabetic patients, aged 34-56 years, were related to the characteristics of these subjects and to the presence and severity of microangiopathy as ascertained by standardised methods. The patients were from nine different populations and ranged in number from 193 to 686 per population (London, Warsaw, Berlin (FRG), New Delhi, Tokyo, Havana, Oklahoma Indians, Arizona Pima Indians, and a national sample in Switzerland). In the total group, mean fasting plasma glucose was 8.1 mmol/l for those on diet alone, 9.7 mmol/l for those on oral agents, and 12.7 mmol/l for insulin-treated patients, of whom 25% had values exceeding 16.5 mmol/l. Since many variables were measured in each patient, it was possible to take into account many confounding factors in evaluating the relationship of plasma glucose levels to retinopathy and nephropathy.

To determine whether individual subjects with Type 1 (insulin-dependent) diabetes or Type 2 (non-insulin-dependent) diabetes, who are treated with insulin, could be reliably distinguished, C-peptide concentrations and urinary C-peptide excretion were measured in 10 Caucasoids and 10 Pima Indians. All the subjects had developed diabetes before 21 years of age and were receiving insulin treatment. Fasting C-peptide concentrations were significantly higher in the Pima Indians (0.73 +/- 0.17 versus 0.02 +/- 0.01 nmol/l in Caucasoids; p less than 0.001), but there were slight overlaps in individual values. Urinary C-peptide excretion, an index of 24-h-insulin excretion, was also higher in the Pima Indian group (27.6 +/- 1.85 versus 0.72 +/- 0.18 pmol/min in Caucasoids; p less than 0.001) and there was no overlap in the individual values between the groups. The Pima Indians with early onset diabetes have been previously shown to have Type 2 diabetes, and the Caucasoids with an early onset are most likely to have Type 1 diabetes. These results suggest that distinction between these two major types of diabetes can be made effectively by using C-peptide measurements provided that overt renal disease is absent. This differentiation between insulin-treated patients will be useful for a variety of research applications and possibly in making clinical management decisions.

Agrement avec Wilkin pour suggerer que les differences interlaboratoires pour les associations des anticorps anti-insuline et des anticorps anti-ilots pancreas peuvent etre attribuables aux limites de detection des dosages