David J. Pettitt

Birth weight and non-insulin dependent diabetes : Thrifty genotype, thrifty phenotype, or surviving small baby genotype?

Abstract Objective : To determine the prevalence of diabetes in relation to birth weight in Pima Indians. Design : Follow up study of infants born during 1940-72 who had undergone a glucose tolerance test at ages 20-39 years. Setting : Gila River Indian community, Arizona. Subjects : 1179 American Indians. Main outcome measure: Prevalence of non-insulin dependent diabetes mellitus (plasma glucose concentration >=11.1 mmol/l two hours after ingestion of carbohydrate). Results : The prevalence was greatest in those with the lowest and highest birth weights. The age adjusted prevalences for birth weights <2500 g, 2500-4499 g, and >=4500 g were 30%, 17%, and 32%, respectively. When age, sex, body mass index, maternal diabetes during pregnancy, and birth year were controlled for, subjects with birth weights <2500 g had a higher rate than those with weights 2500-4499 g (odds ratio 3.81; 95% confidence interval 1.70 to 8.52). The risk for subsequent diabetes among higher birthweight infants (>=4500 g) was associated with maternal diabetes during pregnancy. Most diabetes, however, occurred in subjects with intermediate birth weights (2500-4500 g). Conclusions : The relation of the prevalence of diabetes to birth weight in the Pima Indians is U shaped and is related to parental diabetes. Low birth weight is associated with non-insulin dependent diabetes. Given the high mortality of low birthweight infants selective survival in infancy of those genetically predisposed to insulin resistance and diabetes provides an explanation for the observed relation between low birth weight and diabetes and the high prevalence of diabetes in many populations.

An autosomal genomic scan for loci linked to type II diabetes mellitus and body-mass index in Pima Indians

Genetic factors influence the development of type II diabetes mellitus, but genetic loci for the most common forms of diabetes have not been identified. A genomic scan was conducted to identify loci linked to diabetes and body-mass index (BMI) in Pima Indians, a Native American population with a high prevalence of type II diabetes. Among 264 nuclear families containing 966 siblings, 516 autosomal markers with a median distance between adjacent markers of 6.4 cM were genotyped. Variance-components methods were used to test for linkage with an age-adjusted diabetes score and with BMI. In multipoint analyses, the strongest evidence for linkage with age-adjusted diabetes (LOD = 1.7) was on chromosome 11q, in the region that was also linked most strongly with BMI (LOD = 3.6). Bivariate linkage analyses strongly rejected both the null hypothesis of no linkage with either trait and the null hypothesis of no contribution of the locus to the covariation among the two traits. Sib-pair analyses suggest additional potential diabetes-susceptibility loci on chromosomes 1q and 7q.

Childhood Obesity and Metabolic Imprinting: The Ongoing Effects of Maternal Hyperglycemia

OBJECTIVE—The purpose of this study was to determine how the range of measured maternal glycemia in pregnancy relates to risk of obesity in childhood. RESEARCH DESIGN AND METHODS—Universal gestational diabetes mellitus (GDM) screening (a 50-g glucose challenge test [GCT]) was performed in two regions (Northwest and Hawaii) of a large diverse HMO during 1995–2000, and GDM was diagnosed/treated using a 3-h 100-g oral glucose tolerance test (OGTT) and National Diabetes Data Group (NDDG) criteria. Measured weight in offspring (n = 9,439) was ascertained 5–7 years later to calculate sex-specific weight-for-age percentiles using U.S. norms (1963–1994 standard) and then classified by maternal positive GCT (1 h ≥ 7.8 mmol/l) and OGTT results (1 or ≥2 of the 4 time points abnormal: fasting, 1 h, 2 h, or 3 h by Carpenter and Coustan and NDDG criteria). RESULTS—There was a positive trend for increasing childhood obesity at age 5–7 years (P < 0.0001; 85th and 95th percentiles) across the range of increasing maternal glucose screen values, which remained after adjustment for potential confounders including maternal weight gain, maternal age, parity, ethnicity, and birth weight. The risk of childhood obesity in offspring of mothers with GDM by NDDG criteria (treated) was attenuated compared with the risks for the groups with lesser degrees of hyperglycemia (untreated). The relationships were similar among Caucasians and non-Caucasians. Stratification by birth weight also revealed these effects in children of normal birth weight (≤4,000 g). CONCLUSIONS—Our results in a multiethnic U.S. population suggest that increasing hyperglycemia in pregnancy is associated with an increased risk of childhood obesity. More research is needed to determine whether treatment of GDM may be a modifiable risk factor for childhood obesity.

Severe Periodontitis and Risk for Poor Glycemic Control in Patients with Non-Insulin-Dependent Diabetes Mellitus

This study tested the hypothesis that severe periodontitis in persons with non-insulin-dependent diabetes mellitus (NIDDM) increases the risk of poor glycemic control. Data from the longitudinal study of residents of the Gila River Indian Community were analyzed for dentate subjects aged 18 to 67, comprising all those: 1) diagnosed at baseline with NIDDM (at least 200 mg/dL plasma glucose after a 2-hour oral glucose tolerance test); 2) with baseline glycosylated hemoglobin (HbA1 ) less than 9%; and 3) who remained dentate during the 2-year follow-up period. Medical and dental examinations were conducted at 2-year intervals. Severe periodontitis was specified two ways for separate analyses: 1) as baseline periodontal attachment loss of 6 mm or more on at least one index tooth; and 2) baseline radiographic bone loss of 50% or more on at least one tooth. Clinical data for loss of periodontal attachment were available for 80 subjects who had at least one follow-up examination, 9 of whom had two follow-up examinations at 2-year intervals after baseline. Radiographic bone loss data were available for 88 subjects who had at least one follow-up examination, 17 of whom had two follow-up examinations. Poor glycemic control was specified as the presence of HbA1 of 9% or more at follow-up. To increase the sample size, observations from baseline to second examination and from second to third examinations were combined. To control for non-independence of observations, generalized estimating equations (GEE) were used for regression modeling. Severe periodontitis at baseline was associated with increased risk of poor glycemic control at follow-up. Other statistically significant covariates in the GEE models were: 1) baseline age; 2) level of glycemic control at baseline; 3) having more severe NIDDM at baseline; 4) duration of NIDDM; and 5) smoking at baseline. These results support considering severe periodontitis as a risk factor for poor glycemic control and suggest that physicians treating patients with NIDDM should be alert to the signs of severe periodontitis in managing NIDDM. J Periodontol 1996;67:1085-1093.

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.

Excessive Obesity in Offspring of Pima Indian Women with Diabetes during Pregnancy

We studied the relation in Pima Indians between obesity in children and diabetes during pregnancy in their mothers. Sixty-eight children of 49 women who had had diabetes during pregnancy had a higher prevalence of obesity than 541 children of 134 women who subsequently had diabetes (prediabetics) or than 1326 children of 446 women who remained nondiabetic. At 15 to 19 years of age, 58 per cent of the offspring of diabetics weighed 140 per cent or more of their desirable weight, as compared with 17 per cent of the offspring of nondiabetics and 25 per cent of those of prediabetics (P less than 0.001). Obesity in the offspring was directly related to maternal diabetes, since the association was not substantially confounded by maternal obesity. The findings strongly suggest that the prenatal environment of the offspring of diabetic women results in the development of obesity in childhood and early adulthood.

The Natural History of Impaired Glucose Tolerance in the Pima Indians

Among 384 Pima Indians with impaired glucose tolerance according to World Health Organization criteria who were followed for 1.6 to 11.5 years (median, 3.3), non-insulin-dependent diabetes mellitus (NIDDM) developed in 118 (31 percent), glucose tolerance remained impaired in 100 (26 percent), and glucose tolerance returned to normal in 166 (43 percent). The cumulative incidence of NIDDM was 25 and 61 percent at 5 and 10 years, respectively. The risk of development of diabetes was 6.3 times (95 percent confidence interval, 3.8 to 10.6) as high as in a normoglycemic control group (n = 752). Variables predicting deterioration to NIDDM were age up to the age of 40, after which increasing age had a beneficial effect; higher plasma glucose levels during fasting and after carbohydrate loading; and higher serum insulin levels after fasting and lower levels after carbohydrate loading, suggesting that insulin resistance and decreased beta-cell responsiveness are important determinants of the clinical outcome of impaired glucose tolerance. Obese subjects had 2.9 times (95 percent confidence interval, 2.0 to 10.9) the incidence of NIDDM as the nonobese. Obesity was not, however, predictive of progression to NIDDM after an adjustment for plasma glucose and serum insulin levels. We conclude that in this population approximately one fourth of subjects with impaired glucose tolerance have NIDDM at five years and two thirds at 10 years (approximately one third revert to normal) and that age and plasma glucose and insulin levels are the best predictors of clinical outcome.

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]