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AIM: To examine the distribution and association of sociodemographic, adherence, and barriers-to-care factors in relation to glycaemic control within insulin regimens in US children with Type 1 diabetes in the SEARCH for Diabetes in Youth Study. METHODS: Self- or parent-reported data from 1095 children with Type 1 diabetes aged 10-17 years were collected on insulin regimen, sociodemographics, diabetes self-management, diabetes-related family conflict and barriers to care. Multivariable logistic regression analysis identified poor glycaemic control correlates within each insulin regimen. RESULTS: Participants included 694 children on insulin pump therapy, 188 receiving basal-bolus injections, and 213 on a mixed insulin regimen. Of these, 28.5%, 45.2% and 51.2%, respectively, had poor glycaemic control [HbA1c ≥ 80 mmol/mol (9.5%)]. Family conflict between parent and child regarding diabetes management was the only factor significantly associated with poor glycaemic control in all insulin regimens (insulin pump, P≤ 0.0001; basal-bolus injections, P=0.0002; mixed insulin regimen, P=0.0103). For children on insulin pump, poor control was significantly associated with non-white race (P=0.0008), living in multiple households (P=0.0331), having Medicaid insurance (P=0.0090), and decreased insulin adherence (P<0.0001). For children on a mixed insulin regimen, living in multiple households (P=0.0256) and not spending enough time with healthcare provider (P=0.0058) correlated with poor control. CONCLUSIONS: A high percentage of US children with Type 1 diabetes had poor glycaemic control, especially those not using an insulin pump. Early identification of children with risk factors associated with poor glycaemic control within insulin regimens and addressing diabetes-related family conflict may allow interventions to improve diabetes management.

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AIMS/HYPOTHESIS: Few studies have explored the epidemiology of beta cell loss in youth with diabetes. This report describes the evolution and major determinants of beta cell function, assessed by fasting C-peptide (FCP), in the SEARCH for Diabetes in Youth study. METHODS: Participants were 1,277 youth with diabetes (948 positive for diabetes autoantibodies [DAs] and 329 negative for DAs), diagnosed when aged <20 years, who were followed from a median of 8 months post diagnosis, for approximately 30 months. We modelled the relationship between rate of change in log FCP and determinants of interest using repeated measures general linear models. RESULTS: Among DA-positive youth, there was a progressive decline in beta cell function of 4% per month, independent of demographics (age, sex, race/ethnicity), genetic susceptibility to autoimmunity (HLA risk), HbA(1c) and BMI z score, or presence of insulin resistance. Among DA-negative youth, there was marked heterogeneity in beta cell loss, reflecting an aetiologically mixed group. This group likely includes youths with undetected autoimmunity (whose decline is similar to that of DA-positive youth) and youth with non-autoimmune, insulin-resistant diabetes, with limited decline (~0.7% per month). CONCLUSIONS/INTERPRETATION: SEARCH provides unique estimates of beta cell function decline in a large sample of youth with diabetes, indicating that autoimmunity is the major contributor. These data contribute to a better understanding of clinical evolution of beta cell function in youth with diabetes, provide strong support for the aetiological classification of diabetes type and may inform tertiary prevention efforts targeted at high-risk groups.

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AIMS/HYPOTHESIS: Although diagnosed type 2 diabetes has increased in the past decade, little is known about accompanying changes in fasting plasma glucose (FPG), HbA(1c) and fasting serum insulin (FI) levels in the non-diabetic population. METHODS: Using population estimates from National Health and Nutrition Examination Surveys, we compared distribution of FPG, HbA(1c) and FI in non-diabetic US persons who were >or=20 years old in 1999 to 2006 with that in persons of the same age in 1988 to 1994. RESULTS: Age-, sex- and race-adjusted mean FPG levels between the two study periods did not change, but mean HbA(1c) and FI levels increased (0.10% and 4.8 pmol/l, respectively; p < 0.001 for both). The increased HbA(1c) level was driven largely by an upward shift in the lower end of the HbA(1c) distribution. In contrast, the increased FI level was driven primarily by an upward shift in the middle and higher end of FI distribution, especially among persons aged 20 to 44 years. After adjustments for BMI or waist circumference, the increase in the mean HbA(1c) level was attenuated (0.06%; p < 0.001), whereas the mean FPG level decreased by 0.1 mmol/l (p < 0.001) and the mean FI level no longer demonstrated significant change. CONCLUSIONS/INTERPRETATION: Despite little change in the distribution of FPG levels, HbA(1c) and FI levels increased in the non-diabetic population in the past decade. The increase in FI levels suggests that levels of insulin resistance were greater among US adults, especially young adults, than in the previous decade.

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BACKGROUND: The present analyses were conducted to examine the extent to which insulin sensitivity and insulin secretion, assessed using simple indices derived from an oral glucose tolerance test, are influenced by genetic factors, and to assess whether these genetic factors overlap with those influencing susceptibility to type 2 diabetes in Pima Indians. METHODS: Indices calculated from fasting and 2-h post-load insulin (I(0), I(120)) and glucose (G(0), G(120)) concentrations included insulin sensitivity index [ISI(0)=10(4)/(I(0).G(0))] and corrected insulin response [CIR(120)=I(120)/[G(120).(G(120)-70 mg/dl)]]. Heritability (h(2)) was determined using variance components methods in 1421 non-diabetic individuals from 446 sibships. Among 595 individuals in 186 sibships, genome-wide quantitative trait linkage analyses of ISI(0) and CIR(120) were conducted and affected-sibling analyses of diabetic siblings stratified by prediabetic measurements of ISI(0) and CIR(120) were also performed. RESULTS: Both ISI(0) (h(2)=0.37+/-0.06) and CIR(120) (h(2)=0.25+/-0.07) were moderately heritable. Modest evidence for linkage with CIR(120) (logarithm of odds (LOD)=1.6) was observed on chromosome 1q in a region previously shown to have linkage with young-onset diabetes in Pimas. When diabetic siblings were stratified by CIR(120), evidence for linkage in this region was strongest (LOD=1.5) among those with a low CIR(120). Additional regions with modest evidence for linkage with ISI(0) were observed on chromosomes 9p (LOD=2.0) and 14p (LOD=1.7). CONCLUSIONS: The present analyses suggest that insulin sensitivity and insulin secretion are influenced by genetic factors in Pima Indians. The linkage analyses suggest that the putative diabetes-susceptibility gene on chromosome 1q affects insulin secretion. Published in 2001 by John Wiley & Sons, Ltd.

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Hereditary hemochromatosis (HHC) is an autosomal recessive disorder of iron metabolism characterized by increased iron absorption and deposition in the liver, pancreas, heart, joints, and pituitary gland. Without treatment, death may occur from cirrhosis, primary liver cancer, diabetes, or cardiomyopathy. In 1996, HFE, the gene for HHC, was mapped on the short arm of chromosome 6 (6p21.3). Two of the 37 allelic variants of HFE described to date (C282Y and H63D) are significantly correlated with HHC. Homozygosity for the C282Y mutation was found in 52-100% of previous studies on clinically diagnosed probands. In this review, 5% of HHC probands were found to be compound heterozygotes (C282Y/H63D), and 1.5% were homozygous for the H63D mutation; 3.6% were C282Y heterozygotes, and 5.2% were H63D heterozygotes. In 7% of cases, C282Y and H63D mutations were not present. In the general population, the frequency of the C282Y/C282Y genotype is 0.4%. C282Y heterozygosity ranges from 9.2% in Europeans to nil in Asian, Indian subcontinent, African/Middle Eastern, and Australasian populations. The H63D carrier frequency is 22% in European populations. Accurate data on the penetrance of the different HFE genotypes are not available. Extrapolating from limited clinical observations in screening studies, an estimated 40--70% of persons with the C282Y homozygous genotype will develop clinical evidence of iron overload. A smaller proportion will die from complications of iron overload. To date, population screening for HHC is not recommended because of uncertainties about optimal screening strategies, optimal care for susceptible persons, laboratory standardization, and the potential for stigmatization or discrimination.

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Like most essential nutrients, Fe needs to be maintained in the body at a defined level for optimal health, with appropriate adaptation to varying Fe needs and supply. The primary mechanism for controlling Fe level is the regulation of Fe absorption. Several different proteins have been identified as contributors to the process. Despite a complex regulatory system, Fe disorders (both Fe deficiency and Fe overload) occur. Fe deficiency is a common problem worldwide, resulting from inadequate dietary Fe and blood loss. Complications include pre-term labour, developmental delay, and impaired work efficiency. No specific genetic syndromes causing isolated Fe deficiency have been described, but animal studies and clinical observations suggest that such a relationship may be a possibility. Conversely, the known causes of Fe overload are genetic. Fe overload is less common than Fe deficiency, but can result in serious medical complications, including cirrhosis, primary liver cancer, diabetes, cardiomyopathy and arthritis. The most common and best characterized syndrome of Fe overload is hereditary haemochromatosis (HHC), an autosomal recessive disorder. Mutations in the HFE protein cause HHC, but the clinical presentation is variable. Of particular interest is the factor that some FIFE genotypes appear to be associated with protection from Fe deficiency. Other genetic variants in the regulatory pathway may influence the likelihood of Fe deficiency and Fe overload. Studies of genetic variants in HFE and other regulatory proteins provide important tools for studying the biological processes in Fe regulation. This work is likely to lead to new insights into Fe disorders and potentially to new therapeutic approaches. It will not be complete, however, until coordinated study of both genetic and nutritional factors is undertaken.

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Diabetic nephropathy is the leading cause of renal failure in industrialized countries. There is strong evidence that diabetic nephropathy is influenced by genetic factors. Studies in the Pima Indians as well as in other populations demonstrate that diabetic nephropathy aggregates in families. The hypothesis that the familial aggregation reflects the effect of a major gene was formally tested by segregation analysis of diabetic nephropathy in Pima Indians with type 2 diabetes. The segregation analysis provided strong evidence for a major genetic effect on the prevalence of diabetic nephropathy; this suggests that some of the genetic determinants of diabetic nephropathy may have effects of sufficient magnitude to be detected by linkage analysis. Therefore, we analyzed data from a genome-wide scan to identify susceptibility loci for nephropathy in diabetic Pima Indians. Analyses conducted by both parametric (model-based) and nonparametric methods revealed tentative evidence for nephropathy susceptibility loci on chromosomes 3q, 7q, 18q, and 20p.

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A genome-wide linkage study was analyzed to identify loci that influence serum lipid concentrations in Pima Indians. Linkage analyses were conducted for total cholesterol measured in 998 siblings from 292 nuclear families, for total triglycerides in 547 siblings from 188 families, and for high density lipoprotein (HDL) cholesterol in 590 siblings from 201 families. Genotypes were generated for 516 autosomal microsatellite markers. Multipoint variance components methods were used to assess linkage. The strongest evidence for linkage with total cholesterol was on chromosome 19p (lod score 3.89), in the vicinity of the marker D19S1034, which is near the low density lipoprotein receptor gene. The strongest evidence for linkage with HDL cholesterol was on chromosome 3q (lod score 2.64) near D3S3053. For triglycerides, the strongest evidence for linkage was on chromosome 2p near D2S1788 (lod score 1.70) and on chromosome 3p near D3S2406 (lod score 1.77). This genomic scan provides evidence for a locus influencing total cholesterol concentration on chromosome 19p. It also suggests a locus influencing HDL cholesterol on chromosome 3q.

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Intrauterine exposure to diabetes is associated with an excess of diabetes and obesity in the offspring, but the effects of intrauterine exposure are confounded by genetic factors. To determine the role of the intrauterine diabetic environment per se, the prevalence of diabetes and the mean BMI were compared in siblings born before and after their mother was recognized as having diabetes. Nuclear families in which at least one sibling was born before and one after the mother was diagnosed with type 2 diabetes were selected. Consequently, the siblings born before and after differed in their exposure to diabetes in utero. A total of 58 siblings from 19 families in which at least one sibling had diabetes were examined at similar ages (within 3 years). The risk of diabetes was significantly higher in siblings born after the mother developed diabetes than in those born before the mother's diagnosis of diabetes (odds ratio 3.7, P = 0.02). In 52 families, among 183 siblings without diabetes, the mean BMI was 2.6 kg/m2 higher in offspring of diabetic than in offspring of nondiabetic pregnancies (P = 0.003). In contrast, there were no significant differences in risk of diabetes or BMI between offspring born before and after the father was diagnosed with diabetes. Intrauterine exposure to diabetes per se conveys a high risk for the development of diabetes and obesity in offspring in excess of risk attributable to genetic factors alone.

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OBJECTIVE: The 1997 American Diabetes Association (ADA) and the 1985 and 1999 World Health Organization (WHO) criteria for diabetes and hyperglycemia differ. The appropriateness of these diagnostic criteria in terms of individuals identified as abnormal and their prognosis has been debated. The purpose of this study is to compare the classifications of people by these criteria and to compare fasting and postload plasma glucose concentrations in the prediction of diabetes. RESEARCH DESIGN AND METHODS: The frequencies of diabetes by the 3 sets of criteria were compared in 5,023 adult Pima Indians not taking hypoglycemic drugs. Among nondiabetic subjects, fasting plasma glucose (FPG) and 2-h postload plasma glucose (2-h PG) concentrations and categories of impaired glucose regulation or diabetes were evaluated as predictors of diabetes defined by 1999 WHO criteria. RESULTS: The frequency of diabetes was 12.5% by 1997 ADA criteria, 14.6% by 1985 WHO criteria, and 15.3% by 1999 WHO criteria. The incidence of diabetes was strongly related to higher FPG and 2-h PG, each of which had very similar predictive powers. Impaired glucose tolerance (IGT) was more common than impaired fasting glucose (IFG) (15 vs. 5%), but the 5-year incidence of diabetes was higher in IFG than IGT (37 vs. 24%). CONCLUSIONS: The prevalence and incidence of diabetes are somewhat lower with the ADA criteria than with the 1985 or 1999 WHO criteria. The intermediate categories of glycemia differ substantially IFG defines a smaller number of people who are at higher risk of developing diabetes than those with IGT. More people at high risk of diabetes could be identified by using either IFG or IGT, as recommended by the 1999 WHO criteria, or by using the FPG concentration alone, but with a lower cutoff value.

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OBJECTIVE: The 1997 American Diabetes Association (ADA) and 1999 World Health Organization (WHO) criteria for diabetes and hyperglycemia were evaluated and compared with respect to prediction of microvascular and macrovascular disease and mortality RESEARCH DESIGN AND METHODS: The prevalence of retinopathy and nephropathy at baseline and during the subsequent 10 years and mortality rates were examined in relation to baseline fasting plasma glucose (FPG) and 2-h postload plasma glucose (2-h PG) among 5,023 Pima Indian adults and in relation to the cut points defined by the ADA and WHO criteria. RESULTS: The frequencies of retinopathy and nephropathy were directly related to baseline FPG and 2-h PG with approximate thresholds near or below the current diagnostic criteria for diabetes (FPG > or =7.0 and 2-h PG > or = 11.1 mmol/l). The rates of retinopathy were 4.7% in impaired fasting glucose (IFG) and 20.9% in diabetes by ADA criteria; 1.6% for impaired glucose tolerance (IGT) and 19.7% for diabetes by 1985 WHO criteria; and 1.2% for IGT and 19.2% for diabetes by the 1999 WHO criteria. Mortality rates from cardiovascular-renal-related diseases were higher in diabetic individuals (FPG > or =7.0 or 2-h PG > 11.1 mmol/l) than in those with normal FPG and 2-h PG but were not elevated in those with IFG or IGT. CONCLUSIONS: Retinopathy and nephropathy were directly related to higher FPG or 2-h PG. FPG, which identifies those at high risk of microvascular disease and mortality, can be used to predict these outcomes and to diagnose diabetes when oral glucose tolerance testing is not practical.

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OBJECTIVE: To examine the 10-year mortality and effect of diabetes duration on overall and cause-specific mortality in diabetic subjects in the Verona Diabetes Study (VDS). RESEARCH DESIGN AND METHODS: Records from diabetes clinics, family physicians, and a drug consumption database were used to identify 5,818 subjects > or =45 years of age with type 2 diabetes who were alive and residing in Verona, Italy on 31 December 1986. Vital status of each subject was ascertained on 31 December 1996. Underlying causes of death were determined from death certificates. Death rates and death rate ratios (DRRs) were computed and standardized to the population of Verona in 1991. RESULTS: During the study, 2,328 subjects died; 974 deaths were attributable to cardiovascular disease, 517 to neoplasms, 324 to diabetes-related diseases, 134 to digestive diseases, 250 to other natural causes, and 48 to external causes. There were 81 subjects who died of unknown causes. Death rates from natural causes were higher in men than in women (DRR 1.4, 95% CI 1.2-1.5) and rose in both sexes with increasing duration of diabetes (P = 0.001). Among the natural causes of death, those for diabetes-related diseases were strongly related to diabetes duration (P = 0.001). a modest relationship with duration was also found for ischemic heart disease in men (P = 0.07). CONCLUSIONS: Cardiovascular disease was the principal cause of death among people with type 2 diabetes in the VDS. Rates for natural causes of death rose with increasing duration of diabetes. Deaths from diabetes-related diseases in both sexes and from ischemic heart disease in men were largely responsible for this increase.

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Familial aggregation of diabetic nephropathy suggests the existence of genes determining susceptibility to nephropathy in addition to those leading to diabetes. In the present study, complex segregation analysis was performed in diabetic members of Pima Indian families to determine whether familial aggregation of nephropathy in this population could reflect the action of a single major gene. Nephropathy, defined by a urinary protein-to-creatinine ratio (PCR) > or = 500 mg/g, was analyzed as a discrete trait in a class C regressive logistic model. Individuals with PCR <500 mg/g were considered unaffected. Segregation analysis was performed both for nephropathy at the last examination (prevalent cases) and for duration of diabetes at the onset of nephropathy (incident cases). The REGD program was used for the analysis of the prevalent cases and the REGTL program for the incident cases, both from the Statistical Analysis for Genetic Epidemiology package (Case Western University, Cleveland, OH). The analysis of prevalent cases included 2,107 Pima Indians from 715 nuclear families. A subset of 504 of these families containing 1,403 individuals was used in the analysis of incident cases. Analysis of prevalent cases supported the existence of a gene with a major role, in that hypotheses of no major effect and of no transmission of a major effect were rejected (P = 0.00001; P = 0.003), whereas Mendelian transmission was not rejected (P = 0.85). A dominant model provided the best fit, but a recessive model could not be rejected. The analysis of incident cases, however, did not support a major gene effect on duration of diabetes at the onset of nephropathy, and analyses of lifetime occurrence of nephropathy were inconclusive. The analysis of prevalent cases supports the hypothesis of a major genetic effect on susceptibility to diabetic nephropathy in Pima Indians, but the analysis of incident cases does not support a genetic effect on duration of diabetes at the onset of nephropathy. The discrepancy may reflect the difficulty in precisely dating onset of nephropathy. The parameters of the model derived from segregation analysis of prevalent cases may be useful in linkage studies to detect nephropathy susceptibility loci.

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The metabolic characteristics of type 2 diabetes, insulin resistance, and diminished insulin secretion are costly to measure directly. To evaluate the utility of several simple indices derived from insulin and glucose measurements, the indices were examined from 1982 to 1997 with respect to correlation with more sophisticated measures of insulin sensitivity and secretion in Pima Indians in the Gila River Indian Community of Arizona. Ability to predict the incidence of diabetes in 1,731 persons was also examined. Indices were calculated from fasting and 2-hour glucose (G0, G120) and insulin (I0, I120) concentrations obtained during an oral glucose tolerance test. Fasting serum insulin concentration and the insulin sensitivity index (10(4)/(I0 x G0)) each showed a moderate correlation with the estimate of insulin sensitivity derived from the hyperinsulinemic-euglycemic clamp (absolute value r approximately 0.60). They also strongly predicted the incidence of diabetes (incidence rate ratio comparing the most and least insulin-resistant tertile groups approximately 3.0). Corrected insulin response (I120/(G120 x (G120 - 70))) was modestly correlated with insulin secretion as measured by an intravenous glucose tolerance test (r = 0.35). Impaired insulin secretion assessed by this index predicted incidence of diabetes, particularly after control for insulin sensitivity index (incidence rate ratio = 1.6). Thus, simple indices of insulin sensitivity and secretion may be reasonable surrogates for more sophisticated measures in epidemiologic studies.

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PURPOSE: To determine the contribution of the C282Y and H63D mutations in the HFE gene to clinical expression of hereditary hemochromatosis. METHODS: Pooled analysis of 14 case-control studies reporting HFE genotype data, to evaluate the association of different HFE genotypes with iron overload. In addition, we used data from the pooled analysis and published data to estimate the penetrance of the C282Y/C282Y genotype. RESULTS: Homozygosity for the C282Y mutation carried the largest risk for iron overload (OR = 4383, 95% CI 1374 to >10,000) and accounted for the majority of hemochromatosis cases (attributable fraction (AF) = 0.73). Risks for other genotypes were much smaller: OR = 32 for genotype C282Y/H63D (95% CI 18.5 to 55.4, AF = 0.06); OR = 5.7 for H63D/H63D (95% CI 3.2 to 10.1, AF = 0.01); OR = 4.1 for C282Y heterozygosity (95% CI 2.9 to 5.8, with heterogeneity in study results, making this association uncertain); and OR = 1.6 for H63D heterozygosity (95% CI 1 to 2.6, AF = 0.03). Estimates of penetrance for the C282Y/C282Y genotype were highly sensitive to estimates of the prevalence of iron overload disease. At a prevalence of 2.5 per 1000 or less, penetrance of the C282Y/C282Y genotype is unlikely to exceed 50%. Penetrance of other HFE genotypes is much lower. CONCLUSIONS: C282Y homozygosity confers the highest risk for iron overload but the H63D mutation is also associated with increased risk. Our data indicate a gradient of risk associated with different HFE genotypes and thus suggest the presence of other modifiers, either genetic or environmental, that contribute to the clinical expression of hemochromatosis.

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OBJECTIVE: To prospectively evaluate progression to diabetes in individuals with impaired glucose regulation as defined according to fasting glucose alone or an oral glucose tolerance test (OGTT) (i.e., both fasting and postload glucose) to compare the ability of these two screening methods to identify people at high risk of developing diabetes. RESEARCH DESIGN AND METHODS: A working population of 1,245 nondiabetic telephone company employees aged 40-59 years was studied by OGTT in 1980. Participants were classified according to baseline fasting glucose only (as encouraged by the American Diabetes Association [ADA]) or OGTT (as recommended by the 1998 World Health Organization [WHO] consultation). Progression to diabetes was evaluated 11.5 years later according to the 1997 ADA criteria of a fasting plasma glucose level > or =7.0 mmol/l. RESULTS: With the use of the OGTT, baseline prevalence of impaired glucose regulation was substantially higher than that with fasting glucose alone (7.2 vs. 3.2%); the two groups only overlap for 40.9% of the cases because a fairly large number of people with postload hyperglycemia (59.1%) have normal fasting glucose. Progression to diabetes in participants with normal fasting glucose and postload hyperglycemia is significantly more frequent than that of people with normoglycemia (32.5 vs. 7.2%; P < 0.001) and not significantly different from that of people with both fasting and postload hyperglycemia (i.e., 44.0%). However, the former are not identified as being at unusually high risk of diabetes unless an OGTT is performed. When the use of fasting glucose alone or OGTT was validated as a marker of progression to diabetes, sensitivity was substantially higher for the OGTT (33.3 vs. 9.0%) without major differences in specificity (92.6 vs. 97.0%). CONCLUSIONS: These data (the only data so far available in Caucasians) support the viewpoint that for the identification of people at high risk of diabetes, the use of the OGTT should be maintained.

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OBJECTIVE: To investigate the mechanisms underlying the association between birth weight and type 2 diabetes in a population-based study of 3,061 Pima Indians aged 5-29 years. RESEARCH DESIGN AND METHODS: Glucose and insulin concentrations were measured during a 75-g oral glucose tolerance test, and insulin resistance was estimated according to the homeostatic model (homeostasis model assessment-insulin resistance [HOMA-IR]). Relationships between birth weight, height, weight, fasting and postload concentrations of glucose and insulin, and HOMA-IR were examined with multiple regression analyses. RESULTS: Birth weight was positively related to current weight and height (P < 0.0001, controlled for age and sex, in each age-group). The 2-h glucose concentrations showed a U-shaped relationship with birth weight in subjects > 10 years of age, and this relation was independent of current body size. In 2,272 nondiabetic subjects, after adjustment for weight and height, fasting and 2-h insulin concentrations and HOMA-IR were negatively correlated with birth weight. CONCLUSIONS: Low-birth-weight Pimas are thinner at ages 5-29 years, yet they are more insulin resistant relative to their body size than those of normal birth weight. By contrast, those with high birth weight are more obese but less insulin resistant relative to their body size. The insulin resistance of low-birth-weight Pima Indians may explain their increased risk for type 2 diabetes.

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