Variations in the vitamin D-binding protein (Gc locus) are associated with oral glucose tolerance in nondiabetic Pima Indians

Electrophoretic variants of the vitamin D-binding protein (DBP) have been associated with type 2 diabetes as well as with metabolic characteristics that predispose to type 2 diabetes in several populations. The Gc gene that encodes DBP maps to chromosome 4q12, a region that has recently been found to be potentially linked to plasma glucose and insulin concentrations in Pima Indians. Therefore, the gene that encodes DBP was analyzed as a candidate gene for our linkage findings in the Pima Indians. Sequence analysis of the coding exons identified two previously described missense polymorphisms at codons 416 and 420, which are the genetic basis for the three common electrophoretic variants of DBP (Gc1f, Gc1s, and Gc2). These variants in DBP were associated with differences in oral glucose tolerance in nondiabetic Pima Indians.     

An autosomal genomic scan for loci linked to prediabetic phenotypes in Pima Indians

Type 2 diabetes mellitus is a common chronic disease that is thought to have a substantial genetic basis. Identification of the genes responsible has been hampered by the complex nature of the syndrome. Abnormalities in insulin secretion and insulin action predict the development of type 2 diabetes and are, themselves, highly heritable traits. Since fewer genes may contribute to these precursors of type 2 diabetes than to the overall syndrome, such genes may be easier to identify. We, therefore, undertook an autosomal genomic scan to identify loci linked to prediabetic traits in Pima Indians, a population with a high prevalence of type 2 diabetes. 363 nondiabetic Pima Indians were genotyped at 516 polymorphic microsatellite markers on all 22 autosomes. Linkage analyses were performed using three methods (single-marker, nonparametric multipoint [MAPMAKER/SIBS], and variance components multipoint). These analyses provided evidence for linkage at several chromosomal regions, including 3q21-24 linked to fasting plasma insulin concentration and in vivo insulin action, 4p15-q12 linked to fasting plasma insulin concentration, 9q21 linked to 2-h insulin concentration during oral glucose tolerance testing, and 22q12-13 linked to fasting plasma glucose concentration. These results suggest loci that may harbor genes contributing to type 2 diabetes in Pima Indians. None of the linkages exceeded a LOD score of 3.6 (a 5% probability of occurring in a genome-wide scan). These findings must, therefore, be considered tentative until extended in this population or replicated in others.     

Relationship of hepatic and peripheral insulin resistance with plasminogen activator inhibitor-1 in Pima Indians

Plasminogen activator inhibitor-1 (PAI-1) is related to insulin resistance and several components of the insulin resistance syndrome, and PAI-1 levels are elevated in subjects with non-insulin-dependent diabetes mellitus. Many Pima Indians are obese, insulin-resistant, and hyperinsulinemic, and they have high rates of diabetes but a low risk of ischemic heart disease. In contrast to whites and Asians, PAI-1 activity is similar between nondiabetic and diabetic Pima Indians. We therefore examined the association of PAI-1 with hepatic and peripheral insulin action measured using the hyperinsulinemic-euglycemic clamp. To investigate if insulin per se has any effect on PAI-1 in vivo, we also assessed the effects of endogenous (during a 75-g oral glucose load) and exogenous (during hyperinsulinemic clamp) insulin on PAI-1 antigen. Twenty-one (14 men and seven women; mean age, 26.3 +/- 4.8 years) Pima Indians underwent a 75-g oral glucose tolerance test (OGTT) and a sequential hyperinsulinemic-euglycemic clamp. Peripheral insulin action was measured as absolute glucose uptake (M value) and normalized to estimated metabolic body size (EMBS). Hepatic insulin action was measured as percent suppression of basal hepatic glucose output during hyperinsulinemia. PAI-1 antigen was determined using a two-site enzyme-linked immunosorbent assay that detects only free PAI-1. PAI-1 antigen concentrations were significantly related to body mass index ([BMI] rs = .54, P = .012), waist (rs=.52, P=.016) and thigh (rs=.63, P=.002) circumference, and fasting plasma insulin concentration (rs=.59, P=.004). PAI-1 antigen concentrations were not significantly associated with peripheral glucose uptake (M value) during either low-dose (rs= -.01, P=NS) or high-dose (rs= -.11, P=NS) insulin infusion. PAI-1 antigen was negatively correlated with basal hepatic glucose output (rs= -.57, P=.013) and percent suppression of hepatic glucose output during hyperinsulinemia (rs= -.69, P=.005). However, this relationship was largely due to the confounding effects of BMI, waist and thigh girth, fasting insulin, and 2-hour postload glucose concentrations, and was not significant when controlled for these variables (partial rs= -.30, P=NS). There was no significant relationship of PAI-1 antigen concentration with glucose storage or glucose oxidation. Despite a threefold increase in plasma insulin concentrations during the OGTT, there were no significant changes in PAI-1 antigen concentrations (median, 57, 61, 55, and 44 ng/mL at 0, 60, 120, and 180 minutes, respectively; P=NS by ANOVA). During the hyperinsulinemic clamp, mean plasma insulin concentrations at the end of low-dose (240 pmol/m2/min) and high-dose (2,400 pmol/m2/min) infusions were 1,005 and 14,230 pmol/L, respectively. However, PAI-1 antigen concentrations at the end of low-dose and high-dose insulin infusions were similar to those at baseline (median, 63, 43, and 58 ng/mL, respectively; P=NS by ANOVA). PAI-1 antigen in Pima Indians is related to several components of the insulin resistance syndrome. However, direct measurement of insulin resistance indicates that hepatic but not peripheral insulin resistance is related to PAI-1 antigen. Neither endogenous nor exogenous hyperinsulinemia for short periods had any significant effect on PAI-1 antigen concentrations. Short-term hyperinsulinemia is unlikely to be an important regulator of PAI-1 in Pima Indians. The relationship of PAI-1 antigen to hepatic insulin resistance is largely dependent on the relationship of PAI-1 to indices of obesity and fasting insulin concentrations.     

Relation of the white blood cell count to obesity and insulin resistance: effect of race and gender

Recent reports suggest that the white blood cell (WBC) count is related to plasma insulin concentrations and insulin resistance in healthy individuals. The present study examines whether these relations are independent of obesity and the pattern of body fat distribution and tests whether race and gender affect these relations. WBC counts, insulin responses to a 75 gram oral glucose tolerance test (OGTT) and glucose disposal during a two-step hyperinsulinemic euglycemic clamp were measured in 300 men and women (149 Pima Indians, 100 whites, and 51 blacks) with a wide range of obesity. WBC counts were lower in blacks than Pima Indians or whites and tended to be higher in women than men. The subgroups were comparable in age and body weight, but percent body fat and plasma insulin concentrations were higher and glucose disposal during the glucose clamp was lower in Pima Indians than in blacks or whites. In the group as a whole, the WBC count correlated with obesity (body mass index and percent body fat), the waist to thigh ratio (an index of the pattern of body fat distribution), and plasma insulin concentrations and was negatively related to age and glucose disposal during the clamp. In multiple regression analyses, only age, race and obesity were significantly associated with the WBC count. When the analyses were restricted to Pima men, in whom correlations between the WBC count and the metabolic variables appeared the strongest, the WBC count remained significantly associated with plasma insulin concentrations, but not glucose disposal, after controlling for age and obesity. The results of this study indicate that age, race, and obesity are significantly associated with the WBC count in healthy individuals. Plasma insulin concentrations, but not insulin resistance per se, may also be weakly associated with the WBC count, but this may be population specific.     

Association of the glycogen synthase locus on 19q13 with NIDDM in Pima Indians

Skeletal muscle glycogen synthase (encoded by GYS1 on chromosome 19q13.3) is the rate-limiting enzyme in insulin-mediated non-oxidative glucose disposal. Our previous studies have demonstrated an impairment of insulin-stimulated GYS1 activities in insulin-resistant Pima Indians, and associations of non-insulin-dependent diabetes mellitus (NIDDM) with the GYS1 locus were reported recently in Finnish and Japanese populations. We have performed linkage and association analyses of GYS1 and seven additional DNA markers on 19q with NIDDM, and with parameters of insulin action in the Pima Indians. We have found a significant association of NIDDM with GYS1 genotypes (p = 0.009), and with common GYS1 alleles (p = 0.022) in the Pima Indians. We have performed a detailed comparative analysis of the GYS1 gene, mRNA, and protein product in insulin-sensitive and insulin-resistant Pima Indians. No mutations in GYS1 coding sequences were detected; nor did we find alterations of GYS1 mRNA expression or of its basal enzymatic activity in insulin-resistant Pima Indians. These results contrasted with a 25% reduction of immunoreactive protein in insulin-resistant subjects as detected by Western blotting with an antibody specific for the C-terminal end of GYS1 (t-test p = 0.024; Wilcoxon's rank-sum test, p = 0.04). Because no mutations were detected in the DNA encoding this epitope, the difference in immunoreactivity may reflect post-translational modification(s) of the protein rather than a difference in the gene itself, or it could have occurred by chance. We conclude that our data do not indicate alterations in the GYS1 gene as the cause for the observed association, and that a different locus near GYS1 may be the contributing genetic element.     

Detecting panic disorder in emergency department chest pain patients: a validated model to improve recognition

Non-insulin-dependent diabetes mellitus (NIDDM) and the renal disease attributable to it have been characterized extensively in the Pima Indians, a group of American Indians who form the Gila River Indian Community in Arizona. Both of these diseases are common in this community, and their onset and duration are known with greater certainty than in other populations because research examinations, which include oral glucose tolerance tests and measures of urinary protein excretion, have been performed frequently on most members of the population for the past 30 years. Studies of glomerular structure and hemodynamic function in diabetic Pima Indians indicate that glomerular hyperfiltration often develops at the onset of NIDDM and remains elevated until after overt nephropathy appears. Structurally, the glomeruli in subjects with microalbuminuria are not clearly distinguishable from those in subjects with normoalbuminuria, but macroalbuminuria is characterized by extensive glomerular sclerosis, mesangial expansion, and widening of epithelial cell foot processes that together lead to a rapid decline in the glomerular filtration rate. The decline in glomerular function in subjects with macroalbuminuria is due both to a loss of ultrafiltration surface area and to reduction in glomerular hydraulic permeability.     

Catalytic activity of phospholipase A2 in serum in experimental fat embolism in pigs

In a population-based epidemiological study, 991 Pima Indians with non-insulin-dependent (Type 2) diabetes mellitus (NIDDM) and 288 without diabetes aged > or =15 years were examined for retinopathy by fundus photography with a 45 degrees fundus camera after mydriasis. The photographs were graded using a modified Airlie-House classification scheme. The associations of several factors with retinopathy were studied by logistic regression. Non-proliferative retinopathy was present in 11.2 % (19/169) subjects at the time of diagnosis of diabetes and in 8.3% (4/48) in newly diagnosed subjects who had a documented non-diabetic oral glucose tolerance test within 4 years prior to diagnosis of diabetes. The prevalence of retinopathy in subjects with impaired glucose tolerance was 12% (8/68). Retinopathy at the time of diagnosis of diabetes was significantly associated with lower body mass index and higher systolic blood pressure but not glycaemia. Retinopathy was present in 375 (37.8 %) diabetic subjects and 14 (5.2 %) non-diabetic subjects. Among all subjects with diabetes (duration 0-37 years), stepwise multivariate analysis showed non-proliferative retinopathy to be associated with duration of diabetes, mean blood pressure, fasting plasma glucose, treatment with insulin and albuminuria. Proliferative retinopathy was seen in 34 (2.7%) of diabetic and none of the non-diabetic subjects, and was associated with 2 h post-load glucose concentrations, as well as albuminuria, insulin treatment, younger age, and diastolic blood pressure. These data confirm the need for fundus examination at the time of diagnosis of diabetes and during long-term follow-up. Albuminuria and blood pressure are potentially modifiable risk factors and the impact of treating these on incidence and progression of diabetic retinopathy need to be assessed.     

Diabetic retinopathy, promoter (4G/5G) polymorphism of PAI-1 gene, and PAI-1 activity in Pima Indians with type 2 diabetes

OBJECTIVE: To examine the relationship between plasma plasminogen activator inhibitor 1 (PAI-1) activity and PAI-1 gene (4G/5G) polymorphism and diabetic retinopathy in Pima Indians with type 2 diabetes. RESEARCH DESIGN AND METHODS: We studied 171 Pima Indians with type 2 diabetes between the ages of 30-70 years in a population-based epidemiological survey. Plasma PAI-1 activity was measured by a spectrophotometric assay and PAI-1 4G/5G promoter genotype by the polymerase chain reaction (PCR) using allele-specific primers. Retinopathy was assessed by ophthalmoscopy after pupillary dilation and classified as any retinopathy or as nonproliferative and proliferative. RESULTS: Retinopathy was present in 70 (41%) subjects, and 4 (2.3%) subjects had proliferative retinopathy. Plasma PAI-1 activity was not significantly different among subjects with and without retinopathy (17.1 +/- vs. 19.7 +/- 9.1 arbitrary units (AU)/ml, P = 0.09). PAI-1 activity was negatively correlated with duration of diabetes (rs = -0.18, P = 0.02). In a logistic regression analysis controlled for age, sex, BMI, and duration of diabetes, any retinopathy was significantly associated with fasting plasma glucose concentrations (P < 0.05), 2-h postload glucose (P = 0.02), and HbA1c (P = 0.008), but not with PAI-1 activity (P = 0.48). The prevalence of retinopathy in the three genotype groups differed significantly (4G/4G, 4G/5G, and 5G/5G were 44, 49, and 24%, respectively; chi 2 = 8.22, df = 2, P = 0.016) and remained significant after controlling for age, sex, BMI, duration of diabetes, glycated hemoglobin, and urine albumin-to-creatine ratio in a logistic regression analysis. The odds ratios for retinopathy in subjects with 4G/4G and 4G/5G, compared with the 5G/5G genotype, were 2.0 and 3.1, respectively. CONCLUSIONS: Although diabetic retinopathy in Pima Indians with type 2 diabetes is not associated with PAI-1 activity, subjects with the 4G/4G and 4G/5G genotype had a higher prevalence of retinopathy compared with 5G/5G PAI-1genotype. These preliminary findings indicate that in Pima Indians with type 2 diabetes, presence of the 4G allele of the PAI-1 gene was associated with a higher risk of diabetic retinopathy.     

Feto-placentary pathology in human parvovirus B19 infection

Non-insulin-dependent diabetes mellitus is associated with obesity in 80 to 90%. The presence of obesity enhances insulin resistance, which increases the demands on insulin secretion and causes deterioration of glucose tolerance. Hyperinsulinism has some metabolic sequelae which increase the risk of the development and progression of atherosclerosis. Reduction of body weight is a basic therapeutic provision in obese diabetics. It results not only in better compensation of diabetes but also other metabolic parameters and blood pressure as it leads to a higher tissue sensitivity for insulin. This can delay the development of long-term complications of diabetes mellitus.     

Computed tomography-determined body composition in relation to cardiovascular risk factors in Indian and matched Swedish males

Relationships between cardiovascular risk factors, body composition, and tissue distributions were examined in 10 Indian and 10 Swedish males matched by age, height, and weight. The body was divided into 29 compartments by means of a multiscan computed tomography (CT) technique. Fasting glucose, insulin, and triglycerides (TG) were higher in Indians than in Swedes. During the oral glucose tolerance test (OGTT), the glucose area was similar in both groups, whereas the insulin area was 80% larger in Indians. Adipose tissue (AT) and skin volumes were larger and remaining lean tissues were smaller in Indians. Indians had proportionally less muscle and more skeleton in the legs, but no ethnic difference could be demonstrated with respect to AT distribution. The visceral AT to total AT volume ratio was positively related to insulin and TG, and with higher risk factors for Indians at any given ratio. TG and glucose were negatively related to the leg muscle to total muscle volume ratio, and this ratio was smaller in Indians. It is concluded that the metabolic disturbances of Indians are not necessarily dependent on a preponderance of visceral AT, and also that an upper-body muscle distribution-recognized as a new phenotypic companion to the metabolic syndrome-is statistically related to cardiovascular risk factors.     

Linkage of chromosomal markers on 4q with a putative gene determining maximal insulin action in Pima Indians

Insulin action in vivo varies widely in nondiabetic Pima Indians. Not all of this variance is attributable to individual differences in obesity, physical fitness, sex, or age, and after correcting for these co-variates, measures of insulin action aggregate in families. Insulin action at maximally stimulating insulin concentrations has a trimodal frequency distribution, particularly among obese individuals. This is consistent with the hypothesis that a codominantly inherited autosomal gene, unrelated to obesity, determines MaxM in the population. Preliminary sib-pair linkage analyses indicated the possibility of linkage between MaxM and the GYPA/B locus (encoding the MNSs red cell surface antigens) on chromosome 4q. To confirm and extend these findings, 10 additional loci on 4q were typed in 123 siblings and many of their parents from 46 nuclear families. The results indicate significant (P < 0.001) linkage of the FABP2 and ANX5 loci on 4q with MaxM, and of FABP2 with fasting insulin concentration. No linkage was found between the 4q markers and obesity. Our findings indicate that a gene on 4q, near the FABP2 and ANX5 loci, contributes to in vivo insulin action in Pima Indians.     

Pima Indian males have lower beta-adrenergic sensitivity than Caucasian males

The sympathetic nervous system controls cardiovascular homeostasis and regulates energy metabolism. Pima Indians, a population with a low prevalence of hypertension and a high prevalence of obesity, have low sympathetic nervous activity, compared with Caucasians. Preliminary findings suggest that they may also have a low beta-adrenergic sensitivity. We studied beta-adrenergic sensitivity in 87 nondiabetic normotensive individuals [52 Pima Indians (35 males/17 females) and 35 Caucasians (24 males/11 females)], matched for age and body weight. Chronotropic sensitivity to beta-adrenergic stimulation was assessed by the dose of isoproterenol necessary to increase heart rate by 25 beats per minute [chronotropic dose-25 (CD25)]. Despite a similar basal heart rate and arterial blood pressure, Pimas tended to have lower beta-adrenergic sensitivity than Caucasians (CD25 = 2.37 +/- 2.27 vs. 1.57 +/- 1.38 microg, P = 0.07; mean +/- SD). This difference was significant in males (CD25 = 3.03 +/- 2.39 vs. 1.85 +/- 1.56 microg, P = 0.02) but not in females (CD25 = 1.01 +/- 1.17 vs. 0.96 +/- 0.61 microg, P = 0.99). In males only, CD25 was positively correlated to percent body fat (r = 0.36, P < 0.01). After adjustment for percent body fat, beta-adrenergic sensitivity was still significantly lower in Pima than in Caucasian males (CD25 = 3.44 +/- 2.24 vs. 2.57 +/- 1.60 microg, P = 0.05). In conclusion, our data suggest that increased adiposity is accompanied by decreased beta-adrenergic sensitivity in males only. However, at each level of adiposity, Pima Indian males have lower beta-adrenergic sensitivity than Caucasian males. In combination with a low sympathetic nervous system activity, a reduced beta-adrenergic sensitivity may contribute to the low prevalence of hypertension and the high prevalence of obesity observed in Pima Indians.     

Incidence of diabetes mellitus in women following impaired glucose tolerance in pregnancy is lower than following impaired glucose tolerance in the non-pregnant state

Impaired glucose tolerance (IGT), which is asymptomatic and requires a glucose tolerance test for detection, is a well-known risk factor for diabetes mellitus. Outside the research setting it is rarely identified in people who lack specific risk factors for diabetes except during pregnancy, at which time screening with an oral glucose challenge is a routine procedure. A 75-g oral glucose tolerance test was performed during the latter part of pregnancy or during a routine epidemiology survey in 15-39-year-old Pima Indian women with no history of abnormal glucose tolerance. Those with IGT by World Health Organization criteria were included in this study. Diabetes incidence in women was compared between those whose IGT was first detected during pregnancy and those who were not pregnant when IGT was first recognized. Seventeen of 73 pregnant women and 114 of 244 non-pregnant women developed diabetes within 10 years. When controlled for plasma glucose concentration, age, body mass index, parity and duration of follow-up, those who were not pregnant were at higher risk of developing diabetes than those who were pregnant (hazard rate ratio = 1.71, 95% confidence interval = 1.01-2.91). Previous studies had reported that women with IGT during pregnancy are at higher risk of diabetes than women with normal glucose tolerance. This study suggests that women with IGT during pregnancy are at lower risk than non-pregnant women with a similar plasma glucose concentration who, in the clinical setting, are likely to remain unrecognized.     

Familial and metabolic factors related to blood pressure in Pima Indian children

High blood pressure, abnormal glucose tolerance, and obesity are frequently associated with each other, but the mechanism of these associations is poorly understood. Studying them in children may help in understanding the pathogenesis of hypertension. Blood pressure, height, weight, and plasma glucose and serum insulin concentrations during a 75-g oral glucose tolerance test were measured in 1,698 Pima Indian children aged 6-17 years who participated in an ongoing epidemiologic study. Weight relative to height was used as an index of obesity. The parents of many of the children were also examined. Fasting and 2-hour glucose and insulin concentrations, adjusted for age, sex, and relative weight, were positively related to systolic blood pressure but not to diastolic blood pressure. Relative weight, 2-hour glucose, and fasting insulin concentrations were independently and significantly associated with systolic blood pressure in a stepwise regression analysis that included age and sex. After parental hypertension was taken into account, maternal but not paternal non-insulin-dependent diabetes mellitus, controlled for the child's relative weight and glucose and insulin concentrations, was significantly associated with higher blood pressure in children. The stronger association with maternal diabetes suggests a greater sharing of environmental factors between mother and child than between father and child, but familial similarities in obesity and glucose and insulin concentrations, the diabetic intrauterine milieu, and shared environmental factors probably all contribute to this association.     

A comparison of recurrent and primary herpes simplex keratitis in NIH inbred mice

OBJECTIVE: To compare the incidence rates of hypertension and non-insulin dependent diabetes mellitus in relation to ethnicity and other characteristics in a rapidly developing community. DESIGN: Prospective surveillance of a total community for five years. SUBJECTS: Cohort of 2491 men and women aged 35 to 69 years (79% response), of African, Indian and "other' (mainly Afro-European) descent. RESULTS: During surveillance, secular increases occurred in fasting blood glucose concentrations in both sexes and in body mass index (BMI) in men, with apparent secular reductions in systolic blood pressure in both sexes. Incidence rates of hypertension did not differ significantly with ethnicity, ranging between 33 and 41 per 1000 person-years in men and between 27 and 32 per 1000 person-years in women. In men, the incidence of diabetes (per 1000 person-years) in Indians (24) was significantly higher than in Africans (13) and others (11). In women, the diabetic incidence was similar to that for men in Indians (23) and Africans (14), but in others was twice that in men (21). In both sexes, weight gain was an important risk factor for hypertension, whereas risk of diabetes increased with BMI at baseline. The increased risk of diabetes in Indians among men was independent of baseline BMI and blood glucose. CONCLUSION: Apart from the increased risk of diabetes in Indians, ethnicity had no significant influence on incidence rates of hypertension and diabetes in Trinidad. Secular increases in blood glucose in both sexes and in BMI in men probably contributed to the concurrent increase in mortality from coronary heart disease in this community.     

Low prevalences of chronic widespread pain and shoulder disorders among the Pima Indians

OBJECTIVE: To establish the prevalence of shoulder disease and chronic widespread pain in Pima Indians. METHODS: Cross sectional analyses of data from 4230 subjects for shoulder disease and 105 subjects for chronic widespread pain participating in population surveys RESULTS: The prevalence of shoulder disease was 4.4% (95% CI, 3.8-5.1), age-sex adjusted to the 1980 US census population. This is lower than in a study of Caucasians [prevalence ratio (PR) = 0.29, 95% CI, 0.20-0.42 for men and PR = 0.55, 95% CI, 0.41-0.73 for women]. Shoulder disease was associated with non-insulin-dependent diabetes mellitus (PR = 1.67, 95% CI, 1.19-2.36). No chronic widespread pain was identified (95% CI, 0-3.5%). CONCLUSION: Prevalence of these pain syndromes in Pima Indians is lower than in predominantly Caucasian populations. These findings suggest that these populations have different pain perception or different patterns of risk factors for these disorders.     

Perinatal complications following gestational diabetes mellitus how 'sweet' is ill?

OBJECTIVE: We tested the effect of patient compliance, fasting plasma glucose on oral glucose tolerance test, maternal body constitution, and the method of treatment (diet versus insulin) on the perinatal outcome of patients with gestational diabetes mellitus. STUDY DESIGN: A prospective population-based study compared the perinatal outcome of patients with gestational diabetes mellitus (n = 470) (diabetic with regard to the parameters specified above) and a contemporaneous control group (nondiabetic, n = 250). RESULTS: The diabetic and control groups were matched in demographic characteristics. Patient compliance reduced the rate of macrosomia (14.4%) and neonatal hypoglycemia (3.4%) but not to the levels of the control group (5.2% and 1.2% respectively, p < 0.05). The level of fasting plasma glucose on the oral glucose tolerance test had no effect on perinatal outcome. Intensified (insulin) treatment reduced the rate of macrosomia and large-for-gestational age infants in the subgroups with intermediate and high levels of fasting plasma glucose on the oral glucose tolerance test (9.5%/14.2% and 12.2%/24.2% respectively), again not to levels of the control group (5.2%/10.8%). Obese patients were found to have more perinatal complications than lean patients. Intensified (insulin) treatment has proved to be beneficial in terms of reducing the rate of perinatal complications in the obese patients, but not to the corresponding levels of the control group. Such treatment had no effect on the lean patients. CONCLUSIONS: Strict control of maternal hyperglycemia and high patient compliance are imperative for an effective reduction of perinatal complication in patients with gestational diabetes mellitus. The desired plasma glucose level in the glycemic control of these patients should be further reduced, thus bringing the rate of perinatal complications to that of the normal population.     

Early electrocardiographic abnormalities in Trypanosoma cruzi-seropositive children

OBJECTIVE: The incidence of diabetic nephropathy in type 2 diabetes differs widely by race. Although clinical proteinuria is reportedly more common in East Asian type 2 diabetic patients than in their Caucasian counterparts, data on the incidence of microalbuminuria are not available. This study was undertaken to investigate the incidence and the determinants of microalbuminuria in Korean type 2 diabetic patients. RESEARCH DESIGN AND METHODS: A cohort of 188 Korean type 2 diabetic patients with initial normoalbuminuria were followed prospectively for 5.5 +/- 0.9 years in an outpatient clinic of a university hospital. The incidence of elevated urinary albumin excretion (UAE) (> 20 micrograms/min) and its relationship with baseline characteristics and follow-up data were determined. RESULTS: Of the 146 patients who finished the study, 37 showed persistently elevated UAE during follow-up, giving an incidence of 52/1,000 person-years. Age, duration of diabetes, and baseline UAE were significantly higher in the progressors than in the nonprogressors. More patients in the progressor group had retinopathy at baseline and at the end of follow-up. The mean values of fasting plasma glucose, HbA1, and systolic and diastolic blood pressure during the follow-up period were significantly higher in the progressors than in the nonprogressors. Cox proportional hazards analysis revealed that presence of retinopathy, duration of diabetes, mean fasting plasma glucose, and mean systolic blood pressure during follow-up are independent variables that have a statistically significant influence on the development of microalbuminuria. CONCLUSIONS: The incidence of microalbuminuria in Korean type 2 diabetic patients is lower than that reported in Pima Indians with type 2 diabetes but is as high as that in Caucasians with type 1 diabetes. Presence of diabetic retinopathy, poor glycemic control, and high blood pressure are risk factors for development of microalbuminuria in Koreans with type 2 diabetes.     

Global estimates for prevalence of diabetes mellitus and impaired glucose tolerance in adults. WHO Ad Hoc Diabetes Reporting Group

OBJECTIVE: To assemble standardized estimates of abnormal glucose tolerance in adults in diverse communities worldwide and provide guidelines for the derivation of comparable estimates in future epidemiological studies. RESEARCH DESIGN AND METHODS: The project was limited to population-based investigations that had used current WHO criteria for diagnosis and classification of abnormal glucose tolerance. Raw data were obtained by WHO from surveys conducted during 1976-1991 of over 150,000 persons from 75 communities in 32 countries. Data within the truncated age range of 30-64 yr were adjusted to the standard world population of Segi. Age-specific prevalences also are reported for selected populations. RESULTS: Within the chosen age range, diabetes was absent or rare (< 3%) in some traditional communities in developing countries. In European populations, age-standardized prevalence varied from 3 to 10%. Some Arab, migrant Asian Indian, Chinese, and Hispanic American populations were at higher risk with prevalences of 14-20%. The highest prevalences were found in the Nauruans (41%) and the Pima/Papago Indians (50%). Age-standardized prevalence of IGT was low (< 3%) in some Chinese, traditional American Indian, and Pacific island populations. Moderate (3-10%) or high (11-20%) prevalences of IGT were observed in many populations worldwide. The highest estimates for prevalence of IGT were seen in female Muslim Asian Indians in Tanzania (32%) and in urban male Micronesians in Kiribati (28%). Prevalence of diabetes rose with age in all populations in which age-specific data were examined. This trend was most pronounced in those at moderate to high risk. The ratio of prevalence of diabetes in men versus women varied markedly between populations with little discernable trend, although IGT was generally more common in women. In most communities, at least 20% of diabetes cases were unknown before the survey, and in many communities, > 50% were previously undiagnosed. In both Chinese and Indian migrant populations, relative prevalence was high when compared with indigenous communities. CONCLUSIONS: Diabetes in adults is now a global health problem, and populations of developing countries, minority groups, and disadvantaged communities in industrialized countries now face the greatest risk.     

Treatment with protease inhibitors associated with peripheral insulin resistance and impaired oral glucose tolerance in HIV-1-infected patients

BACKGROUND: The use of protease inhibitors in the treatment of HIV-1 infection is associated with the new onset of diabetes mellitus, hyperlipidaemia and lipodystrophy. It is unclear whether these findings are coincidental or whether they reflect a causative effect of protease inhibitors. OBJECTIVE: To evaluate the effect of treatment with protease inhibitors on insulin sensitivity, oral glucose tolerance and serum lipids in HIV-infected patients in order to determine whether treatment with protease inhibitors can cause peripheral insulin resistance. DESIGN: Cross-sectional controlled study in HIV-infected patients treated with protease inhibitors to assess insulin sensitivity, oral glucose tolerance and changes in serum lipids. METHODS: Sixty-seven patients treated with protease inhibitors, 13 therapy-naive patients and 18 HIV-negative control subjects were tested for insulin sensitivity (intravenous insulin tolerance test). In a subgroup of 24 treated patients, oral glucose tolerance was determined. Serum lipids prior to and under treatment with protease inhibitors were compared. RESULTS: Patients on protease inhibitors had a significantly decreased insulin sensitivity when compared with therapy-naive patients (median, 75 and 156 micromol/l/min, respectively; P < 0.001). All treated patients with impaired (n=4) or diabetic (n=9) oral glucose tolerance, and four out of 11 patients with normal glucose tolerance showed peripheral insulin resistance; all therapy-naive patients had normal insulin sensitivity. Treatment with protease inhibitors led to a significant increase in total triglycerides and cholesterol in the 67 treated patients (median increase, 113 and 37 mg/ml, respectively). CONCLUSION: Treatment with protease inhibitors is associated with peripheral insulin resistance, leading to impaired or diabetic oral glucose tolerance in some of the patients, and with hyperlipidaemia. Overall, there is a large variation in the severity and clinical presentation of protease inhibitor-associated metabolic side-effects.