Harmonic Vibrational Frequencies: Approximate Global Scaling Factors for TPSS, M06, and M11 Functional Families Using Several Common Basis Sets.

We propose new approximate global multiplicative scaling factors for the DFT calculation of ground state harmonic vibrational frequencies using functionals from the TPSS, M06, and M11 functional families with standard correlation consistent cc-pVxZ and aug-cc-pVxZ (x = D, T, and Q), 6-311G split valence family, Sadlej and Sapporo polarized triple-ζ basis sets. Results for B3LYP, CAM-B3LYP, B3PW91, PBE, and PBE0 functionals with these basis sets are also reported. A total of 99 harmonic frequencies were calculated for 26 gas-phase organic and nonorganic molecules typically found in detonated solid propellant residue. Our proposed approximate multiplicative scaling factors are determined using a least-squares approach comparing the computed harmonic frequencies to experimental counterparts well established in the scientific literature. A comparison of our work to previously published global scaling factors is made to verify method reliability and the applicability of our molecular test set.

Predicting decline of kidney function in lupus nephritis using urine biomarkers.

OBJECTIVE: To evaluate candidate biomarkers to predict future renal function decline (RFD) in children and adults with lupus nephritis (LN). METHODS: At the time of enrollment into prospective observational LN cohort studies liver-type fatty acid binding protein (LFABP), albumin, monocyte chemoattractant protein-1 (MCP-1), uromodulin, transferrin, and hepcidin were measured in urine samples of two cohorts of patients with LN, one followed at a pediatric (cohort-1; n = 28) and one at an adult institution (cohort-2; n = 69). The primary outcome was RFD, defined in cohort-1 as a decrease in estimated glomerular filtration rate (eGFR) of ≥20% and in cohort-2 as a sustained increase of ≥25% in serum creatinine concentration (SCr), both from baseline. RESULTS: All patients (n = 97) had normal eGFR or SCr at the time of urine collection at baseline. RFD occurred in 29% (8/28) of patients in cohort-1 during a mean follow-up of 6.1 months, and in 30% (21/69) of those in cohort-2 during a mean follow-up of 60 months. Individually, in cohort-1, levels of MCP-1, transferrin, LFABP, and albumin were higher in the RFD group than those who maintained renal function, with statistical significance for LFABP and albumin. In cohort-2 the RFD group also had higher levels of urine MCP-1 and albumin than others. The combination of LFABP, MCP-1, albumin, and transferrin had good predictive accuracy for RFD in both cohorts (area under the ROC curve = 0.77-0.82). CONCLUSION: The combinatorial urine biomarker LFABP, MCP-1, albumin, and transferrin shows promise as a predictor of renal functional decline in LN, and warrants further investigation.

HLA-DRB1 reduces the risk of type 2 diabetes mellitus by increased insulin secretion.

AIMS/HYPOTHESIS: We sought to identify the physiological implications of genetic variation at the HLA-DRB1 region in full-heritage Pima Indians in Arizona. METHODS: Single-nucleotide polymorphisms from the HLA region on chromosome 6p were tested for association with skeletal muscle mRNA expression of HLA-DRB1 and HLA-DRA, and with type 2 diabetes mellitus and prediabetic traits. RESULTS: The A allele at rs9268852, which tags HLA-DRB1 02(1602), was associated both with higher HLA-DRB1 mRNA expression (n = 133, p = 4.27 × 10(-14)) and decreased risk of type 2 diabetes (n = 3,265, OR 0.723, p = 0.002). Among persons with normal glucose tolerance (n = 266) this allele was associated with a higher mean acute insulin response during an intravenous glucose tolerance test (p = 0.005), higher mean 30 min insulin concentration during an oral glucose tolerance test (p = 0.017) and higher body fat percentage (p = 0.010). The polymorphism was not associated with HLA-DRA mRNA expression or insulin sensitivity. CONCLUSIONS/INTERPRETATION: HLA-DRB1*02 is protective for type 2 diabetes, probably by enhancing self tolerance, thereby protecting against the autoimmune-mediated reduction of insulin secretion.

Assessment of differentially methylated loci in individuals with end-stage kidney disease attributed to diabetic kidney disease: an exploratory study.

BACKGROUND: A subset of individuals with type 1 diabetes mellitus (T1DM) are predisposed to developing diabetic kidney disease (DKD), the most common cause globally of end-stage kidney disease (ESKD). Emerging evidence suggests epigenetic changes in DNA methylation may have a causal role in both T1DM and DKD. The aim of this exploratory investigation was to assess differences in blood-derived DNA methylation patterns between individuals with T1DM-ESKD and individuals with long-duration T1DM but no evidence of kidney disease upon repeated testing to identify potential blood-based biomarkers. Blood-derived DNA from individuals (107 cases, 253 controls and 14 experimental controls) were bisulphite treated before DNA methylation patterns from both groups were generated and analysed using Illumina's Infinium MethylationEPIC BeadChip arrays (n = 862,927 sites). Differentially methylated CpG sites (dmCpGs) were identified (false discovery rate adjusted p ≤ × 10-8 and fold change ± 2) by comparing methylation levels between ESKD cases and T1DM controls at single site resolution. Gene annotation and functionality was investigated to enrich and rank methylated regions associated with ESKD in T1DM. RESULTS: Top-ranked genes within which several dmCpGs were located and supported by functional data with methylation look-ups in other cohorts include: AFF3, ARID5B, CUX1, ELMO1, FKBP5, HDAC4, ITGAL, LY9, PIM1, RUNX3, SEPTIN9 and UPF3A. Top-ranked enrichment pathways included pathways in cancer, TGF-ß signalling and Th17 cell differentiation. CONCLUSIONS: Epigenetic alterations provide a dynamic link between an individual's genetic background and their environmental exposures. This robust evaluation of DNA methylation in carefully phenotyped individuals has identified biomarkers associated with ESKD, revealing several genes and implicated key pathways associated with ESKD in individuals with T1DM.

The impact of disadvantage on the development and progression of diabetic kidney disease.

BACKGROUND: Disadvantaged people include those experiencing economic, social or educational deprivation and, in some cases, those undergoing rapid transition from subsistence to industrial economies. Disadvantaged people worldwide are affected disproportionately by the global epidemic of diabetes. They are also at increased risk of kidney disease attributable to diabetes, and for many, the cost of managing their kidney disease far exceeds their available resources. METHODS: We review factors associated with disadvantage that may increase the risk of diabetic kidney disease, and the barriers to care that hinder attempts to provide an adequate therapeutic response. RESULTS AND CONCLUSIONS: A rapidly rising prevalence and magnitude of obesity among children and adults, increasing frequency of intrauterine exposure to diabetes, and inadequate access to healthcare are responsible, in part, for a surge in the frequency of diabetes and, in turn, diabetic kidney disease among disadvantaged people. These factors may also predispose to an earlier onset of diabetes and kidney disease, thereby perpetuating the disadvantage by reducing the earning potential of those affected through illness and disability.

Secular changes in physical growth and obesity among southwestern American Indian children over four decades.

BACKGROUND AND OBJECTIVES: Most studies describing childhood obesity in the United States are based on cross-sectional surveys and do not include substantial numbers of American Indians (AI). Secular trends in height and weight reflect general health status. This study describes weight trends and transitions among AI children over a 43-year period. METHODS: Anthropometric data were obtained from a prospective study conducted in a southwestern US AI population (1965 through 2007). For cross-sectional analysis, 12 377 observations were available from 6529 children across four birth cohorts (1955-1964, 1965-1974, 1975-1984, 1985-1994). Participants were stratified into three age groups: pre- (5-9 years), early (10-13) and late (14-17) adolescence. Longitudinal analyses included 1737 children with one exam in each age group. RESULTS: In early and late adolescence, weight increased across birth cohorts. Prevalence of obesity among pre-adolescents was 17.5% (95% CI, 15.1%-19.9%) in the 1955-1964 cohort and 33.7% (95% CI, 30.1%-36.4%) in the 1985-1994 cohort. 74% of children overweight in pre-adolescence in the 1985-1994 cohort became obese by late adolescence; in the 1955-1964 cohort, only 43% made this transition. CONCLUSIONS: This study describes the rising prevalence of childhood obesity. Children obese in pre-adolescence remained obese in late adolescence, stressing the need for early intervention.

Glomerular function in Pima Indians with noninsulin-dependent diabetes mellitus of recent onset.

Differential solute clearances were used to characterize glomerular function in 20 Pima Indians with noninsulin-dependent diabetes mellitus (NIDDM) of less than 3 yr duration. 28 Pima Indians with normal glucose tolerance served as controls. In the diabetic group, the glomerular filtration rate (GFR, iothalamate clearance) exceeded the control value by 15% (140 +/- 6 vs. 122 +/- 5 ml/min, P less than 0.01). A corresponding 12% increase in renal plasma flow (RPF) was not statistically significant and did not account fully for the observed hyperfiltration, suggesting a concomitant elevation of the ultrafiltration pressure or coefficient. The median albumin excretion ratio in NIDDM exceeded control by almost twofold (10.1 vs. 5.8 mg/g creatinine), a trend which just failed to achieve statistical significance (P = 0.06). Fractional clearances of dextrans of broad size distribution were also elevated in diabetic subjects, significantly so for larger dextrans of between 48 and 60 A radius. A theoretical analysis of dextran transport through a heteroporous membrane revealed glomerular pores in NIDDM to be uniformly shifted towards pores of larger size than in controls. We conclude that an impairment of barrier size selectivity combined with high GFR elevates the filtered protein load in NIDDM of recent onset. We propose that enhanced transglomerular trafficking of protein may predispose to sclerosis of glomeruli in those Pima Indians with NIDDM who ultimately develop diabetic nephropathy.

Podocyte loss and progressive glomerular injury in type II diabetes.

Kidney biopsies from Pima Indians with type II diabetes were analyzed. Subjects were classified clinically as having early diabetes (n = 10), microalbuminuria (n = 17), normoalbuminuria, despite a duration of diabetes equal to that of the subjects with microalbuminuria (n = 12), or clinical nephropathy (n = 12). Subjects with microalbuminuria exhibited moderate increases in glomerular and mesangial volume when compared with those with early diabetes, but could not be distinguished from subjects who remained normoalbuminuric after an equal duration of diabetes. Subjects with clinical nephropathy exhibited global glomerular sclerosis and more prominent structural abnormalities in nonsclerosed glomeruli. Marked mesangial expansion was accompanied by a further increase in total glomerular volume. Glomerular capillary surface area remained stable, but the glomerular basement membrane thickness was increased and podocyte foot processes were broadened. Broadening of podocyte foot processes was associated with a reduction in the number of podocytes per glomerulus and an increase in the surface area covered by remaining podocytes. These findings suggest that podocyte loss contributes to the progression of diabetic nephropathy.

Isolation and sequence of four small nuclear U RNA genes of Trypanosoma brucei subsp. brucei: identification of the U2, U4, and U6 RNA analogs.

Trypanosomes use trans splicing to place a common 39-nucleotide spliced-leader sequence on the 5' ends of all of their mRNAs. To identify likely participants in this reaction, we used antiserum directed against the characteristic U RNA 2,2,7-trimethylguanosine (TMG) cap to immunoprecipitate six candidate U RNAs from total trypanosome RNA. Genomic Southern analysis using oligonucleotide probes constructed from partial RNA sequence indicated that the four largest RNAs (A through D) are encoded by single-copy genes that are not closely linked to one another. We have cloned and sequenced these genes, mapped the 5' ends of the encoded RNAs, and identified three of the RNAs as the trypanosome U2, U4, and U6 analogs by virtue of their sequences and structural homologies with the corresponding metazoan U RNAs. The fourth RNA, RNA B (144 nucleotides), was not sufficiently similar to known U RNAs to allow us to propose an identify. Surprisingly, none of these U RNAs contained the consensus Sm antigen-binding site, a feature totally conserved among several classes of U RNAs, including U2 and U4. Similarly, the sequence of the U2 RNA region shown to be involved in pre-mRNA branchpoint recognition in yeast, and exactly conserved in metazoan U2 RNAs, was totally divergent in trypanosomes. Like all other U6 RNAs, trypanosome U6 did not contain a TMG cap and was immunoprecipitated from deproteinized RNA by anti-TMG antibody because of its association with the TMG-capped U4 RNA. These two RNAs contained extensive regions of sequence complementarity which phylogenetically support the secondary-structure model proposed by D. A. Brow and C. Guthrie (Nature [London] 334:213-218, 1988) for the organization of the analogous yeast U4-U6 complex.

Correlations of random binary sequences with pre-stated operator intention: a review of a 12-year program.

Strong correlations between output distribution means of a variety of random binary processes and pre-stated intentions of some 100 individual human operators have been established over a 12-year experimental program. More than 1000 experimental series, employing four different categories of random devices and several distinctive protocols, show comparable magnitudes of anomalous mean shifts from chance expectation, with similar distribution structures. Although the absolute effect sizes are quite small, of the order of 10(-4) bits deviation per bit processed, over the huge databases accumulated, the composite effect exceeds 7sigma (p approximately 3.5 x 10(-13)). These data display significant disparities between female and male operator performances, and consistent serial position effects in individual and collective results. Data generated by operators far removed from the machines and exerting their efforts at times other than those of machine operation show similar effect sizes and structural details to those of the local, on-time experiments. Most other secondary parameters tested are found to have little effect on the scale and character of the results, with one important exception: studies performed using fully deterministic pseudorandom sources, either hard-wired or algorithmic, yield null overall mean shifts, and display no other anomalous features.

Cardiometabolic risk profile based on body mass index in American Indian children and adolescents.

BACKGROUND: Childhood obesity is associated with increased cardiometabolic risk. OBJECTIVE: To study the relationship between body mass index (BMI) and cardiometabolic risk factors in American Indian children and adolescents. METHODS: Differences in metabolic variables by age and sex-specific BMI percentiles (2000 Centers for Disease Control and Prevention Growth Charts) were examined in a cross-sectional analysis of 2977 individuals across three age categories. Children with an exam in two consecutive age categories were included in a longitudinal analysis. Spearman's correlations were used to test the association of BMI percentile with anthropometric and biochemical variables. RESULTS: Body mass index percentile correlated with systolic (r = 0.24 to 0.38) and diastolic (r = 0.13 to 0.22) blood pressure, fasting plasma glucose (r = 0.20 to 0.33), 2-h plasma glucose (r = 0.30 to 0.46), total cholesterol (r = 0.12 to 0.23), serum triglycerides (r = 0.40 to 0.51) and HDL cholesterol (r = -0.36 to -0.43) in each age group (5-9, 10-13 and 14-17 years). Among participants examined in multiple age categories, BMI percentile increased over time. Change in BMI percentile from one age category to the next was associated with an increase in fasting glucose, 2-h glucose and triglycerides and a decrease in HDL cholesterol. CONCLUSION: Higher BMI was associated with blood pressure elevation, hyperglycaemia and dyslipidaemia in American Indian children and adolescents.

Effect of hypertension on mortality in Pima Indians.

BACKGROUND: The effect of hypertension on mortality was examined in 5284 Pima Indians, 1698 of whom had type 2 diabetes at baseline or developed it during follow-up. METHODS AND RESULTS: During a median follow-up of 12.2 years (range, 0.01 to 24.8 years), 470 nondiabetic subjects and 488 diabetic subjects died. In the nondiabetic subjects, 45 of the deaths were due to cardiovascular disease, 208 to other natural causes, and 217 to external causes; in the diabetic subjects, 106 of the deaths were due to cardiovascular disease, 85 to diabetic nephropathy, 226 to other natural causes, and 71 to external causes. In the nondiabetic subjects, after adjusting for age, sex, body mass index, and serum cholesterol concentration in a proportional hazards model, hypertension predicted death from cardiovascular disease (death rate ratio [DRR]=2.8; 95% CI, 1.4 to 5. 6; P=0.003). In the diabetic subjects, after additional adjustment for duration of diabetes, plasma glucose concentration, and proteinuria, hypertension strongly predicted deaths from diabetic nephropathy (DRR=3.5; 95% CI, 1.7 to 7.2; P<0.001), but it had little effect on deaths from cardiovascular disease (DRR=1.4; 95% CI, 0.88 to 2.3; P=0.15). CONCLUSIONS: We propose that the weak relationship between hypertension and cardiovascular disease in diabetic Pima Indians is not because of a diminished effect of hypertension on cardiovascular disease in diabetes, but because of a relatively greater effect of hypertension on the progression of diabetic nephropathy. Factors that may account for this finding in Pima Indians include a younger age at onset of type 2 diabetes, a low frequency of heavy smoking, favorable lipoprotein profiles and, possibly, enhanced susceptibility to renal disease.

Intrauterine diabetes exposure and the risk of renal disease in diabetic Pima Indians.

The association between the diabetic intrauterine environment and renal disease was examined cross-sectionally in 503 Pima Indians with type 2 diabetes. Subjects were selected from participants in an ongoing study of diabetes and its complications in the Gila River Indian Community of Arizona. Subjects' exposure to diabetes in utero was established from periodic examinations conducted as part of the study. The prevalence of elevated urinary albumin excretion (UAE) (albumin-to-creatinine ratio > or = 30 mg/g) was 40% (83 of 207) in the offspring of nondiabetic mothers, 43% (105 of 246) in the offspring of prediabetic mothers (i.e., women who were not diabetic at the time of the pregnancy but who developed diabetes after the pregnancy), and 58% (29 of 50) in the offspring of mothers who had diabetes during pregnancy. After controlling for age, sex, duration of diabetes, HbA1c, and mean arterial pressure in the offspring in a logistic regression analysis using generalized estimating equations, maternal diabetes during pregnancy was strongly associated with elevated UAE. The odds of elevated UAE in the offspring of mothers who had diabetes during pregnancy was 3.8 times (95% CI 1.7-8.4) that of the offspring of prediabetic mothers; the odds of elevated UAE in the offspring of nondiabetic and prediabetic mothers were similar (odds ratio of 0.94; 95% CI 0.59-1.5). We concluded that exposure to a diabetic intrauterine environment increases the risk of elevated UAE in diabetic Pima Indians. The effect of this exposure appears to be independent of other susceptibility factors that lead to nephropathy in diabetes.

Effect of glycemia on mortality in Pima Indians with type 2 diabetes.

The effect of plasma glucose concentration on overall and cause-specific mortality was examined in 1,745 Pima Indians (725 men, 1,020 women) > or = 15 years old with type 2 diabetes. During a median follow-up of 10.6 years (range 0.1-24.8), 533 subjects (275 men, 258 women) died; 113 of the deaths were attributable to cardiovascular disease, 96 to diabetes-related diseases (diabetic nephropathy for 92 of these), 249 to other natural causes, and 75 to external causes. After adjusting for age, sex, duration of diabetes, and BMI in a generalized additive proportional hazards model, higher baseline 2-h postload plasma glucose concentration predicted deaths from cardiovascular disease (P = 0.007) and diabetes-related diseases (P = 0.003), but not from other natural causes (P = 0.73). An increment of 5.6 mmol/l (100 mg/dl) in the 2-h plasma glucose concentration was associated with 1.2 times (95% CI 1.1-1.4) the death rate from cardiovascular disease, 1.3 times (95% CI 1.1-1.5) the death rate from diabetes-related diseases, and almost no change in the death rate from other natural causes (rate ratio = 1.0; 95% CI 0.94-1.1). In Pima Indians with type 2 diabetes, higher plasma glucose concentration predicts deaths from cardiovascular and diabetes-related diseases but has little or no effect on deaths from other natural or external causes.

Effect of proteinuria on mortality in NIDDM.

The effect of proteinuria (greater than or equal to approximately 1 g/day) on mortality in non-insulin-dependent diabetes mellitus (NIDDM) was assessed in Pima Indians aged greater than or equal to 45 yr. Among 1426 subjects, 48% with NIDDM at the beginning of followup, there were 489 deaths in 13,345 person-yr of observation. The age- and sex-adjusted mortality rate was 32.7/1000 person-yr (95% Cl = 27.6, 37.8) in diabetic subjects without proteinuria, similar to the rate of 30.1/1000 person-yr (95% Cl = 25.7, 34.4) in nondiabetic subjects without proteinuria. By contrast, in diabetic subjects with proteinuria the mortality rate was 121.4/1000 person-yr (95% Cl = 97.5, 145.3). When controlled for age, sex, and diabetes duration, diabetic subjects with proteinuria had a death rate 3.5 times as high (95% Cl = 2.8, 4.4) as those without proteinuria. Of the excess mortality associated with NIDDM in Pima Indians, 97% was found in subjects with proteinuria. The death rate in diabetic subjects without proteinuria was not appreciably greater than the rate in nondiabetic subjects. Mortality rates from uremia and cardiovascular disease were significantly higher in diabetic Pima Indians with proteinuria than in those without. These relationships are similar to observations reported in people with insulin-dependent diabetes.

Proliferative retinopathy in NIDDM. Incidence and risk factors in Pima Indians.

The incidence of proliferative diabetic retinopathy was determined in the Pima Indians of the Gila River Indian Community in Arizona. Over 4 yr, this complication developed in 25 of 953 subjects greater than or equal to 9 yr of age with non-insulin-dependent diabetes. No cases were diagnosed in less than 35-yr-old subjects, and the incidence was strongly related to the duration of diabetes. The cumulative incidence of proliferative retinopathy after 20 yr duration was 14%. All cases of proliferative retinopathy occurred in subjects with background retinopathy. Younger age at diagnosis of diabetes was associated with a higher incidence of proliferation when subjects with diabetes of similar duration were compared. A higher incidence of proliferative retinopathy, after controlling for age, sex, and diabetes duration, was associated with hypertension, proteinuria, renal insufficiency, absence of Achilles tendon reflex, elevated total serum cholesterol concentration, and insulin therapy.

Insulin treatment, endogenous insulin concentration, and ECG abnormalities in diabetic Pima Indians. Cross-sectional and prospective analyses.

The prevalence and incidence of CHD, defined by ECG abnormalities according to the Tecumseh criteria for Minnesota Codes, were determined in Pima Indians greater than or equal to 25 yr of age. In a cross-sectional analysis, the age-sex-adjusted prevalence (+/- SE) of ECG abnormalities was higher in 1454 NIDDM patients (6.86 +/- 0.65%) than in 1696 nondiabetic subjects (3.23 +/- 0.63%; prevalence rate ratio = 2.12; 95% CI 1.39-3.25). In a prospective analysis, the age-sex-adjusted incidence (+/- SE) of ECG abnormalities was higher in 824 NIDDM patients (12.77 +/- 1.67) than in 935 nondiabetic subjects (5.93 +/- 1.43 cases/1000 person-yr; incidence rate ratio = 2.15; 95% CI 1.26-3.69). The prevalence of ECG abnormalities in insulin-treated NIDDM patients was significantly higher than in NIDDM patients not treated with insulin (age-sex-adjusted OR = 2.83; 95% CI 1.84-4.33); and this association persisted when adjusted for other factors such as sBP, BMI, duration of diabetes, serum cholesterol concentration, and oral hypoglycemic agents (OR = 2.12; 95% CI 1.34-3.37). In the prospective analysis, the incidence of ECG abnormalities in NIDDM patients treated with insulin was higher than in those NIDDM patients not treated with insulin, but, when controlled for age, sex, duration of diabetes, and oral hypoglycemic agents in a proportional-hazards model, the relationship with insulin treatment was not statistically significant (incidence rate ratio = 1.36; 95% CI 0.80-2.31). This suggests that insulin treatment may be a marker of more severe diabetes, and that factors associated with clinical indications for insulin treatment, rather than insulin treatment per se, are related causally to CHD. On the other hand, endogenous fasting and 2-h postload serum insulin concentrations were not associated with ECG abnormalities among 761 NIDDM patients not treated with insulin nor among 1226 nondiabetic subjects. Furthermore, in the prospective study, neither endogenous fasting nor 2-h postload serum insulin was associated with the subsequent development of ECG abnormalities in NIDDM patients or nondiabetic subjects.

Abnormal glucose tolerance during pregnancy in Pima Indian women. Long-term effects on offspring.

The long-term effects on offspring of abnormal glucose tolerance detected during pregnancy were examined in 552 Pima Indian offspring 5-24 yr of age. Fasting hyperinsulinemia, presumably reflecting increased insulin resistance, occurred at an earlier age in the offspring of women who had abnormal glucose tolerance during pregnancy, and these offspring were more obese and had higher rates of abnormal glucose tolerance. When confounding factors were controlled, a 1 mM higher 2-h postload glucose concentration during pregnancy resulted in a significantly higher prevalence of diabetes in the offspring (odds ratio = 162). Maternal 2-h glucose concentration during pregnancy was also a significant predictor of glucose concentration during pregnancy in the offspring (P = 0.011). Thus, the metabolic abnormalities associated with the diabetic pregnancy result in long-term effects on the offspring, including insulin resistance, obesity, and diabetes, which in turn may contribute to transmission of risk for developing the same problems in the next generation.

Insulin and hypertension. Relationship to obesity and glucose intolerance in Pima Indians.

The relationships among blood pressure, obesity, glucose tolerance, and serum insulin concentration were studied in 2873 Pima Indians aged 18-92 yr (mean 37 yr). Age- and sex-adjusted to the Pima population, the prevalence of hypertension (systolic blood pressure greater than or equal to 160 mmHg, diastolic blood pressure greater than or equal to 95 mmHg, or receiving drug treatment) was 7.1% for subjects with normal glucose tolerance compared with 13.0% for subjects with impaired glucose tolerance (IGT) and 19.8% for those with non-insulin-dependent diabetes mellitus (NIDDM) (P less than 0.001). The prevalence ratio of hypertension was 1.8 (95% confidence interval [CI] 1.2-2.5) for IGT and 2.6 (95% CI 2.0-3.2) for NIDDM compared with normal glucose tolerance, controlled for age, sex, and body mass index (BMI). In logistic regression analysis, hypertension was positively related to age, male sex, BMI, glucose tolerance, and fasting but not 2-h postload serum insulin concentration. Among subjects not taking antihypertensive drugs, however, neither fasting nor 2-h postload serum insulin was significantly related to hypertension. Furthermore, in 2033 subjects receiving neither antihypertensive nor antidiabetic drugs, blood pressure was not significantly correlated to fasting insulin concentration, and 2-h postload serum insulin was negatively correlated with diastolic blood pressure. In conclusion, insulin is not significantly related to blood pressure in Pima Indians not receiving antihypertensive drugs. Higher insulin concentrations in drug-treated hypertensive patients might result from the treatment rather than contribute to the pathogenesis of hypertension. Thus, these data do not support a major role for insulin in determining the occurrence of hypertension or regulation of blood pressure in Pima Indians.

Preventing non-insulin-dependent diabetes.

Many risk factors for non-insulin-dependent diabetes mellitus (NIDDM), such as obesity, physical inactivity, and high-fat diet, can potentially be modified. Furthermore, some of the metabolic abnormalities, such as insulin resistance and impaired glucose tolerance, that predict diabetes can be improved by behavior modification and drug treatment. Thus, at least to some extent, NIDDM may be preventable. Several small clinical trials have addressed the hypothesis that NIDDM can be prevented by dietary modification, physical activity, or drug treatment. Some studies suggest a preventive effect, but the conclusions are limited by considerations of sample size, randomization, or intensity of the interventions. Consequently, the hypothesis that NIDDM is preventable requires further testing.