Maternal obesity, gestational diabetes, breastfeeding and childhood overweight at age 2 years.

BACKGROUND: Maternal obesity, excessive gestational weight gain (EGWG), gestational diabetes mellitus (GDM) and breastfeeding are four important factors associated with childhood obesity. OBJECTIVES: The objective of the study was to assess the interplay among these four factors and their independent contributions to childhood overweight in a cohort with standard clinical care. METHODS: The cohort included 15 710 mother-offspring pairs delivered in 2011. Logistic regression was used to assess associations between maternal exposures and childhood overweight (body mass index >85th percentile) at age 2 years. RESULTS: Mothers with pre-pregnancy obesity or overweight were more likely to have EGWG, GDM and less likely to breastfeed ≥6 months. Mothers with GDM had 40-49% lower EGWG rates and similar breastfeeding rates compared with mothers without GDM. Analysis adjusted for exposures and covariates revealed an adjusted odds ratio (95% confidence interval) associated with childhood overweight at age 2 years of 2.34 (2.09-2.62), 1.50 (1.34-1.68), 1.23 (1.12-1.35), 0.95 (0.83-1.10) and 0.76 (0.69-0.83) for maternal obesity, overweight, EGWG, GDM and breastfeeding ≥6 months vs. <6 months, respectively. CONCLUSIONS: In this large clinical cohort, GDM was not associated with, but maternal pre-pregnancy obesity or overweight and EGWG were independently associated with an increased risk, and breastfeeding ≥6 months was associated with a decreased risk of childhood overweight at age 2 years.

Living near a freeway is associated with lower bone mineral density among Mexican Americans.

UNLABELLED: We hypothesized that chronic exposures to traffic combustion products may lower bone mineral density (BMD). We found that proximity to freeways was associated with reduced BMD. Our findings suggest that traffic-related pollution may contribute to the occurrence of osteopenia and osteoporosis. INTRODUCTION: Adults residing in rural areas have been linked with higher BMD. We aimed to determine if this difference is due in part to air pollution by examining the relationships between traffic metrics and ambient air pollution with total body and pelvic BMD. METHODS: Mexican American adults (n = 1,175; mean 34 years; 72 % female) who had participated in the BetaGene study of air pollution, obesity, and insulin resistance were included in this analysis. Total body and pelvic BMD were estimated using dual-energy X-ray absorptiometry. Traffic and ambient air pollutant exposures were estimated at residences using location and ambient monitoring data. Variance component models were used to analyze the associations between residential distance to the nearest freeway and ambient air pollutants with BMD. RESULTS: Residential proximity to a freeway was associated with lower total body BMD (p-trend = 0.01) and pelvic BMD (p-trend = 0.03) after adjustment for age, sex, weight, and height. The adjusted mean total body and pelvic BMD in participants living within 500 m of a freeway were 0.02 and 0.03 g/cm(2) lower than participants living greater than 1,500 m from a freeway. These associations did not differ significantly by age, sex, or obesity status. Results were similar after further adjustment for body fat and weekly physical activity minutes. Ambient air pollutants (NO2, O3, and PM2.5) were not significantly associated with BMD. CONCLUSIONS: Traffic-related exposures in overweight and obese Mexican Americans may adversely affect BMD. Our findings indicate that long-term exposures to traffic may contribute to the occurrence of osteoporosis and its consequences.

HOMA and Matsuda indices of insulin sensitivity: poor correlation with minimal model-based estimates of insulin sensitivity in longitudinal settings.

AIMS/HYPOTHESIS: Little is known about the performance of surrogates in assessing changes in insulin sensitivity over time. This report compared updated HOMA of insulin sensitivity (HOMA2-%S) and the Matsuda index from OGTTs with minimal model-based estimates of insulin sensitivity (SI) from frequently sampled IVGTTs (FSIGTs) in longitudinal settings and cross-sectional settings. METHODS: Two longitudinal studies were used: one a natural observational study in which 338 individuals were followed for a median of 4 years; one a clinical treatment study in which 97 individuals received pioglitazone treatment and were followed for 1 year. Pairs of OGTTs and FSIGTs were performed at baseline and follow-up. Correlations were computed. Impact of measurement uncertainty was investigated through simulation studies. RESULTS: Correlations between HOMA2-%S and SI from baseline or follow-up data were in the range reported previously (0.61-0.69). By contrast, correlations for changes over time were only 0.35-0.39. The corresponding correlations between the Matsuda index and SI were 0.66-0.72 for cross-sectional data and 0.40-0.48 for longitudinal change. Correlations for changes were significantly lower than the cross-sectional correlations in both studies (p < 0.03). Simulation results demonstrated that the reduced correlations for change were not explained by error propagation, supporting a real limitation of surrogates to fully capture longitudinal changes in insulin sensitivity. CONCLUSIONS/INTERPRETATION: HOMA and Matsuda indices derived from cross-sectional data should be used cautiously in assessing longitudinal changes in insulin sensitivity.

Effect of pioglitazone on body composition and bone density in subjects with prediabetes in the ACT NOW trial.

AIMS: This study examined the effects of pioglitazone on body weight and bone mineral density (BMD) prospectively in patients with impaired glucose tolerance as pioglitazone (TZD) increases body weight and body fat in diabetic patients and increases the risk of bone fractures. METHODS: A total of 71 men and 163 women aged 49.3 (10.7) years [mean (s.d.)]; body mass index (BMI), 34.5 (5.9) kg/m(2) were recruited at five sites for measurements of body composition by dual energy X-ray absorptiometry at baseline and at conversion to diabetes or study end, if they had not converted. RESULTS: Mean follow-up was 33.6 months in the pioglitazone group and 32.1 months in the placebo group. Body weight increased 4.63 ± 0.60 (m ± s.e.) kg in the pioglitazone group compared to 0.98 ± 0.62 kg in the PIO group (p < 0.0001). Body fat rose 4.89 ± 0.42 kg in the pioglitazone group compared to 1.41 ± 0.44 kg, (p < 0.0001) in placebo-treated subjects. The increase in fat was greater in legs and trunk than in the arms. BMD was higher in all regions in men and significantly so in most. PIO decreased BMD significantly in the pelvis in men and women, decreased BMD in the thoracic spine and ribs of women and the lumbar spine and legs of men. Bone mineral content also decreased significantly in arms, legs, trunk and in the total body. CONCLUSIONS: Pioglitazone increased peripheral fat more than truncal fat and decreased BMD in several regions of the body.

Systematic evaluation of validated type 2 diabetes and glycaemic trait loci for association with insulin clearance.

AIMS/HYPOTHESIS: Insulin clearance is a highly heritable trait, for which few quantitative trait loci have been discovered. We sought to determine whether validated type 2 diabetes and/or glycaemic trait loci are associated with insulin clearance. METHODS: Hyperinsulinaemic-euglycaemic clamps were performed in two Hispanic-American family cohorts totalling 1329 participants in 329 families. The Metabochip was used to fine-map about 50 previously identified loci for type 2 diabetes, fasting glucose, fasting insulin, 2 h glucose or HbA1c. This resulted in 17,930 variants, which were tested for association with clamp-derived insulin clearance via meta-analysis of the two cohorts. RESULTS: In the meta-analysis, 38 variants located within seven loci demonstrated association with insulin clearance (p < 0.001). The top signals for each locus were rs10241087 (DGKB/TMEM195 [TMEM195 also known as AGMO]) (p = 4.4 × 10(-5)); chr1:217605433 (LYPLAL1) (p = 3.25 × 10(-4)); rs2380949 (GLIS3) (p = 3.4 × 10(-4)); rs55903902 (FADS1) (p = 5.6 × 10(-4)); rs849334 (JAZF1) (p = 6.4 × 10(-4)); rs35749 (IGF1) (p = 6.7 × 10(-4)); and rs9460557 (CDKAL1) (p = 6.8 × 10(-4)). CONCLUSIONS/INTERPRETATION: While the majority of validated loci for type 2 diabetes and related traits do not appear to influence insulin clearance in Hispanics, several of these loci do show evidence of association with this trait. It is therefore possible that these loci could have pleiotropic effects on insulin secretion, insulin sensitivity and insulin clearance.

Insulin clearance: confirmation as a highly heritable trait, and genome-wide linkage analysis.

AIMS/HYPOTHESIS: We have previously documented a high heritability of insulin clearance in a Hispanic cohort. Here, our goal was to confirm the high heritability in a second cohort and search for genetic loci contributing to insulin clearance. METHODS: Hyperinsulinaemic-euglycaemic clamps were performed in 513 participants from 140 Hispanic families. Heritability was estimated for clamp-derived insulin clearance and a two-phase genome-wide linkage scan was conducted using a variance components approach. Linkage peaks were further investigated by candidate gene association analysis in two cohorts. RESULTS: The covariate-adjusted heritability of insulin clearance was 73%, indicating that the majority of the phenotypic variance is due to genetic factors. In the Phase 1 linkage scan, no signals with a logarithm of odds (LOD) score >2 were detected. In the Phase 2 scan, two linkage peaks with an LOD >2 for insulin clearance were identified on chromosomes 15 (LOD 3.62) and 20 (LOD 2.43). These loci harbour several promising candidate genes for insulin clearance, with 12 single nucleotide polymorphisms (SNPs) on chromosome 15 and six SNPs on chromosome 20 being associated with insulin clearance in both Hispanic cohorts. CONCLUSIONS/INTERPRETATION: In a second Hispanic cohort, we confirmed that insulin clearance is a highly heritable trait and identified chromosomal loci that harbour genes regulating insulin clearance. The identification of such genes may improve our understanding of how the body clears insulin, thus leading to improved risk assessment, diagnosis, prevention and therapy of diabetes, as well as of other hyperinsulinaemic disorders, such as the metabolic syndrome and polycystic ovary syndrome.

Racial and ethnic disparities in diabetes risk after gestational diabetes mellitus.

AIMS/HYPOTHESIS: To investigate racial/ethnic disparities in diabetes risk after gestational diabetes mellitus (GDM). METHODS: This is a retrospective cohort study of women enrolled in the Kaiser Permanente Southern California health plan from 1995 to 2009. GDM status was identified on the basis of plasma glucose levels during pregnancy. The incidence of diabetes after the first delivery complicated by GDM before 31 December 2009 (n = 12,998) was compared with the experience for women without GDM (n = 64,668) matched on maternal age at delivery, race/ethnicity and year of delivery (1:5 ratio). Matched Cox regression was used to compare the RRs of diabetes associated with GDM within and across racial/ethnic groups. RESULTS: Compared with the women without GDM, the HRs (95% CI) of diabetes for women after GDM were 6.5 (5.2, 8.0) in non-Hispanic white, 7.7 (6.8, 8.7) in Hispanic, 9.9 (7.5, 13.1) in black and 6.3 (5.0, 7.9) in Asian/Pacific Islanders after adjustment for parity, maternal education, comorbidity and number of outpatient visits before the index pregnancy. The HR of diabetes for black women was significantly higher than that for non-Hispanic white women (p = 0.032). Further adjustment for prepregnancy BMI reduced the diabetes risk association with GDM for each racial/ethnic group, but did not explain the risk differences across groups. CONCLUSIONS/INTERPRETATIONS: Racial/ethnic disparities exist in risk of diabetes after GDM. Black women with GDM had the highest risk of developing diabetes. This highlights the importance of developing an effective diabetes screening and prevention programme in women with GDM, particularly black women with GDM.

Determinants of glucose tolerance in impaired glucose tolerance at baseline in the Actos Now for Prevention of Diabetes (ACT NOW) study.

AIMS/HYPOTHESIS: The aim of the study was to examine the determinants of oral glucose tolerance in 602 persons with impaired glucose tolerance (IGT) who participated in the Actos Now for Prevention of Diabetes (ACT NOW) study. METHODS: In addition to the 602 IGT participants, 115 persons with normal glucose tolerance (NGT) and 50 with impaired fasting glucose (IFG) were identified during screening and included in this analysis. Insulin secretion and insulin sensitivity indices were derived from plasma glucose and insulin during an OGTT. The acute insulin response (AIR) (0-10 min) and insulin sensitivity (S(I)) were measured with the frequently sampled intravenous glucose tolerance test (FSIVGTT) in a subset of participants. RESULTS: At baseline, fasting plasma glucose, 2 h postprandial glucose (OGTT) and HbA(1c) were 5.8 +/- 0.02 mmol/l, 10.5 +/- 0.05 mmol/l and 5.5 +/- 0.04%, respectively, in participants with IGT. Participants with IGT were characterised by defects in early (DeltaI (0-30)/DeltaG (0-30) x Matsuda index, where DeltaI is change in insulin in the first 30 min and DeltaG is change in glucose in the first 30 min) and total (DeltaI(0-120)/DeltaG(0-120) x Matsuda index) insulin secretion and in insulin sensitivity (Matsuda index and S(I)). Participants with IGT in whom 2 h plasma glucose was 7.8-8.3 mmol/l had a 63% decrease in the insulin secretion/insulin resistance (disposition) index vs participants with NGT and this defect worsened progressively as 2 h plasma glucose rose to 8.9-9.94 mmol/l (by 73%) and 10.0-11.05 mmol/l (by 80%). The Matsuda insulin sensitivity index was reduced by 40% in IGT compared with NGT (p < 0.005). In multivariate analysis, beta cell function was the primary determinant of glucose AUC during OGTT, explaining 62% of the variance. CONCLUSION: Our results strongly suggest that progressive beta cell failure is the main determinant of progression of NGT to IGT.

The association of smoking and subclinical atherosclerosis in Type 2 diabetes: modification by duration of diabetes.

BACKGROUND: Diabetes is a relatively common disease in the United States, and cardiovascular disease is the major cause of morbidity and mortality among persons with diabetes. While smoking is one of the most well-established risk factors for heart disease and atherosclerosis, the effect of smoking on atherosclerosis among diabetic patients has not been thoroughly investigated. The primary objective of this paper was to evaluate the impact of smoking on atherosclerosis among Type 2 diabetic patients and to evaluate whether smoking associations with atherosclerosis are modified by diabetes-related variables. METHODS: We used cross-sectional baseline data from a randomized controlled trial to evaluate the associations between smoking and common carotid artery intima-media thickness (IMT) in 299 subjects with Type 2 diabetes. There were 34 (11%) current cigarette smokers, 73 (24%) former cigarette smokers, and 192 (64%) subjects who had never smoked regularly. RESULTS: There was an increasing trend in mean carotid IMT with both longer duration and increased frequency of smoking (adjusted P for trend 0.04 and 0.02, respectively). The mean +/- SE carotid IMT was non-significantly thicker (0.872 +/- 0.01 mm) in diabetic patients who had ever smoked than never smokers (0.842 +/- 0.01 mm) after controlling for age, gender and other potential confounders (P = 0.08). The negative effects of ever smoking (P = 0.01 for interaction), number of cigarettes smoked daily (P = 0.003 for interaction) and duration of smoking (P = 0.03 for interaction) on carotid IMT were accentuated with longer duration of diabetes. CONCLUSION: Smoking is associated with subclinical atherosclerosis in diabetic persons and interacts with duration of diabetes to accentuate atherosclerosis. The association between carotid IMT and duration of diabetes increases with both the frequency and duration of smoking.

Variation in the resistin gene is associated with obesity and insulin-related phenotypes in Finnish subjects.

AIMS/HYPOTHESIS: Resistin is a peptide hormone produced by adipocytes that is present at high levels in sera of obese mice and may be involved in glucose homeostasis through regulation of insulin sensitivity. Several studies in humans have found associations between polymorphisms in the resistin gene and obesity, insulin sensitivity and blood pressure. An association between variation in the resistin gene and type 2 diabetes has been reported in some, but not all studies. The aim of this study was to analyse variants of the resistin gene for association with type 2 diabetes and related traits in a Finnish sample. METHODS: In 781 cases with type 2 diabetes, 187 spouse controls and 222 elderly controls of Finnish origin, we genotyped four previously identified non-coding single-nucleotide polymorphisms (SNPs): -420C>G from the promoter region, +156C>T and +298G>A from intron 2, and +1084G>A from the 3' untranslated region. We then tested whether these SNPs were associated with type 2 diabetes and related traits. RESULTS: The SNPs were not significantly associated with type 2 diabetes. However, SNPs -420C>G, +156C>T and +298G>A and the common haplotype for these three markers were associated with increased values of weight-related traits and diastolic blood pressure in cases, lower weight in elderly control subjects, and lower insulin sensitivity and greater acute insulin response in spouses. Furthermore, the +1084G allele was associated with lower HDL cholesterol in both cases and controls, higher systolic blood pressure and waist circumference in cases, and greater acute insulin response in spouse controls. CONCLUSIONS/INTERPRETATION: Our results add to growing evidence that resistin is associated with variation in weight, fat distribution and insulin resistance.

Duplication of the optic disc: true or pseudo? A coloboma or not a coloboma?

PURPOSE: To present an unusual case of optic disc pseudoduplication with colobomata. METHODS: Clinical evaluation, fundus photography and literature review. RESULTS: Optic disc duplication is a rare clinical entity. CONCLUSIONS: We report what we believe to be the first case of pseudoduplication of the optic disc with coexistent bilateral optic disc colobomata.

Decreased red blood cell aggregation subsequent to improved glycaemic control in Type 2 diabetes mellitus.

AIMS: Reports of rheological changes following intensification of metabolic control are limited and not concordant. The present study was designed to test the hypothesis that intensification of management of Type 2 diabetes (T2DM) with diet, exercise and insulin improves haemorheological behaviour by reducing red blood cell (RBC) aggregation. METHODS: Blood was sampled from 55 subjects before and following 14 +/- 3 weeks of intensified management. RBC aggregation was measured in vitro for cells in plasma or in an aggregating 70 kD dextran solution. Plasma viscosity and whole blood viscosity were also measured. RESULTS: During treatment, fasting glucose fell 27%, HbA1c fell 21%, and serum triglycerides and total cholesterol fell 28% and 12%, respectively (P < 0.0001 for each). The extent and strength of RBC aggregation in plasma fell by 10-13% (P < 0.002). Similar decreases of RBC aggregation were seen for cells suspended in dextran (P < 0.002). Plasma viscosity decreased by 3% (P < 0.02) and high shear blood viscosity by 6-7% (P < 0.0001). Changes of RBC aggregation in plasma and in dextran were significantly correlated, supporting a cellular rather than a plasmatic origin for these changes. However, there were no significant correlations between RBC aggregation changes and changes of fasting glucose, HbA1c, serum triglycerides, serum cholesterol, or plasma fibrinogen. CONCLUSIONS: Intensified metabolic control results in a reduction of RBC aggregation that appears to be intrinsic to RBC. Since increased RBC aggregation can impair microcirculatory flow, it is possible that haemorheological factors may contribute to the reduction of microvascular complications resulting from improved metabolic control in T2DM.

Autoantibodies and human leucocyte antigen class II in first-degree family members of Mexican-American type 1 diabetic patients.

As part of a genetic study of type 1 diabetes in Mexican-Americans, 360 first-degree relatives of 108 type 1 diabetic probands were studied. Islet cell antibody (ICA), insulin autoantibody, glutamic acid decarboxylase (GAD(65)), and protein tyrosine phosphatase autoantibodies were measured and human leucocyte antigen (HLA) class II alleles DRB1 and DQB1 genotyping was performed. ICA was positive in 37% of the probands and 5.8% of the relatives. A subgroup of 26 probands (12 ICA+, 14 ICA-) was tested for GAD(65) and was found positive. 4/14 ICA+ first-degree relatives were GAD(65) positive. Four relatives, positive for two antibodies, subsequently developed type 1 diabetes. Life-Table analysis of first-degree relatives with autoantibodies indicated an 80% disease-free survival at 3.5 yr. HLA-DRB1 was found to be associated with the presence of ICA in both probands and relatives, whereas HLA-DPB1 was associated with autoantibody in relatives of type 1 diabetic probands. These results suggest that autoimmunity occurs in type 1 diabetes families of Mexican descent in similar frequencies to that of non-Hispanic, Caucasian families. The presence of autoantibodies appears to be regulated in part by HLA class II genes, even in the absence of overt diabetes.

A randomized controlled trial using glycemic plus fetal ultrasound parameters versus glycemic parameters to determine insulin therapy in gestational diabetes with fasting hyperglycemia.

OBJECTIVE: To compare management based on maternal glycemic criteria with management based on relaxed glycemic criteria and fetal abdominal circumference (AC) measurements in order to select patients for insulin treatment of gestational diabetes mellitus (GDM) with fasting hyperglycemia. RESEARCH DESIGN AND METHODS: In a pilot study, 98 women with fasting plasma glucose (FPG) concentrations of 105-120 mg/dl were randomized. The standard group received insulin treatment. The experimental group received insulin if the AC, measured monthly, was > or =70th percentile and/or if any venous FPG measurement was >120 mg/dl. Power was projected to detect a 250-g difference in birth weights. RESULTS: Gestational ages, maternal glycemia, and AC percentiles were similar at randomization. After initiation of protocol, venous FPG (P = 0.003) and capillary blood glucose levels (P = 0.049) were significantly lower in the standard group. Birth weights (3,271 +/- 458 vs. 3,369 +/- 461 g), frequencies of birth weights >90th percentile (6.3 vs 8.3%), and neonatal morbidity (25 vs. 25%) did not differ significantly between the standard and experimental groups, respectively. The cesarean delivery rate was significantly lower (14.6 vs. 33.3%, P = 0.03) in the standard group; this difference was not explained by birth weights. In the experimental group, infants of women who did not receive insulin had lower birth weights than infants of mothers treated with insulin (3,180 +/- 425 vs. 3,482 +/- 451 g, P = 0.03). CONCLUSIONS: In women with GDM and fasting hyperglycemia, glucose plus fetal AC measurements identified pregnancies at low risk for macrosomia and resulted in the avoidance of insulin therapy in 38% of patients without increasing rates of neonatal morbidity.

Coincident linkage of fasting plasma insulin and blood pressure to chromosome 7q in hypertensive hispanic families.

BACKGROUND: Insulin resistance (IR) and hyperinsulinemia are phenotypically associated with hypertension. We have previously provided evidence that blood pressure (BP) and IR cosegregate in Hispanic families, suggesting that this association has a genetic component. In the present study, we provide further support for the hypothesis of a genetic basis for the BP-IR relationship from a genetic linkage study. METHODS AND RESULTS: A 10-cM genome scan was conducted in 390 Hispanic family members of 77 hypertensive probands. Detailed measurements of BP, glucose, insulin levels, and insulin sensitivity (euglycemic clamp) were performed in adult offspring of probands. Multipoint variance component linkage analysis was used. A region on chromosome 7q seemed to influence both IR and BP. The greatest evidence for linkage was found for fasting insulin (lod score=3.36 at 128 cM), followed by systolic BP (lod score=2.06 at 120 cM). Fine mapping with greater marker density in this region increased the maximum lod score for fasting insulin to 3.94 at 125 cM (P=0.00002); lod score for systolic BP was 2.51 at 112 cM. Coincident mapping at this locus also included insulin sensitivity measured by the homeostasis assessment model (HOMA) and serum leptin concentrations. Insulin sensitivity by euglycemic clamp did not map to the same locus. CONCLUSIONS: Our results demonstrate that a major gene determining fasting insulin is located on chromosome 7q. Linkage of BP, HOMA, and leptin levels to the same region suggests this locus may broadly influence traits associated with IR and supports a genetic basis for phenotypic associations in IR syndrome.

Prospective evaluation of the effect of initiating indinavir-based therapy on insulin sensitivity and B-cell function in HIV-infected patients.

OBJECTIVE: To determine whether initiation of antiretroviral therapy that includes the protease inhibitor indinavir causes insulin resistance or abnormal B-cell function in study subjects with HIV infection. METHODS: Nonwasted, HIV-infected study subjects who did not have concurrent diabetes were prospectively evaluated by oral and intravenous glucose tolerance testing at baseline, at 2 weeks after starting indinavir monotherapy, and at another 6 weeks after initiating indinavir-based triple-therapy. RESULTS: Mean CD4 count at entry was 282 cells/microl and median HIV RNA was 33,000 copies/ml; all experienced a virologic response. Fasting glucose increased from 83.2 +/- 3.7 mg/dl at baseline to 86.8 +/- 3.2 at week 2 and 91.7 +/- 3.5 at week 8 (p =.003). Insulin sensitivity by minimal model analysis decreased by 30.5% over 8 weeks, from 3.83 +/- 0.63 min-1 per microU/ml x 10-4 to 3.09 +/- 0.53 at week 2 and 2.66 +/- 0.35 at week 8 (p =.01). Insulin secretion by the acute insulin response to intravenous glucose did not change (baseline 822 +/- 283 microU/ml x min, week 8 880 +/- 289; p = 0.4), and the insulin response to oral glucose (30 minute insulin:glucose ratio) fell from 1.69 +/- 0.54 microU/ml per mg/dl at baseline to 1.18 +/- 0.34 at week 8 (p =.05). CONCLUSION: During 8 weeks of indinavir-based therapy, fasting glucose increased and insulin sensitivity decreased, without a compensatory increase in insulin release. This combination of insulin resistance without augmented B-cell response may explain the hyperglycemia and other metabolic abnormalities seen in some protease inhibitor-treated patients.

The peroxisome proliferator-activated receptor-gamma2 Pro12A1a variant: association with type 2 diabetes and trait differences.

Recent studies have identified a common proline-to-alanine substitution (Pro12Ala) in the peroxisome proliferator-activated receptor-gamma2 (PPAR-gamma2), a nuclear receptor that regulates adipocyte differentiation and possibly insulin sensitivity. The Pro12Ala variant has been associated in some studies with diabetes-related traits and/or protection against type 2 diabetes. We examined this variant in 935 Finnish subjects, including 522 subjects with type 2 diabetes, 193 nondiabetic spouses, and 220 elderly nondiabetic control subjects. The frequency of the Pro12Ala variant was significantly lower in diabetic subjects than in nondiabetic subjects (0.15 vs. 0.21; P = 0.001). We also compared diabetes-related traits between subjects with and without the Pro12Ala variant within subgroups. Among diabetic subjects, the variant was associated with greater weight gain after age 20 years (P = 0.023) and lower triglyceride levels (P = 0.033). Diastolic blood pressure was higher in grossly obese (BMI >40 kg/m2) diabetic subjects with the variant. In nondiabetic spouses, the variant was associated with higher fasting insulin (P = 0.033), systolic blood pressure (P = 0.021), and diastolic blood pressure (P = 0.045). These findings support a role for the PPAR-gamma2 Pro12Ala variant in the etiology of type 2 diabetes and the insulin resistance syndrome.

Evidence for joint genetic control of insulin sensitivity and systolic blood pressure in hispanic families with a hypertensive proband.

BACKGROUND: The clustering of hypertension, insulin resistance, and obesity remains unexplained. We tested for genetic and nongenetic influences on the association among these traits in Hispanic families with hypertension. METHODS AND RESULTS: Blood pressure and body mass index (BMI) were measured in 331 members of 73 Hispanic families in which an index case (proband) had hypertension. Insulin sensitivity (S(I)) was measured by euglycemic clamp in 287 probands and their spouses (parents' generation) or their adult offspring. Correlation analysis examined relationships among traits within and between generations. Path analysis estimated genetic and nongenetic contributions to variability in systolic blood pressure (SBP), S(I), and the correlation between them. In the offspring, there was a significant correlation between individuals for each trait, as well as significant correlations within and between individuals for all possible pairs of traits. Between generations, SBP, S(I), and BMI in parents correlated with the same traits in their offspring; BMI in parents correlated with S(I) and SBP in offspring; and S(I) in parents correlated with SBP in offspring. Path analysis estimated that among offspring, genetic effects unrelated to BMI accounted for 60.8% of the variation in SBP, 36.8% of the variation in S(I), and 31.5% of the correlation between SBP and S(I) after adjustment for age and sex. Heritable effects related to BMI accounted for an additional 14.0% of variation in SBP, 26.8% of variation in S(I), and 56.3% of variation in their correlation. CONCLUSIONS: Clustering of hypertension and insulin resistance in Hispanic Americans is accounted for in part by heritable factors both associated with and independent of BMI.