Asian Indian Subjects Research Articles

Improved Clinical Outcomes with the Combination Therapy of a Glucagon-like Peptide-1 Receptor Agonists and a Sodium-glucose Cotransporter-2 Inhibitor in Overweight/Obese People with Type 2 Diabetes: Real-world Evidence from the Indian Subcontinent.

Type 2 diabetes (T2D) mellitus is increasing exponentially in India, with overweight/obesity being prime contributors. This study aimed at assessing the clinical impact of the combination therapy of a glucagon-like peptide-1 receptor agonist (GLP-1RA) injection (inj.) and a sodium-glucose cotransporter-2 inhibitor (SGLT-2i) in overweight/obese patients from the Indian subcontinent. In two real-world evidence (RWE) studies (RWE1 and 2), we retrospectively observed the effect of the combination therapy of a GLP-1RA, injection dulaglutide (DU) 1.5 mg/week, and an SGLT-2i, canagliflozin (CAN) 100 mg/day at weeks 16, 32, and 52 on HbA1c, body weight (weight), systolic blood pressure (SBP), lipids, change in doses of antidiabetic agents (ADA) and antihypertensive agents (AHA) in overweight/obese Asian Indian subjects with T2D, who had suboptimal glycemic control. A total of 95 T2D patients [51 males (M), 44 females (F)] completed the two RWE studies. In RWE 1, 40 patients (20 M/20 F), mean [standard deviation (SD)] age 49.4 (10.7) years (Y), weight 92.6 (6.6) kg, body mass index (BMI) 30.6 (2.3) kg/m2, duration of T2D 8.1 (3.2) Y, completed the study. At week 32, the mean (SD) reduction in A1c (%) was -1.3% [8.4 (0.7) to 7.1 (0.3); p < 0.01] and mean (SD) weight (kg) loss was -5.5 [92.6 (6.6) to 87.9 (7.02); p < 0.00001]. This group was then followed up until week 52. In RWE 2, 55 patients (31 M/24 F), age 51 (5.8) Y, weight 92.6 ± 3.4 kg, BMI 31.1 ± 2.1 kg/m2, SBP 142.4 ± 3.9 mm Hg, estimated glomerular filtration rate (eGFR) 62 ± 5 mL/minute/1.73 m2, with 8.4 ± 3.3 Y duration of diabetes met the inclusion criteria. In 71% of subjects, A1c decreased by -1.4% [8.5 ± 0.4 to 7.1 ± 0.2; p < 0.0001] at week 16 and was 6.8 ± 0.3 (p = 0.0002) in 18% at week 32. A statistically significant (SS) improvement in glycemic control, weight, and improvement in cardiovascular (CV) risk factors was observed with the GLP-1RA/SGLT-2i combination, which was well tolerated.

Insights into atypical segmental layer thicknesses and phase retardation in thick corneas using ultrahigh-resolution polarization-sensitive optical coherence tomography

BackgroundAccurately assessing corneal structural status is challenging when thickness deviates from the average. Polarization-sensitive optical coherence tomography (PS-OCT) measures tissue-specific polarization changes, providing additional contrast for accurate segmentations and aids in phase retardation (PR) measurements. Previous studies have shown PR's effectiveness in identifying sub-clinical keratoconus (KC) in asymmetric cases. Thus, this study aims to assess PR distribution in thick corneas with and without KC.MethodsIn this retrospective and cross-sectional study, 45 thick corneas from 30 Asian-Indian subjects, categorized into healthy (n = 26) and KC (n = 19) groups were analyzed. All eyes underwent standard clinical evaluations, tomographic assessments, and corneal biomechanics measurements. PR and individual layer thicknesses were measured using custom-designed ultrahigh-resolution PS-OCT. PR en-face maps were generated. Individual layer thicknesses and PR analysis was conducted across multiple zones, extending up to 8–10 mm in diameter. All eyes in the study had not undergone interventions, received topical medications, or had previous corneal disease history.ResultsSignificant differences were found in spherical and cylindrical powers, keratometry, pachymetry, and biomechanical indices (all P < 0.01). Thickness profiles from PS-OCT showed significant differences in the 4–8 mm zones only. Bowman's layer thickness significantly differed only in the central 2 mm zone (P = 0.02). The median PR values showed marginal differences in the central 2 mm zone (P = 0.0565). Additionally, there were significant differences observed in the 2–4 mm and 4–6 mm zones (P = 0.0274 and P = 0.0456, respectively). KC eyes exhibited an atypical PR distribution and corneal thinning, while normal eyes maintained a uniform Bowman’s layer thickness and PR maps with larger areas of higher PR.ConclusionThe study revealed distinctive PR distribution in thick corneas among healthy and KC groups. Using an ultrahigh-resolution PS-OCT the significance of Bowman's layer thickness in these groups was also emphasized. The study offered potential improvements in clinical diagnostics by enhancing our understanding of corneal structure and its altered function.

Prenatal Exposure to Tobacco and Cannabis in Six Race/Ethnicity Groups during the First Three Years after Legalization of Cannabis for Recreational Use in California.

There are known health concerns linked to prenatal tobacco and cannabis exposures. This study aims to objectively determine the level of exposure to tobacco and cannabis in pregnant individuals from six race/ethnicity groups (Black, Hispanic, Asian Indian, Native American, Vietnamese, and White) in the first three years following legalization of recreational marijuana use in 2018 in California. We used a cross-sectional sample of prenatal screening program participants (2018-2020) from southern and central California (N = 925). Exposures were estimated by a lab analysis of cotinine (tobacco) and 11-hydroxy-Δ9-tetrahydrocannabinol (OH-THC, cannabis) in banked serum. Disparities in tobacco exposure were evident, with Black subjects experiencing the highest smoking rate (16%) followed by Native American (10%) and White (8%) subjects, and ≤2% among Hispanic, Asian Indian, and Vietnamese subjects. Environmental tobacco exposure generally showed a similar pattern of exposure to tobacco smoking across race/ethnicity groups. Cannabis detection ranged from 5% among Hispanic subjects to 12% and 13% among White and Black subjects, respectively, and was higher among tobacco users and those exposed to environmental tobacco smoke than those with no cotinine detected. Tobacco and cannabis exposure were generally greatest in younger subjects and those with indices of a lower economic status; however, among Black subjects, cannabis exposure was greatest in older subjects and those with a higher socioeconomic status. Race/ethnicity, age, and socioeconomic factors can inform targeting of high-exposure groups for intervention.

Topography and Choroidal Thickness Measurement in Healthy Asian Indian Subjects using RTVue XR 100 Optical Coherence Tomography.

The purpose was to study the choroidal thickness and its profile, derived from different point locations in healthy Asian Indian subjects using RTVue XR 100 optical coherence tomography (OCT) and to determine its correlation with age, refractive error, and axial length. In this cross-sectional study, 300 eyes of 150 healthy subjects, with no ocular pathology, were scanned in a single session, using a line scan protocol of RTVue XR 100 OCT. Choroidal thickness was measured at the subfoveal region, and six measurements were obtained on either side of the fovea (temporal and nasal) at 500 μm interval apart, up to 3000 μm. The correlation between subfoveal choroidal thickness and age, refractive error, and axial length was assessed. Three hundred eyes of 150 healthy subjects were included in the analysis. Median age of the study participants was 55 years (interquartile range [IQR]: 44-61). The median subfoveal choroidal thickness was 235 μm (IQR: 210-263). The choroidal thickness was minimum at nasal 3000 μm from the fovea, while it was maximum in the subfoveal region. The point zones which were near the fovea showed thicker choroidal thickness than the outer zones, both nasally and temporally (P < 0.00001 at all locations), and at all point locations the choroid were thicker temporally than nasally (All P < 0.00001). Subfoveal choroidal thickness showed negative correlation with age (coefficient = -0.62, P = 0.03) and axial length (correlation = -8.52, P = 0.02). A decrease in subfoveal choroidal thickness of 0.62 μm/year was found by regression analysis. Our study provides normative database and topographic profile of choroidal thickness in the normal Asian Indian eyes using RTVue XR 100 OCT.

TCF7L2 gene associated postprandial triglyceride dysmetabolism- a novel mechanism for diabetes risk among Asian Indians.

Aim TCF7L2 gene is believed to increase the risk of T2DM by its effects on insulin secretion. However, the exact mechanism of this enhanced risk is not clearly known. While TCF7L2 gene has been shown to affect lipid metabolism, these effects have remained largely unexplored in the context of diabetes risk.MethodsPostprandial lipid responses to a standardized fat challenge test were performed in 620 Asian Indian subjects (310 with NGT and 310 with T2DM/prediabetes) and compared between the risk and wild genotypes of the rs7903146 TCF7L2 gene. In 30 subjects scheduled to undergo abdominal surgery (10 each with NGT, Prediabetes and T2DM), adipocyte TCF7L2 gene expression was also performed by real time qPCR and confirmed by protein expression in western blot.ResultsT allele of rs7903146 TCF7L2 gene was confirmed as the risk allele for T2DM (OR=1.8(1.2-2.74), p=0.005). TT+CT genotypes of rs7903146 TCF7L2 gene showed significantly higher 4hrTg (p<0.01), TgAUC (p<0.01), peakTg (p<0.01) as well as higher postprandial plasma glucose (p=.006) levels and HOMA-IR (p=0.03) and significantly lower adiponectin levels (p=0.02) as compared to CC genotype. The expression of TCF7L2 gene in VAT was 11-fold higher in prediabetes group as compared to NGT (P<0.01) and 5.7-fold higher in T2DM group as compared to NGT group(P=0.003) and was significantly associated with PPTg and glucose levels.ConclusionThere is significant PPTg dysmetabolism associated with the risk allele of rs7903146 polymorphism as well as adipocyte expression of TCF7L2 gene. Significant upregulation of TCF7L2 gene expression in VAT that correlates with PPTg and glycaemia is also seen in Asian Indians with glucose intolerance. Modulation of PPTg metabolism by TCF7L2 gene and the resultant PPHTg may be a novel mechanism that contributes to its diabetes risk in them.

Heterogeneity in cardio-metabolic risk factors and atherosclerotic cardiovascular disease among Asian groups in the United States

ObjectiveThe Asian American population in the U.S. comprises various, ethnically diverse subgroups. Traditionally, this population has been studied as a single, aggregated group, potentially masking differences in risk among subgroups. Analyses using disaggregated data can help better characterize the health needs of different Asian subpopulations and inform targeted, effective public health interventions. We assessed the prevalence of cardiovascular disease (CVD) risk factors and atherosclerotic CVD (ASCVD) and their associations with socioeconomic factors among Chinese, Asian Indian, Filipino and Other Asian subjects, compared with non-Hispanic White (NHW) subjects in the U.S. Methods: Cross-sectional study using data from 298,286 adults from the National Health Interview Survey (NHIS) from 2007 to 2018. We utilized chi-squared tests to compare characteristics across subgroups. Weighted proportions and unadjusted and adjusted logistic regression models were utilized to examine the associations between Asian subgroups, self-reported CVD risk factors and self-reported ASCVD, as well as between socioeconomic factors within each Asian subgroup. Results: Asian Indian subjects had the highest prevalence of diabetes (12.5%), while Filipino subjects had the highest prevalence of hyperlipidemia (27.7%), hypertension (29.8%) and obesity (19.8%). Despite this, the prevalence of self-reported ASCVD was lower in all Asian groups compared with NHWs. Chinese subjects had the lowest odds of having each of the CVD risk factors assessed. Conclusion: We found considerable heterogeneity in the distribution of risk factors as well as ASCVD among Asian subgroups in the US. Compared with health system or community-based reports, the prevalence of risk factors and ASCVD may be underestimated in some Asian NHIS subgroups. There is an urgent need for efforts to improve recruitment of Asian participants of heterogeneous socioeconomic backgrounds in national surveys, as well as to perform a thorough assessment of risk factors and disease in this population, not relying solely on self-report.

Comparison of islet cell function, insulin sensitivity, and incretin axis between Asian-Indians with either impaired fasting glucose or impaired glucose tolerance, and normal healthy controls

AimsThe objective of this study was to compare the islet cell function, insulin sensitivity, and incretin axis between Asian-Indian subjects with either impaired fasting glucose (IFG), or impaired glucose tolerance (IGT), and normal glucose tolerance (NGT). Materials and methodsPrediabetes subjects underwent a mixed meal tolerance test(MMTT) after overnight fasting. Samples for glucose, insulin, glucagon, and glucagon-like peptide-1 (GLP-1) were collected at 0, 30, 60, and 120 min. Insulin secretion sensitivity index -2 (ISSI-2) for beta-cell function and Matsuda index for insulin sensitivity were assessed. Alpha cell function was assessed by measuring the area under the curve (AUC) 0-120 glucagon/AUC0-120 glucose. ResultsA total of sixty subjects were recruited with 20 in each group. The beta-cell function represented by ISSI-2 was impaired in prediabetes subjects as compared to NGT group (IFG: 2.09 ± 0.44 vs. NGT: 3.04 ± 0.80, P < 0.0001, and IGT: 2.33 ± 0.59 vs. NGT: 3.04 ± 0.80, P = 0.002). Similarly, AUC0-120 glucagon/AUC0-120 glucose was also lower in prediabetes group as compared to healthy controls (IFG: 0.41(0.54) vs. NGT: 1.07(0.39), P = 0.003 and IGT: 0.57(0.38) vs. NGT: 1.07(0.39), P = 0.001). ConclusionAsian-Indian prediabetes subjects have reduced beta-cell function with lesser glucagon secretion during MMTT as compared to normal healthy controls.

PBPK Model of Coproporphyrin I: Evaluation of the Impact of SLCO1B1 Genotype, Ethnicity, and Sex on its Inter-Individual Variability.

Coproporphyrin I (CPI) is an endogenous biomarker of OATP1B activity and associated drug‐drug interactions. In this study, a minimal physiologically‐based pharmacokinetic model was developed to investigate the impact of OATP1B1 genotype (c.521T>C), ethnicity, and sex on CPI pharmacokinetics and interindividual variability in its baseline. The model implemented mechanistic descriptions of CPI hepatic transport between liver blood and liver tissue and renal excretion. Key model parameters (e.g., endogenous CPI synthesis rate, and CPI hepatic uptake clearance) were estimated by fitting the model simultaneously to three independent CPI clinical datasets (plasma and urine data) obtained from white (n = 16, men and women) and Asian‐Indian (n = 26, all men) subjects, with c.521 variants (TT, TC, and CC). The optimized CPI model successfully described the observed data using c.521T>C genotype, ethnicity, and sex as covariates. CPI hepatic active was 79% lower in 521CC relative to the wild type and 42% lower in Asian‐Indians relative to white subjects, whereas CPI synthesis was 23% higher in male relative to female subjects. Parameter sensitivity analysis showed marginal impact of the assumption of CPI synthesis site (blood or liver), resulting in comparable recovery of plasma and urine CPI data. Lower magnitude of CPI‐drug interaction was simulated in 521CC subjects, suggesting the risk of underestimation of CPI‐drug interaction without prior OATP1B1 genotyping. The CPI model incorporates key covariates contributing to interindividual variability in its baseline and highlights the utility of the CPI modeling to facilitate the design of prospective clinical studies to maximize the sensitivity of this biomarker.

Identification of biomarkers for early diagnosis of diabetic nephropathy disease using direct flow through mass spectrometry

Background and aimsAlbuminuria is not an effective marker for early diagnosis of diabetic renal complication with several subjects progressing to chronic kidney disease without any albuminuria. A biomarker that can predict early changes of the diabetic kidney will be useful in effective management of type 2 diabetes. Mass spectrometry based metabolomics approach offers tremendous promise for the identification of novel metabolite biomarkers. MethodsA case-control approach was carried out to identify renal biomarkers among Asian Indian subjects in a hospital setting. A total of 29 subjects were included in the study that included groups of diabetic controls, diabetic subjects with eGFR >90 ml/min/1.72 m2 and diabetic subjects with eGFR between 60 and 89 ml/min/1.72 m2 and eGFR between 15 and 30 ml/min/1.72 m2. We employed an un-targeted mass spectrometry method for the identification of plasma metabolites. ResultsA total of 1414 and 975 metabolites were identified in the positive and negative ion mode respectively. 19 metabolites were up regulated and 18 metabolites were down regulated in CKD2 and CKD4 groups when compared to control. Correlation analysis of the differential metabolites revealed Pregnenolone sulfate, creatinine and ganglioside GA1 to be negatively correlated and hexyl glucoside, all-trans-carophyll yellow and PG to be positively correlated with eGFR. ConclusionWe have identified Pregnenolone sulfate, GA1, PG and all-trans-Carophyll yellow as biomarkers for early identification of diabetic nephropathy. These markers could aid in better management of diabetic nephropathy that may result delaying the progression of the disease.

Branched-chain and aromatic amino acids and cardiometabolic risk in Black African and Asian Indian populations.

Studies have shown that systemic levels of branched-chain amino acids (BCAAs) and aromatic amino acids (AAAs) are elevated in cardiometabolic diseases (CMDs) in populations resident in high income countries. However, little is known about the association of BCAAs and AAAs with metabolic syndrome and its components in Asian Indian (AI) and Black African (BA) populations. The aim of this study was to describe the association of BCAAs and AAAs with the metabolic syndrome, its individual components and insulin resistance in AI and BA populations. Serum samples collected from AI (n = 349) and BA (n = 369) subjects were used to measure levels of BCAAs and AAAs by ultra-pressure liquid chromatography tandem mass spectrometry (UPLC-MS/MS). Anthropometric, demographic and cardiometabolic variables were measured in all subjects. The sum of BCAAs and AAAs was higher in AIs compared to BAs. The BCAAs and AAAs were positively associated with insulin resistance, metabolic syndrome and its individual components. This was particularly the case for AI subjects, in unadjusted regression models. However, these associations were non-significant after adjusting for co-variates, particularly visceral adipose tissue (VAT). Triglyceride levels were significantly associated with valine and leucine levels in BAs even after adjustment for co-variates. Lastly, we found that fasting circulatory BCAA and AAA levels are strongly correlated with VAT in both populations. This study identified specific associations of serum valine and leucine levels with triglycerides in BAs. The association of amino acids with CMDs was observed in AIs, but was found to be the result of confounding by VAT. Further studies are required to determine whether BCAAs and AAAs are aetiological factors in CMDs and how VAT modulates their serum levels.

Abstract #810874: Empagliflozin-Linagliptin Fixed Dose Combination (FDC) as an Add on to Metformin in Asian Indian Subjects

Abstract #810874: Empagliflozin-Linagliptin Fixed Dose Combination (FDC) as an Add on to Metformin in Asian Indian Subjects

Acyl ethanolamides in Diabetes and Diabetic Nephropathy: Novel targets from untargeted plasma metabolomic profiles of South Asian Indian men

The pathophysiology of diabetic nephropathy (DN) in type 2 diabetes (T2D) patients is minimally understood. We compared untargeted high-resolution accurate mass (HRAM) orbitrap-based plasma metabolomic profiles of 31 T2D-DN (with estimated glomerular filtration rate ≤80 mL/min/1.73 m2), 29 T2D and 30 normal glucose tolerance (NGT) Indian men. Of the 939 plasma metabolites that were differentially abundant amongst the NGT, T2D and T2D-DN (ANOVA, False Discovery Rate – FDR adjusted p-value < 0.05), 48 were associated with T2D irrespective of the renal function of the subjects. Acyl ethanolamides and acetylcholine were decreased while monoacylglycerols (MAGs) and cortisol were elevated in both T2D and T2D-DN. Sixteen metabolites, including amino acid metabolites Imidazolelactate and N-Acetylornithine, changed significantly between NGT, T2D and T2D-DN. 192 metabolites were specifically dysregulated in T2D-DN (ratio ≥2 or ≤0.5 between T2D-DN and T2D, similar abundance in NGT and T2D). These included increased levels of multiple acylcarnitine and amino acid metabolites. We observed a significant dysregulation of amino acid and fatty acid metabolism in South Asian Indian male T2D-DN subjects. Unique to this study, we report a reduction in acyl ethanolamide levels in both T2D and T2D-DN males. Those with dysregulation in acyl ethanolamides, which are endogenous agonists of GPR119, are likely to exhibit improved glycemic control with GPR119 agonists.

Pattern of Lipid Abnormalities Among South Asian Indians With Cushing's Syndrome and the Short Term Impact of Surgical Correction of Hypercortisolism.

Atherosclerotic cardiovascular events are one of the common causes of mortality in patients with Cushing's syndrome (CS). Atherogenic dyslipidemia is more common among South Asian Indians as compared to other ethnicities and is likely to worsen among patients with CS. This retrospective study was done over 5 years at a single institute to evaluate the pattern of lipid abnormalities in subjects with CS and the changes in lipid parameters after surgical control of hypercortisolemia. The study was done in two parts. In the first part, records of patients with CS diagnosed over 3 years were retrospectively reviewed. Hormonal and metabolic parameters including fasting plasma glucose (FPG), post prandial plasma glucose (PPPG), HbA1c, serum lipids, serum cortisol and plasma ACTH were recorded. In the second part, lipid parameters were rechecked among patients who underwent surgery and a median follow up of 4±2 months after remission. Out of the 126 patients diagnosed with endogenous CS over 3 years, 100 patients were eligible for inclusion in the study. At baseline, sixty five (65%) patients had dyslipidemia as defined by the NCEP-ATPIII criteria. 47 out of 63 (74.6%) subjects achieved remission after surgical management of CS. 32 (68.1%) of these patients had dyslipidemia prior to surgery. After excluding 1 death, 26 of 46 (56.5%) subjects had dyslipidemia after the follow up period. Lipid abnormalities are common among South Asian Indian subjects with endogenous CS and the pattern persists in most of them, 3 months after surgical correction of hypercortisolism.

Comparison of Novel MicroRNA and Cell-Free DNA Biomarkers of Beta-Cell Death and Diabetes Progression

Type 1 diabetes (T1D) is characterized by the loss of insulin-producing beta-cells. We currently lack diagnostic tools to measure T1D progression. Using systematic approaches involving unprejudiced discovery analyses in human tissues and clinical samples, we identify microRNAs that are: i) associated with insulin expression during embryonic development (N&amp;gt;60); ii) predictive of and necessary for insulin transcription (N=698); and iii) dysregulated in individuals with (vs. without) T1D (N=200). Insulin cfDNA (assessed by ddPCR) and microRNA (assessed by TaqMan qPCR) biomarkers were measured in around; i) N=400 Australian T1D individuals; ii) N=30 longitudinal samples from children at risk of T1D; iii) N=100 clinical trial samples from individuals receiving IFN-a or Exenatide vs. placebo; iv) N=400 Hong Kong Chinese individuals with T1D; v) N=700 Danish individuals at diagnosis of T1D and vi) N=400 Asian Indian T1D subjects. Among N=600 Australian samples, we identified miRNAs (N=5) that were significantly increased in the circulation of T1D individuals (vs. controls), decreased (at least 2 Fold Change/FC, P&amp;lt;0.05, N=7miRNAs) in T1DCx+ vs. T1DCx- (no T1D complications) or significantly increased (2 FC, P&amp;lt;0.05, N=5) in T1D individuals with detectable C-peptide vs. non-detectable C-peptide. Our studies highlight the potential of circulating microRNAs and cfDNA in quantifying beta cell death before clinical diagnosis of T1D. These data demonstrate that microRNA/cfDNA signatures not only facilitate the potential prediction of diabetes progression, but can also help in stratifying individuals at risk of T1D as well as assess treatment efficacies in trials aiming to retard beta-cell death. We also present our preliminary analysis of cross-ethnic variation in these cfDNA/miRNA biomarkers and present ongoing/future studies to develop a diagnostic test for T1D prediction. Disclosure M. Joglekar: None. R. Farr: None. W. Wong: None. K. Rother: None. A. Jenkins: Research Support; Self; Medtronic, Mylan, Sanofi-Aventis. C.S. Yajnik: None. R.C. Ma: Research Support; Self; AstraZeneca, Bayer AG, Merck Sharp &amp; Dohme Corp., Pfizer Inc.. Advisory Panel; Self; Boehringer Ingelheim GmbH, Nippon Boehringer Ingelheim Co. Ltd.. M.E. Craig: None. T. Jones: None. A. Hardikar: None.

Further Studies to Support the Use of Coproporphyrin I and III as Novel Clinical Biomarkers for Evaluating the Potential for Organic Anion Transporting Polypeptide 1B1 and OATP1B3 Inhibition.

In a recent study, limited to South Asian Indian subjects (n = 12), coproporphyrin (CP) I and CPIII demonstrated properties appropriate for an organic anion-transporting polypeptide (OATP) 1B endogenous probe. The current studies were conducted in healthy volunteers of mixed ethnicities, including black, white, and Hispanic subjects, to better understand the utility of these biomarkers in broader populations. After oral administration with 600 mg rifampin, AUC(0-24h) values were 2.8-, 3.7-, and 3.6-fold higher than predose levels for CPI and 2.6-, 3.1-, and 2.4-fold higher for CPIII, for the three populations, respectively. These changes in response to rifampin were consistent with previous results. The sensitivity toward OATP1B inhibition was also investigated by evaluating changes of plasma CP levels in the presence of diltiazem and itraconazole [administered as part of an unrelated drug-drug interaction (DDI) investigation], two compounds that were predicted to have minimal inhibitory effect on OATP1B. Administration of diltiazem and itraconazole did not increase plasma CPI and CPIII concentrations relative to prestudy levels, in agreement with predictions from in vitro parameters. Additionally, the basal CP concentrations in subjects with SLCO1B1 c.521TT genotype were comparable to those with SLCO1B1 c.521TC genotype, similar to studies with probe substrates. However, subjects with SLCO1B1 c.388AG and c.388GG genotypes (i.e., increased OATP1B1 transport activity for certain substrates) had lower concentrations of CPI than those with SLCO1B1 c.388AA. Collectively, these findings provide further evidence supporting the translational value of CPI and CPIII as suitable endogenous clinical probes to gauge OATP1B activity and potential for OATP1B-mediated DDIs.

Association of Vitamin D Levels and type 2 Diabetes Mellitus in Asian Indians is Independent of Obesity.

A large proportion of subjects with type 2 diabetes mellitus (T2DM) in India are non-obese. Asian-Indian subjects with diabetes have been shown to have low vitamin D levels. Whether low vitamin D levels and T2DM in Asian-Indians is attributable to the associated obesity as in caucasians is unclear. Hence we studied the association of vitamin D levels and T2DM in Asian-Indians with or without obesity. Total of 213 subjects were recruited in four groups, group 1-Non-obese diabetic, group 2-Non-obese non-diabetic, group 3-Obese diabetic and group 4-Obese non-diabetic. Subjects recruited under various groups were matched for age and sex. Anthropometry, skin-fold thickness, fasting and postprandial plasma glucose, HbA1c, fasting insulin, lipids and vitamin D levels were measured in all study subjects and were compared between the groups. Mean age of study population was 41.23±7.43 years. Mean BMI in groups 1,2,3 and 4 was 21.34±1.41, 20.53±2.27, 27.72±2.94 and 27.62±3.37 kg/m2 respectively. Overall 64.3% study subjects had vitamin D deficiency and 27.7% had insufficient vitamin D levels. Significantly lower vitamin D levels were found in diabetic groups 1 and 3 compared to non-diabetic groups 2 and 4. No significant difference was observed in vitamin D levels between groups 1 and 3. Similarly, no significant difference was observed in vitamin D levels between groups 2 and 4. Vitamin D levels did not show any significant correlation with BMI, waist or body fat. Vitamin D levels do not appear to be related to obesity in diabetic as well non-diabetic Asian-Indian individuals.

A randomized double blind controlled trial to investigate the effects of vitamin D supplementation on maternal and new-born baby’s vitamin D status in Asian-Indian subjects

A randomized double blind controlled trial to investigate the effects of vitamin D supplementation on maternal and new-born baby’s vitamin D status in Asian-Indian subjects

Association of NFKB1 gene polymorphism (rs28362491) with levels of inflammatory biomarkers and susceptibility to diabetic nephropathy in Asian Indians.

AIMTo investigate the association of NFKB1 gene -94 ATTG insertion/deletion (rs28362491) polymorphism with inflammatory markers and risk of diabetic nephropathy in Asian Indians.METHODSA total of 300 subjects were recruited (100 each), normoglycemic, (NG); type 2 diabetes mellitus (T2DM) without any complications (DM) and T2DM with diabetic nephropathy [DM-chronic renal disease (CRD)]. Analysis was carried out by polymerase chain reaction-restriction fragment length polymorphism and ELISA. Pearson’s correlation, analysis of variance and logistic regression were used for statistical analysis.RESULTSThe allelic frequencies of -94 ATTG insertion/deletion were 0.655/0.345 (NG), 0.62/0.38 (DM) and 0.775/0.225 (DM-CRD). The -94 ATTG ins allele was associated with significantly increased levels of urinary monocyte chemoattractant protein-1 (uMCP-1); uMCP-1 (P = 0.026) and plasma tumor necrosis factor-alpha (TNF-α); TNF-α (P = 0.030) and almost doubled the risk of diabetic nephropathy (OR = 1.91, 95%CI: 1.080-3.386, P = 0.025).CONCLUSION-94 ATTG ins/ins polymorphism might be associated with increased risk of developing nephropathy in Asian Indian subjects with diabetes mellitus.

Spectrum of phenotype and genotype of congenital isolated hypogonadotropic hypogonadism in Asian Indians.

Congenital isolated hypogonadotropic hypogonadism (IHH) is caused due to defect in GnRH neuronal development, migration and action. Although genetic aetiology of IHH is increasingly being studied, Asian Indian data on phenotypic spectrum and genetic basis are scarce. To investigate the phenotypic and genotypic spectrum of IHH in Asian Indian subjects. A cohort of 135 IHH probands were characterized phenotypically for reproductive and nonreproductive features and screened for rare sequence variations (RSVs) in five genes KAL1, FGFR1, FGF8, GNRHR and KISS1R. Of 135 probands [56 normosmic IHH (nIHH) and 79 Kallmann syndrome (KS)], 20 were familial cases. KS group had more male dominance (M:F ratio of 8:1) as compared to nIHH group (M:F ratio of 1·5:1). Complete absence of puberty was more prevalent in KS probands (81% in KS vs 46% in nIHH). The prevalence of MRI abnormalities was more in anosmic group (92·8%) as compared to hyposmic (37·5%) and normosmic groups (15·4%). No particular nonreproductive phenotypic predominance was seen in any group. Genotyping revealed rare sequence variation (RSV) detection rate of 15·5% in five genes studied: (KAL1 - 4·4%, FGFR1 - 4·4%, GNRHR - 6·7%, oligogenicity - 1·5%). Prevalence of RSV was more common in familial cases (35%) as compared to sporadic (12·2%). GNRHR RSV p.C279Y (not reported in patients of ethnicities other than south Asians) was recurring in four unrelated patients. In our cohort, 60% were KS with majority of males and a severe reproductive phenotype as against nIHH. Contribution of the genetic burden for the five genes studied was 15·5%. RSV p.C279Y in GNRHR may have a founder effect originating from south Asia. This study provides a model for molecular and phenotypic representation of Asian Indian subjects with IHH.

High prevalence of cardiovascular risk factors in Durban South African Indians: The Phoenix Lifestyle Project.

Previous studies show a high prevalence of cardiovascular (CV) risk factors in South African (SA) Asian Indians, with the emergence of premature coronary artery disease in young Indian subjects. To determine the prevalence of CV risk factors in this population. This was a cross-sectional study of randomly selected adults aged 15 - 64 years from the suburb of Phoenix in Durban, KwaZulu-Natal Province, SA. All participants had demographic, anthropometric and biochemical measurements using the modified World Health Organization (WHO) STEPwise survey methods. Hypertension, obesity, lipid abnormalities and diabetes mellitus (DM) were diagnosed using WHO criteria. Age-standardised frequencies for glycaemic indices were calculated according to the WHO standard world population distribution. Of the 1 428 subjects who responded (response rate 72.1%), complete data for analysis were available on 1 378 (1 001 women). The mean age was 45.5 (standard deviation 13) years. There were high prevalences of hypertension (47.5%), DM (20.1%), total body obesity (raised body mass index) (32.4%) and increased waist circumference (73.1%). The 'thin-fat' Asian phenotype (isolated abdominal obesity) was found in only 4.8% of participants. High prevalences of total body obesity (32.1%), increased waist circumference (31.3%) and insulin resistance (28.2%) were documented in the youngest age group. Over half of the males and 14.6% of females were current smokers. Diabetic dyslipidaemia was found in 61 subjects (4.4%). In multivariate analysis, age, triglycerides and waist circumference measurement were significant independent risk factors associated with DM and, together with fasting glucose, also predicted hypertension. Compared with Asian Indian subjects with similar environmental exposure in previous studies, the magnitude of change in risk factor prevalence over the past two decades has been of epidemic proportions.