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Ullal J.,Eastern Virginia Medical School | McFarland R.,Glytec | Bachand M.,Diabetes Center | Aloi J.,Section on Endocrinology and Metabolism
Diabetes Technology and Therapeutics | Year: 2016

Background: Efforts at improving quality metrics in diabetes focus on minimizing adverse events and avoiding re-admissions to the hospital. Our experience with Glucommander™ (Glytec, Greenville, SC), a cloud-based insulin management software system, suggested that its use in the emergency department (ED) would be useful in treating patients with mild diabetic ketoacidosis (DKA). Materials and Methods: Thirty-five patients seen in the ED with hyperglycemic crises and diagnosed with DKA during one calendar year were reviewed. A retrospective chart review was performed on patients who were placed on Glucommander™ for DKA management. We excluded patients with significant acidosis or concomitant medical illnesses. Results: Initial average capillary glucose level was 487 ± 68 mg/dL, average time to target glucose was 5 h 11 min, and rate of hypoglycemia (blood glucose level <70 mg/dL) was less than 0.3%. Sixteen patients treated with the protocol were discharged from the ED directly, and 19 were admitted. Patients were maintained for an average of 14 ± 1 h on the Glucommander™ protocol. There was a significantly higher anion gap (P = 0.002) and lower serum bicarbonate level (P = 0.006) in the admitted group. We found very low evidence of re-admission (6%) within 30 days of discharge from the ED for DKA patients. No significant glucose-related adverse events were noted. Conclusions: Use of Glucommander™ for guiding the insulin treatment of mild DKA in the ED can decrease admissions to the hospital for DKA by 45%. Low rates of hypoglycemia make this an option to improve efficiency of utilization of inpatient hospital beds. The cost savings for nonadmissions were estimated at $78,000 over the 12 months of the study. Our results suggest that Glucommander™ is a safe and efficient tool for use in the ED to manage mild to moderate DKA. © Mary Ann Liebert, Inc. 2016.

Elbein S.C.,Section on Endocrinology and Metabolism | Gamazon E.R.,University of Chicago | Das S.K.,Section on Endocrinology and Metabolism | Rasouli N.,University of Colorado at Denver | And 2 more authors.
American Journal of Human Genetics | Year: 2012

To date, 68 loci have been associated with type 2 diabetes (T2D) or glucose homeostasis traits. We report here the results of experiments aimed at functionally characterizing the SNPs replicated for T2D and glucose traits. We sought to determine whether these loci were associated with transcript levels in adipose, muscle, liver, lymphocytes, and pancreatic β-cells. We found an excess of trans, rather than cis, associations among these SNPs in comparison to what was expected in adipose and muscle. Among transcripts differentially expressed (FDR < 0.05) between muscle or adipose cells of insulin-sensitive individuals and those of insulin-resistant individuals (matched on BMI), trans-regulated transcripts, in contrast to the cis-regulated ones, were enriched. The paucity of cis associations with transcripts was confirmed in a study of liver transcriptome and was further supported by an analysis of the most detailed transcriptome map of pancreatic β-cells. Relative to location- and allele-frequency-matched random SNPs, both the 68 loci and top T2D-associated SNPs from two large-scale genome-wide studies were enriched for trans eQTLs in adipose and muscle but not in lymphocytes. Our study suggests that T2D SNPs have broad-reaching and tissue-specific effects that often extend beyond local transcripts and raises the question of whether patterns of cis or trans transcript regulation are a key feature of the architecture of complex traits. © 2012 The American Society of Human Genetics.

Das S.K.,Section on Endocrinology and Metabolism | Ma L.,Section on Endocrinology and Metabolism | Sharma N.K.,Section on Endocrinology and Metabolism
International Journal of Obesity | Year: 2015

Obese subjects with a similar body mass index (BMI) exhibit substantial heterogeneity in gluco-and cardiometabolic heath phenotypes. However, defining genes that underlie the heterogeneity of metabolic features among obese individuals and determining metabolically healthy and unhealthy phenotypes remain challenging. We conducted unsupervised hierarchical clustering analysis of subcutaneous adipose tissue transcripts from 30 obese men and women ≥40 years old. Despite similar BMIs in all subjects, we found two distinct subgroups, one metabolically healthy (group 1) and one metabolically unhealthy (group 2). Subjects in group 2 showed significantly higher total cholesterol (P=0.005), low-density lipoprotein cholesterol (P=0.006), 2-h insulin during oral glucose tolerance test (P=0.015) and lower insulin sensitivity (S I, P=0.029) compared with group 1. We identified significant upregulation of 141 genes (for example, MMP9 and SPP1) and downregulation of 17 genes (for example, NDRG4 and GINS3) in group 2 subjects. Intriguingly, these differentially expressed transcripts were enriched for genes involved in cardiovascular disease-related processes (P=2.81 × 10 -11-3.74 × 10 -02) and pathways involved in immune and inflammatory response (P=8.32 × 10 -5-0.04). Two downregulated genes, NDRG4 and GINS3, have been located in a genomic interval associated with cardiac repolarization in published GWASs and zebra fish knockout models. Our study provides evidence that perturbations in the adipose tissue gene expression network are important in defining metabolic health in obese subjects. © 2015 Macmillan Publishers Limited.

Mondal A.K.,Section on Endocrinology and Metabolism | Sharma N.K.,Section on Endocrinology and Metabolism | Elbein S.C.,Section on Endocrinology and Metabolism | Das S.K.,Section on Endocrinology and Metabolism
Physiological Genomics | Year: 2013

Type 2 diabetes (T2D)-associated SNPs are more likely to be expression quantitative trait loci (eQTLs). The allelic expression imbalance (AEI) analysis is the measure of relative expression between two allelic transcripts and is the most sensitive measurement to detect cis-regulatory effects. We performed AEI screening to detect cis-regulators for genes expressed in transformed lymphocytes of 190 Caucasian (CA) and African American (AA) subjects to identify functional variants for T2D susceptibility in the chromosome 1q21-24 region of linkage. Among transcribed SNPs studied in 115 genes, significant AEI (P < 0.001) occurred in 28 and 30 genes in CA and AA subjects, respectively. Analysis of the effect of selected AEI-SNPs (≥10% mean AEI) on total gene expression further established the cis-eQTLs in thioesterase superfamily member-4 (THEM4) (rs13320, P = 0.027), and IGSF8 (rs1131891, P = 0.02). Examination of published genome-wide association data identified significant associations (P < 0.01) of three AEI-SNPs with T2D in the DIAGRAM-v3 dataset. Six AEI single nucleotide polymorphisms, including rs13320 (P = 1.35E-04) in THEM4, were associated with glucose homeostasis traits in the MAGIC dataset. Evaluation of AEI-SNPs for association with glucose homeostasis traits in 611 nondiabetic subjects showed lower AIRG (P = 0.005) in those with TT/TC genotype for rs13320. THEM4 expression in adipose was higher (P = 0.005) in subjects carrying the T allele; in vitro analysis with luciferase construct confirmed the higher expression of the T allele. Resequencing of THEM4 exons in 192 CA subjects revealed four coding nonsynonymous variants, but did not explain transmission of T2D in 718 subjects from 67 Caucasian pedigrees. Our study indicates the role of a cis-regulatory SNP in THEM4 that may influence T2D predisposition by modulating glucose homeostasis. © 2013 the American Physiological Society.

Sharma N.K.,Section on Endocrinology and Metabolism | Langberg K.A.,Section on Endocrinology and Metabolism | Mondal A.K.,Section on Endocrinology and Metabolism | Das S.K.,Section on Endocrinology and Metabolism
PLoS ONE | Year: 2013

Recent studies have identified links between phospholipid composition and altered cellular functions in animal models of obesity, but the involvement of phospholipid biosynthesis genes in human obesity are not well understood. We analyzed the transcript of four phospholipid biosynthesis genes in adipose and muscle from 170 subjects. We examined publicly available genome-wide association data from the GIANT and MAGIC cohorts to investigate the association of SNPs in these genes with obesity and glucose homeostasis traits, respectively. Trait-associated SNPs were genotyped to evaluate their roles in regulating expression in adipose. In adipose tissue, expression of PEMT, PCYT1A, and PTDSS2 were positively correlated and PCYT2 was negatively correlated with percent fat mass and body mass index (BMI). Among the polymorphisms in these genes, SNP rs4646404 in PEMT showed the strongest association (p = 3.07E-06) with waist-to-hip ratio (WHR) adjusted for BMI. The WHR-associated intronic SNP rs4646343 in the PEMT gene showed the strongest association with its expression in adipose. Allele "C" of this SNP was associated with higher WHR (p = 2.47E-05) and with higher expression (p = 4.10E-04). Our study shows that the expression of PEMT gene is high in obese insulin-resistant subjects. Intronic cis-regulatory polymorphisms may increase the genetic risk of obesity by modulating PEMT expression. © 2013 Sharma et al.

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