Endocrinology, Diabetes, and Metabolism Commons^™

Risk Of Type 2 Diabetes Among Individuals With Excess Weight: Weight Trajectory Effects, Arthur H Owora, David B Allison, Xuan Zhang, Nana Gletsu-Miller, Kishore M Gadde

Children’s Nutrition Research Center Staff Publications

PURPOSE OF REVIEW: Increased risk of type 2 diabetes mellitus (T2D) among individuals with overweight or obesity is well-established; however, questions remain about the temporal dynamics of weight change (gain or loss) on the natural course of T2D in this at-risk population. Existing epidemiologic evidence is limited to studies that discretely sample and assess excess weight and T2D risk at different ages with limited follow-up, yet changes in weight may have time-varying and possibly non-linear effects on T2D risk. Predicting the impact of weight change on the risk of T2D is key to informing primary prevention. We critically review the …

Adiposity, Insulin Resistance, Cardiorespiratory Fitness, And Bone Health In Hispanic Children, Reem S Shawar, Maurice Puyau, Roman Shypailo, Salma Musaad, Nancy F Butte, Fida Bacha

Faculty, Staff and Students Publications

CONTEXT: Childhood obesity disproportionately affects Hispanic youth. The skeletal system appears to be a target organ of the adverse effects of obesity. Yet, the relationship between adiposity and bone health in youth and the modulating factors are not well understood.

OBJECTIVE: This work aims to examine the relationship between adiposity, insulin resistance (IR), cardiorespiratory fitness (CRF), and bone mass in Hispanic youth.

METHODS: A total of 951 Hispanic youth (50% male), aged 4 to 19 years, participated in this cross-sectional design study from the Viva La Familia Study at Children's Nutrition Research Center. Bone mineral content (BMC) and density (BMD), …

Genetic Variants In Aldh1l1 And Gldc Influence The Serine-To-Glycine Ratio In Hispanic Children, Sergey A Krupenko, Shelley A Cole, Ruixue Hou, Karin Haack, Sandra Laston, Nitesh R Mehta, Anthony G Comuzzie, Nancy F Butte, V Saroja Voruganti

Children’s Nutrition Research Center Staff Publications

Background: Glycine is a proteogenic amino acid that is required for numerous metabolic pathways, including purine, creatine, heme, and glutathione biosynthesis. Glycine formation from serine, catalyzed by serine hydroxy methyltransferase, is the major source of this amino acid in humans. Our previous studies in a mouse model have shown a crucial role for the 10-formyltetrahydrofolate dehydrogenase enzyme in serine-to-glycine conversion.

Objectives: We sought to determine the genomic influence on the serine-glycine ratio in 803 Hispanic children from 319 families of the Viva La Familia cohort.

Methods: We performed a genome-wide association analysis for plasma serine, glycine, and the serine-glycine ratio …

Calcium/Calmodulin-Dependent Protein Kinase Kinase 2 Regulates Hepatic Fuel Metabolism, Brittany A Stork, Adam Dean, Andrea R Ortiz, Pradip Saha, Nagireddy Putluri, Maricarmen D Planas-Silva, Iqbal Mahmud, Kimal Rajapakshe, Cristian Coarfa, Stefan Knapp, Philip L Lorenzi, Bruce E Kemp, Benjamin E Turk, John W Scott, Anthony R Means, Brian York

Faculty, Staff and Students Publications

OBJECTIVE: The liver is the primary internal metabolic organ that coordinates whole body energy homeostasis in response to feeding and fasting. Genetic ablation or pharmacological inhibition of calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2) has been shown to significantly improve hepatic health and peripheral insulin sensitivity upon overnutrition with high fat diet. However, the precise molecular underpinnings that explain this metabolic protection have remained largely undefined.

METHODS: To characterize the role of CaMKK2 in hepatic metabolism, we developed and challenged liver-specific CaMKK2 knockout (CaMKK2

RESULTS: Consistent with previous findings, we show that hepatic CaMKK2 ablation significantly improves indices of peripheral insulin …

Effect Of A Glp-1 Mimetic On The Insulin Response To Oral Sugar Testing In Horses, Darko Stefanovski, Mary A Robinson, Andrew Van Eps

Faculty, Staff and Student Publications

BACKGROUND: Insulin dysregulation (ID) is the most important risk factor for the development of laminitis in horses and therapies to control it are needed.

HYPOTHESIS/OBJECTIVES: To assess the effects of a single dose of the synthetic GLP-1 analog exenatide on postprandial insulin dynamics. We hypothesized that exenatide would improve insulin sensitivity and lower postprandial blood insulin concentrations.

STUDY DESIGN: Randomized, crossover, experimental study.

ANIMALS: Six horses (3 mares, 3 geldings; 2 with normal insulin regulation [NIR] and 4 with mild ID).

METHODS: Horses completed both study arms: subcutaneous administration of exenatide (or no treatment) 30 min before an oral sugar …

Regulation Of Age-Associated Insulin Resistance By Mt1-Mmp-Mediated Cleavage Of Insulin Receptor, Xuanming Guo, Pallavi Asthana, Susma Gurung, Shuo Zhang, Sheung Kin Ken Wong, Samane Fallah, Chi Fung Willis Chow, Sijia Che, Lixiang Zhai, Zening Wang, Xin Ge, Zhixin Jiang, Jiayan Wu, Yijing Zhang, Xiaoyu Wu, Keyang Xu, Cheng Yuan Lin, Hiu Yee Kwan, Aiping Lyu, Zhongjun Zhou, Zhao-Xiang Bian, Hoi Leong Xavier Wong

Faculty, Staff and Student Publications

Insulin sensitivity progressively declines with age. Currently, the mechanism underlying age-associated insulin resistance remains unknown. Here, we identify membrane-bound matrix metalloproteinase 14 (MT1-MMP/MMP14) as a central regulator of insulin sensitivity during ageing. Ageing promotes MMP14 activation in insulin-sensitive tissues, which cleaves Insulin Receptor to suppress insulin signaling. MT1-MMP inhibition restores Insulin Receptor expression, improving insulin sensitivity in aged mice. The cleavage of Insulin Receptor by MT1-MMP also contributes to obesity-induced insulin resistance and inhibition of MT1-MMP activities normalizes metabolic dysfunctions in diabetic mouse models. Conversely, overexpression of MT1-MMP in the liver reduces the level of Insulin Receptor, impairing hepatic insulin …

Organ Fat In Latino Youth At Risk For Type 2 Diabetes, Janiel L Pimentel, Kiley B Vander Wyst, Erica G Soltero, Armando Peña, Houchun H Hu, Smita S Bailey, Amber Pokorney, Stephanie L Ayers, Ana Martinez Valencia, Micah L Olson, Gabriel Q Shaibi

Children’s Nutrition Research Center Staff Publications

Purpose: Obesity in youth increases the risk for type 2 diabetes (T2D) and elevated abdominal adipose tissue and organ fat may be particularly deleterious. The purpose of this study was to examine associations among measures of adiposity including total, visceral, and organ fat (hepatic and pancreatic) and whether these measures were independently associated with glycemia in Latino youth at risk for diabetes.

Methods: Latino adolescents (47 boys and 32 girls, 13.7 ± 1.4 years) with obesity (BMIz 2.3 ± 0.3) were assessed for total fat by DXA and visceral and organ fat by 3 T magnetic resonance imaging. Glycemic indicators …

Berberine Remodels Adipose Tissue To Attenuate Metabolic Disorders By Activating Sirtuin 3, Dan Li, Chao Yang, Jian-Zhong Zhu, Eduardo Lopez, Tian Zhang, Qiang Tong, Cheng Peng, Li-Gen Lin

Faculty, Staff and Students Publications

Adipose tissue remodelling is considered a critical pathophysiological hallmark of obesity and related metabolic diseases. Berberine (BBR), a natural isoquinoline alkaloid, has potent anti-hyperlipidaemic and anti-hyperglycaemic effects. This study aimed to explore the role of BBR in modulating adipose tissue remodelling and the underlying mechanisms. BBR protected high fat diet (HFD)-fed mice against adiposity, insulin resistance and hyperlipidemia. BBR alleviated adipose tissue inflammation and fibrosis by inhibiting macrophage infiltration, pro-inflammatory macrophage polarization and the abnormal deposition of extracellular matrix, and the effect was mediated by BBR directly binding and activating the deacetylase Sirtuin 3 (SIRT3) and suppressing the activation of …

Metabolic Inflexibility In Youth With Obesity: Is It A Feature Of Obesity Or Distinctive Of Youth Who Are Metabolically Unhealthy?, Nour Y Gebara, Joon Young Kim, Fida Bacha, Sojung Lee, Silva Arslanian

Children’s Nutrition Research Center Staff Publications

Background:

Individuals with obesity have metabolic inflexibility with diminished fasting fat oxidation and blunted increase in respiratory quotient (RQ) in insulin-stimulated states. However, it is unclear if metabolic inflexibility is a characteristic of obesity per se or is unique to youth who have metabolically unhealthy obesity (MUO) compared with metabolically healthy obesity (MHO).

Objective:

We investigated metabolic flexibility in youth with MUO, MHO and normal weight (NW) and compared their metabolic characteristics.

Patients/Design:

Youth (n=188) were divided, based on cut-off points for in vivo insulin sensitivity (IS) of adolescents with NW, into 137 with MUO and 51 with MHO. Fasting …

Metabolic Inflexibility In Youth With Obesity: Is It A Feature Of Obesity Or Distinctive Of Youth Who Are Metabolically Unhealthy?, Nour Y Gebara, Joon Young Kim, Fida Bacha, Sojung Lee, Silva Arslanian

Faculty, Staff and Students Publications

Individuals with obesity have metabolic inflexibility with diminished fasting fat oxidation and blunted increase in respiratory quotient (RQ) in insulin-stimulated states. However, it is unclear if metabolic inflexibility is a characteristic of obesity per se or is unique to youth who have metabolically unhealthy obesity (MUO) compared with metabolically healthy obesity (MHO). We investigated metabolic flexibility in youth with MUO, MHO and normal weight (NW) and compared their metabolic characteristics. Youth (n = 188) were divided, based on cut-off points for in vivo insulin sensitivity (IS) of adolescents with NW, into 137 with MUO and 51 with MHO. Fasting hepatic …

Isoform-Specific Functions Of Pparγ In Gene Regulation And Metabolism, Wenxiang Hu, Chunjie Jiang, Mindy Kim, Yang Xiao, Hannah J Richter, Dongyin Guan, Kun Zhu, Brianna M Krusen, Arielle N Roberts, Jessica Miller, David J Steger, Mitchell A Lazar

Faculty, Staff and Students Publications

Peroxisome proliferator-activated receptor γ (PPARγ) is a nuclear receptor that is a vital regulator of adipogenesis, insulin sensitivity, and lipid metabolism. Activation of PPARγ by antidiabetic thiazolidinediones (TZD) reverses insulin resistance but also leads to weight gain that limits the use of these drugs. There are two main PPARγ isoforms, but the specific functions of each are not established. Here we generated mouse lines in which endogenous PPARγ1 and PPARγ2 were epitope-tagged to interrogate isoform-specific genomic binding, and mice deficient in either PPARγ1 or PPARγ2 to assess isoform-specific gene regulation. Strikingly, although PPARγ1 and PPARγ2 contain identical DNA binding domains, …

Plasma Diaphanous Related Formin 1 Levels Are Associated With Altered Glucose Metabolism And Insulin Resistance In Patients With Polycystic Ovary Syndrome: A Case Control Study, Xing Li, Mingyu Liao, Jiaqing Shao, Weixin Li, Liu Shi, Dong Wang, Juan Ni, Qiuyue Shen, Fan Yang, Guiliang Peng, Ling Zhou, Yuling Zhang, Zheng Sun, Hongting Zheng, Min Long

Faculty, Staff and Students Publications

BACKGROUND: Diaphanous related formin 1 (DIAPH1) is a novel component of advanced glycation end product (AGE) signal transduction that was recently found to participate in diabetes-related disorders, obesity, and androgen hormones. We investigated whether plasma DIAPH1 levels were a potential prognostic predictor for polycystic ovary syndrome (PCOS).

METHODS: The levels of circulating plasma DIAPH1 and indicators of glucose, insulin, lipid metabolism, liver enzymes, kidney function, sex hormones, and inflammation were measured in 75 patients with PCOS and 77 healthy participants. All of the participants were divided into normal-weight (NW) and overweight/obese (OW) subgroups. Statistical analyses were performed with R studio. …

A Novel Model Of Gestational Diabetes: Acute High Fat High Sugar Diet Results In Insulin Resistance And Beta Cell Dysfunction During Pregnancy In Mice, Akansha Mishra, Simone Hernandez Ruano, Pradip K Saha, Kathleen A Pennington

Faculty, Staff and Students Publications

Gestational diabetes mellitus (GDM) affects 7–18% of all pregnancies. Despite its high prevalence, there is no widely accepted animal model. To address this, we recently developed a mouse model of GDM. The goal of this work was to further characterize this animal model by assessing insulin resistance and beta cell function. Mice were randomly assigned to either control (CD) or high fat, high sugar (HFHS) diet and mated 1 week later. At day 0 (day of mating) mice were fasted and intraperitoneal insulin tolerance tests (ipITT) were performed. Mice were then euthanized and pancreata were collected for histological analysis. Euglycemic …

De Novo Glycine Synthesis Is Reduced In Adults With Morbid Obesity And Increases Following Bariatric Surgery, Hong Chang Tan, Jean W Hsu, E Shyong Tai, Shaji Chacko, Vieon Wu, Chun Fan Lee, Jean-Paul Kovalik, Farook Jahoor

Faculty, Staff and Students Publications

BACKGROUND: Glycine is a dietary non-essential amino acid that is low in obesity and increases following bariatric surgery. However, the exact mechanism responsible remains unclear and it is unknown whether hypoglycinemia is a cause or consequence of insulin resistance.

OBJECTIVE: Using multiple isotopically labeled tracers, we aimed to determine the underlying kinetic changes responsible for hypoglycinemia in obesity by: 1) Comparing glycine kinetics between participants with morbid obesity (BMI ≥ 32.5 kg/m

METHODS: [1,2-

RESULTS: Compared to controls, participants with morbid obesity had significantly lower plasma glycine concentrations at 163 (153-171) vs. 201 (172-227) µmol/L and significantly reduced

CONCLUSION: Hypoglycinemia …

Resistin Levels Decrease As Insulin Resistance Increases In A Mexican-American Cohort, Absalon D Gutierrez, Carlos A Flores, Sapna Naik, Minjae Lee, Parisa Asgarisabet, Masha Resman, Miryoung Lee, Joseph B Mccormick, Susan P Fisher-Hoch

Faculty, Staff and Student Publications

AIMS: Links between resistin, insulin resistance (IR), and resistin-stimulated cytokine signaling remain unknown in Mexican-Americans. A Mexican-American cohort was examined to determine (1) relationships between circulating resistin and IR, (2) resistin's associations with cytokines and demographic and anthropometric variables, and (3) similar measurements with other adipokines.

METHODS: For cross sectional analyses, 953 adults (367 males and 586 females) in the Cameron County Hispanic Cohort (CCHC) were stratified into three groups: normal glucose tolerance, prediabetes, and diabetes mellitus. Differences in resistin and other adipokine levels were examined using linear regression via unadjusted model (Model 1), model adjusted for cytokines (Model 2), …

High-Fructose, High-Fat Diet Alters Muscle Composition And Fuel Utilization In A Juvenile Iberian Pig Model Of Non-Alcoholic Fatty Liver Disease, Heather C Spooner, Stefani A Derrick, Magdalena Maj, Rodrigo Manjarín, Gabriella V Hernandez, Deepali S Tailor, Parisa S Bastani, Rob K Fanter, Marta L Fiorotto, Douglas G Burrin, Michael R La Frano, Angelos K Sikalidis, Jason M Blank

Children’s Nutrition Research Center Staff Publications

Non-alcoholic fatty liver disease (NAFLD) is a serious metabolic condition affecting millions of people worldwide. A “Western-style diet” has been shown to induce pediatric NAFLD with the potential disruption of skeletal muscle composition and metabolism. To determine the in vivo effect of a “Western-style diet” on pediatric skeletal muscle fiber type and fuel utilization, 28 juvenile Iberian pigs were fed either a control diet (CON) or a high-fructose, high-fat diet (HFF), with or without probiotic supplementation, for 10 weeks. The HFF diets increased the total triacylglycerol content of muscle tissue but decreased intramyocellular lipid (IMCL) content and the number of …

Tcf7l2 Genetic Variants Do Not Influence Insulin Sensitivity Or Secretion Indices In Autoantibody-Positive Individuals At Risk For Type 1 Diabetes, Maria J Redondo, Megan V Warnock, Ingrid M Libman, Laura E Bocchino, David Cuthbertson, Susan Geyer, Alberto Pugliese, Andrea K Steck, Carmella Evans-Molina, Dorothy Becker, Jay M Sosenko, Fida Bacha, Type 1 Diabetes Trialnet Study Group

Children’s Nutrition Research Center Staff Publications

Objective: We aimed to test whether type 2 diabetes (T2D)-associated TCF7L2 genetic variants affect insulin sensitivity or secretion in autoantibody-positive relatives at risk for type 1 diabetes (T1D).

Research design and methods: We studied autoantibody-positive TrialNet Pathway to Prevention study participants (N = 1,061) (mean age 16.3 years) with TCF7L2 single nucleotide polymorphism (SNP) information and baseline oral glucose tolerance test (OGTT) to calculate indices of insulin sensitivity and secretion. With Bonferroni correction for multiple comparisons, P values < 0.0086 were considered statistically significant.

Results: None, one, and two T2D-linked TCF7L2 alleles were present in 48.1%, 43.9%, and 8.0% of the participants, respectively. Insulin sensitivity …

Rap1 In The Vmh Regulates Glucose Homeostasis, Kentaro Kaneko, Hsiao-Yun Lin, Yukiko Fu, Pradip K Saha, Ana B De La Puente-Gomez, Yong Xu, Kousaku Ohinata, Peter Chen, Alexei Morozov, Makoto Fukuda

Faculty, Staff and Students Publications

The hypothalamus is a critical regulator of glucose metabolism and is capable of correcting diabetes conditions independently of an effect on energy balance. The small GTPase Rap1 in the forebrain is implicated in high-fat diet-induced (HFD-induced) obesity and glucose imbalance. Here, we report that increasing Rap1 activity selectively in the medial hypothalamus elevated blood glucose without increasing the body weight of HFD-fed mice. In contrast, decreasing hypothalamic Rap1 activity protected mice from diet-induced hyperglycemia but did not prevent weight gain. The remarkable glycemic effect of Rap1 was reproduced when Rap1 was specifically deleted in steroidogenic factor-1-positive (SF-1-positive) neurons in the …

Ube2i Deletion In Adipocytes Causes Lipoatrophy In Mice, Aaron R Cox, Natasha Chernis, Kang Ho Kim, Peter M Masschelin, Pradip K Saha, Shawn M Briley, Robert Sharp, Xin Li, Jessica B Felix, Zheng Sun, David D Moore, Stephanie A Pangas, Sean M Hartig

Faculty, Staff and Students Publications

OBJECTIVE: White adipose tissue (WAT) expansion regulates energy balance and overall metabolic homeostasis. The absence or loss of WAT occurring through lipodystrophy and lipoatrophy contributes to the development of hepatic steatosis and insulin resistance. We previously demonstrated that sole small ubiquitin-like modifier (SUMO) E2-conjugating enzyme Ube2i represses human adipocyte differentiation. The role of Ube2i during WAT development remains unknown.

METHODS: To determine how Ube2i impacts body composition and energy balance, we generated adipocyte-specific Ube2i knockout mice (Ube2i

RESULTS: Surprisingly, Ube2i

CONCLUSIONS: Our results demonstrate that Ube2i expression in mature adipocytes allows WAT expansion during postnatal growth. Deletion of Ube2i in …

Rev-Erb In Gabaergic Neurons Controls Diurnal Hepatic Insulin Sensitivity, Guolian Ding, Xin Li, Xinguo Hou, Wenjun Zhou, Yingyun Gong, Fuqiang Liu, Yanlin He, Jia Song, Jing Wang, Paul Basil, Wenbo Li, Sichong Qian, Pradip Saha, Jinbang Wang, Chen Cui, Tingting Yang, Kexin Zou, Younghun Han, Christopher I Amos, Yong Xu, Li Chen, Zheng Sun

Faculty, Staff and Students Publications

Systemic insulin sensitivity shows diurnal rhythm with a peak at wakening1,2. The molecular mechanism underlying such a temporal pattern is unclear. Here we demonstrate that nuclear receptors Rev-erbα/β in the GABAergic neurons in the suprachiasmatic nucleus (SCNGABA) control the diurnal rhythm of insulin-mediated suppression of hepatic glucose production in mice, without affecting diurnal eating or locomotor behaviors under the regular light-dark cycles. Rev-erb regulates the rhythmic expression of genes involved in neurotransmission in the SCN and modulates the oscillatory firing activity of SCNGABA neurons. Chemogenetic stimulation of SCNGABA neurons at wakening causes glucose intolerance, while restoration …

Loss Of Bone Morphogenetic Protein-Binding Endothelial Regulator Causes Insulin Resistance, Hua Mao, Luge Li, Qiying Fan, Aude Angelini, Pradip K Saha, Huaizhu Wu, Christie M Ballantyne, Sean M Hartig, Liang Xie, Xinchun Pi

Faculty, Staff and Students Publications

Accumulating evidence suggests that chronic inflammation of metabolic tissues plays a causal role in obesity-induced insulin resistance. Yet, how specific endothelial factors impact metabolic tissues remains undefined. Bone morphogenetic protein (BMP)–binding endothelial regulator (BMPER) adapts endothelial cells to inflammatory stress in diverse organ microenvironments. Here, we demonstrate that BMPER is a driver of insulin sensitivity. Both global and endothelial cell-specific inducible knockout of BMPER cause hyperinsulinemia, glucose intolerance and insulin resistance without increasing inflammation in metabolic tissues in mice. BMPER can directly activate insulin signaling, which requires its internalization and interaction with Niemann-Pick C1 (NPC1), an integral membrane protein that …

Deficiency Of Stat1 In Cd11c+ Cells Alters Adipose Tissue Inflammation And Improves Metabolic Dysfunctions In Mice Fed A High-Fat Diet, Antu Antony, Zeqin Lian, Xiaoyuan Dai Perrard, Jerry Perrard, Hua Liu, Aaron R Cox, Pradip Saha, Lothar Hennighausen, Sean M Hartig, Christie M Ballantyne, Huaizhu Wu

Faculty, Staff and Students Publications

CD11c+ macrophages/dendritic cells (MDCs) are increased and display the classically activated M1-like phenotype in obese adipose tissue (AT) and may contribute to AT inflammation and insulin resistance. Stat1 is a key transcription factor for MDC polarization into the M1-like phenotype. Here, we examined the role of Stat1 in obesity-induced AT MDC polarization and inflammation and insulin resistance using mice with specific knockout of Stat1 in MDCs (cKO). Stat1 was upregulated and phosphorylated, indicating activation, early and persistently in AT and AT MDCs of wild-type mice fed a high-fat diet (HFD). Compared with littermate controls, cKO mice fed an HFD (16 …

Metabolic Flexibility Across The Spectrum Of Glycemic Regulation In Youth, Fida Bacha, Sara Klinepeter Bartz, Maurice Puyau, Anne Adolph, Susan Sharma

Children’s Nutrition Research Center Staff Publications

BACKGROUNDMetabolic flexibility (MF) refers to the relative ability to utilize lipid and carbohydrate substrates and to transition between them. It is not clear whether MF is impaired in obese youth and what the determining factors are.METHODSWe investigated the determinants of MF (increased respiratory exchange ratio [ΔRER] under insulin-stimulated conditions) in pubertal youth (n = 104; 15.6 ± 1.8 years) with obesity across the spectrum of glucose tolerance compared with normal weight (NW) controls, including body composition (fat-free mass [FFM], %body fat), visceral adipose fat (VAT) (MRI), glycemia, and insulin sensitivity (IS) [3-hour hyperinsulinemic-euglycemic clamp with measurement of lipolysis ([2H5] glycerol), …

Association Of Baseline Characteristics With Insulin Sensitivity And Β-Cell Function In The Glycemia Reduction Approaches In Diabetes: A Comparative Effectiveness (Grade) Study Cohort, Neda Rasouli, Naji Younes, Kristina M Utzschneider, Silvio E Inzucchi, Ashok Balasubramanyam, Andrea L Cherrington, Faramarz Ismail-Beigi, Robert M Cohen, Darin E Olson, Ralph A Defronzo, William H Herman, John M Lachin, Steven E Kahn

Faculty, Staff and Students Publications

OBJECTIVE: We investigated sex and racial differences in insulin sensitivity, β-cell function, and glycated hemoglobin (HbA

RESEARCH DESIGN AND METHODS: This is a cross-sectional analysis of baseline data from 3,108 GRADE (Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study) participants. All had type 2 diabetes diagnosedβ-cell function were evaluated using the HOMA of insulin sensitivity and estimates from oral glucose tolerance tests, including the Matsuda Index, insulinogenic index, C-peptide index, and oral disposition index (DI).

RESULTS: The cohort was 56.6 ± 10 years of age (mean ± SD), 63.8% male, with BMI 34.2 ± 6.7 kg/m

CONCLUSIONS: In the …

Association Of Baseline Characteristics With Insulin Sensitivity And Β-Cell Function In The Glycemia Reduction Approaches In Diabetes: A Comparative Effectiveness (Grade) Study Cohort, Neda Rasouli, Naji Younes, Kristina M Utzschneider, Silvio E Inzucchi, Ashok Balasubramanyam, Andrea L Cherrington, Faramarz Ismail-Beigi, Robert M Cohen, Darin E Olson, Ralph A Defronzo, William H Herman, John M Lachin, Steven E Kahn, Grade Research Group

Faculty, Staff and Students Publications

OBJECTIVE: We investigated sex and racial differences in insulin sensitivity, β-cell function, and glycated hemoglobin (HbA

RESEARCH DESIGN AND METHODS: This is a cross-sectional analysis of baseline data from 3,108 GRADE (Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study) participants. All had type 2 diabetes diagnosedβ-cell function were evaluated using the HOMA of insulin sensitivity and estimates from oral glucose tolerance tests, including the Matsuda Index, insulinogenic index, C-peptide index, and oral disposition index (DI).

RESULTS: The cohort was 56.6 ± 10 years of age (mean ± SD), 63.8% male, with BMI 34.2 ± 6.7 kg/m

CONCLUSIONS: In the …

Stat1 Dissociates Adipose Tissue Inflammation From Insulin Sensitivity In Obesity, Aaron R Cox, Natasha Chernis, David A Bader, Pradip K Saha, Peter M Masschelin, Jessica B Felix, Robert Sharp, Zeqin Lian, Vasanta Putluri, Kimal Rajapakshe, Kang Ho Kim, Dennis T Villareal, Reina Armamento-Villareal, Huaizhu Wu, Cristian Coarfa, Nagireddy Putluri, Sean M Hartig

Faculty, Staff and Students Publications

Obesity fosters low-grade inflammation in white adipose tissue (WAT) that may contribute to the insulin resistance that characterizes type 2 diabetes. However, the causal relationship of these events remains unclear. The established dominance of STAT1 function in the immune response suggests an obligate link between inflammation and the comorbidities of obesity. To this end, we sought to determine how STAT1 activity in white adipocytes affects insulin sensitivity. STAT1 expression in WAT inversely correlated with fasting plasma glucose in both obese mice and humans. Metabolomic and gene expression profiling established STAT1 deletion in adipocytes (STAT1a-KO) enhanced mitochondrial function …

Β-Cell Impairment And Clinically Meaningful Alterations In Glycemia In Obese Youth Across The Glucose Tolerance Spectrum, Joon Young Kim, Hala Tfayli, Fida Bacha, Sojung Lee, Nour Gebara, Silva Arslanian

Children’s Nutrition Research Center Staff Publications

Background/aims: In obese youth, it is not clear what degree of β-cell impairment translates to glucose dysregulation commensurate with shifts from normal glucose tolerance (NGT) to impaired glucose tolerance (IGT) to type 2 diabetes. We aimed to investigate the quantitative relationship between β-cell (clamp-measured disposition index [DI]) and OGTT glucose area under the curve (G-AUC) in obese youth across the spectrum of glucose tolerance.

Methods: Data from 152 youth (58 African-American [AA] and 94 American-White [AW]; 73 NGT, 48 IGT, and 31 type 2 diabetes) who completed a 3-h hyperinsulinemic (80 mu/m2/min)-euglycemic clamp, and a 2-h hyperglycemic (225 mg/dL) clamp …

Mir-30a Targets Gene Networks That Promote Browning Of Human And Mouse Adipocytes, Pradip K Saha, Mark P Hamilton, Kimal Rajapakshe, Vasanta Putluri, Jessica B Felix, Peter Masschelin, Aaron R Cox, Mandeep Bajaj, Nagireddy Putluri, Cristian Coarfa, Sean M Hartig

Faculty, Staff and Students Publications

MicroRNA-30a (miR-30a) impacts adipocyte function, and its expression in white adipose tissue (WAT) correlates with insulin sensitivity in obesity. Bioinformatic analysis demonstrates that miR-30a expression contributes to 2% of all miRNA expression in human tissues. However, molecular mechanisms of miR-30a function in fat cells remain unclear. Here, we expanded our understanding of how miR-30a expression contributes to antidiabetic peroxisome proliferator-activated receptor-γ (PPARγ) agonist activity and metabolic functions in adipocytes. We found that WAT isolated from diabetic patients shows reduced miR-30a levels and diminished expression of the canonical PPARγ target genes ADIPOQ and FABP4 relative to lean counterparts. In human adipocytes, …

Loss Of Uncoupling Protein 3 Attenuates Western Diet-Induced Obesity, Systemic Inflammation, And Insulin Resistance In Rats, Tyler M Lomax, Sadia Ashraf, Gizem Yilmaz, Romain Harmancey

Faculty, Staff and Student Publications

OBJECTIVE: Uncoupling protein 3 (UCP3) is a mitochondrial carrier related to fatty acid metabolism. Although gene variants of UCP3 are associated with human obesity, their contribution to increased adiposity remains unclear. This study investigated the impact that loss of UCP3 has on diet-induced obesity in rats.

METHODS: Male UCP3 knockout rats (ucp3

RESULTS: Loss of UCP3 decreased fat mass gain, white adipocytes size, and systemic inflammation. The ucp3

CONCLUSIONS: Loss of UCP3 partially protects rats from diet-induced obesity. This phenotype is related to induction of a compensatory antioxidant mechanism and prevention of iBAT whitening.

Metabolic Dysregulation In The Atp7b-/- Wilson's Disease Mouse Model, Clavia Ruth Wooton-Kee, Matthew Robertson, Ying Zhou, Bingning Dong, Zhen Sun, Kang Ho Kim, Hailan Liu, Yong Xu, Nagireddy Putluri, Pradip Saha, Cristian Coarfa, David D Moore, Alli M Nuotio-Antar

Faculty, Staff and Students Publications

Inactivating mutations in the copper transporter Atp7b result in Wilson’s disease. The Atp7b−/− mouse develops hallmarks of Wilson’s disease. The activity of several nuclear receptors decreased in Atp7b−/− mice, and nuclear receptors are critical for maintaining metabolic homeostasis. Therefore, we anticipated that Atp7b−/− mice would exhibit altered progression of diet-induced obesity, fatty liver, and insulin resistance. Following 10 wk on a chow or Western-type diet (40% kcal fat), parameters of glucose and lipid homeostasis were measured. Hepatic metabolites were measured by liquid chromatography–mass spectrometry and correlated with transcriptomic data. Atp7b−/− mice fed a chow diet presented …