Researchers

Research Interests

My group is interested in how nutrient sensing at a cellular level results in physiological changes in lipid and carbohydrate storage.  One major project in the lab focuses on the role of the mTORC1 complex, a protein kinase that serves as a cellular fuel gauge and regulates lipid synthesis, glycogen storage, mitochondrial function and insulin sensitivity.  For more information on my group please visit our Lab Homepage.  For a full list of publications  see here.

Research Area

Current Work: My current research focuses on the interaction of genetic and environmental factors in the prediction, prevention and management of prediabetes, diabetes and diabetes complications. My current NIN-funded projects include the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC), the Diabetes Prevention Program/ Diabetes Prevention Program Outcomes Study (DPP/DPPOS), and the Pathobiology and Reversibility of Prediabetes in a Biracial Cohort (PROP-ABC) study. I am also Principal Investigator/Co-investigator on 6 Phase III/IV cardiovascular outcomes trials sponsored by industry.

My research utilizes several methodologies that track in vivo physiology, including hyperinsulinemic euglycemic clamp, indirect calorimetry, analysis of body composition, assessment of beta-cell function, among others. I have successfully trained more than 20 research fellows, who have gone on to pursue careers in biomedicine.

Previous Work:

• Regulation and Metabolic Significance of Leptin in Humans
• Pathophysiology and reversal of hypoglycemia associated autonomic failure
• Regulation of epidemal growth factor (EGF) in human and murine endocrine systems;

Techniques and Technologies

In vivo patient-oriented human physiologic protocols, including

• Hyperinsulinemic euglycemic clamp
• Stepped hypoglycemic clamp
• Indirect calorimetry for assessment of energy expenditure
• Methodologies for assessment of betacell function
• Body composition analysis
• Fat and tissue biopsy and analysis
• Gene expression and metabolomics
• GCP and GRP in clinical trials protocols

Current Funding Source(s):

• NIH (NIDDK): UC4 DK104155 & UC4 DK104166.
• JDRF: 1-PNF-2014-180-A-V & Sub-12284-JDRF 25-2012-770.

My current research is focussed on type 1 diabetes in humans and the NOD mouse model. We are interested in developing a better understanding of why autoimmunity to the beta cells develop and what molecular abnormalities preceeds the early signs of autoimmune pathology. Our studies are focussed on immune cells (the perpetrators of the immune destruction) and the islets of Langerhans (the victims of the autoimmune reactions). We have used both proteomics and transcritomics to collect comprehensive gene expression profiles and discover pathways and processes that are abnormal at the early and later stages of disease. Although my earlier work was exclusively done in the NOD mouse model of type 1 diabetes, lately I have been able to use human tissue due to the nPOD tissue bank/consortium. This organization collects tissue from organ donors with diabetes relevant phenotypes and distribute it to approved investigators for research.

Previous Work: My earliest research training was in autoimmunity of diabetes and it’s contribution to disease in a mouse model of Coxsackie virus induced diabetes. I then did postdoctoral research at the Jackson laboratory working on projects related to mapping of the iNOS gene and induction of tolerance by intrathymic injections of islets/antigens. As a newly recruited assistant professor at UTHSC I worked on studies of human islet function and engraftment in immunodeficient NOD-SCID mice. This work included transfection of islets with genes that could improve their ability to engraft and/or resist immune rejection.

Techniques and Technologies

Recently used in our group:

• Isolation and culture of mouse islets.
• Characterization of islet function in vivo and in vitro, in mice.
• Characterization of proetomes by 2D-gels.
• Characterization of transcriptomes.
• Data mining of transcriptome/proteome datasets for enrichment of pathways, ontologies and transcription factor binding sites.

Previous experience with:

• Transplantation of islets into mice.
• Reconstitution of SCID mice with human immune system (cells).
• Chemical (STZ) induction of diabetes in mice.
• Injections into the thymus of mice.

For more information, a list of my publications can be found here.

Dr. Becca Krukowski is a clinical psychologist and has been an Assistant Professor in the Department of Preventive Medicine at the University of Tennessee Health Science Center since 2012.  Her major research interests are obesity prevention and treatment, particularly in relation to behavioral interventions, gestational weight gain, policy, and the food environment.

Research Projects

Dissemination of the Look Ahead Weight Management Treatment in the Military, Co-Investigator, 2012-2017.

Internet Assisted Obesity Treatment Enhanced by Financial Incentives, Co-Investigator, 2015-2020.

Effects of Maternal Body Composition on Offspring Body Phenotype: Potential Fetal Programming, Co-Investigator, 2009-2016.

Research Area

Current Work

Our group is interested in the discovery and development of novel therapeutics for cancer (hormonal cancers), metabolic and musculoskeletal diseases with emphasis on nuclear hormone receptor targets. We have identified that estrogen receptor β (ERβ) is an important therapeutic target for obesity and cardio-metabolic diseases. Drugs targeting ERβ alleviate obesity induced by different methods in preclinical models. Studies are ongoing to understand the mechanim of action for these beneficial effects of ERβ. As obesity is an etiology of non-alcoholic steatohepatitis (NASH), we have also embarked on a quest to determine the role of ERβ in NASH. We use both cell culture and animal models to evaluate our hypothesis related to obesity and metabolic diseases.

Previous Work

I was trained as a post-doctoral fellow in the department of molecular and cellular biology at Baylor College of Medicine. Since then, I served in biopharmaceutical industry for 10 years before transitioning back into academics. I have till date developed 7 programs from concept to preclinical or clinical development, mostly for hormonal cancers and metabolic diseases. My previous and current work are on nuclear hormone receptors.

Techniques and Technologies

• Whole animal body composition (echoMRI)
• Cell signaling and protein phosphorylation
• Adipocyte and myocyte differentiation
• Obesity and musculoskeletal models (transgenic and induce-models)
• All molecular biological methods

Research Interests

The goals of my research have been to conduct clinical research in the health care area of diabetes and endocrinology to help determine the pathophysiology of cause and complications related to diabetes and to determine biomarkers which may be used for early diagnosis, prevention, and /or treatment of the complications of diabetes; thus, leading to provide better healthcare to patients. Some of the studies in diabetes for which I have been the PI or Co-PI and also the recruiter for over 500 patients include: the Genomics and Proteomics of Type 2 Diabetes in T-lymphocytes and Muscle; the Glucommander studies for controlling glucose in hospital patients with Type 2 Diabetes (T2DM); the All to Target Study for T2DM; effect of sex hormones on insulin sensitivity in the Mechanisms of Action in DPP Intervention; DCCT; the Effect of Pioglitazone on Prevention of Diabetes in IGT (ACTos NOW); and two ADA-supported grants to study the effect of high protein vs high carbohydrate diets on weight loss, cardiovascular risk factors, markers of oxidative stress, lipid peroxidation and proinflammatory cytokines in obese women and prediabetic subjects. In addition to the recruitment and study testing, these studies required me to have much interactive time with the patients from one year up to five years.

I have conducted clinical research studies on the pathogenesis and treatment of diabetes in patients with hyperglycemic crises (DKA and hyperosmolar state), obese, prediabetic and T2DM subjects. I have also investigated the effects of hyperglycemia, hyperlipidemia, hyperglycemia crises as well as insulin-induced hypoglycemia on CD4 and CD8 lymphocytes and endothelial cells with respect to proinflammatory markers, activation and insulin signaling. I have also studied the effects of hyperglycemia and obesity on cardiovascular risk factors, markers of oxidative stress, cytokines, lipid peroxidation, metabolomes, DNA methylation, and metabolic hormones.

My current research studying the effect of high protein vs high carbohydrate diets on weight loss, metabolic hormones, cardiovascular risk factors, oxidative stress, lipid peroxidation, inflammatory markers, and DNA methylation in obese human subjects with normal glucose tolerance and those with prediabetes has produced exciting information about the reversibility of prediabetes. This is leading me to the next step of reversing newly diagnosed Type 2 Diabetes. I am involved with other investigators around the United States with their research, and as Medical Laboratory Director of the UT Endocrinology Laboratory, our lab performs laboratory assays for those investigators, our studies other investigators on the UT campus. I have trained numerous students, residents, fellows, and other faculty in clinical Endocrinology and diabetes, research and various laboratory experimental designs and methods.

Research Interests

Drs. Quarles and Pi lab is focused on the new endocrine axis has been proposed whereby bone regulates energy metabolism through the systemic effects of the bone derived hormone, osteocalcin (Ocn), to regulate insulin secretion through activation of a putative G-protein coupled receptor in β-cells as well as insulin sensitivity and energy expenditure through additional effects on other organ systems. We have discovered that the “nutrient” G-protein coupled receptor, GPRC6A, is capable of sensing Ocn. In addition, global knockout of Gprc6a in mice results in glucose intolerance and impaired insulin secretion. Gprc6a is highly expressed in mouse pancreatic β-cell line where it mediates the effects of Ocn to activate ERK and insulin secretion. Administration of Ocn stimulates ERK activity in the pancreas and increases serum insulin levels in wild-type mice, but these responses are markedly attenuated in Gprc6a-/- mice. Gprc6a-/- mice also have decreased islet size and number, suggesting that GPRC6A also regulates β-cell mass. These data suggest that GPRC6A is the receptor mediating the effects of Ocn in a bone-pancreas feed forward loop that involves insulin targeting of insulin receptors (IR) in osteoblasts to increase bone formation and osteoclast-mediated bone resorption that releases bioactive undecarboxylated Ocn which targets a putative receptor (i.e., GPRC6A) in β-cells to regulate insulin secretion and β-cell mass. We are also looking for collaborators with expertise in insulin resistence and gluconeogenesis in muscle, fat and liver.

Techniques and Technologies

• In vivo tissue specific knockouts and in vitro gene knockdown by siRNA and CRISP/CAS
• Isolation and culture of mouse islets
• Characterization of islet function in vivo and in vitro
• Characterization of cultured mouse and rat β-cells: MIN6 and INS-1
• Mouse GTT and ITT
• Characterization of G-protein coupled receptor signaling pathway