Over 50% of obese African-Americans (AA) presenting with newly diagnosed, severe hyperglycemia and/or unprovoked diabetic ketoacidosis (DKA) display clinical, metabolic, and immunogenetic features of type 2 diabetes. Prior studies by our group and other investigators indicate that a) at presentation, obese AA with history of severe hyperglycemia and/or DKA have markedly decreased pancreatic insulin secretion and impaired insulin action, b) absent or low prevalence of positive beta-cell autoantibodies , and.c) aggressive diabetic management results in significant improvement in beta-cell function and insulin sensitivity sufficient to allow discontinuation of insulin therapy in >90% of patients within 3 months of follow-up. These patients have been referred to as having ketosis-prone type 2 diabetes (KPDM). Most patients with KPDM, however, experience a hyperglycemic relapse within a year of insulin discontinuation. Consequently, patients with """"""""KPDM"""""""" are an ideal model to follow throughout their clinical course in order to correlate their response to treatment with the mechanism(s) and markers of short- and long-term remission and, hopefully, future prevention. Better characterization of the natural history of KPDM would facilitate the direction of long-term therapy, consideration of new treatment modalities, and likely decrease the recurrence of DKA which is associated with increased mortality and morbidity.
The specific aims of this proposal are to 1) correlate specific molecular markers in skeletal muscle with patient outcome, beta-cell function, and insulin sensitivity and 2) determine whether pioglitazone therapy will delay an insulin-deficient relapse by improving or preserving beta-cell function and insulin action. The study design is characterized as a prospective, case- cohort study that later incorporates a randomized control trial to evaluate the longitudinal effects of pioglitazone versus sitagliptin versus placebo on maintaining near-normoglycemic remission after the discontinuation of insulin therapy. In addition to testing acute insulin response (glucagon-stimulation test) and immunogenetic factors (pancreatic antibodies and HLA class II typing), subjects will be assessed for differences in insulin sensitivity and secretion at presentation of KPDM and at follow-up of 12 weeks or less (short and long-term outcomes). Assessment of beta-cell function will be performed at designated intervals for individuals that attain near-normoglycemic remission and enter the intervention arm of the study.
Investigating subjects with KPDM will increase knowledge about p-cell function, insulin resistance, guide long-term therapy, fuel avenues for novel therapies, and decrease the recurrence of DKA and admissions.
|Vellanki, Priyathama; Smiley, Dawn D; Stefanovski, Darko et al. (2016) Randomized Controlled Study of Metformin and Sitagliptin on Long-term Normoglycemia Remission in African American Patients With Hyperglycemic Crises. Diabetes Care 39:1948-1955|
|Beck Jr, George R; Khazai, Natasha B; Bouloux, Gary F et al. (2013) The effects of thiazolidinediones on human bone marrow stromal cell differentiation in vitro and in thiazolidinedione-treated patients with type 2 diabetes. Transl Res 161:145-55|
|Smiley, Dawn; Umpierrez, Guillermo E; Hermayer, Kathie et al. (2013) Differences in inpatient glycemic control and response to subcutaneous insulin therapy between medicine and surgery patients with type 2 diabetes. J Diabetes Complications 27:637-41|
|Chaudhuri, Ajay; Umpierrez, Guillermo E (2012) Oxidative stress and inflammation in hyperglycemic crises and resolution with insulin: implications for the acute and chronic complications of hyperglycemia. J Diabetes Complications 26:257-8|
|McDonnell, Marie E; Umpierrez, Guillermo E (2012) Insulin therapy for the management of hyperglycemia in hospitalized patients. Endocrinol Metab Clin North Am 41:175-201|
|Gosmanov, Aidar R; Smiley, Dawn D; Peng, Limin et al. (2012) Vascular effects of intravenous intralipid and dextrose infusions in obese subjects. Metabolism 61:1370-6|
|Umpierrez, Guillermo E; Spiegelman, Ronnie; Zhao, Vivian et al. (2012) A double-blind, randomized clinical trial comparing soybean oil-based versus olive oil-based lipid emulsions in adult medical-surgical intensive care unit patients requiring parenteral nutrition. Crit Care Med 40:1792-8|
|Weiss, Tamara; Skelton, Kelly; Phifer, Justine et al. (2011) Posttraumatic stress disorder is a risk factor for metabolic syndrome in an impoverished urban population. Gen Hosp Psychiatry 33:135-42|
|Farrokhi, Farnoosh; Smiley, Dawn; Umpierrez, Guillermo E (2011) Glycemic control in non-diabetic critically ill patients. Best Pract Res Clin Endocrinol Metab 25:813-24|
|Smiley, Dawn; Chandra, Prakash; Umpierrez, Guillermo E (2011) Update on diagnosis, pathogenesis and management of ketosis-prone Type 2 diabetes mellitus. Diabetes Manag (Lond) 1:589-600|
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