This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. ABSTRACT Ketosis-prone diabetes (KPD) is a heterogeneous syndrome characterized by adult patients who present with diabetic ketoacidosis (DKA). Multiple, severe forms of beta cell dysfunction appear to underlie the pathophysiology of KPD. Utilizing a large, longitudinally followed cohort of KPD patients, with repeated clinical and biochemical measurements, immunologic tests and genetic analysis, we have identified four clinically and pathophysiologically distinct subgroups of KPD, distinguished by the presence or absence of beta cell autoimmunity (A+ or A-) and the presence or absence of beta cell functional reserve (B+ or B-). The resulting AB classification system of KPD is accurate and highly predictive of clinical outcomes. One unique subgroup of KPD is new-onset, unprovoked A-B+ KPD, characterized by: 1) presentation with DKA as the first manifestation of diabetes;2) absence of a specific stress or other precipitating event for the DKA;3) onset usually after age 40;4) obese / overweight;5) 3:1 male predominance. Following recovery from the acute episode of DKA, A-B+ KPD patients usually manifest increased beta cell functional reserve, good long-term glycemic control, and insulin independence in over 45%. The purpose of this study is to determine if the initial severe defect and subsequent partial recovery of beta cell function in A-B+ KPD is associated with changes in beta cell mass. The design of this pilot study is to compare beta cell function and mass over time in A-B+ KPD patients, typical (non-ketotic) type 2 diabetics, and non-diabetic controls. We hypothesize that beta cell mass will show a progressive decline over time in the typical type 2 diabetic patients, while the KPD patients (following recovery from DKA) will show an initial increase followed by long-term maintenance of beta cell mass. To test this hypothesis, we propose to carry out a Pilot Study with the following Specific Aims: 1. To measure insulin secretory responses to arginine, glucose, and glucose-potentiated arginine in 3 groups of 10 adult subjects: a) new-onset, unprovoked A-B+ KPD, b) new onset """"""""typical"""""""" (non-ketotic) type 2 diabetes, and c) normal, glucose-tolerant controls;at baseline and after 6 months and 12 months;2. To estimate beta cell mass in these 3 groups at baseline, and after 6 and 12 months, using prior (published) data correlating these physiologic tests with known quantities of transplanted islet cells;3. To use the data from Aims 1 and 2 to estimate variations of response and effect size in the measurements, and thus design a statistically rigorous larger-scale trial in the future. Beta cell function and mass will be compared between these 3 groups by measuring quantitative insulin secretory responses to arginine and glucose, as well as glucose-potentiated arginine-induced insulin secretion (GPAIS). GPAIS has been shown to correlate well with beta cell mass. The two diabetic groups will receive treatment for diabetes using standard algorithms in our dedicated DKA Clinic at Ben Taub General Hospital throughout the study period.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
General Clinical Research Centers Program (M01)
Project #
5M01RR000188-47
Application #
8356774
Study Section
National Center for Research Resources Initial Review Group (RIRG)
Project Start
2010-12-01
Project End
2011-11-30
Budget Start
2010-12-01
Budget End
2011-11-30
Support Year
47
Fiscal Year
2011
Total Cost
$792
Indirect Cost
Name
Baylor College of Medicine
Department
Pediatrics
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
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