Ketosis Prone Diabetes in African-Americans
Ketosis Prone Diabetes in African-Americans
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 indicate that these patients a) have
 markedly decreased insulin secretion and impaired insulin action at presentation, b) absent
 or low prevalence of beta-cell autoantibodies and c) are able to discontinue aggressive
 insulin therapy in ~70% of cases 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. The
 specific aims of this proposal are to 1) identify clinical, metabolic, and immunogenetic
 markers that alone, or in combination, are predictive of short- and long-term
 near-normoglycemic remission and 2) determine whether pioglitazone or sitagliptin therapy
 will delay an insulin-deficient relapse once insulin is discontinued. The Principal
 Investigator hypothesizes that measures of beta-cell function at presentation, alone or in
 combination with measures of insulin sensitivity, will correlate with the ability of a
 patient to achieve and remain in near-normoglycemic remission. She also hypothesizes that
 intervention compared to placebo will preserve beta-cell function, improve insulin
 sensitivity, and prevent an insulin-deficient relapse. This prospective, cohort study with a
 RCT arm would better characterize the natural history of KPDM, facilitate the direction of
 long-term therapy, and likely decrease the recurrence of DKA which is associated with
 increased mortality and morbidity.
More than half of obese African-Americans (AA) with newly diagnosed diabetes presenting with
 diabetic ketoacidosis (DKA) display clinical, metabolic, and immunogenetic features of type 2
 diabetes during follow-up. Prior studies by our group and other investigators indicate that,
 at presentation, these patients a) have markedly decreased insulin secretion and impaired
 insulin action, b) have low prevalence of positive B-cell autoantibodies, and c) respond to
 aggressive diabetic management with significant improvement in B-cell function and insulin
 sensitivity sufficient to allow discontinuation of insulin therapy. Upon discontinuation of
 insulin, the period of near-normoglycemia remission (defined as the ability to discontinue
 insulin injections for ≥ one week and remain in good metabolic control - fasting blood
 glucose ≤ 120 mg/dl and A1c ≤ 7%) may last for a few months to several years. These patients
 are referred to as having atypical diabetes, Flatbush diabetes, or ketosis-prone type 2
 diabetes (KPDM). Patients with "KPDM" are therefore 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 determine the optimal therapeutic approach in
 order to prevent future glycemic decompensation.
Inclusion Criteria:

 -  36 Obese AA subjects with DKA or severe hyperglycemia and 8 obese nondiabetic
 subjects, age 19-65. All studies will be performed in the GCRC at Grady Memorial
 Hospital.

 -  Subjects with a BMI ≥ 28 kg/m2 will be included.

 -  Diagnostic criteria for DKA will include:

 -  a plasma glucose > 250 mg/dl,

 -  a venous pH < 7.30,

 -  a serum bicarbonate < 18 mEq/l, and

 -  high serum ketones.

 -  Obese hyperglycemic patients will have:

 -  a blood glucose on admission > 400 mg/dl,

 -  a serum bicarbonate > 18 mEq/l, and

 -  negative ketones.

 Exclusion Criteria:

 -  Patients with significant medical or surgical illness, including but not limited to
 myocardial ischemia, congestive heart failure, chronic renal insufficiency, liver
 failure, and infectious processes;

 -  Patients with recognized endocrine disorders, such as hypercortisolism, acromegaly, or
 hyperthyroidism;

 -  Bleeding disorders, or abnormalities in coagulation studies;

 -  Pregnancy.