Ketosis Prone Diabetes in African-Americans
Condition: Ketosis Prone Diabetes; Diabetic Ketoacidosis; Severe Hyperglycemia
MeSH terms: Diabetes Mellitus; Hyperglycemia; Ketosis; Diabetic Ketoacidosis; Diabetes Mellitus, Type 1
Study type: Observational

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): pioglitazone
Intervention type(s): Drug
Intervention description(s): Obese AA subjects with DKA or severe hyperglycemia that are able to discontinue insulin at 12 weeks or less will be randomized (blinded fashion) to receive either placebo or pioglitazone qd. The subjects will be followed while in the study arm and beta-cell function will be assessed using OGTT at set intervals.
Other intervention name(s): Actos (pioglitazone)
Intervention MeSH terms: Pioglitazone
Observational model: Cohort
Time perspective: Prospective
Sampling method: Probability Sample
Study population: 
        36 Obese AA subjects with DKA or severe hyperglycemia and 8 obese nondiabetic subjects, age
        19-65.
      
Biospecimen description: 
      The study has IRB approval for blood sample collection for future DNA analyses and HLA
      typing.
    
Keywords: ketosis-prone diabetes; diabetic ketoacidosis; obesity; insulin dependence; mechanisms