Ketosis Prone Diabetes in African-Americans

NCT ID: NCT00426413

Last Updated: 2013-11-13

Basic Information

• Recruitment Status: COMPLETED
• Total Enrollment: 44 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2007-05-31
• Study Completion Date: 2010-08-31

Brief 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.

Conditions

Ketosis Prone Diabetes; Diabetic Ketoacidosis; Severe Hyperglycemia

Keywords

ketosis-prone diabetes; diabetic ketoacidosis; obesity; insulin dependence; mechanisms

Study Design

• Observational Model Type: COHORT
• Study Time Perspective: PROSPECTIVE

Study Groups

1

Obese AA subjects with DKA or severe hyperglycemia

pioglitazone

Intervention Type: DRUG

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.

2

obese nondiabetic subjects, age 19-65.

No interventions assigned to this group

3

Any subjects with recurrent DKA. Recurrent DKA is defined as more than one admission to Grady Memorial Hospital.

No interventions assigned to this group

Interventions

pioglitazone

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.

Intervention Type: DRUG

Other Intervention Names

Actos (pioglitazone)

Eligibility Criteria

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.

• Minimum Eligible Age: 19 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Emory University

OTHER

Sponsor Role: lead

Responsible Party

Dawn Smiley MD

Principal Investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Dawn D Smiley, MD

Role: PRINCIPAL_INVESTIGATOR

Emory University

Locations

Grady Memorial Hospital

Atlanta, Georgia, United States

Countries

United States

References

Vellanki P, Stefanovski D, Anzola II, Smiley DD, Peng L, Umpierrez GE. Long-term changes in carbohydrate tolerance, insulin secretion and action in African-American patients with obesity and history of hyperglycemic crises. BMJ Open Diabetes Res Care. 2020 May;8(1):e001062. doi: 10.1136/bmjdrc-2019-001062.

Reference Type: DERIVED

PMID: 32475838 (View on PubMed)

Other Identifiers

GCRC 1703

Identifier Type: OTHER

Identifier Source: secondary_id

897-2003

Identifier Type: OTHER

Identifier Source: secondary_id

IRB00024857

Identifier Type: -

Identifier Source: org_study_id