Mechanism Underlying Beta-cell Failure in Obese African Americans With History of Hyperglycemic Crises

Study Overview
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Brief Summary
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Obesity is common in African American (AA) patients with newly diagnosed diabetes who present with diabetic ketoacidosis (DKA). Despite the presentation with severe symptoms of insulinopenia and ketoacidosis, clinical and immunogenetic observations indicate that most obese AA patients with DKA have type 2 diabetes. In such patients, previous studies reveal that: a) at presentation, obese AA patients with DKA have markedly decreased pancreatic insulin secretion, lower than in obese non-DKA patients admitted with comparable hyperglycemia, but significantly greater than in lean patients with DKA; b) aggressive diabetic management results in significant improvement in beta-cell function and insulin sensitivity sufficient to allow discontinuation of insulin therapy within 3 months of follow-up. Based on these observations the researchers conclude that similar to obese patients with hyperglycemia, most obese AA with DKA have type 2 diabetes, and that although defects in both insulin secretion and insulin action are present, transient b-cell failure is the primary defect in the development of ketoacidosis.

Detailed Description
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Obese AA patients with a history of DKA who later experience near-normoglycemia remission represent an ideal population in which to define the sequence of events that lead to b-cell dysfunction in type 2 diabetes. The researchers hypothesize that obese AA with DKA will prove particularly susceptible to beta-cells dysfunction due to sustained elevations of plasma glucose (glucose toxicity) and/or free fatty acid levels (lipotoxicity). This study will test beta-cell response by administering a glucose infusion to diabetic African Americans with a history of DKA, diabetic African Americans without a history of DKA, and non-diabetic African Americans.

Official Title
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Mechanism Underlying Beta-cell Failure in Obese African Americans With History of Hyperglycemic Crises

Conditions
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Diabetes Mellitus, Type 2

Intervention / Treatment
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* Drug: Intralipid 20%
* Drug: Glucose infusion


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Obese African American subjects (body mass index (BMI) equal or greater than 30) Age 18-65 Patients with a history of diabetic ketoacidosis as defined by the American Diabetes Association (ADA) criteria Patients admitted with hyperglycemia but without ketoacidosis (blood glucose greater than 400ml/dl without evidence of ketosis/ketones Obese nondiabetic controls (BMI >30; ruled out for diabetes with a 75g oral glucose tolerance test) Exclusion Criteria: Patients with positive autoimmune markers (islet cell or glutamic acid decarboxylase (GAD) autoantibodies) 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 or suspected endocrine disorders associated with increased insulin resistance, such as hypercortisolism, acromegaly, or hyperthyroidism Patients with bleeding disorders, thrombocytopenia, or abnormalities in coagulation studies Patients with fasting hyperglycemia (blood glucose > 120 mg/dl) after discontinuation of insulin therapy Pregnancy

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Participants with ketosis-prone diabetes<br>Obese African Americans with type 2 diabetes with history of diabetic ketoacidosis (DKA) receiving Intralipid 20% and a glucose infusion. | Drug: Intralipid 20%<br>* Participants receive a 48-hour infusion with Intralipid at 40 milliliters per hour (mL/hr).<br>Drug: Glucose infusion<br>* Participants receive a glucose infusion consisting of 10% dextrose infused intravenously at a rate of 200 mg/m^2/min for 20 hours.<br>|
| Active Comparator: Participants with ketosis-resistant diabetes<br>Obese African American with type 2 diabetes with hyperglycemia without ketosis receiving Intralipid 20% and a glucose infusion. | Drug: Intralipid 20%<br>* Participants receive a 48-hour infusion with Intralipid at 40 milliliters per hour (mL/hr).<br>Drug: Glucose infusion<br>* Participants receive a glucose infusion consisting of 10% dextrose infused intravenously at a rate of 200 mg/m^2/min for 20 hours.<br>|
| Active Comparator: Non-diabetic control group<br>Obese African Americans without diabetes receiving a glucose infusion. | Drug: Glucose infusion<br>* Participants receive a glucose infusion consisting of 10% dextrose infused intravenously at a rate of 200 mg/m^2/min for 20 hours.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| First-Phase Insulin Release (FPIR) | An arginine stimulation test was used to evaluate beta-cell function and insulin secretion. Increased glucose in the blood causes insulin to be released, beginning with a spike in insulin in the first 10 minutes and plateauing 2 to 3 later. Diminished first-phase insulin release is an early indicator of beta-cell dysfunction. Two sequential arginine stimulation tests were performed, the first set before and the second after completion of the 20-hour dextrose infusion. The first-phase insulin release (FPIR) was calculated as the sum of the insulin levels at 2, 3, 4, and 5 minutes after the arginine infusion. FPIR is expected to rise after the dextrose (glucose) infusion and FPIR generally rises less in persons with impaired glucose tolerance. | Hour 0, Hour 20 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Beta-cell Failure | Pancreatic beta-cells can adapt to insulin resistance during the early stages of diabetes but continuous exposure of beta-cells to prolonged hyperglycemia can cause irreversible damage due to glucotoxicity. This study aimed to evaluate whether hyperglycemia-induced reduced beta-cell failure was the result of beta-cell exhaustion or beta-cell desensitization, however, no participants experienced beta-cell failure so this original analysis could not be performed. | Hour 20 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hyperglycemia