Diabetes Mellitus, Type 2
Conditions
Keywords
Hyperglycemia
Brief summary
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
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.
Interventions
DRUGIntralipid 20%
Participants receive a 48-hour infusion with Intralipid at 40 milliliters per hour (mL/hr).
DRUGGlucose infusion
Participants receive a glucose infusion consisting of 10% dextrose infused intravenously at a rate of 200 mg/m\^2/min for 20 hours.
Sponsors
American Diabetes Association
Emory University
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| First-Phase Insulin Release (FPIR) | Hour 0, Hour 20 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Beta-cell Failure | Hour 20 | 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. |
Countries
United States
Participant flow
Recruitment details
Participant enrollment began in March 2004 and all study follow-up was completed in December 2009. The study was conducted at the Clinical Research Center at Grady Memorial Hospital in Atlanta, Georgia.
Participants by arm
| Arm | Count |
|---|---|
| Ketosis-prone Diabetics Obese African Americans with type 2 diabetes and a history of diabetic ketoacidosis (DKA) receiving a 48-hour infusion of Intralipid 20% at 40 mL/hour and a glucose infusion of 10% dextrose infused at a rate of 200 mg/m\^2/min for 20 hours. | 8 |
| Ketosis-resistant Diabetics Obese African Americans with type 2 diabetes with hyperglycemia without ketosis receiving a 48-hour infusion of Intralipid 20% at 40 mL/hour and a glucose infusion of 10% dextrose infused at a rate of 200 mg/m\^2/min for 20 hours. | 7 |
| Non-diabetic Control Group Obese African Americans without diabetes receiving a glucose infusion of 10% dextrose infused at a rate of 200 mg/m\^2/min for 20 hours. | 13 |
| Total | 28 |
Baseline characteristics
| Characteristic | Ketosis-prone Diabetics | Total | Non-diabetic Control Group | Ketosis-resistant Diabetics |
|---|---|---|---|---|
| Age, Continuous | 42.8 years STANDARD_DEVIATION 10.6 | 44 years STANDARD_DEVIATION 9 | 40 years STANDARD_DEVIATION 9.3 | 49.7 years STANDARD_DEVIATION 8.1 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 8 Participants | 28 Participants | 13 Participants | 7 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment United States | 8 Participants | 28 Participants | 13 Participants | 7 Participants |
| Sex: Female, Male Female | 2 Participants | 16 Participants | 12 Participants | 2 Participants |
| Sex: Female, Male Male | 6 Participants | 12 Participants | 1 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 8 | 0 / 7 | 0 / 13 |
| other Total, other adverse events | 1 / 8 | 1 / 7 | 0 / 13 |
| serious Total, serious adverse events | 0 / 8 | 0 / 7 | 0 / 13 |
Outcome results
Primary
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.
Time frame: Hour 0, Hour 20
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ketosis-prone Diabetics | First-Phase Insulin Release (FPIR) | Before glucose infusion | 264 microunits/ml | Standard Deviation 80 |
| Ketosis-prone Diabetics | First-Phase Insulin Release (FPIR) | After glucose infusion | 359 microunits/ml | Standard Deviation 42 |
| Ketosis-resistant Diabetics | First-Phase Insulin Release (FPIR) | Before glucose infusion | 339 microunits/ml | Standard Deviation 221 |
| Ketosis-resistant Diabetics | First-Phase Insulin Release (FPIR) | After glucose infusion | 381 microunits/ml | Standard Deviation 147 |
| Non-diabetic Control Group | First-Phase Insulin Release (FPIR) | Before glucose infusion | 197 microunits/ml | Standard Deviation 33 |
| Non-diabetic Control Group | First-Phase Insulin Release (FPIR) | After glucose infusion | 299 microunits/ml | Standard Deviation 30 |
Secondary
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.
Time frame: Hour 20
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ketosis-prone Diabetics | Number of Participants With Beta-cell Failure | 0 Participants |
| Ketosis-resistant Diabetics | Number of Participants With Beta-cell Failure | 0 Participants |
| Non-diabetic Control Group | Number of Participants With Beta-cell Failure | 0 Participants |