Type 2 Diabetes, Glucose Metabolism Disorders, Glucose, High Blood
Conditions
Keywords
Type 2 Diabetes, Diabetes
Brief summary
Type 2 diabetes is a chronic condition that affects the ability of the body to regulate glucose (sugar). When glucose levels are low, the liver can make glucose to increase levels in the body. This important process is called endogenous glucose production (EGP). Previous studies suggest that the central nervous system (CNS), including the brain, helps to coordinate this process by communicating with the liver through potassium channels. Control of EGP can be impaired in people with type 2 diabetes, which may contribute to the high levels of glucose seen in these individuals. The purpose of this study is to understand how activating these potassium channels in the control centers of the brain with a medication called diazoxide might inhibit the amount of glucose made by the liver. This is particularly important for people with diabetes who have very high production of glucose, which in turn causes hyperglycemia (high levels of sugar in the blood) that leads to diabetes complications.
Detailed description
In this study, the investigators will study healthy participants through a procedure called a pancreatic clamp study. During the clamp procedure, glucose (a sugar) and insulin (a hormone produced in the pancreas that regulates the amount of glucose in the blood) are infused with an intravenous catheter, and blood samples are collected periodically throughout the procedure to measure blood sugar levels and the levels of several hormones that are found in the body and are related to glucose metabolism. Endogenous glucose production (the production of sugar by the liver) will be measured in patients given diazoxide (a medication that activates potassium channels in the brain that may affect glucose production in the liver through brain-liver signaling), compared with when a placebo is given. All experiments will consist of 240 min insulin/somatostatin (250 μg/hr) infusions with replacement of glucoregulatory hormones (glucagon 1 ng/kg·min; growth hormone 3 ng/kg·min). Throughout the study, the plasma glucose concentration will be maintained at basal levels ( \ 90 mg/dl). This will be attained by infusion of insulin at adequate rates to maintain normoglycemia without requiring glucose infusion. Primed continuous infusions of High-performance liquid chromatography-purified \[3-3H\]-glucose will be initiated at t=0 (21.6 μCi bolus, then 0.15 μCi/min), to measure glucose fluxes. All infusions will be stopped at t=240 min. From t=0 to t=240 min, blood samples will be obtained for determinations of plasma glucose, insulin, glucagon, C-peptide, cortisol, growth hormone, free fatty acids (FFA), glycerol, and lactate, and for 3-3H-glucose determinations. This registration is exclusive to Aim 1 of the study protocol, which determined the effect of diazoxide on hepatic glucose production in nondiabetic, healthy, young individuals under fixed hormonal conditions. Euglycemic (90 mg/dl x 4 hours) pancreatic clamp studies (n= 10), with either saline or diazoxide infusion.
Interventions
DRUGDiazoxide
4 mg/kg body weight total dosage administered orally
DRUGPlacebo
Oral saline
Sponsors
National Institutes of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
American Diabetes Association
Meredith Hawkins
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
DOUBLE (Subject, Investigator)
Intervention model description
All participants received placebo or diazoxide in a randomized, double-blinded fashion.
Eligibility
Sex/Gender
ALL
Age
21 Years to 45 Years
Healthy volunteers
Yes
Inclusion criteria
* Healthy volunteers * Be no more than 140% of body weight * No concurrent illnesses
Exclusion criteria
* No clinical history or laboratory evidence of hyperlipidemia (LDL cholesterol \< 160 mg/dL) * Clinical history of Hypertension * Clinical history of Heart disease * Clinical history of Cerebrovascular disease * Clinical history of Seizures * Clinical history of Bleeding disorders * Clinical history of Muscle disease * Smokers * Mentally disabled persons * Prisoners * Pregnancy * Clinical history of ethanol or drug or toxin exposure which could be associated with neuropathy * Subjects incapable of giving voluntary informed consent * History of bleeding disorder * Clinical history of prolonged Prothrombin Time (PT) or Partial Thromboplastin Time
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Rate of Endogenous Glucose Production (EGP) | Final 60 minutes (t=180-240 minutes) of the pancreatic clamp, 6-7 hours after dosing | Rate of EGP (a measure of the body's production of sugar) was measured using analysis of blood samples taken throughout the pancreatic clamp procedure under various treatment conditions (e.g., diazoxide or placebo) by monitoring changes in the level of a non-radioactive, naturally occurring form of glucose (sugar). Rates were summarized by treatment (Diazoxide or Placebo) in mg/kg/min sing basic descriptive statistics. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| All Participants Participants were administered 4 mg/kg body weight total dosage of diazoxide orally followed by saline orally after a two-week washout period.
Diazoxide: 4 mg/kg body weight total dosage administered orally.
Placebo: Oral saline | 10 |
| Total | 10 |
Baseline characteristics
| Characteristic | All Participants | — |
|---|---|---|
| Age, Categorical <=18 years | 0 Participants | — |
| Age, Categorical >=65 years | 0 Participants | — |
| Age, Categorical Between 18 and 65 years | 10 Participants | — |
| Age, Continuous | 33.0 years STANDARD_DEVIATION 2.5 | — |
| Body Mass Index (BMI) | 27.4 kg/m^2 STANDARD_DEVIATION 1.5 | — |
| Race and Ethnicity Not Collected | — | — Participants |
| Region of Enrollment United States | 10 participants | — |
| Sex: Female, Male Female | 3 Participants | — |
| Sex: Female, Male Male | 7 Participants | — |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 10 | 0 / 10 |
| other Total, other adverse events | 1 / 10 | 0 / 10 |
| serious Total, serious adverse events | 0 / 10 | 0 / 10 |
Outcome results
Primary
Rate of Endogenous Glucose Production (EGP)
Rate of EGP (a measure of the body's production of sugar) was measured using analysis of blood samples taken throughout the pancreatic clamp procedure under various treatment conditions (e.g., diazoxide or placebo) by monitoring changes in the level of a non-radioactive, naturally occurring form of glucose (sugar). Rates were summarized by treatment (Diazoxide or Placebo) in mg/kg/min sing basic descriptive statistics.
Time frame: Final 60 minutes (t=180-240 minutes) of the pancreatic clamp, 6-7 hours after dosing
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Diazoxide | Rate of Endogenous Glucose Production (EGP) | 1.15 mg/kg/min | Standard Error 0.13 |
| Placebo | Rate of Endogenous Glucose Production (EGP) | 1.63 mg/kg/min | Standard Error 0.17 |