Glucose Tolerance Impaired, Insulin Sensitivity, Type 2 Diabetes
Conditions
Keywords
Fasting plasma glucagon, Glucagon receptor antagonist
Brief summary
With REMD's glucagon receptor antagonist, the study team propose to provide a comprehensive examination of the effect of elevated plasma glucagon concentrations in Type 2 Diabetes Mellitus (T2D) patients on: (i) glucose tolerance; (ii) insulin sensitivity in liver, muscle, and adipocytes; (iii) beta cell function; (iv) adipocyte inflammation.
Detailed description
Subjects with T2DM inadequately controlled on current medications will participate in a glucose tolerance test, euglycemic insulin clamp combined with 3-3H-glucose and 14-C glycerol infusion, adipose tissue biopsy, before and 12 weeks after treatment with REMD 477 or placebo.
Interventions
DRUGREMD-477
A biologic glucagon receptor agonist to which randomized subjects are assigned 2:1
Placebo for REMD-477 to which subjects will be randomized 1:2.
Sponsors
The University of Texas Health Science Center at San Antonio
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Subject)
Masking description
Participants will be blinded to the study drug or placebo randomization.
Intervention model description
A randomized 2-arm placebo controlled trial
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
1. Type 2 diabetic subjects, males/females; 2. age = 18-70 years 3. BMI = 25-40 kg/m2; 4. HbA1c = 7.5-10.0%; 5. Type 2 Diabetics who are drug naïve or treated with metformin, sulfonylureas, SGLT-2 inhibitors or any combination thereof. 6. Subjects must be on a stable dose of antidiabetic medications for at least 3 months prior to study. 7. Patients must be able to communicate meaningfully with the investigator and must be legally competent to provide written informed consent. 8. Female patients must be non-lactating and must either be at least two years post-menopausal, or be using adequate contraceptive precautions (i.e. oral contraceptives, approved hormonal implant, intrauterine device, diaphragm with spermicide, condom with spermicide), or be surgically sterilized (i.e. bilateral tubal ligation, bilateral oophorectomy). Female patients who have undergone a hysterectomy are eligible for participation in the study. Female patients (except for those patients who have undergone a hysterectomy or a bilateral oophorectomy) are eligible only if they have a negative pregnancy test throughout the study period
Exclusion criteria
1. Subjects with a personal or family history of pancreatic neuroendocrine tumors or multiple endocrine neoplasia, due to the potential increased of pancreatic alpha cell carcinogenicity associated with glucagon receptor antagonists. 2. Subjects with a contraindication to MRI including artificial heart valves or pacemakers 3. Patients with a known sensitivity to humanized antibodies 4. Subjects treated with GLP-1 RAs or insulin are excluded. 5. Subjects treated with a non-antidiabetic medication that may impact insulin sensitivity, such as systemic steroids, or lipase inhibitors (orlistat, Alli or Xenical) 6. Hematocrit \< 34 vol% 7. Serum creatinine \> 1.8 mg/dl 8. AST (SGOT) \> 2 times upper limit of normal 9. ALT (SGPT) \> 2 times upper limit of normal 10. Any major organ system disease as identified by medical history, physical exam, and screening blood tests, EKG 11. Subjects who cannot give written, voluntary consent 12. Subjects with a major psychiatric disturbance 13. Only subjects whose body weight has been stable (±3-4 pounds) over the three months prior to study will be included. 14. Patients must not have type 1 diabetes 15. Patients must not have a fasting plasma glucose of greater than 270 mg/dl or HbA1c \> 10.0% 16. Patients must not have received a thiazolidinedione, GLP-1 agonist, or insulin for more than one week during the year prior to randomization 17. Patients with a history of clinically significant heart disease (New York Heart Classification greater than class 2; more than non-specific ST-T wave changes on the EKG), peripheral vascular disease (history of claudication), or pulmonary disease (dyspnea on exertion of one flight or less; abnormal breath sounds on auscultation) will not be studied.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Glycated Hemoglobin (HbA1c) | Baseline to 13 weeks | Change in HbA1c measured at baseline and after intervention administration |
| Fasting Plasma glucose (FPG) | Baseline to 13 weeks | Change in fasting plasma glucose measured at baseline and after intervention administration |
| Plasma glucose (PG) | Baseline to 13 weeks | Change in plasma PG measured at baseline and after intervention administration using an oral glucose tolerance test (OGTT) |
| Hepatic insulin sensitivity | Baseline to 13 weeks | Change in hepatic glucose production (HGP) |
| Whole body glucose disposal | Baseline to 13 weeks | Change in whole body glucose disposal measured in mg/kg/min |
| Plasma Free Fatty Acids (FFA) | Baseline to 13 weeks | Change in plasma free fatty acids |
| Muscle Insulin sensitivity | Baseline to 13 weeks | Change in muscle insulin sensitivity measured by insulin-stimulated glucose uptake during low dose high dose insulin clamp. |
Countries
United States
Outcome results
None listed