Study of the Pharmacologic Action of a GPR119 Agonist on Glucagon Counter-regulation During Insulin-induced Hypoglycemia in Type 1 Diabetes Mellitus

Diabetes Mellitus, Type 1 Clinical Trial

— PHROG  

Official title:

A Randomized, Placebo-controlled, Double-blinded Cross-over Study of the Pharmacologic Action of a GPR119 Agonist on Glucagon Counter-regulation During Insulin-induced Hypoglycemia in Type 1 Diabetes Mellitus

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04432090
• Other study ID #: 1552172
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: April 21, 2021
• Est. completion date: June 2024

Study information

• Verified date: February 2024
• Source: AdventHealth Translational Research Institute
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to test if a specific research medication could increase the response to low blood glucose in people with type 1 diabetes. The response of the body to low blood sugar will be measured in healthy people as a reference point.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 67
• Est. completion date: June 2024
• Est. primary completion date: November 11, 2022
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 20 Years and older

Eligibility

Inclusion Criteria:

Type 1 diabetes cohort

1. Age >20 years

2. Diagnosis of T1DM according to American Diabetes Association (ADA) criteria continuously requiring insulin for survival

3. Diabetes diagnosis performed more than 5 years before enrollment

4. Fasting C-peptide levels < 0.7 ng/mL with a concurrent plasma glucose concentration > 90 mg/dL

5. For female participants: agrees not to become pregnant during the study and for at least 2 weeks after the last dose of the study medication. For male participants: agrees not to donate sperm or not to get a woman pregnant during the study and for at least 2 weeks after the last dose of the study medication.

Healthy subject cohort

1. Age >20 years

2. General good health

3. Creatinine clearance >80 mL/min based on MDRD equation

4. Fasting blood glucose (FBG) >70 mg/dL and <100 mg/dL

5. No history of diabetes

Exclusion Criteria:

1. BMI >30 kg/m2 and <18.5 kg/m2

2. No evidence by history, EKG or exams of symptomatic cardiovascular disease (unstable angina, myocardial infarction or coronary revascularization within 6 months, clinically significant abnormalities on EKG, presence of cardiac pacemaker, implanted cardiac defibrillator)

3. Evidence of autonomic neuropathy

4. Liver disease (AST or ALT >2.5 times the upper limit of normal)

5. Kidney disease (creatinine >1.6 mg/dl or estimated GFR <60 ml/min).

6. Dyslipidemia, including triglycerides >500 mg/dl, LDL >200 mg/dl or unstable hyperlipidemia. Treatment with a single lipid lowering agents is allowed if stable within the previous 3 months.

7. Anemia (hemoglobin <12 g/dl in men, <11 g/dl in women)

8. Thyroid dysfunction (suppressed thyroid stimulating hormone (TSH), elevated TSH <10 µIU/ml if symptomatic or elevated TSH >10 µIU/ml if asymptomatic)

9. Uncontrolled hypertension (BP >160 mmHg systolic or >100 mmHg diastolic) or treatment with more than 2 antihypertensive medications

10. History of cancer within the last 5 years (skin cancers, with the exception of melanoma, may be acceptable).

11. History of organ transplant

12. History of HIV, active Hepatitis B or C, or Tuberculosis

13. Pregnancy, lactation or 6 months postpartum from the scheduled date of collection

14. Females of childbearing potential (any female except those with tubal ligation, hysterectomy, or absence of menses >2 years) unwilling to use an approved method of contraception (one medically accepted method of contraception with =99% effectiveness when used consistently and correctly: implantable uterine device (IUD), hormonal contraception). Male participants: unwilling to use appropriate contraception (e.g. condoms) and/or their partner uses a medically accepted form of contraception during the study.

15. History of Major Depression in the last 5 years

16. History of an eating disorder

17. History of bariatric surgery

18. History of drug or alcohol abuse (> 3 drinks per day) within the last 5 years

19. Psychiatric disease prohibiting adherence to study protocol

20. Use of oral or injectable anti-hyperglycemic agents: metformin, sulfonylureas, DPP IV inhibitors, SGLT-2 inhibitors, thiazolidinediones, acarbose, GLP-1 analogs

21. Current use of beta-adrenergic blocking agents or their use was stopped less than one month before recruitment

22. Initiation or change in hormone replacement therapy within the past 3 months (including, but not limited to thyroid hormone or estrogen replacement therapy)

23. Use of any medications known to influence glucose, fat and/or energy metabolism within the last 3 months (e.g., growth hormone therapy, glucocorticoids [steroids], prescribed medications for weight loss, etc.)

24. Current night shift worker

25. Presence of any condition that, in the opinion of the Investigator, compromises participant safety or data integrity or the participant's ability to complete study visits Additional exclusion Criteria for type 1 diabetes cohort

26. History of T2DM or any form of diabetes other than T1DM

27. Hypoglycemia unawareness as assessed using the GOLD score

28. Using a predictive low blood glucose suspend mode on an insulin pump or a hybrid closed loop algorithm for insulin delivery. For those applying these strategies for everyday management of blood glucose and willing to participate, the algorithm will be stopped at enrollment where possible.

29. Two or more episode of severe hypoglycemia per month in the past six months.

30. QTcF >450 ms for males and >470 ms for females

31. Using non-insulin agents to control blood glucose levels.

32. No evidence of moderate or severe end-organ diabetic complications of retinopathy, nephropathy or neuropathy. Non-proliferative retinopathy and microalbuminura will be allowed.

Additional exclusion Criteria for the healthy cohort

33. Insulin treatment

Related Conditions & MeSH terms

• Diabetes Mellitus
• Diabetes Mellitus, Type 1
• Hypoglycemia

Intervention

Drug:
• Placebo
Each group will receive either a pill that contains the study medication (MBX-2982) or a pill that does not contain the medication (placebo)
• Study Medication (MBX-2982)
Each group will receive either a pill that contains the study medication (MBX-2982) or a pill that does not contain the medication (placebo)

Other:
• No medication for this group
This group will be studied to establish the norm of the measurement that will be performed to obtain the study outcomes.

Locations

Country	Name	City	State
United States	AdventHealth Translational Research Institute	Orlando	Florida

Sponsors (1)

Lead Sponsor	Collaborator
AdventHealth Translational Research Institute

Country where clinical trial is conducted

United States, 

References & Publications (18)

Bolli G, Calabrese G, De Feo P, Compagnucci P, Zega G, Angeletti G, Cartechini MG, Santeusanio F, Brunetti P. Lack of glucagon response in glucose counter-regulation in type 1 (insulin-dependent) diabetics: absence of recovery after prolonged optimal insulin therapy. Diabetologia. 1982 Feb;22(2):100-5. doi: 10.1007/BF00254837. — View Citation

Christensen M, Calanna S, Sparre-Ulrich AH, Kristensen PL, Rosenkilde MM, Faber J, Purrello F, van Hall G, Holst JJ, Vilsboll T, Knop FK. Glucose-dependent insulinotropic polypeptide augments glucagon responses to hypoglycemia in type 1 diabetes. Diabetes. 2015 Jan;64(1):72-8. doi: 10.2337/db14-0440. Epub 2014 Jul 22. — View Citation

Cryer PE. Mechanisms of hypoglycemia-associated autonomic failure in diabetes. N Engl J Med. 2013 Jul 25;369(4):362-72. doi: 10.1056/NEJMra1215228. No abstract available. — View Citation

Davis SN, Mann S, Briscoe VJ, Ertl AC, Tate DB. Effects of intensive therapy and antecedent hypoglycemia on counterregulatory responses to hypoglycemia in type 2 diabetes. Diabetes. 2009 Mar;58(3):701-9. doi: 10.2337/db08-1230. Epub 2008 Dec 10. — View Citation

Ekberg JH, Hauge M, Kristensen LV, Madsen AN, Engelstoft MS, Husted AS, Sichlau R, Egerod KL, Timshel P, Kowalski TJ, Gribble FM, Reiman F, Hansen HS, Howard AD, Holst B, Schwartz TW. GPR119, a Major Enteroendocrine Sensor of Dietary Triglyceride Metabolites Coacting in Synergy With FFA1 (GPR40). Endocrinology. 2016 Dec;157(12):4561-4569. doi: 10.1210/en.2016-1334. Epub 2016 Oct 25. — View Citation

Farngren J, Persson M, Schweizer A, Foley JE, Ahren B. Vildagliptin reduces glucagon during hyperglycemia and sustains glucagon counterregulation during hypoglycemia in type 1 diabetes. J Clin Endocrinol Metab. 2012 Oct;97(10):3799-806. doi: 10.1210/jc.2012-2332. Epub 2012 Aug 1. — View Citation

Flock G, Holland D, Seino Y, Drucker DJ. GPR119 regulates murine glucose homeostasis through incretin receptor-dependent and independent mechanisms. Endocrinology. 2011 Feb;152(2):374-83. doi: 10.1210/en.2010-1047. Epub 2010 Nov 10. — View Citation

Frier BM. Hypoglycaemia in diabetes mellitus: epidemiology and clinical implications. Nat Rev Endocrinol. 2014 Dec;10(12):711-22. doi: 10.1038/nrendo.2014.170. Epub 2014 Oct 7. — View Citation

Gerich JE, Langlois M, Noacco C, Karam JH, Forsham PH. Lack of glucagon response to hypoglycemia in diabetes: evidence for an intrinsic pancreatic alpha cell defect. Science. 1973 Oct 12;182(4108):171-3. doi: 10.1126/science.182.4108.171. — View Citation

Gerich JE. Lilly lecture 1988. Glucose counterregulation and its impact on diabetes mellitus. Diabetes. 1988 Dec;37(12):1608-17. doi: 10.2337/diab.37.12.1608. — View Citation

Hypoglycemia in the Diabetes Control and Complications Trial. The Diabetes Control and Complications Trial Research Group. Diabetes. 1997 Feb;46(2):271-86. — View Citation

Lauffer LM, Iakoubov R, Brubaker PL. GPR119 is essential for oleoylethanolamide-induced glucagon-like peptide-1 secretion from the intestinal enteroendocrine L-cell. Diabetes. 2009 May;58(5):1058-66. doi: 10.2337/db08-1237. Epub 2009 Feb 10. — View Citation

Li NX, Brown S, Kowalski T, Wu M, Yang L, Dai G, Petrov A, Ding Y, Dlugos T, Wood HB, Wang L, Erion M, Sherwin R, Kelley DE. GPR119 Agonism Increases Glucagon Secretion During Insulin-Induced Hypoglycemia. Diabetes. 2018 Jul;67(7):1401-1413. doi: 10.2337/db18-0031. Epub 2018 Apr 18. — View Citation

Rizza RA, Cryer PE, Gerich JE. Role of glucagon, catecholamines, and growth hormone in human glucose counterregulation. Effects of somatostatin and combined alpha- and beta-adrenergic blockade on plasma glucose recovery and glucose flux rates after insulin-induced hypoglycemia. J Clin Invest. 1979 Jul;64(1):62-71. doi: 10.1172/JCI109464. — View Citation

Segerstolpe A, Palasantza A, Eliasson P, Andersson EM, Andreasson AC, Sun X, Picelli S, Sabirsh A, Clausen M, Bjursell MK, Smith DM, Kasper M, Ammala C, Sandberg R. Single-Cell Transcriptome Profiling of Human Pancreatic Islets in Health and Type 2 Diabetes. Cell Metab. 2016 Oct 11;24(4):593-607. doi: 10.1016/j.cmet.2016.08.020. Epub 2016 Sep 22. — View Citation

Szewczyk JW, Acton J, Adams AD, Chicchi G, Freeman S, Howard AD, Huang Y, Li C, Meinke PT, Mosely R, Murphy E, Samuel R, Santini C, Yang M, Zhang Y, Zhao K, Wood HB. Design of potent and selective GPR119 agonists for type II diabetes. Bioorg Med Chem Lett. 2011 May 1;21(9):2665-9. doi: 10.1016/j.bmcl.2010.12.086. Epub 2010 Dec 22. — View Citation

UK Hypoglycaemia Study Group. Risk of hypoglycaemia in types 1 and 2 diabetes: effects of treatment modalities and their duration. Diabetologia. 2007 Jun;50(6):1140-7. doi: 10.1007/s00125-007-0599-y. Epub 2007 Apr 6. — View Citation

Yue JT, Burdett E, Coy DH, Giacca A, Efendic S, Vranic M. Somatostatin receptor type 2 antagonism improves glucagon and corticosterone counterregulatory responses to hypoglycemia in streptozotocin-induced diabetic rats. Diabetes. 2012 Jan;61(1):197-207. doi: 10.2337/db11-0690. Epub 2011 Nov 21. — View Citation

* Note: There are 18 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Maximal glucagon concentration during hypoglycemia		Day 14, Day 28, 6 hours
Primary	Total area under the curve (AUC) for glucagon during hypoglycemia.		Day 14, Day 28, 6 hours
Primary	Incremental AUC for glucagon during hypoglycemia (above baseline levels during euglycemia)		Day 14, Day 28, 6 hours