Glucagon Response to Prandial Insulin Administration in Persons With Type 1 Diabetes

NCT04079881 | Terminated Phase 1 Results DMC FDA Drug

• 1 other identifier: 201909013
• Study Type: interventional
• Target: 1
• Locations: 1 country
• Sites: 1

Brief Summary

Glucagon regulation and response in persons with T1D at the basal state and in response to various stimuli remains unclear. Dr. Philip Cryer has previously reported that, in T1D young adults with a course of the disease of 16+9 years, the absence of endogenous insulin secretion results in increased glucagon secretion after a mixed meal, concluding that endogenous insulin reciprocally regulates the alpha-cell glucagon secretion and also suggesting that glucagon dysregulation may play an important role in post-prandial hyperglycemia in T1D. Interestingly, recent research on human islets have shown that insulin inhibits counter-regulatory glucagon secretion by a paracrine effect mediated by SGLT2-dependent stimulation of somatostatin release. An important gap in our knowledge is whether the timing of prandial insulin doses affects the glucagon response to a hyperglycemic stimulus in patients with T1D who have undetectable C-peptide. Whether appropriately timed exogenous insulin can modify the glucagon response to glucose fluctuations has not been studied. As such, this pilot study aims to characterize the glucagon response to meal-time hyperglycemia and to compare the difference in glucagon secretion when mealtime bolus insulin is given before the meal versus after the meal with the objective of understanding factors that contribute to the peak post-prandial blood glucose and AUC of blood glucose after a mixed meal in this target population.

Conditions

Type 1 Diabetes; Hyperglycemia, Postprandial

Keywords

glucagon; post-prandial glucose; type 1 diabetes

Outcome Measures

Primary Outcomes (1)

• AUC Postprandial Glucagon

  Glucagon levels done fasting, 30, 60, 120, and 180 minutes

  4 hours

Secondary Outcomes (1)

• AUC Postprandial Glucose

  4 hours

Study Arms (2)

A (Pre-prandial insulin administration) : B (post-prandial insulin administration)

EXPERIMENTAL

VISIT 1: Pre-prandial insulin: will give short acting insulin (Humalog, Lispro, etc) with the same regimen patient was using at home 20 min prior the meal. Then VISIT 2: Post-prandial insulin: will give short acting insulin (Humalog, Lispro, etc) with the same regimen patient was using at home 20 min post the meal.

Drug: Insulin

B (post-prandial insulin administration) : A (Pre-prandial insulin administration) :b

EXPERIMENTAL

VISIT 1: Post-prandial insulin: will give short acting insulin (Humalog, Lispro, etc) with the same regimen patient was using at home 20 min post the meal. Then VISIT 2: Pre-prandial insulin: will give short acting insulin (Humalog, Lispro, etc) with the same regimen patient was using at home 20 min prior the meal.

Drug: Insulin

Interventions

Insulin DRUG

to give pre-prandial and post-prandial insulin (will use patient insulin dose patient use at home) to patients with T1D and evaluate the response of post-prandial glucagon and post-prandial hyperglycemia.

Also known as: Pre-prandial insulin, postprandial insulin

A (Pre-prandial insulin administration) : B (post-prandial insulin administration); B (post-prandial insulin administration) : A (Pre-prandial insulin administration) :b

Eligibility Criteria

• Age: 18 Years - 90 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• persons with T1D for \>5 years age \>18.
• HbA1c \<9.5%
• Patients using either MDI or insulin pumps will be included.
• Patients using CGM will continue the use during the study, however glucoses will be measured by laboratory methods.
• Persons of all races, ethnicity and genders will be included
• Participants should have normal hemoglobin, hematocrit and eGFR \>60 ml/min/1.73m2.

You may not qualify if:

• Persons with type 2 diabetes, monogenic diabetes, pancreatic diseases.
• Pregnancy, prisoners, other vulnerable populations or persons unable to understand the protocol and provide written informed consent.
• Persons who take daily steroids, any route, for any purpose

Sponsors & Collaborators

• Washington University School of Medicine: lead

Study Sites (1)

Washington University in St Louis

St Louis, Missouri, 63110, United States

Location

Related Publications (7)

• Cryer PE. Minireview: Glucagon in the pathogenesis of hypoglycemia and hyperglycemia in diabetes. Endocrinology. 2012 Mar;153(3):1039-48. doi: 10.1210/en.2011-1499. Epub 2011 Dec 13.

  PMID: 22166985 BACKGROUND

• Cooperberg BA, Cryer PE. Insulin reciprocally regulates glucagon secretion in humans. Diabetes. 2010 Nov;59(11):2936-40. doi: 10.2337/db10-0728. Epub 2010 Aug 23.

  PMID: 20811038 BACKGROUND

• Vergari E, Knudsen JG, Ramracheya R, Salehi A, Zhang Q, Adam J, Asterholm IW, Benrick A, Briant LJB, Chibalina MV, Gribble FM, Hamilton A, Hastoy B, Reimann F, Rorsman NJG, Spiliotis II, Tarasov A, Wu Y, Ashcroft FM, Rorsman P. Insulin inhibits glucagon release by SGLT2-induced stimulation of somatostatin secretion. Nat Commun. 2019 Jan 11;10(1):139. doi: 10.1038/s41467-018-08193-8.

  PMID: 30635569 BACKGROUND

• Schiffrin A, Suissa S, Weitzner G, Poussier P, Lalla D. Factors predicting course of beta-cell function in IDDM. Diabetes Care. 1992 Aug;15(8):997-1001. doi: 10.2337/diacare.15.8.997.

  PMID: 1505333 BACKGROUND

• Yosten GLC. Alpha cell dysfunction in type 1 diabetes. Peptides. 2018 Feb;100:54-60. doi: 10.1016/j.peptides.2017.12.001.

  PMID: 29412832 BACKGROUND

• Porksen S, Nielsen LB, Kaas A, Kocova M, Chiarelli F, Orskov C, Holst JJ, Ploug KB, Hougaard P, Hansen L, Mortensen HB; Hvidore Study Group on Childhood Diabetes. Meal-stimulated glucagon release is associated with postprandial blood glucose level and does not interfere with glycemic control in children and adolescents with new-onset type 1 diabetes. J Clin Endocrinol Metab. 2007 Aug;92(8):2910-6. doi: 10.1210/jc.2007-0244. Epub 2007 May 22.

  PMID: 17519307 BACKGROUND

• Brown RJ, Sinaii N, Rother KI. Too much glucagon, too little insulin: time course of pancreatic islet dysfunction in new-onset type 1 diabetes. Diabetes Care. 2008 Jul;31(7):1403-4. doi: 10.2337/dc08-0575.

  PMID: 18594062 BACKGROUND

MeSH Terms

Conditions

Diabetes Mellitus, Type 1; Hyperglycemia

Interventions

Insulin

Condition Hierarchy (Ancestors)

Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases; Autoimmune Diseases; Immune System Diseases

Intervention Hierarchy (Ancestors)

Proinsulin; Insulins; Pancreatic Hormones; Peptide Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Peptides; Amino Acids, Peptides, and Proteins

Limitations and Caveats

Study was terminated before completion due to COVID pandemic and loss of funding.

Results Point of Contact

• Title: Janet McGill, MD
• Organization: Wash Univ School of Medicine

jmcgill@wustl.edu

(314) 362-8681

Study Officials

• Janet McGill, MD

  Wash. Univ. School of Medicine

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Participants are randomly assigned receive intervention A then intervention B or to receive intervention B than intervention A

Study Record Dates

• First Submitted: August 29, 2019
• First Posted: September 6, 2019
• Study Start: February 13, 2020
• Primary Completion: July 1, 2020
• Study Completion: July 1, 2020
• Last Updated: October 7, 2022
• Results First Posted: March 2, 2022

Record last verified: 2022-09

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)