The Effect of ß-cell Specific Glucokinase Mutation on Glucose Homeostasis and Insulin Secretion in a MODY-2 Family

This study is not yet open for participant recruitment.
Verified October 2013 by Sheba Medical Center
Sponsor:
Information provided by (Responsible Party):
Sheba Medical Center
ClinicalTrials.gov Identifier:
NCT01960231
First received: September 30, 2013
Last updated: October 8, 2013
Last verified: October 2013
  Purpose

Type 2 diabetes mellitus patients exhibit many glucose homeostasis abnormalities in different tissues and organs. Among the more important defects are disturbed hepatic glucose metabolism and defective pancreatic β-cell function. Hexokinase IV, commonly known as glucokinase, is the predominant hexokinase expressed in the liver, the pancreatic β-cells (where it functions as the glucose sensor for insulin secretion) and in glucose-sensory cells in the hypothalamus and gut.

The glucokinase gene contains two distinct promoters. The downstream one is active only in hepatocytes and the upstream promoter is active only in extrahepatic glucose sensory-cells. Alternative promoters enable differential regulation of gene transcription in liver and extrahepatic sites. In pancreatic β-cells, glucokinase expression at the mRNA level is largely constitutive, whereas in the liver it undergoes large adaptive changes in response to nutritional states, enabling larger changes in glucokinase activity than would otherwise be possible by post-transcriptional regulation alone.

Most of the MODY-2 patients were found to have glucokinase mutations located in areas that are common to the liver and pancreas. The diabetes in these patients is related both to defect in insulin secretion and abnormal hepatic glucose metabolism. Point mutation in the pancreatic specific promoter was recently described as a cause for impaired fasting glucose [Diabetes 58:1929-1935, 2009]. The investigator have recently identified a MODY-2 family with a genetic defect that is located in the pancreatic promoter, sparing the liver promoter. This family demonstrates that abnormal insulin secretion alone (perhaps together with other extrahepatic glucose sensors) is enough to cause diabetes.

In this study, the investigators would like to use an oral glucose tolerance test (OGTT) and continuous glucose monitoring (CGM) technique in order to elucidate the relative roll of the hepatic glucokinase in normal glucose homeostasis. This issue is complicated by the fact that in addition to glucokinase, hexokinase isoenzymes I, II and III are also expressed at very low levels in hepatocytes. They are an important back-up mechanism when glucokinase activity is compromised, as in liver cirrhosis or murine models with liver-specific glucokinase knock-down. However, impaired hepatic glycogen synthesis was demonstrated in MODY-2 subjects (JCI 1996:98:1755). By comparing members of the investigators MODY-2 family with members of other MODY-2 families and normal controls the investigators hope to shade some light on this question.


Condition Intervention
MODY-2 Diabetes
Other: OGTT

Study Type: Observational
Study Design: Time Perspective: Prospective

Resource links provided by NLM:


Further study details as provided by Sheba Medical Center:

Primary Outcome Measures:
  • fasting and post glucose load glucose level [ Time Frame: 1 year ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • fasting and post glucose load Insulin [ Time Frame: 1 year ] [ Designated as safety issue: No ]
  • fasting and post glucose load c-peptide [ Time Frame: 1 year ] [ Designated as safety issue: No ]

Other Outcome Measures:
  • glucose metabolism measured by CGMS [ Time Frame: 1 year ] [ Designated as safety issue: No ]

Estimated Enrollment: 30
Study Start Date: October 2013
Estimated Study Completion Date: December 2014
Estimated Primary Completion Date: December 2014 (Final data collection date for primary outcome measure)
Groups/Cohorts Assigned Interventions
pancreas specific MODY-2 Other: OGTT

  Eligibility

Ages Eligible for Study:   12 Years to 80 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Sampling Method:   Non-Probability Sample
Study Population

MODY-2 family

Criteria

Inclusion Criteria:

  1. MODY 2 patients with documented mutations in the glucokinase promoter or coding region.
  2. Healthy non-diabetic individuals matched for age, sex and BMI with recruited MODY2 patients.
  3. Age range - 12-80; males and females

Exclusion Criteria:

  1. Unable to provide written informed consent.
  2. Unable to safely stop glycemia related medications for the duration of the test + wash-out period.
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01960231

Contacts
Contact: Jacob Ilany, MD 972-3-5302021 jacob.ilani@sheba.health.gov.il

Locations
Israel
Sheba Medical Center Not yet recruiting
ramat Gan, Israel, 52621
Contact: Ayana Paster, RD    972-3-5302021      
Sponsors and Collaborators
Sheba Medical Center
Investigators
Principal Investigator: Jacob Ilany, MD Sheba Medical Center
  More Information

No publications provided

Responsible Party: Sheba Medical Center
ClinicalTrials.gov Identifier: NCT01960231     History of Changes
Other Study ID Numbers: SHEBA-13-0464-JI-CTIL
Study First Received: September 30, 2013
Last Updated: October 8, 2013
Health Authority: Israel: Ministry of Health

ClinicalTrials.gov processed this record on April 22, 2014