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

June 18, 2017 updated by: Sheba Medical Center

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.

Study Overview

Status

Unknown

Conditions

Intervention / Treatment

Study Type

Observational

Enrollment (Anticipated)

30

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

      • ramat Gan, Israel, 52621
        • Recruiting
        • Sheba Medical Center
        • Contact:
          • Ayana Paster, RD
          • Phone Number: 972-3-5302021

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

10 years to 78 years (Child, Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Sampling Method

Non-Probability Sample

Study Population

MODY-2 family

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Observational Models: Other
  • Time Perspectives: Prospective

Cohorts and Interventions

Group / Cohort
Intervention / Treatment
pancreas specific MODY-2

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
fasting and post glucose load glucose level
Time Frame: 1 year
1 year

Secondary Outcome Measures

Outcome Measure
Time Frame
fasting and post glucose load Insulin
Time Frame: 1 year
1 year
fasting and post glucose load c-peptide
Time Frame: 1 year
1 year

Other Outcome Measures

Outcome Measure
Time Frame
glucose metabolism measured by CGMS
Time Frame: 1 year
1 year

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Investigators

  • Principal Investigator: Jacob Ilany, MD, Sheba Medical Center

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

October 1, 2013

Primary Completion (Anticipated)

December 1, 2017

Study Completion (Anticipated)

December 1, 2017

Study Registration Dates

First Submitted

September 30, 2013

First Submitted That Met QC Criteria

October 8, 2013

First Posted (Estimate)

October 10, 2013

Study Record Updates

Last Update Posted (Actual)

June 20, 2017

Last Update Submitted That Met QC Criteria

June 18, 2017

Last Verified

June 1, 2017

More Information

Terms related to this study

Other Study ID Numbers

  • SHEBA-13-0464-JI-CTIL

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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