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

This study is currently recruiting participants. (see Contacts and Locations)
Verified May 2014 by Sheba Medical Center
Sponsor:
Information provided by (Responsible Party):
Sheba Medical Center
ClinicalTrials.gov Identifier:
NCT01960231
First received: September 30, 2013
Last updated: May 26, 2014
Last verified: May 2014

September 30, 2013
May 26, 2014
October 2013
December 2014   (final data collection date for primary outcome measure)
fasting and post glucose load glucose level [ Time Frame: 1 year ] [ Designated as safety issue: No ]
Same as current
Complete list of historical versions of study NCT01960231 on ClinicalTrials.gov Archive Site
  • 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 ]
Same as current
glucose metabolism measured by CGMS [ Time Frame: 1 year ] [ Designated as safety issue: No ]
Same as current
 
The Effect of ß-cell Specific Glucokinase Mutation on Glucose Homeostasis and Insulin Secretion in a MODY-2 Family
Not Provided

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.

Not Provided
Observational
Time Perspective: Prospective
Not Provided
Not Provided
Non-Probability Sample

MODY-2 family

MODY-2 Diabetes
Other: OGTT
pancreas specific MODY-2
Intervention: Other: OGTT
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
30
December 2014
December 2014   (final data collection date for primary outcome measure)

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.
Both
12 Years to 80 Years
Yes
Contact: Jacob Ilany, MD 972-3-5302021 jacob.ilani@sheba.health.gov.il
Israel
 
NCT01960231
SHEBA-13-0464-JI-CTIL
No
Sheba Medical Center
Sheba Medical Center
Not Provided
Principal Investigator: Jacob Ilany, MD Sheba Medical Center
Sheba Medical Center
May 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP