MODY-2 Diabetes Clinical Trial
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.
| Status | Recruiting |
| Enrollment | 30 |
| Est. completion date | December 2017 |
| Est. primary completion date | December 2017 |
| Accepts healthy volunteers | Accepts Healthy Volunteers |
| Gender | All |
| Age group | 12 Years to 80 Years |
| Eligibility |
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. |
| Country | Name | City | State |
|---|---|---|---|
| Israel | Sheba Medical Center | ramat Gan |
| Lead Sponsor | Collaborator |
|---|---|
| Sheba Medical Center |
Israel,
| Type | Measure | Description | Time frame | Safety issue |
|---|---|---|---|---|
| Other | glucose metabolism measured by CGMS | 1 year | ||
| Primary | fasting and post glucose load glucose level | 1 year | ||
| Secondary | fasting and post glucose load Insulin | 1 year | ||
| Secondary | fasting and post glucose load c-peptide | 1 year |