Betacel dysfunction induced by impaired pancreas anatomy and insulin sensitivity in subjects with heterozygous EXT1 or EXT2 Mutations

A recent Genome Wide Association Study (GWAS) identified novel risk loci for
type 2 diabetes including EXT-2. This gene codes for exostosin, which is an
enzyme involved in the elongation of heparan sulfate, a glycosaminoglycan
present throughout the human body. Patients with EXT-1 and EXT-2 mutations are
characterized by the hereditary multiple exostoses/ multiple osteochondromas
(HME/MO) syndrome, an autosomal dominant syndrome causing multiple benign
epiphysial bone tumors during (pre-) puberty due to 50% reduction in heparan
sulfate synthesis. However, mice with these mutations are also characterized by
insulin secretion problems as well as a smaller size of the pancreas. We
therefore performed hyperglycaemic normoinsulinemic clamps in these HME/MO
patients and found that these subjects are characterized by impaired insulin
secretion and 50% reduction in betacell capacity compared to unaffected related
controls (BEEM study, MEC 08/262). Elaborating on these findings, we now would
like to investigate whether human subjects with these mutations are also
characterized by smaller pancreas size (assessed by MRI), which could cast new
light on the causes of type 2 diabetes mellitus.

Assessment of glucose homeostasis and pancreas size (MRI) in 10 subjects with
heterozygous mutations in EXT-1, in 10 subjects with heterozygous mutations in
EXT-2 and 10 unaffected related controls as well as 10 subjects with known type
2 diabetes mellitus.

Case control study

This study does not have specific advantages for the study subjects. The
results of this observational study may help researchers understanding the role
of heparan sulfates in the development of type 2 diabetes mellitus. Subjects
will be asked to fast during 12 hours. This is not considered to be harmfull. A
total amount of 30 ml blood wil be collected, this is not considered to be
harmfull. MRI pancreas imaging is a non-invasive technique (no radiation) which
takes about 30 minutes. We will use gadolinium as an intravenous contrast agent
which could potentially be harmful in subject with renal dysfunction. We will
therefore screen renal function by measuring plasma creatine before MRI and
subjects with renal dysfunction will be excluded from participation. We believe
the information gathered from this study outweighs the burden of these
interventions.