The gene MAPK8IP1, encoding islet-brain-1, is a candidate for type 2 diabetes

Area of Science:

• Genetics
• Endocrinology
• Molecular Biology

Background:

• Type 2 diabetes is a complex genetic disease with late onset, influenced by environmental factors.
• Susceptibility genes for type 2 diabetes remain largely unidentified.
• Islet-brain-1 (IB1), encoded by MAPK8IP1, is a DNA-binding protein that regulates the glucose transporter GLUT2 (SLC2A2).

Purpose of the Study:

• To investigate the role of IB1 in beta-cell function and its potential link to type 2 diabetes.
• To evaluate the impact of reduced IB1 expression on insulin and glucose transporter gene expression.
• To identify genetic variations in MAPK8IP1 associated with type 2 diabetes.

Main Methods:

• Expression of MAPK8IP1 antisense RNA in a beta-cell line to reduce IB1 protein levels.
• Quantification of SLC2A2 and INS mRNA expression.
• Detection of MAPK8IP1 transcripts and IB1 protein in human pancreatic islets.
• Sibpair analysis in French families with type 2 diabetes.
• In vitro functional analysis of a MAPK8IP1 missense mutation (559N).

Main Results:

• Reduced IB1 protein led to significant decreases in SLC2A2 and INS mRNA expression.
• MAPK8IP1 transcripts and IB1 protein were detected in human islets.
• Sibpair analysis excluded MAPK8IP1 as a major diabetes locus in French families.
• A novel missense mutation (559N) in MAPK8IP1 segregated with diabetes in one family.
• The mutation impaired IB1's ability to protect against apoptosis and counteract JNK pathway inhibition of INS transcription.

Conclusions:

• MAPK8IP1 is a candidate gene for type 2 diabetes, playing a crucial role in beta-cell function.
• A novel non-MODY form of diabetes associated with a MAPK8IP1 mutation has been identified.
• IB1 is a key regulator of beta-cell function, impacting insulin and glucose transporter expression and beta-cell survival.