Abstract
Aims: Procolipase (CLPS) is secreted from the exocrine pancreas into the gastrointestinal
tract and becomes proteolytically cleaved into colipase and the pentapeptide enterostatin.
While colipase is an indispensable cofactor for pancreatic lipase, enterostatin acts
as a hormone that inhibits insulin secretion and confers satiety signals to the brain,
thereby restricting further food intake in animal models. As both high fat diet and
obesity contribute to insulin resistance, we investigated whether genetic variability
of CLPS associates with metabolic traits in non-diabetic humans at diabetes risk.
Methods: Tagging single nucleotide polymorphisms (SNPs) in the human CLPS locus on chr6p21.1
were selected using HapMap data. 498 humans, phenotyped for different glucose and
lipid metabolic traits, were genotyped by bidirectional sequencing and multivariate
linear regression analyses were undertaken.
Results: 2 tagging SNPs (rs3748050 in the Kozak sequence: A/G and rs3748051 in intron 1: A/G),
covering 100% of CLPS variability including 8 kb of its promoter, were genotyped for
association analyses. The minor alleles of both tagging SNPs associated significantly
with a reduced insulin secretion (−20.2%, both SNPs) in various estimation models
derived from the oral glucose tolerance test (OGTT; rs3748050/51: 30 min C-peptide
levels: p=0.001/0.01, insulinogenic index: p=0.02/0.02, AUC C-peptide/AUC glucose:
p=0.01/0.01) after adjustment for relevant covariates. No significant associations
with fasting total cholesterol (c), HDL-c, LDL-c, triglycerides and free fatty acids
were found (all p > 0.11).
Conclusions: CLPS genetic variability associates with insulin secretory function in non-diabetic
humans and may represent a novel candidate gene for development of type 2 diabetes.
Key words
type 2 diabetes - genetic association study - procolipase - insulin secretion - insulin
sensitivity - enterostatin
References
Correspondence
peter.weyrich@med.uni-tuebingen.de
