Abstract
Pancreastatin (PST), a chromogranin A-derived peptide, is a potent physiological inhibitor of glucose-induced insulin secretion. PST also triggers glycogenolysis in liver and reduces glucose uptake in adipocytes and hepatocytes. Here, we probed for genetic variations in PST sequence and identified two variants within its functionally important carboxyl terminus domain: E287K and G297S. To understand functional implications of these amino acid substitutions, we tested the effects of wild-type (PST-WT), PST-287K, and PST-297S peptides on various cellular processes/events. The rank order of efficacy to inhibit insulin-stimulated glucose uptake was: PST-297S > PST-287K > PST-WT. The PST peptides also displayed the same order of efficacy for enhancing intracellular nitric oxide and Ca(2+) levels in various cell types. In addition, PST peptides activated gluconeogenic genes in the following order: PST-297S ≈ PST-287K > PST-WT. Consistent with these in vitro results, the common PST variant allele Ser-297 was associated with significantly higher (by ∼17 mg/dl, as compared with the wild-type Gly-297 allele) plasma glucose level in our study population (n = 410). Molecular modeling and molecular dynamics simulations predicted the following rank order of α-helical content: PST-297S > PST-287K > PST-WT. Corroboratively, circular dichroism analysis of PST peptides revealed significant differences in global structures (e.g. the order of propensity to form α-helix was: PST-297S ≈ PST-287K > PST-WT). This study provides a molecular basis for enhanced potencies/efficacies of human PST variants (likely to occur in ∼300 million people worldwide) and has quantitative implications for inter-individual variations in glucose/insulin homeostasis.
Highlights
Pancreastatin is a potent physiological regulator of plasma glucose/insulin
This study provides a molecular basis for enhanced potencies/efficacies of human PST variants and has quantitative implications for inter-individual variations in glucose/insulin homeostasis
Identification of Non-synonymous Genetic Variations in the Human PST Sequence—To probe for genetic variations in the PST peptide that might alter its function we re-sequenced the genomic region of CHGA in 410 individuals (i.e. 820 chromosomes)
Summary
Results: We discovered two human variants of pancreastatin that are profoundly more potent than the wild-type peptide. Conclusion: Higher potencies of the variants correlate well with their enhanced propensity to adopt longer helical structures than the wild-type peptide. Pancreastatin (PST), a chromogranin A-derived peptide, is a potent physiological inhibitor of glucose-induced insulin secretion. PST peptides activated gluconeogenic genes in the following order: PST-297S ≈ PST-287K > PST-WT Consistent with these in vitro results, the common PST variant allele Ser-297 was associated with significantly higher (by ϳ17 mg/dl, as compared with the wild-type Gly-297 allele) plasma glucose level in our study population (n ؍410). This study provides a molecular basis for enhanced potencies/efficacies of human PST variants (likely to occur in ϳ300 million people worldwide) and has quantitative implications for inter-individual variations in glucose/insulin homeostasis
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