Islet Amyloid Polypeptide Gene Research Articles

Islet amyloid polypeptide (amylin): no evidence of an abnormal precursor sequence in 25 Type 2 (non-insulin-dependent) diabetic patients

Islet amyloid polypeptide is the major protein component of the islet amyloid of patients with Type 2 (non-insulin-dependent) diabetes mellitus. Since the synthesis of a structurally abnormal or mutant protein may contribute to the formation of amyloid deposits, we have examined the possibility that a mutant form of islet amyloid polypeptide or its precursor contributes to the formation of islet amyloid in Type 2 diabetic patients. We have sequenced the islet amyloid polypeptide precursor coding regions of the gene of 25 patients with Type 2 diabetes. Genomic DNA fragments corresponding to exon 2 and 3 of the islet amyloid polypeptide gene were amplified from patients' peripheral blood leucocyte DNAs using the polymerase chain reaction and specific oligonucleotide primer sets, and then directly sequenced. The nucleotide sequences of the amplified regions of both alleles of the islet amyloid polypeptide gene of these 25 patients were identical to one another and to the sequence of an islet amyloid polypeptide allele isolated from a human fetal liver genomic library. These findings suggest that a primary structural abnormality of islet amyloid polypeptide or its precursor is unlikely to play a significant role in the formation of islet amyloid in Type 2 diabetic patients.

The human islet amyloid polypeptide (IAPP) gene: Organization, chromosomal localization and functional identification of a promoter region

We report the isolation and characterization of the human gene encoding islet amyloid polypeptide (IAPP). Previously characterized cDNA sequences correspond to three exons of which the first is noncoding. A functional promoter region was identified in the 5' flanking DNA; however, this was farther upstream than expected. Northern blot analysis of human insulinoma RNA revealed three IAPP mRNAs of sizes 1.2, 1.8 and 2.1 kb, in agreement with three polyadenylation signals present in the 3' end of the gene. In situ hybridization to metaphase chromosomes resulted in two distinct peaks on chromosome 12, at 12p12-p13 and 12q13-q14. Southern blot analysis of genomic DNA suggested a single IAPP locus but also indicated the presence of additional homologous sequences in human genomic DNA.

Altered islet amyloid polypeptide (amylin) gene expression in rat models of diabetes.

The response of the islet amyloid polypeptide gene to chronic dexamethasone treatment in adult rats was investigated. After 12 daily injections, rats were severely underweight and fasting blood glucose levels were elevated. When pancreatic mRNA was analysed, a 16-fold elevation in islet amyloid polypeptide mRNA was observed with only a four-fold increase in insulin mRNA levels. Pancreatic islet amyloid polypeptide and insulin mRNA levels were also determined 12 days after streptozotocin treatment. In these rats, which were not severely diabetic, the reduction in islet amyloid polypeptide mRNA levels was sixfold less than the reduction in insulin mRNA levels. In both these models of diabetes the ratio of islet amyloid polypeptide to insulin mRNA levels was raised. This would not be expected if the physiological role of islet amyloid polypeptide is as a simple hyperglycaemic agent opposing insulin action or release.

The complete islet amyloid polypeptide precursor is encoded by two exons

Islet amyloid polypeptide (IAPP) is the 37-amino acid peptide subunit of amyloid found in pancreatic islets of type 2 diabetic patients and in insulinomas. Recently, we isolated the human gene encoding IAPP [(1988) FEBS Lett. 239, 227–232]. We now report the nucleotide sequences of a human insulinoma cDNA encoding a complete IAPP precursor, and of the corresponding parts of the IAPP gene. Two exons, which are approx. 5 kb apart in the human genome, encode the 89-amino acid pre-pro-IAPP. At least one additional exon is present further upstream in the IAPP gene. A putative signal sequence at the amino-terminus of the precursor suggests that IAPP is a secreted protein.