This report describes the form of diabetes mellitus, permanent neonatal (PNDM), caused by mutational variants in the human insulin (INS) gene. This disease exhibits autosomal dominant inheritance. The human gene INS encodes proinsulin, which is post-translationally processed to yield the two polypeptide chains (A and B) of insulin. Binding of insulin to the insulin receptor stimulates glucose uptake, and is critical to regulation of glucose metabolism.
Multiple UAS constructs of the human Hsap\INS gene have been introduced into flies, including wild-type and a variant associated with PNDM. Variant(s) implicated in human disease tested (as transgenic human gene, INS): the C96Y variant form has been introduced into flies.
The fly peptide most closely related to human insulin is encoded by Ilp3, one of the Drosophila insulin-like peptide genes. These genes are expressed in a small clusters of cells, insulin-producing cells (IPCs), in the brain; the IPCs appear to be functionally analogous to the human pancreatic islet beta cells.
[updated Sep. 2017 by FlyBase; FBrf0222196]
[DIABETES MELLITUS, PERMANENT NEONATAL, 4; PNDM4](https://omim.org/entry/618858)
[INSULIN; INS](https://omim.org/entry/176730)
Neonatal diabetes mellitus (NDM) is defined as insulin-requiring hyperglycemia within the first 6 months of life. It is a rare, with an estimated incidence of 1 in 400,000 neonates (Shield, 2000; pubmed:10895036). In about half of the neonates, diabetes is transient and resolves at a median age of 3 months, whereas the rest have a permanent insulin-dependent form of diabetes (PNDM). [from MIM:606176; 2017.09.11]
Permanent neonatal diabetes mellitus-4 (PNDM4) is characterized by chronic hyperglycemia due to severe nonautoimmune insulin deficiency diagnosed in the first months of life (summary by Polak et al., 2008; pubmed:18171712). [[from MIM:618858; 2022.03.29]
Permanent neonatal diabetes mellitus can be caused heterozygous or homozygous mutation in the INS gene. [from MIM:606176; 2017.09.11]
Permanent neonatal diabetes mellitus-4 (PNDM4) is caused by heterozygous or homozygous mutation in the INS gene. [from MIM:618858; 2022.03.29]
Binding of insulin to the insulin receptor stimulates glucose uptake, and thus is critical to glucose metabolism.
Insulin, synthesized by the beta cells of the islets of Langerhans, consists of 2 dissimilar polypeptide chains, A and B, which are linked by 2 disulfide bonds. Insulin chains A and B are derived from a single precursor, proinsulin, which is converted to insulin by the enzymatic removal of a segment that connects the amino end of the A chain to the carboxyl end of the B chain. [from MIM:176730; 2017.09.11]
There are multiple similar genes in both species.
Low-scoring ortholog of human gene INS; there are multiple similar genes in both species. Dmel\Ilp3 shares 25% identity and 42% similarity with human INS.
