ABSTRACT
Permanent neonatal diabetes mellitus (PNDM) is a rare disorder usually presenting within 6 months of birth. Although several genes have been linked to this disorder, in almost half the cases documented in Italy, the genetic cause remains unknown. Because the Akita mouse bearing a mutation in the Ins2 gene exhibits PNDM associated with pancreatic beta cell apoptosis, we sequenced the human insulin gene in PNDM subjects with unidentified mutations. We discovered 7 heterozygous mutations in 10 unrelated probands. In 8 of these patients, insulin secretion was detectable at diabetes onset, but rapidly declined over time. When these mutant proinsulins were expressed in HEK293 cells, we observed defects in insulin protein folding and secretion. In these experiments, expression of the mutant proinsulins was also associated with increased Grp78 protein expression and XBP1 mRNA splicing, 2 markers of endoplasmic reticulum stress, and with increased apoptosis. Similarly transfected INS-1E insulinoma cells had diminished viability compared with those expressing WT proinsulin. In conclusion, we find that mutations in the insulin gene that promote proinsulin misfolding may cause PNDM.
Subject(s)
DNA-Binding Proteins/biosynthesis , Diabetes Mellitus/genetics , Heat-Shock Proteins/biosynthesis , Insulin/genetics , Insulin/physiology , Molecular Chaperones/biosynthesis , Mutation , Nuclear Proteins/biosynthesis , Proinsulin/biosynthesis , Amino Acid Sequence , DNA Mutational Analysis , Endoplasmic Reticulum Chaperone BiP , Female , Heterozygote , Humans , Infant , Male , Molecular Sequence Data , Pedigree , Regulatory Factor X Transcription Factors , Transcription Factors , X-Box Binding Protein 1ABSTRACT
To verify whether a diabetes family history might be a risk factor for the development, in adult age, of metabolic disorders, leptin, anthropometric and endocrine parameters were analysed in 95 babies with grandparents affected by type 2 diabetes (DF) and in 95 matched babies without diabetes family history (NDF). A sexual dimorphism for leptin was present in the NDF group (males: 6.7+/-4.1 ng/ml; females: 12.3+/-6.5; p < 0.0001) but not in the DF group (males: 9.0+/-5.5; females: 10.8+/-6.4), due to the significant increase in DF male leptin level, compared to that of NDF males (p < 0.05). In DF males only, leptin was positively correlated with body length, PI, C-peptide, IGF-1 and IGF1BP3. These results suggest that the increase in DF male leptin could be a compensatory mechanism for reduced insulin sensitivity in a pre-clinical alteration of glucose metabolism.
