Background: IGF-I receptor (IGF1R) plays an essential role in human intrauterine and postnatal development. Few heterozygous mutations in IGF1R leading to IGF-I resistance and intrauterine and postnatal growth retardation have been described to date. Objective: The clinical and functional relevance of a novel heterozygous IGF1R mutation identified in a girl with short stature and six relatives was evaluated. Patients: Affected individuals showed birth lengths between −1.40 and −1.82 sd score (SDS) and birth weights between −1.84 and −2.19 SDS. Postnatal growth retardation ranged between −1.51 and −3.93 height SDS. Additional phenotypic findings were variable including microcephaly, clinodactyly, delayed menarche, and diabetes mellitus type 2. Genetic analyses were initiated due to elevated IGF-I levels of the girl. Results: Denaturing HPLC screening and direct DNA sequencing revealed a heterozygous G3464C IGF1R mutation in exon 19 located within a phylogenetically conserved motif of the kinase domain. The resultant mutation of glycine 1125 to alanine (G1125A) did not affect IGF1R protein expression in transiently transfected COS-7 cells and Igf1R deficient mouse fibroblasts but abrogated IGF-I-induced receptor autophosphorylation and phosphorylation of downstream kinases protein kinase B/Akt and MAPK/Erk (mouse proteins are reported). Cotransfection of wild-type and mutant IGF1R resulted in reduced autophosphorylation of 36 ± 10% of wild-type levels, suggesting a partial dominant-negative effect. Conclusion: The identified G1125A mutation results in a kinase-deficient IGF1R, which is likely to cause the phenotype of intrauterine and postnatal growth retardation.

Type-1 diabetes mellitus (T1DM) is one of the most well-defined and complex metabolic disorders, characterized by hyperglycemia, with a constantly increasing incidence in children and adolescents. While current knowledge regarding the molecules related to the pathogenesis and diagnosis of T1DM is vast, the discovery of new molecules, such as micro ribonucleic acids (micro-RNAs, miRNAs), as well as their interactions with T1DM, has spurred novel prospects in the diagnosis of the disease. This review aims at summarizing current knowledge regarding miRNAs’ biosynthesis and action pathways and their role as gene expression regulators in T1DM. MiRNAs follow a complex biosynthesis pathway, including cleaving and transport from nucleus to cytoplasm. After assembly of their final form, they inhibit translation or cause messenger RNA (mRNA) degradation, resulting in the obstruction of protein synthesis. Many studies have reported miRNA involvement in T1DM pathogenesis, mainly through interference with pancreatic b-cell function, insulin production and secretion. They are also found to contribute to β-cell destruction, as they aid in the production of autoreactive agents. Due to their elevated accumulation in various biological specimens, as well as their involvement in T1DM pathogenesis, their role as biomarkers in early preclinical T1DM diagnosis is widely hypothesized, with future studies concerning their diagnostic value deemed a necessity.

Cystic-fibrosis-related diabetes mellitus is frequently underdiagnosed and associated with deterioration of overall clinical status. The purpose of this prospective study was to investigate the influence of insulin on nutrition, lung function and clinical status of cystic fibrosis patients. For a period of 5 y, and at 6-mo intervals, body mass index, forced expiratory volume in 1 sec, Shwachman score, intravenous glucose tolerance test and first-phase insulin response were determined in 30 cystic fibrosis patients (age range 10-35 y) with exocrine pancreatic insufficiency. During the study period, six patients (3M and 3F; age range 15-22 y) developed diabetes and required insulin therapy. The decrease of first-phase insulin response coincided with deterioration of nutritional and clinical status, which improved significantly 6 mo after the institution of insulin.Insulin, as an anabolic hormone, could have an influence on body mass, which may affect pulmonary function and clinical condition in cystic fibrosis. It is important to identify cystic fibrosis individuals at risk of developing diabetes so that early insulin therapy is instituted.