A plasmid DNA vaccine encoding mouse proinsulin II reduced the incidence of diabetes in a mouse model of type I diabetes when administered to hyperglycemic (therapeutic mode) or normoglycemic (prophylactic mode) NOD mice.
We screened the INS gene by direct sequencing in 38 PND patients and in one child with nonautoimmune early-infancy diabetes, where no mutation in GCK, KCNJ11, and ABCC8 was identified.
Functional and genetic data support the hypothesis that the gene responsible for the lymphopenia, Lyp, is also a diabetes susceptibility gene, named Iddm1.
However, the T allele (conferring higher risk of diabetes) at rs7903146 was associated with higher fasting proinsulin at baseline (P<0.001), higher baseline proinsulin:insulin ratio (p<0.0001) and increased proinsulin:insulin ratio over a median of 2.5 years of follow-up (P = 0.003).
We reproduced the association of diabetes-associated variants with proinsulin/insulin ratios, and also examined the association of a TCF7L2 haplotype with obesity in the Framingham Heart Study (FHS).
A total of 40 individuals with diabetes (1.8% of early onset sub-group and 0.6% of adult onset sub-group) were carriers of known pathogenic missense variants in the GCK, HNF1A, HNF4A, ABCC8, and INS genes.
We hope to emphasize instead the homogeneity of nephropathy risk in both IDDM and NIDDM and also the idea that a common genetic susceptibility exists for all types of diabetes and is conditional on cumulative exposure to hyperglycemia.
A total of 218 sets of matched case-control questionnaire data established that paternal IDDM (odds ratio (OR) = 16.11, 95% confidence interval (CI) 1.94-133.7, p < = 0.001) is independently associated with increased risk, and higher birth order (OR = 0.64, CI 0.44-0.94, p = 0.021) and paternal age greater than 25 years (age 25-39 OR = 0.52, CI 0.30-0.89; age 40 + OR = 0.23, CI 0.08-0.67, p = 0.009) with decreased risk of diabetes.
The possible association of human growth hormone (hGH) and insulin (INS) gene regions with metabolic control in diabetes was investigated in 98 subjects with non-insulin-dependent diabetes mellitus (NIDDM); 54 control subjects from the same population were also studied.
In accordance with this finding, the mutation was found to be highly prevalent in a diabetes mellitus subset termed slowly progressive IDDM; the mutation was identified in 3 out of 27 subjects enrolled in the prospective study of islet cell antibody (ICA)-positive, initially non-insulin-dependent diabetic Japanese patients, who are at high risk of progressing to insulin dependence over several years.
We identified one missense mutation (G32S) in the INS gene and two mutations (R131Q and R203S) in the HNF1α gene that could be associated with diabetes.
INS mutations have a broad spectrum of clinical presentations, ranging from severe neonatal onset to mild adult onset, which suggests that the products of different mutant INS alleles behave differently and utilize distinct mechanisms to induce diabetes.
Given the frequent tendency of heterozygous INS mutations to exhibit dominant negative disease pathogenesis, it is likely that the mutant preproinsulin perturbed the non-mutant counterpart progression and processing within the β-cells, and this resulted to a permanent form of congenital diabetes.
The insulin gene variable number tandem repeat (INS-VNTR) is proposed to exert pleiotropic genetic effects on birth weight and diabetes susceptibility.
Naturally occurring human mutations at the site of conformational change impair the folding of proinsulin and cause permanent neonatal-onset diabetes mellitus.