Potential viral pathogenic mechanism in human type 1 diabetes.

In type 1 diabetes, as a result of as yet unknown triggering events, auto-aggressive CD8(+) T cells, together with a significant number of other inflammatory cells, including CD8(+) T lymphocytes with unknown specificity, infiltrate the pancreas, leading to insulitis and destruction of the insulin-producing beta cells. Type 1 diabetes is a multifactorial disease caused by an interactive combination of genetic and environmental factors. Viruses are major environmental candidates with known potential effects on specific key points in the pathogenesis of type 1 diabetes and recent findings seem to confirm this presumption. However, we still lack well-grounded mechanistic explanations for how exactly viruses may influence type 1 diabetes aetiology. In this review we provide a summary of experimentally defined viral mechanisms potentially involved in the ontology of type 1 diabetes and discuss some novel hypotheses of how viruses may affect the initiation and natural history of the disease.

Biochemical and Clinical Features of Insulinoma in a Patient with Turner Syndrome.

Turner syndrome (TS), i.e., mosaic or nonmosaic states with only one normal X chromosome in females, is characterized by a wide spectrum of somatic, hormonal, and metabolic features. Here we report an unusual case of recurrent hypoglycemia in a 53-year-old woman with TS. Biochemical work-up following a 72h fast revealed detectable, inappropriate for low glucose insulin levels and elevated proinsulin and beta-hydroxybutyrate (BOHB) levels. MR and multiphase CT showed a solid 2.5 cm pancreatic tail mass with absent uptake in the 111In-pentetreotide (Octreoscan) scan. Subsequent hepatic vein blood sampling after intra-arterial calcium stimulation showed sharp increase in insulin and modest increase in proinsulin levels. The patient underwent excision of the mass with resolution of symptoms. Histopathologic examination confirmed the neuroendocrine etiology of the tumor. This is, to our knowledge, the third report of TS and concomitant insulinoma. Impaired counterregulatory response to hypoglycemia in patients with TS may result in symptomatic hypoglycemia with only mild insulin elevation and elevated proinsulin in setting of hypoglycemia may be the only indication of insulinoma in these patients. BOHB levels should not be used for ruling out EHH in patients with TS.

Development and Standardization of an Improved Type 1 Diabetes Genetic Risk Score for Use in Newborn Screening and Incident Diagnosis.

OBJECTIVE: Previously generated genetic risk scores (GRSs) for type 1 diabetes (T1D) have not captured all known information at non-HLA loci or, particularly, at HLA risk loci. We aimed to more completely incorporate HLA alleles, their interactions, and recently discovered non-HLA loci into an improved T1D GRS (termed the "T1D GRS2") to better discriminate diabetes subtypes and to predict T1D in newborn screening studies. RESEARCH DESIGN AND METHODS: In 6,481 case and 9,247 control subjects from the Type 1 Diabetes Genetics Consortium, we analyzed variants associated with T1D both in the HLA region and across the genome. We modeled interactions between variants marking strongly associated HLA haplotypes and generated odds ratios to create the improved GRS, the T1D GRS2. We validated our findings in UK Biobank. We assessed the impact of the T1D GRS2 in newborn screening and diabetes classification and sought to provide a framework for comparison with previous scores. RESULTS: The T1D GRS2 used 67 single nucleotide polymorphisms (SNPs) and accounted for interactions between 18 HLA DR-DQ haplotype combinations. The T1D GRS2 was highly discriminative for all T1D (area under the curve [AUC] 0.92; P < 0.0001 vs. older scores) and even more discriminative for early-onset T1D (AUC 0.96). In simulated newborn screening, the T1D GRS2 was nearly twice as efficient as HLA genotyping alone and 50% better than current genetic scores in general population T1D prediction. CONCLUSIONS: An improved T1D GRS, the T1D GRS2, is highly useful for classifying adult incident diabetes type and improving newborn screening. Given the cost-effectiveness of SNP genotyping, this approach has great clinical and research potential in T1D.

Viruses and Type 1 diabetes: a dynamic labile equilibrium.

Type 1 diabetes (T1D) results from the specific immune-mediated destruction of the insulin-producing ß-cells of the pancreas. In genetically susceptible individuals, a still undetermined initiating 'hit' triggers a cascade of events that eventually leads to autoreactive CD8 T cells infiltrating the pancreatic islets and, subsequently, destroying them. There is increasing evidence that viruses, especially enteroviruses, are major environmental candidates; however, despite decades of investigation, we still lack certainty with regard to the causation of T1D. Moreover, studies in animal models of diabetes suggest a protective role of certain enteroviral infections upon diabetes contraction, making the quest for viral involvement in T1D even more difficult. Analyzing the foundation and the results of the most current work in the field, this article gives a brief overview of current knowledge, as well as providing an outlook for future directions.