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High soluble IL-7 receptor (sIL-7R) serum levels and associated single nucleotide polymorphisms in the IL7RA gene were found in autoimmune diseases including type 1 diabetes. Further determinants on sIL-7R and IL-7 availability as well as changes during type 1 diabetes disease course remain elusive. Here we performed multiparameter analysis to identify influential genetic and disease-associated factors on sIL-7R and IL-7 serum levels during type 1 diabetes disease course (239 children) and in healthy controls (101 children). We found higher sIL-7R serum concentrations at type 1 diabetes onset and decreasing levels during therapy whereas IL-7 was only higher in long term patients as compared to controls. Multiple linear regression analyses revealed several factors, including IL7RA SNP rs6897932 and HLA risk haplotypes, influencing sIL-7R levels but not IL-7, which was solely associated with the sIL-7R. This study revealed unexpected complexity in the regulation of the sIL-7R but not for IL-7.

Dextromethorphan (DXM) acts as cough suppressant via its central action. Cell-protective effects of this drug have been reported in peripheral tissues, making DXM potentially useful for treatment of several common human diseases, such as type 2 diabetes mellitus (T2DM). Pancreatic islets are among the peripheral tissues that positively respond to DXM, and anti-diabetic effects of DXM were observed in two placebo-controlled, randomized clinical trials in humans with T2DM. Since these effects were associated with central side effects, we here developed chemical derivatives of DXM that pass the blood-brain barrier to a significantly lower extent than the original drug. We show that basic nitrogen-containing residues block central adverse events of DXM without reducing its anti-diabetic effects, including the protection of human pancreatic islets from cell death. These results show how to chemically modify DXM, and possibly other morphinans, as to exclude central side effects, while targeting peripheral tissues, such as pancreatic islets.

Background Congenital hyperinsulinaemic hypoglycaemia is characterised by low serum concentrations of ketones, fatty acids, and branched chain aminoacids, and by a requirement for glucose infusion of more than 10 mg/kg per min to maintain euglycaemia. The disorder is caused by physiologically inappropriate insulin secretion. We have recently described a form of hypoglycaemia with a similar metabolic profile, but with undetectable insulin, relatively low glucose requirement, and left-sided hemihypertrophy caused by an activating mutation in AKT2 . Methods Four children (aged 4 months to 11 years) with hypoglycaemia in the absence of elevated serum insulin and ketones and wild-type AKT2 sequence underwent whole-exome sequencing with their parents. Variants were verified with Sanger sequencing and restriction fragment length polymorphism assays. Serum starved primary dermal fibroblasts were used for immunoblotting against phosphorylated AKT to look for basal hyperactivation of the PI3K–AKT pathway. Findings Tissue and lymphocyte DNA from one patient with hypoglycaemia, macrocephaly, and fibrous liver disease revealed a mosaic mutation (p.Glu726Lys) in PIK3CA , encoding the p110α catalytic subunit of phosphoinositide-3-kinase. Dermal fibroblasts showed a small but significant (pAKT Thr308 p PIK3CA mutations in other forms of overgrowth. Another child, who presented with infantile hypoglycaemia and jejunal atresia, had mutations in two constituents of mTORC2 ( mTOR and MLST8 ), which lies upstream from AKT2 in the insulin signalling pathway. Since one variant was inherited from each unaffected parent, these constituents are being evaluated functionally as a possible di-genic explanation for neonatal hypoglycaemia. Interpretation Collectively these studies suggest the existence of a genetically heterogenous group of disorders that are metabolic phenocopies of AKT2-driven fasting hypoglycaemia. Further investigation of this group of naturally occurring human experiments of nature promises to yield novel information about the in-vivo regulation of fasting glucose metabolism and its perturbation in common disease. Funding Rosetrees Trust, Wellcome Trust.