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Objective Previous studies showed that inhibiting lymphocyte costimulation reduces declining beta cell function in individuals newly-diagnosed with type 1 diabetes. We tested whether abatacept would delay or prevent progression of type 1 diabetes from normal (NGT) to abnormal (AGT) glucose tolerance or to diabetes and the effects of treatment on immune and metabolic responses. Research Design and Methods We conducted a phase-2, randomized, placebo-controlled, double-masked trial of abatacept in antibody-positive participants with NGT who received monthly abatacept/placebo infusions for 12 months. The endpoint was AGT or diabetes, assessed by oral glucose-tolerance tests. Results 101 participants received abatacept and 111 placebo. Eighty-one (35 abatacept/46 placebo) met the endpoint of AGT or type 1 diabetes diagnosis (HR=0.702 (0.452, 1.09)(p=0.11) The C-peptide responses to OGTTs were higher in the abatacept arm (p Conclusions Although abatacept treatment for one year did not significantly delay progression to glucose intolerance in at-risk individuals, it impacted immune cell subsets and preserved insulin secretion suggesting that costimulation blockade may modify progression of type 1 diabetes.

Mutations in HNF1A cause Maturity Onset Diabetes of the Young (HNF1A-MODY). To understand mechanisms of β-cell dysfunction, we generated stem cell-derived pancreatic endocrine cells with hypomorphic mutations in HNF1A. HNF1A-deficient β-cells display impaired basal and glucose stimulated-insulin secretion, reduced intracellular calcium levels in association with a reduction in CACNA1A expression, and accumulation of abnormal insulin granules in association with SYT13 down-regulation. Knockout of CACNA1A and SYT13 reproduce the relevant phenotypes. In HNF1A deficient β-cells, glibenclamide, a sulfonylurea drug used in the treatment of HNF1A-MODY patients, increases intracellular calcium, and restores insulin secretion. While insulin secretion defects are constitutive in β-cells null for HNF1A, β-cells heterozygous for hypomorphic HNF1A (R200Q) mutations lose the ability to secrete insulin gradually; this phenotype is prevented by correction of the mutation. Our studies illuminate the molecular basis for the efficacy of treatment of HNF1A-MODY with sulfonylureas, and suggest promise for the use of cell therapies.

The clinical care of patients with type 1 diabetes (T1D) has greatly improved over the past few decades; however, it remains impossible to completely normalize blood sugar utilizing currently available tools. Research is underway with a goal to improve the care and, ultimately, to cure T1D by preserving beta cells. This review will outline the progress that has been made in trials aimed at preserving insulin secretion in T1D by modifying the immune assault on the pancreatic beta cell. Although not yet ready for clinical use, successful trials have been conducted in new-onset T1D that demonstrated utility of three experimental agents with disparate modes of action (anti-T cell, anti-B cell, and costimulation blockade) to preserve insulin secretion. In contrast, prevention studies have so far failed to produce positive results but have shown that such studies are feasible and have identified new promising agents for study.

This study assessed gingival bleeding in diabetic children during the mixed dentition period.Three hundred fifty-five 6- to 13-year-old diabetic (99% type 1) and nondiabetic control children in the mixed dentition stage were evaluated from a total cohort of 700 6- to 18-year-old children. Gingival status was assessed, and data on important diabetes-related variables were collected. Analyses were performed using Poisson's regression.Diabetic children had significantly more gingival bleeding than controls for both primary and permanent teeth. The risk of gingival bleeding around the primary teeth in cases was 35% more than in the control group (P=.001); and the risk of gingival bleeding around the permanent teeth in cases was 57% more than in the controls (P.001). The number of teeth with bleeding had a very modest, but statistically significant, association with: (1) mean HbA1c; (2) body mass index (BMI)-for-age percentile; and (3) duration of diabetes.These findings demonstrate that diabetic children are at a significantly higher risk for gingival bleeding. Diabetes-related oral complications affect the primary periodontium as early as age 6 and possibly earlier. The emphasis on oral hygiene may be valuable in preventing future periodontal complications in diabetic patients.