Sustained excess BMI increases the risk of type 1 diabetes (T1D) in autoantibodypositive relatives without diabetes of patients. We tested whether elevated BMI also accelerates the progression of islet autoimmunity before T1D diagnosis. RESEARCH DESIGN AND METHODS We studied 706 single autoantibody-positive pediatric TrialNet participants (ages 1.6-18.6 years at baseline). Cumulative excess BMI (ceBMI) was calculated for each participant based on longitudinally accumulated BMI ‡85th age-and sex-adjusted percentile. Recursive partitioning analysis and multivariable modeling defined the age cut point differentiating the risk for progression to multiple positive autoantibodies. RESULTS At baseline, 175 children (25%) had a BMI ‡85th percentile. ceBMI range was 29.2 to 15.6 kg/m 2 (median 21.91), with ceBMI ‡0 kg/m 2 corresponding to persistently elevated BMI ‡85th percentile. Younger age increased the progression to multiple autoantibodies, with age cutoff of 9 years defined by recursive partitioning analysis. Although ceBMI was not significantly associated with progression from single to multiple autoantibodies overall, there was an interaction with ceBMI ‡0 kg/m 2 , age, and HLA (P 5 0.009). Among children ‡9 years old without HLA DR3-DQ2 and DR4-DQ8, ceBMI ‡0 kg/m 2 increased the rate of progression from single to multiple positive autoantibodies (hazard ratio 7.32, P 5 0.004) and conferred a risk similar to that in those with T1D-associated HLA haplotypes. In participants <9 years old, the effect of ceBMI on progression to multiple autoantibodies was not significant regardless of HLA type. CONCLUSIONS These data support that elevated BMI may exacerbate islet autoimmunity prior to clinicalT1D, particularly inchildren with lower risk based on age and HLA.Interventions to maintain normal BMI may prevent or delay the progression of islet autoimmunity. The global rise in incidence of type 1 diabetes (T1D) has intensified efforts to identify modifiable risk factors in order to prevent or delay onset of clinical diabetes (1). Although there are several genetic loci for T1D susceptibility, heritability does not completely predict appearance of islet autoantibodies or disease development (2), highlighting the role of other influences such as the environment (3). The parallel rise in obesity (4,5) and T1D incidence suggests a potential link between elevated body weight and T1D progression (6-9). The accelerator hypothesis proposes that obesity-induced insulin resistance triggers the autoimmune-mediated b-cell

The environment within the Endoplasmic Reticulum (ER) influences Insulin biogenesis. In particular, ER stress may contribute to the development of Type 2 Diabetes (T2D) and Cystic Fibrosis Related Diabetes (CFRD), where evidence of impaired Insulin processing, including elevated secreted Proinsulin/Insulin ratios, are observed. Our group has established the role of a novel ER chaperone ERp29 (ER protein of 29 kDa) in the biogenesis of the Epithelial Sodium Channel, ENaC. The biogenesis of Insulin and ENaC share may key features, including their potential association with COP II machinery, their cleavage into a more active form in the Golgi or later compartments, and their ability to bypass such cleavage and remain in a less active form. Given these similarities we hypothesized that ERp29 is a critical factor in promoting the efficient conversion of Proinsulin to Insulin. Here, we confirmed that Proinsulin associates with the COP II vesicle cargo recognition component, Sec24D. When Sec24D expression was decreased, we observed a corresponding decrease in whole cell Proinsulin levels. In addition, we found that Sec24D associates with ERp29 in co-precipitation experiments and that ERp29 associates with Proinsulin in co-precipitation experiments. When ERp29 was overexpressed, a corresponding increase in whole cell Proinsulin levels was observed, while depletion of ERp29 decreased whole cell Proinsulin levels. Together, these data suggest a potential role for ERp29 in regulating Insulin biosynthesis, perhaps in promoting the exit of Proinsulin from the ER via Sec24D/COPII vesicles.

Context Paltusotine is a once-daily, oral, non-peptide small-molecule somatostatin receptor type 2 (SST2) agonist in clinical development for treatment of acromegaly. Objective To evaluate change in IGF-I levels in patients switched from octreotide LAR or lanreotide depot monotherapy to paltusotine. Design Phase 2, open-label, prospective, multicenter, multinational, non-randomized, single-arm exploratory study in which dosage up-titrations were performed in a double-blinded manner. Setting 26 global sites. Participants Patients with acromegaly switched to paltusotine from injected SRL-based therapy. Interventions Patients received 13-week treatment with once-daily oral paltusotine (10-40 mg/day). Main Outcome Measures Primary endpoint was change from baseline to week 13 in IGF-I for patients who switched from long-acting octreotide or lanreotide monotherapy to paltusotine (Group 1). All patients underwent a 4-week paltusotine washout at end of treatment period (weeks 13-17). IGF-I, GH, patient reported outcome, and safety data were collected. Results Forty-seven patients enrolled. In Group 1 (n = 25), IGF-I and GH showed no significant change between SRL baseline and end of paltusotine treatment at week 13 (median change in IGF-I = -0.03×upper limit of normal [ULN], P = 0.6285; GH = -0.05 ng/mL, P = 0.6285). IGF-I and GH rose significantly in the 4 weeks after withdrawing paltusotine (median change in IGF-I = 0.55×ULN, P &lt; 0.0001 [median increase 39%]; GH = 0.72 ng/mL, P &lt; 0.0001 [109.1% increase]). No patients discontinued due to adverse events; no treatment-related serious adverse events were reported. Conclusions These results suggest once daily, oral paltusotine is effective in maintaining IGF-I values in patients with acromegaly who switched from injected SRLs. Paltusotine was well tolerated with a safety profile consistent with other SRLs.

Background: The introduction of insulin pumps with bolus calculators (BCs) has improved glycemic outcomes and quality of life for those with type 1 diabetes. Despite the increased reliance on BCs, the formulas used to derive recommended boluses are not standardized. Our objective was to examine whether recommendations from different pump BCs vary significantly for identical clinical scenarios. Methods: Three commercially available insulin pump BCs were programmed with identical settings and then presented with combinations of blood glucose (BG) and carbohydrates (CHOs) to generate a 4-unit bolus. At one- and two-hour time points, while there was insulin-on-board (IOB) present, we simulated various BG and CHO scenarios in order to compare BC-recommended doses. Results: Differences in suggested doses were noted between BCs, as well as within the same brand. The greatest variation was apparent when BG was below target. Doses suggested by one BC varied depending on whether the IOB resulted from a previous dose given for BG or CHO, while the other two BCs adjusted for total IOB regardless of the source. Conclusions: In this simulation study, there were large differences in recommended doses between BCs due to the unique way each manufacturer incorporates IOB into their formulas as well as the pharmacokinetics used to derive the IOB amount. Providers should be aware that identical pump settings will result in a different dose recommendation for each pump brand and advise patients accordingly.

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