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Browsing by Subject "Insulin-secreting cells"
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Item Altered β-Cell Prohormone Processing and Secretion in Type 1 Diabetes(American Diabetes Association, 2021) Rodriguez-Calvo, Teresa; Chen, Yi-Chun; Verchere, C. Bruce; Haataja, Leena; Arvan, Peter; Leete, Pia; Richardson, Sarah J.; Morgan, Noel G.; Qian, Wei-Jun; Pugliese, Alberto; Atkinson, Mark; Evans-Molina, Carmella; Sims, Emily K.; Pediatrics, School of MedicineAnalysis of data from clinical cohorts, and more recently from human pancreatic tissue, indicates that reduced prohormone processing is an early and persistent finding in type 1 diabetes. In this article, we review the current state of knowledge regarding alterations in islet prohormone expression and processing in type 1 diabetes and consider the clinical impact of these findings. Lingering questions, including pathologic etiologies and consequences of altered prohormone expression and secretion in type 1 diabetes, and the natural history of circulating prohormone production in health and disease, are considered. Finally, key next steps required to move forward in this area are outlined, including longitudinal testing of relevant clinical populations, studies that probe the genetics of altered prohormone processing, the need for combined functional and histologic testing of human pancreatic tissues, continued interrogation of the intersection between prohormone processing and autoimmunity, and optimal approaches for analysis. Successful resolution of these questions may offer the potential to use altered prohormone processing as a biomarker to inform therapeutic strategies aimed at personalized intervention during the natural history of type 1 diabetes and as a pathogenic anchor for identification of potential disease-specific endotypes.Item Doc2b Protects β-Cells Against Inflammatory Damage and Enhances Function(American Diabetes Association, 2018-07) Aslamy, Arianne; Oh, Eunjin; Olson, Erika M.; Zhang, Jing; Ahn, Miwon; Moin, Abu Saleh Md; Tunduguru, Ragadeepthi; Salunkhe, Vishal A.; Veluthakal, Rajakrishnan; Thurmond, Debbie C.; Cellular & Integrative Physiology, IU School of MedicineLoss of functional β-cell mass is an early feature of type 1 diabetes. To release insulin, β-cells require soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complexes, as well as SNARE complex regulatory proteins like double C2 domain-containing protein β (Doc2b). We hypothesized that Doc2b deficiency or overabundance may confer susceptibility or protection, respectively, to the functional β-cell mass. Indeed, Doc2b+/- knockout mice show an unusually severe response to multiple-low-dose streptozotocin (MLD-STZ), resulting in more apoptotic β-cells and a smaller β-cell mass. In addition, inducible β-cell-specific Doc2b-overexpressing transgenic (βDoc2b-dTg) mice show improved glucose tolerance and resist MLD-STZ-induced disruption of glucose tolerance, fasting hyperglycemia, β-cell apoptosis, and loss of β-cell mass. Mechanistically, Doc2b enrichment enhances glucose-stimulated insulin secretion (GSIS) and SNARE activation and prevents the appearance of apoptotic markers in response to cytokine stress and thapsigargin. Furthermore, expression of a peptide containing the Doc2b tandem C2A and C2B domains is sufficient to confer the beneficial effects of Doc2b enrichment on GSIS, SNARE activation, and apoptosis. These studies demonstrate that Doc2b enrichment in the β-cell protects against diabetogenic and proapoptotic stress. Furthermore, they identify a Doc2b peptide that confers the beneficial effects of Doc2b and may be a therapeutic candidate for protecting functional β-cell mass.Item Effect of Verapamil on Pancreatic Beta Cell Function in Newly Diagnosed Pediatric Type 1 Diabetes: A Randomized Clinical Trial(American Medical Association, 2023) Forlenza, Gregory P.; McVean, Jennifer; Beck, Roy W.; Bauza, Colleen; Bailey, Ryan; Buckingham, Bruce; DiMeglio, Linda A.; Sherr, Jennifer L.; Clements, Mark; Neyman, Anna; Evans-Molina, Carmella; Sims, Emily K.; Messer, Laurel H.; Ekhlaspour, Laya; McDonough, Ryan; Van Name, Michelle; Rojas, Diana; Beasley, Shannon; DuBose, Stephanie; Kollman, Craig; Moran, Antoinette; CLVer Study Group; Pediatrics, School of MedicineImportance: In preclinical studies, thioredoxin-interacting protein overexpression induces pancreatic beta cell apoptosis and is involved in glucotoxicity-induced beta cell death. Calcium channel blockers reduce these effects and may be beneficial to beta cell preservation in type 1 diabetes. Objective: To determine the effect of verapamil on pancreatic beta cell function in children and adolescents with newly diagnosed type 1 diabetes. Design, setting, and participants: This double-blind, randomized clinical trial including children and adolescents aged 7 to 17 years with newly diagnosed type 1 diabetes who weighed 30 kg or greater was conducted at 6 centers in the US (randomized participants between July 20, 2020, and October 13, 2021) and follow-up was completed on September 15, 2022. Interventions: Participants were randomly assigned 1:1 to once-daily oral verapamil (n = 47) or placebo (n = 41) as part of a factorial design in which participants also were assigned to receive either intensive diabetes management or standard diabetes care. Main outcomes and measures: The primary outcome was area under the curve values for C-peptide level (a measure of pancreatic beta cell function) stimulated by a mixed-meal tolerance test at 52 weeks from diagnosis of type 1 diabetes. Results: Among 88 participants (mean age, 12.7 [SD, 2.4] years; 36 were female [41%]; and the mean time from diagnosis to randomization was 24 [SD, 4] days), 83 (94%) completed the trial. In the verapamil group, the mean C-peptide area under the curve was 0.66 pmol/mL at baseline and 0.65 pmol/mL at 52 weeks compared with 0.60 pmol/mL at baseline and 0.44 pmol/mL at 52 weeks in the placebo group (adjusted between-group difference, 0.14 pmol/mL [95% CI, 0.01 to 0.27 pmol/mL]; P = .04). This equates to a 30% higher C-peptide level at 52 weeks with verapamil. The percentage of participants with a 52-week peak C-peptide level of 0.2 pmol/mL or greater was 95% (41 of 43 participants) in the verapamil group vs 71% (27 of 38 participants) in the placebo group. At 52 weeks, hemoglobin A1c was 6.6% in the verapamil group vs 6.9% in the placebo group (adjusted between-group difference, -0.3% [95% CI, -1.0% to 0.4%]). Eight participants (17%) in the verapamil group and 8 participants (20%) in the placebo group had a nonserious adverse event considered to be related to treatment. Conclusions and relevance: In children and adolescents with newly diagnosed type 1 diabetes, verapamil partially preserved stimulated C-peptide secretion at 52 weeks from diagnosis compared with placebo. Further studies are needed to determine the longitudinal durability of C-peptide improvement and the optimal length of therapy.Item Insulin Receptor-Expressing T Cells Appear in Individuals at Risk for Type 1 Diabetes and Can Move into the Pancreas in C57BL/6 Transgenic Mice(American Association of Immunologists, 2021) Nandedkar-Kulkarni, Neha; Esakov, Emily; Gregg, Brigid; Atkinson, Mark A.; Rogers, Douglas G.; Horner, James D.; Singer, Kanakadurga; Lundy, Steven K.; Felton, Jamie L.; Al-Huniti, Tasneem; Kalinoski, Andrea Nestor; Morran, Michael P.; Gupta, Nirdesh K.; Bretz, James D.; Balaji, Swapnaa; Chen, Tian; McInerney, Marcia F.; Pediatrics, School of MedicineInsulin receptor (IR) expression on the T cell surface can indicate an activated state; however, the IR is also chemotactic, enabling T cells with high IR expression to physically move toward insulin. In humans with type 1 diabetes (T1D) and the NOD mouse model, a T cell-mediated autoimmune destruction of insulin-producing pancreatic β cells occurs. In previous work, when purified IR+ and IR- T cells were sorted from diabetic NOD mice and transferred into irradiated nondiabetic NOD mice, only those that received IR+ T cells developed insulitis and diabetes. In this study, peripheral blood samples from individuals with T1D (new onset to 14 y of duration), relatives at high-risk for T1D, defined by positivity for islet autoantibodies, and healthy controls were examined for frequency of IR+ T cells. High-risk individuals had significantly higher numbers of IR+ T cells as compared with those with T1D (p < 0.01) and controls (p < 0.001); however, the percentage of IR+ T cells in circulation did not differ significantly between T1D and control subjects. With the hypothesis that IR+ T cells traffic to the pancreas in T1D, we developed a (to our knowledge) novel mouse model exhibiting a FLAG-tagged mouse IR on T cells on the C57BL/6 background, which is not susceptible to developing T1D. Interestingly, these C57BL/6-CD3FLAGmIR/mfm mice showed evidence of increased IR+ T cell trafficking into the islets compared with C57BL/6 controls (p < 0.001). This transgenic animal model provides a (to our knowledge) novel platform for investigating the influence of IR expression on T cell trafficking and the development of insulitis.Item OGTT Glucose Response Curves, Insulin Sensitivity, and β-Cell Function in RISE: Comparison Between Youth and Adults at Randomization and in Response to Interventions to Preserve β-Cell Function(American Diabetes Association, 2021) Arslanian, Silva A.; El Ghormli, Laure; Kim, Joon Young; Tjaden, Ashley H.; Barengolts, Elena; Caprio, Sonia; Hannon, Tamara S.; Mather, Kieren J.; Nadeau, Kristen J.; Utzschneider, Kristina M.; Kahn, Steven E.; RISE Consortium; Pediatrics, School of MedicineWe examined the glucose response curves (biphasic [BPh], monophasic [MPh], incessant increase [IIn]) during an oral glucose tolerance test (OGTT) and their relationship to insulin sensitivity (IS) and β-cell function (βCF) in youth versus adults with impaired glucose tolerance or recently diagnosed type 2 diabetes. RESEARCH DESIGN AND METHODS: This was both a cross-sectional and a longitudinal evaluation of participants in the RISE study randomized to metformin alone for 12 months or glargine for 3 months followed by metformin for 9 months. At baseline/randomization, OGTTs (85 youth, 353 adults) were categorized as BPh, MPh, or IIn. The relationship of the glucose response curves to hyperglycemic clamp-measured IS and βCF at baseline and the change in glucose response curves 12 months after randomization were assessed. RESULTS: At randomization, the prevalence of the BPh curve was significantly higher in youth than adults (18.8% vs. 8.2%), with no differences in MPh or IIn. IS did not differ across glucose response curves in youth or adults. However, irrespective of curve type, youth had lower IS than adults (P < 0.05). βCF was lowest in IIn versus MPh and BPh in youth and adults (P < 0.05), yet compared with adults, youth had higher βCF in BPh and MPh (P < 0.005) but not IIn. At month 12, the change in glucose response curves did not differ between youth and adults, and there was no treatment effect. CONCLUSIONS: Despite a twofold higher prevalence of the more favorable BPh curve in youth at randomization, RISE interventions did not result in beneficial changes in glucose response curves in youth compared with adults. Moreover, the typical β-cell hypersecretion in youth was not present in the IIn curve, emphasizing the severity of β-cell dysfunction in youth with this least favorable glucose response curve.Item The Deterrence of Rapid Metabolic Decline Within 3 Months After Teplizumab Treatment in Individuals at High Risk for Type 1 Diabetes(American Diabetes Association, 2021) Sims, Emily K.; Cuthbertson, David; Herold, Kevan C.; Sosenko, Jay M.; Pediatrics, School of MedicineEnd points that provide an early identification of treatment effects are needed to implement type 1 diabetes prevention trials more efficiently. To this end, we assessed whether metabolic end points can be used to detect a teplizumab effect on rapid β-cell decline within 3 months after treatment in high-risk individuals in the TrialNet teplizumab trial. Glucose and C-peptide response curves (GCRCs) were constructed by plotting mean glucose and C-peptide values from 2-h oral glucose tolerance tests on a two-dimensional grid. Groups were compared visually for changes in GCRC shape and movement. GCRC changes reflected marked metabolic deterioration in the placebo group within 3 months of randomization. By 6 months, GCRCs resembled typical GCRCs at diagnosis. In contrast, GCRC changes in the teplizumab group suggested metabolic improvement. Quantitative comparisons, including two novel metabolic end points that indicate GCRC changes, the within-quadrant end point and the ordinal directional end point, were consistent with visual impressions of an appreciable treatment effect at the 3- and 6-month time points. In conclusion, an analytic approach combining visual evidence with novel end points demonstrated that teplizumab delays rapid metabolic decline and improves the metabolic state within 3 months after treatment; this effect extends for at least 6 months.