Browsing by Subject "Type 1 Diabetes"

Now showing 1 - 8 of 8
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    Abnormalities in proinsulin processing in islets from individuals with longstanding T1D
    (Elsevier, 2019-11) Sims, Emily K.; Syed, Farooq; Nyalwidhe, Julius; Bahnson, Henry T.; Haataja, Leena; Speake, Cate; Morris, Margaret A.; Balamurugan, Appakalai N.; Mirmira, Raghavendra G.; Nadler, Jerry; Mastracci, Teresa L.; Arvan, Peter; Greenbaum, Carla J.; Evans-Molina, Carmella; Pediatrics, School of Medicine
    We recently described the persistence of detectable serum proinsulin in a large majority of individuals with longstanding type 1 diabetes (T1D), including individuals with undetectable serum C-peptide. Here, we sought to further explore the mechanistic etiologies of persistent proinsulin secretion in T1D at the level of the islet, using tissues obtained from human donors. Immunostaining for proinsulin and insulin was performed on human pancreatic sections from the Network for Pancreatic Organ Donors with Diabetes (nPOD) collection (n = 24). Differential proinsulin processing enzyme expression was analyzed using mass spectrometry analysis of human islets isolated from pancreatic sections with laser capture microdissection (n = 6). Proinsulin processing enzyme mRNA levels were assessed using quantitative real-time PCR in isolated human islets (n = 10) treated with or without inflammatory cytokines. Compared to nondiabetic controls, immunostaining among a subset (4/9) of insulin positive T1D donor islets revealed increased numbers of cells with proinsulin-enriched, insulin-poor staining. T1D donor islets also exhibited increased proinsulin fluorescence intensity relative to insulin fluorescence intensity. Laser capture microdissection followed by mass spectrometry revealed reductions in the proinsulin processing enzymes prohormone convertase 1/3 (PC1/3) and carboxypeptidase E (CPE) in T1D donors. Twenty-four hour treatment of human islets with inflammatory cytokines reduced mRNA expression of the processing enzymes PC1/3, PC2, and CPE. Taken together, these data provide new mechanistic insight into altered proinsulin processing in long-duration T1D and suggest that reduced β cell prohormone processing is associated with proinflammatory cytokine-induced reductions in proinsulin processing enzyme expression.
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    Amelioration of type 1 diabetes following treatment of non-obese diabetic mice with INGAP and lisofylline
    (SciRes, 2012-05-01) Tersey, Sarah A.; Carter, Jeffery D.; Rosenberg, Lawrence; Taylor-Fishwick, David A.; Mirmira, Raghavendra G.; Nadler, Jerry L.; Department of Pediatrics, School of Medicine
    Type 1 diabetes mellitus results from the autoimmune and inflammatory destruction of insulin-producing islet β cells, rendering individuals devoid of insulin production. Recent studies suggest that combination therapies consisting of anti-inflammatory agents and islet growth-promoting factors have the potential to cause sustained recovery of β cell mass, leading to amelioration or reversal of type 1 diabetes in mouse models. In this study, we hypothesized that the combination of the anti-inflammatory agent lisofylline (LSF) with an active peptide fragment of islet neogenesis associated protein (INGAP peptide) would lead to remission of type 1 diabetes in the non-obese diabetic (NOD) mouse. We treated groups of spontaneously diabetic NOD mice with combinations of LSF, INGAP peptide, or control saline parenterally for up to 6 weeks. Our results demonstrate that the mice receiving combined treatment with LSF and INGAP peptide exhibited partial remission of diabetes with increased plasma insulin levels. Histologic assessment of pancreata in mice receiving combined therapy revealed the presence of islet insulin staining, increased β cell replication, and evidence of Pdx1-positivity in ductal cells. By contrast, diabetic animals showed severe insulitis with no detectible insulin or Pdx1 staining. We conclude that the novel combination treatment with LSF and INGAP peptide has the potential to ameliorate hyperglycemia in the setting of established type 1 diabetes via the recovery of endogenous β cells and warrant further studies.
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    COVID-19 and Type 1 Diabetes: Addressing Concerns and Maintaining Control
    (ADA, 2021-09) DiMeglio, Linda A.; Pediatrics, School of Medicine
    The worldwide outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been an unprecedented pandemic. Early on, even as the signs and symptoms of coronavirus disease 2019 (COVID-19) were first characterized, significant concerns were articulated regarding its potential impact on people with chronic disease, including type 1 diabetes. Information about the basic and clinical interrelationships between COVID-19 and diabetes has rapidly emerged. Initial rapid reports were useful to provide alerts and guide health care responses and initial policies. Some of these have proven subsequently to have durable findings, whereas others lacked scientific rigor/reproducibility. Many publications that report on COVID-19 and “diabetes” also have not distinguished between type 1 and type 2 (1). Available evidence now demonstrates that people with type 1 diabetes have been acutely affected by COVID-19 in multiple ways. This includes effects from limited access to health care, particularly during lockdown periods, and increased morbidity/mortality in infected adults with type 1 diabetes compared with peers without diabetes.
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    The Effect of Parental Monitoring on Diabetes Management in Adolescents: A Systematic Review of the Literature
    (Office of the Vice Chancellor for Research, 2015-04-17) Pugh, Samantha; Reaper, Amber; Hart, Kayla; Phillips-Salimi, Celeste R.
    Objective: Adolescents with Type 1 Diabetes require parental guidance when it comes to the management of their glycemic control. Little is known regarding how parental monitoring affects adolescents’ diabetes control. A systematic review of the literature was performed to gain more insight into how parental monitoring influences glycemic control in adolescents with Type 1 Diabetes. Methods: Databases used to identify articles included: CINAHL, PsycINFO, and Web of Science. Search terms used were teenagers, adolescents, young adults, Type 1 Diabetes, parental monitoring, diabetes management and glycemic control. Inclusion criteria included: peer-reviewed research articles published between 2000 and 2013; involved a sample of adolescents (ages 8-18); conducted in the United States; written in English; and identified parental monitoring as the main independent variable. Results: Nine studies met the inclusion criteria. Six studies were longitudinal and three were cross-sectional. Seven studies collected data from the adolescent and parent while the other two studies collected data only from the adolescent. Sample sizes ranged from n=81-376. The most common glycemic control outcome factors measured were: hemoglobin A1C scores, adherence and glucose monitoring. Findings showed that parental monitoring is positively associated with adolescents’ adherence to diabetes management. There was mixed evidence regarding the father’s role. One study showed the father’s parental monitoring had significant impact on the adolescent adherence and A1C scores; however, another study reported the opposite. Overall, adolescents’ perception of positive parental monitoring provided better adherence. Conclusion: From the nine studies reviewed, it seems that there is some evidence that parental monitoring is positively associated with beneficial outcomes in glycemic control. However, future research is needed and should examine long-term effects of parental monitoring. Additionally, greater attention is needed on diverse populations such as single parent homes, families from different ethnic backgrounds, families of differing socioeconomic statuses and adolescents without parental figures.
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    Endoplasmic Reticulum Calcium in the Pathogenesis of Type 1 Diabetes
    (2023-12) Weaver, Staci Anne; Evans-Molina, Carmella; Roh, Hyun Cheol; Sims, Emily K.; Wek, Ronald C.
    Type 1 diabetes (T1D) accounts for 5-10% of all diabetes cases and results from immune-mediated destruction of pancreatic β-cells. Individuals with Darier Disease, which is caused by loss of function germline mutation(s) in the sarcoendoplasmic reticulum Ca2+-ATPase pump (SERCA2) gene, have an elevated risk of being diagnosed with T1D (risk ratio, 1.74; 95% CI, 1.13-2.69), suggesting a potential mechanistic relationship between SERCA2 and T1D pathogenesis. To determine the impact of reduced SERCA2 expression on T1D pathogenesis, we generated SERCA2 haploinsufficient mice by backcrossing C57BL6/J-S2+/- mice onto the non-obese diabetic (NOD) background (NOD-S2+/- mice). Female NOD-S2+/- mice showed accelerated T1D onset (14wks vs. 18wks, p<0.0001), elevated circulating anti-insulin antibodies, and increased immune cell infiltration into the islets compared to NOD-WT mice. Single-cell RNA sequencing (scRNA-seq) on islets and spatial proteomics on pancreatic lymph node (PLN) and spleen at 6 wks of age revealed increased immune cell presence in islets and enhanced B and T cell activation in PLN and spleen of NOD-S2+/- mice. Furthermore, scRNA-seq on isolated islets revealed temporal alterations in pathways related to mitochondria function in β cells, and mechanistic studies revealed decreased glucose-stimulated ATP production, reduced mitochondrial membrane potential, decreased islet expression of ATP synthase/mitochondrial complex III, increased mitochondrial Ca2+, and altered mitochondrial ultrastructure in NOD-S2+/- islets at 10 wks of age. In co-culture experiments, NOD-S2+/- B cells showed increased activation and NOD-S2+/- T cells showed increased proliferation and activation when cultured with NOD-WT islets. Interestingly, NOD-S2+/- islets induced B and T cell proliferation and T cell activation when cultured with NOD-WT immune cells. Lastly, administration of a small molecule SERCA activator in NOD-S2+/- mice decreased immune cell infiltration into the islet and delayed T1D onset. In summary, our results demonstrate a novel pathway whereby modulation of SERCA2 impacts islet mitochondrial function, islet immunogenicity, and immune cell proliferation and activation which fuel progression to T1D.
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    The Role of Beta Cell Dysfunction in Early Type 1 Diabetes
    (Wolters Kluwer, 2020-08) Sims, Emily K.; Mirmira, Raghavendra G.; Evans-Molina, Carmella; Pediatrics, School of Medicine
    Purpose of review: Emerging data have suggested that β-cell dysfunction may exacerbate the development and progression of type 1 diabetes (T1D). In this review, we highlight clinical and preclinical studies suggesting a role for β-cell dysfunction during the evolution of T1D and suggest agents that may promote β-cell health in T1D. Recent findings: Metabolic abnormalities exist years before development of hyperglycemia and exhibit a reproducible pattern reflecting progressive deterioration of β-cell function and increases in β-cell stress and death. Preclinical studies indicate that T1D may be prevented by modification of pathways impacting intrinsic β-cell stress and antigen presentation. Recent findings suggest that differences in metabolic phenotypes and β-cell stress may reflect differing endotypes of T1D. Multiple pathways representing potential drug targets have been identified, but most remain to be tested in human populations with preclinical disease. Summary: This cumulative body of work shows clear evidence that β-cell stress, dysfunction, and death are harbingers of impending T1D and likely contribute to progression of disease and insulin deficiency. Treatment with agents targeting β-cell health could augment interventions with immunomodulatory therapies but will need to be tested in intervention studies with endpoints carefully designed to capture changes in β-cell function and health.
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    The Roles of Danio Rerio Nrf2 Paralogs in Response to Oxidative Stress in the Pancreatic Beta Cell
    (2020-06) Doszpoly, Agnes; Linnemann, Amelia; Anderson, Ryan; Wek, Ronald
    Oxidative stress can disrupt cellular homeostasis, leading to cellular dysfunction and apoptosis. The Nrf2 transcription factor regulates the antioxidant response in cells by binding to antioxidant response elements (ARE) in DNA and activating genes of enzymes that combat oxidative stress. During the pathogenesis of diabetes mellitus (DM), β-cells are exposed to increased amounts of reactive oxygen species (ROS) that cause oxidative stress. Zebrafish (ZF) are excellent models for studying the dynamic mechanisms associated with DM pathogenesis, and we recently developed a ZF model of β-cell apoptosis caused by ROS. Two paralogs of Nrf2 have been identified in ZF, Nrf2a and Nrf2b, but their roles in pancreas development and/or β-cell survival are unknown. To investigate their roles, Nrf2a and Nrf2b antisense morpholinos (MO) were injected into Day 0 ZF embryos and analyzed over time. While Nrf2a MO showed no obvious phenotypes compared to WT, Nrf2b MO exhibited reduced pancreas size and islets with disrupted morphology. Ins:NTR Nrf2a MO showed reduced β-cell loss upon exposure to Metronidazole (MTZ) under generation of ROS compared to WT. Sequence analysis of ZF nrf2b in 3-day post-fertilization (dpf) embryos revealed a novel splice variant containing an additional exon that has not been described. Further investigation of Nrf2a and Nrf2b is likely to yield additional insights regarding the function and regulation of the NRF2-signaling pathway and their roles in β-cell protection under oxidative stress.
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    Sex-Specific Bone Phenotype in the Streptozotocin-Induced Murine Model of Diabetes
    (2021-08) Hatch, Jennifer; Wallace, Joseph M.; Allen, Matthew R.; Bone, Robert N.; Li, Jilliang; Na, Sungsoo
    Bone disease and degradation is a ubiquitous problem, the complexity and treatment of which humanity has only begun to understand. Diabetes Mellitus is a disease which, in all forms, profoundly effects the organs of the body, bone included. As is often the case in biology, there are inherent differences between the sexes when considering skeletal development and disease progression and outcome. Although there are several reported mouse models for diabetes, until now there has been no characterization of bone disease in any model where diabetes occurs with equal frequency in males and females in greater than 90% of animals. In this study, a protocol for reliable induction of diabetes in both sexes using intraperitoneal injections of Streptozotocin was developed. The resulting bone phenotype in male and female mice was characterized and compared to weight and age matched control groups. In this model female diabetic mice exhibited a robust deficit in bone quality, while both sexes experienced loss of beta-cell mass and increased glycation of hemoglobin rendering the diabetic mice unable to produce insulin endogenously. Further, these mice were unable to metabolize exogenous insulin injected during insulin tolerance testing. This model is a strong candidate for future exploration of osteoporotic bone disease, Diabetes Mellitus, and the link between estrogen and glucose sensitivity.