IU Indianapolis ScholarWorks :: Browsing by Author "Sims, Emily K."

Browsing by Author "Sims, Emily K."

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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.
Analysis of Incident DKA in the Indiana New Onset T1D Patient Population
(Indiana University, 2020) Beer, Brianna; Moors, Kelly; Evans-Molina, Carmella; Sims, Emily K.; Pediatrics, School of Medicine
Background/Objective: Diabetic ketoacidosis (DKA) is a life-threatening complication of type 1 diabetes (T1D) resulting from ketone body production and metabolic acidosis occurring due to insulin deficiency. We sought to define the occurrence of DKA amongst pediatric patients presenting with new-onset T1D in Indiana and to determine whether patterns of DKA were affected by the COVID-19 pandemic. Methods: This was a retrospective chart review for patients <18 years admitted to Riley Children’s Hospital with a clinical diagnosis of new onset T1D who had available chemistry values. Patients diagnosed from March 23- June 30, 2020 and over the same period in 2019 were included. DKA was classified as mild (bicarbonate 10-15 mmol/L) or severe (bicarbonate <10 mmol/L). Results: Ninety-four patients met inclusion criteria. The total number of incident T1D cases in 2019 and 2020 were similar (48 vs. 46, respectively). Similarly, there was no significant difference in rates of DKA (21 in 2019 vs. 25 in 2020; p>0.05). Of the 94 patients, 49% met criteria for DKA; 79% of cases were classified as severe and 21% as mild. More males were diagnosed with DKA in both 2019 and 2020 (61% of DKA cases). Non-Hispanic whites comprised 75% of all new onset T1D patients and no differences in race or ethnicity were present amongst those presenting in DKA. Conclusion: DKA was present in nearly half of all new onset pediatric T1D cases in Indiana in 2019 and 2020. There was no observed impact of the COVID-19 pandemic on T1D or DKA. Impact and Implications: DKA is common amongst pediatric patients with new onset T1D in Indiana. Prompt recognition of symptoms is needed to prevent this life-threatening complication of T1D.
Analysis of serum Hsp90 as a potential biomarker of β cell autoimmunity in type 1 diabetes
(PLOS, 2019-01-10) Ocaña, Gail J.; Sims, Emily K.; Watkins, Renecia A.; Ragg, Susanne; Mather, Kieren J.; Oram, Richard A.; Mirmira, Raghavendra G.; DiMeglio, Linda A.; Blum, Janice S.; Evans-Molina, Carmella; Microbiology and Immunology, School of Medicine
Heat shock protein 90 (Hsp90) is a protein chaperone that is upregulated and released from pancreatic β cells under pro-inflammatory conditions. We hypothesized that serum Hsp90 may have utility as a biomarker of type 1 diabetes risk and exhibit elevations before the onset of clinically significant hyperglycemia. To this end, total levels of the alpha cytoplasmic isoform of Hsp90 were assayed in autoantibody-positive progressors to type 1 diabetes using banked serum samples from the TrialNet Pathway to Prevention Cohort that had been collected 12 months prior to diabetes onset, with comparison to age, sex, and BMI-category matched autoantibody-positive nonprogressors and healthy controls. Hsp90 levels were higher in autoantibody-positive progressors and nonprogressors ≤ 18 years of age compared to matched healthy controls. However, Hsp90 levels were not different between progressors and nonprogressors in any age group. Hsp90 was positively correlated with age in control subjects, but this correlation was absent in autoantibody positive individuals. In aggregate these data indicate that elevated Hsp90 levels are present in youth with β cell autoimmunity, but are not able to distinguish youth or adult type 1 diabetes progressors from nonprogressors in samples collected 12 months prior to diabetes development.
Associations of HbA1c with the Timing of C‐peptide Responses during the Oral Glucose Tolerance Test at the Diagnosis of Type 1 Diabetes
(Wiley, 2019) Ismail, Heba M.; Evans-Molina, Carmella; DiMeglio, Linda A.; Becker, Dorothy J.; Libman, Ingrid; Sims, Emily K.; Boulware, David; Herold, Kevan C.; Rafkin, Lisa; Skyler, Jay; Cleves, Mario A.; Palmer, Jerry; Sosenko, Jay; Pediatrics, School of Medicine
Background In new onset type 1 diabetes (T1D), overall C‐peptide measures such as area under the curve (AUC) C‐peptide and peak C‐peptide are useful for estimating the extent of β‐cell dysfunction, and for assessing responses to intervention therapy. However, measures of the timing of C‐peptide responsiveness could have additional value. Objectives We assessed the contribution of the timing of C‐peptide responsiveness during oral glucose tolerance tests (OGTTs) to HbA1c variation at T1D diagnosis. Methods We analyzed data from 85 individuals <18 years with OGTTs and HbA1c measurements at diagnosis. Overall [AUC and peak C‐peptide] and timing measures [30‐0 minute C‐peptide (early); 60 to 120 minute C‐peptide sum‐30 minutes (late); 120/30 C‐peptide; time to peak C‐peptide] were utilized. Results At diagnosis, the mean (±SD) age was 11.2±3.3 years, BMI‐z was 0.4±1.1, 51.0% were male and the HbA1c was 43.54±8.46 mmol/mol (6.1±0.8%). HbA1c correlated inversely with the AUC C‐peptide (p<0.001), peak C‐peptide (p<0.001), early and late C‐peptide responses (p<0.001 each), and 120/30 C‐peptide (p<0.001). Those with a peak C‐peptide occurring at ≤60 minutes had higher HbA1c values than those with peaks later (p=0.003). HbA1c variance was better explained with timing measures added to regression models (R2=11.6% with AUC C‐peptide alone; R2=20.0% with 120/30 C‐peptide added; R2=13.7% with peak C‐peptide alone, R2=20.4% with timing of the peak added). Similar associations were seen between the 2‐hr glucose and the C‐peptide measures. Conclusions These findings show that the addition of timing measures of C‐peptide responsiveness better explains HbA1c variation at diagnosis than standard measures alone.
Beta cell extracellular vesicle miR-21-5p cargo is increased in response to inflammatory cytokines and serves as a biomarker of type 1 diabetes
(Springer Nature, 2018-05) Lakhter, Alexander J.; Pratt, Rachel E.; Moore, Rachel E.; Doucette, Kaitlin K.; Maier, Bernhard F.; DiMeglio, Linda A.; Sims, Emily K.; Pediatrics, School of Medicine
AIMS/HYPOTHESIS: Improved biomarkers are acutely needed for the detection of developing type 1 diabetes, prior to critical loss of beta cell mass. We previously demonstrated that elevated beta cell microRNA 21-5p (miR-21-5p) in rodent and human models of type 1 diabetes increased beta cell apoptosis. We hypothesised that the inflammatory milieu of developing diabetes may also increase miR-21-5p in beta cell extracellular vesicle (EV) cargo and that circulating EV miR-21-5p would be increased during type 1 diabetes development. METHODS: MIN6 and EndoC-βH1 beta cell lines and human islets were treated with IL-1β, IFN-γ and TNF-α to mimic the inflammatory milieu of early type 1 diabetes. Serum was collected weekly from 8-week-old female NOD mice until diabetes onset. Sera from a cross-section of 19 children at the time of type 1 diabetes diagnosis and 16 healthy children were also analysed. EVs were isolated from cell culture media or serum using sequential ultracentrifugation or ExoQuick precipitation and EV miRNAs were assayed. RESULTS: Cytokine treatment in beta cell lines and human islets resulted in a 1.5- to threefold increase in miR-21-5p. However, corresponding EVs were further enriched for this miRNA, with a three- to sixfold EV miR-21-5p increase in response to cytokine treatment. This difference was only partially reduced by pre-treatment of beta cells with Z-VAD-FMK to inhibit cytokine-induced caspase activity. Nanoparticle tracking analysis showed cytokines to have no effect on the number of EVs, implicating specific changes within EV cargo as being responsible for the increase in beta cell EV miR-21-5p. Sequential ultracentrifugation to separate EVs by size suggested that this effect was mostly due to cytokine-induced increases in exosome miR-21-5p. Longitudinal serum collections from NOD mice showed that EVs displayed progressive increases in miR-21-5p beginning 3 weeks prior to diabetes onset. To validate the relevance to human diabetes, we assayed serum from children with new-onset type 1 diabetes compared with healthy children. While total serum miR-21-5p and total serum EVs were reduced in diabetic participants, serum EV miR-21-5p was increased threefold compared with non-diabetic individuals. By contrast, both serum and EV miR-375-5p were increased in parallel among diabetic participants. CONCLUSIONS/INTERPRETATION: We propose that circulating EV miR-21-5p may be a promising marker of developing type 1 diabetes. Additionally, our findings highlight that, for certain miRNAs, total circulating miRNA levels are distinct from circulating EV miRNA content.
Beta cells in type 1 diabetes: mass and function; sleeping or dead?
(Springer Nature, 2019-04) Oram, Richard A.; Sims, Emily K.; Evans-Molina, Carmella; Pediatrics, School of Medicine
Histological analysis of donor pancreases coupled with measurement of serum C-peptide in clinical cohorts has challenged the idea that all beta cells are eventually destroyed in type 1 diabetes. These findings have raised a number of questions regarding how the remaining beta cells have escaped immune destruction, whether pools of 'sleeping' or dysfunctional beta cells could be rejuvenated and whether there is potential for new growth of beta cells. In this Review, we describe histological and in vivo evidence of persistent beta cells in type 1 diabetes and discuss the limitations of current methods to distinguish underlying beta cell mass in comparison with beta cell function. We highlight that evidence for new beta cell growth in humans many years from diagnosis is limited, and that this growth may be very minimal if at all present. We review recent contributions to the debate around beta cell abnormalities contributing to the pathogenesis of type 1 diabetes. We also discuss evidence for restoration of beta cell function, as opposed to mass, in recent-onset type 1 diabetes, but highlight the absence of data supporting functional recovery in the setting of long-duration diabetes. Finally, future areas of research are suggested to help resolve the source and phenotype of residual beta cells that persist in some, but not all, people with type 1 diabetes.
Biomarkers of islet beta cell stress and death in type 1 diabetes
(Springer Nature, 2018-11) Sims, Emily K.; Evans-Molina, Carmella; Tersey, Sarah A.; Eizirik, Decio L.; Mirmira, Raghavendra G.; Pediatrics, School of Medicine
Recent work on the pathogenesis of type 1 diabetes has led to an evolving recognition of the heterogeneity of this disease, both with regards to clinical phenotype and responses to therapies to prevent or revert diabetes. This heterogeneity not only limits efforts to accurately predict clinical disease but also is reflected in differing responses to immunomodulatory therapeutics. Thus, there is a need for robust biomarkers of beta cell health, which could provide insight into pathophysiological differences in disease course, improve disease prediction, increase the understanding of therapeutic responses to immunomodulatory interventions and identify individuals most likely to benefit from these therapies. In this review, we outline current literature, limitations and future directions for promising circulating markers of beta cell stress and death in type 1 diabetes, including markers indicating abnormal prohormone processing, circulating RNAs and circulating DNAs.
Biomarkers of β-Cell Stress and Death in Type 1 Diabetes
(Springer, 2016-10) Mirmira, Raghavendra G.; Sims, Emily K.; Syed, Farooq; Evans-Molina, Carmella; Medicine, School of Medicine
The hallmark of type 1 diabetes (T1D) is a decline in functional β-cell mass arising as a result of autoimmunity. Immunomodulatory interventions at disease onset have resulted in partial stabilization of β-cell function, but full recovery of insulin secretion has remained elusive. Revised efforts have focused on disease prevention through interventions administered at earlier disease stages. To support this paradigm, there is a parallel effort ongoing to identify circulating biomarkers that have the potential to identify stress and death of the islet β-cells. Whereas no definitive biomarker(s) have been fully validated, several approaches hold promise that T1D can be reliably identified in the pre-symptomatic phase, such that either β-cell preservation or immunomodulatory agents might be employed in at-risk populations. This review summarizes the most promising protein- and nucleic acid-based biomarkers discovered to date and reviews the context in which they have been studied.
Cause or effect? A review of clinical data demonstrating beta cell dysfunction prior to the clinical onset of type 1 diabetes
(Elsevier, 2019-09) Sims, Emily K.; DiMeglio, Linda A.; Pediatrics, School of Medicine
BACKGROUND: Limited successes of conventional approaches to type 1 diabetes (T1D) prevention and treatment have highlighted the need for improved understanding of risk factors contributing to or hastening progression to clinical diagnosis. SCOPE OF REVIEW: This review summarizes beta cell function metabolic phenotyping data from clinical studies conducted in at-risk individuals before T1D onset and healthy controls. Data are drawn from studies comparing at-risk individuals who progress to T1D to at-risk individuals who do not progress to T1D, as well as from studies comparing at-risk individuals to controls without a T1D family history. MAJOR CONCLUSIONS: Rapid loss of beta cell insulin secretion occurs in the months immediately preceding clinical onset. However, evidence of beta cell dysfunction is present even years earlier. Comparisons to controls without a family history suggest that many individuals in families impacted by T1D have evidence of beta cell dysfunction, even individuals who are unlikely to develop clinical disease. These findings may mean that underlying metabolic beta cell dysfunction contributes to T1D development and may explain some of the heterogeneity observed in the disease.
Chewing the Fat: A Metabolic Role for Ldb1 Beyond the Pancreas?
(Endocrine Society, 2017-04-29) Sims, Emily K.; Pediatrics, School of Medicine

Browsing by Author "Sims, Emily K."

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