Colleen Kelly

Bio: Colleen Kelly is an academic researcher from Saint Louis University. The author has contributed to research in topics: Islet & Type 2 diabetes. The author has an hindex of 3, co-authored 4 publications receiving 242 citations.

Potential Role of Resident Islet Macrophage Activation in the Initiation of Autoimmune Diabetes

Abstract: The purpose of this study was to evaluate the effects of resident islet macrophage activation on beta cell function. Treatment of freshly isolated rat islets with TNF-alpha and LPS results in a potent inhibition of glucose-stimulated insulin secretion. The inhibitory actions of TNF + LPS are mediated by the intraislet production and release of IL-1 followed by IL-1-induced inducible nitric oxide synthase (iNOS) expression by beta cells. The IL-1R antagonist protein completely prevents TNF + LPS-induced nitrite production, iNOS expression and the inhibitory effects on glucose-stimulated insulin secretion by rat islets. Resident macrophages appear to be the source of IL-1, as a 7-day culture of rat islets at 24 degrees C (conditions known to deplete islets of lymphoid cells) prevents TNF + LPS-induced iNOS expression, nitrite production, and the inhibitory effects on insulin secretion. In addition, macrophage depletion also inhibits TNF + LPS-induced IL-1alpha and IL-1beta mRNA expression in rat islets. Immunocytochemical colocalization of IL-1beta with the macrophage-specific marker ED1 was used to provide direct support for resident macrophages as the islet cellular source of IL-1. IL-1beta appears to mediate the inhibitory actions of TNF + LPS on beta cell function as TNF + LPS-induced expression of IL-1beta is fourfold higher than IL-1alpha, and Ab neutralization of IL-1beta prevents TNF + LPS-induced nitrite production by rat islets. These findings support a mechanism by which the activation of resident islet macrophages and the intraislet release of IL-1 may mediate the initial dysfunction and destruction of beta cells during the development of autoimmune diabetes.

Non-adjunctive continuous glucose monitoring for control of hypoglycaemia (COACH): Results of a post-approval observational study.

Abstract: Objective Prior to the Continuous Monitoring and Control of Hypoglycaemia (COACH) study described herein, no study had been powered to evaluate the impact of non-adjunctive RT-CGM use on the rate of debilitating moderate or severe hypoglycaemic events. Research design and methods In this 12-month observational study, adults with insulin-requiring diabetes who were new to RT-CGM participated in a 6-month control phase where insulin dosing decisions were based on self-monitored blood glucose (SMBG) values, followed by a 6-month phase where decisions were based on RT-CGM data (i.e., non-adjunctive RT-CGM use); recommendations for RT-CGM use were made according to sites' usual care. The primary outcome was change in debilitating moderate (requiring second-party assistance) and severe (resulting in seizures or loss of consciousness) hypoglycaemic event frequency. Secondary outcomes included changes in HbA1c and diabetic ketoacidosis (DKA) frequency. Results A total of 519 participants with mean (SD) age 50.3 (16.1) years and baseline HbA1c 8.0% (1.4%) completed the study, of whom 32.8% had impaired hypoglycaemia awareness and 33.5% had type 2 diabetes (T2D). The mean (SE) per-patient frequency of hypoglycaemic events decreased by 63% from 0.08 (0.016) during the SMBG phase to 0.03 (0.010) during the RT-CGM phase (p=0.005). HbA1c decreased during the RT-CGM phase both for participants with type 1 diabetes (T1D) and T2D and there was a trend toward larger reductions among individuals with higher baseline HbA1c. Conclusions Among adults with insulin-requiring diabetes, non-adjunctive use of RT-CGM data is safe, resulting in significantly fewer debilitating hypoglycaemic events than management using SMBG.

928-P: The Use of a Novel CGM-Informed Insulin Bolus Calculator Mobile Application by People with Type 1 and Type 2 Diabetes Improves Time in Range

Abstract: Background and Aims: People with diabetes on basal-bolus insulin regimens face challenges calculating bolus doses. Continuous glucose monitoring (CGM) systems can assist users with bolus dosing optimization through trend arrows. The purpose of this study was to demonstrate the safety and effectiveness of a CGM-informed insulin bolus calculator (IBC, Welldoc, Inc., Columbia, MD, U.S.A.) integrated into a mobile application that applies trend arrow and exercise adjustments to the bolus insulin dose recommendation. This investigational software also provided real-time coaching on CGM data to assist users in improving their time in range (TIR). Methods: Fifty-four participants with diabetes using CGM (Dexcom G6, San Diego, CA, U.S.A.) were enrolled in a 30-day prospective study conducted at two research sites. Participants were asked to use the mobile application to monitor their CGM data and calculate their insulin doses. TIR during the prospective 30-day period was compared to that from 30 days of baseline data. Three populations were defined: 1) the intention-to-treat (ITT) group consisted of all enrolled subjects; 2) the complete cases (CC) group had ≥90% sensor wear time; and 3) the per-protocol (PP) group used the IBC at least 30 times during the study period. Results: In the ITT group, the TIR improved from 68.4% to 71.8% (N=54, P=0.013). In the CC group, the TIR improved from 69.1% to 73.0% (N=49, P=0.005). In the PP group, the TIR improved from 69.2% to 73.0% (N=39, P=0.017). There was no increase in time with low glucose (<70 mg/dL) in all three populations. In a subgroup analysis, TIR increased from 74.7% to 81.4% in those with type 2 diabetes and from 64.4% to 65.2% in those with type 1 diabetes. Conclusions: Use of a novel CGM-informed insulin bolus calculator with trend arrow and exercise dose adjustment by individuals with type 1 and type 2 diabetes was associated with significant improvement in TIR. M.Shomali: Employee; WellDoc. C.Kelly: Consultant; WellDoc, Caladrius Biosciences, Inc., Epigenomics AG, Luna, Nevro Corp., Presidio Medical, Hitachi, Ltd., Resmed, Inc., Seaspine Hldgs, Inc., ViaCyte, Inc. A.K.Iyer: Employee; WellDoc. J.Y.Park: None. G.Aleppo: Advisory Panel; Medscape, Consultant; Bayer Inc., Insulet Corporation, Research Support; Dexcom, Inc., Eli Lilly and Company, Emmes, Insulet Corporation, Fractyl Health, Inc., WellDoc, Speaker's Bureau; Dexcom, Inc. Welldoc Inc.

Glucose-induced β cell production of IL-1β contributes to glucotoxicity in human pancreatic islets

Abstract: In type 2 diabetes, chronic hyperglycemia is suggested to be detrimental to pancreatic beta cells, causing impaired insulin secretion. IL-1beta is a proinflammatory cytokine acting during the autoimmune process of type 1 diabetes. IL-1beta inhibits beta cell function and promotes Fas-triggered apoptosis in part by activating the transcription factor NF-kappaB. Recently, we have shown that increased glucose concentrations also induce Fas expression and beta cell apoptosis in human islets. The aim of the present study was to test the hypothesis that IL-1beta may mediate the deleterious effects of high glucose on human beta cells. In vitro exposure of islets from nondiabetic organ donors to high glucose levels resulted in increased production and release of IL-1beta, followed by NF-kappaB activation, Fas upregulation, DNA fragmentation, and impaired beta cell function. The IL-1 receptor antagonist protected cultured human islets from these deleterious effects. beta cells themselves were identified as the islet cellular source of glucose-induced IL-1beta. In vivo, IL-1beta-producing beta cells were observed in pancreatic sections of type 2 diabetic patients but not in nondiabetic control subjects. Similarly, IL-1beta was induced in beta cells of the gerbil Psammomys obesus during development of diabetes. Treatment of the animals with phlorizin normalized plasma glucose and prevented beta cell expression of IL-1beta. These findings implicate an inflammatory process in the pathogenesis of glucotoxicity in type 2 diabetes and identify the IL-1beta/NF-kappaB pathway as a target to preserve beta cell mass and function in this condition.

Immune cell crosstalk in type 1 diabetes

Abstract: Here, the authors describe the complex interactions between cells of the innate immune system, the implications of these interactions for activation of adaptive immune cells and pancreatic β-cell death and the impact of infectious agents on these processes. The development of type 1 diabetes involves a complex interaction between pancreatic β-cells and cells of both the innate and adaptive immune systems. Analyses of the interactions between natural killer (NK) cells, NKT cells, different dendritic cell populations and T cells have highlighted how these different cell populations can influence the onset of autoimmunity. There is evidence that infection can have either a potentiating or inhibitory role in the development of type 1 diabetes. Interactions between pathogens and cells of the innate immune system, and how this can influence whether T cell activation or tolerance occurs, have been under close scrutiny in recent years. This Review focuses on the nature of this crosstalk between the innate and the adaptive immune responses and how pathogens influence the process.

Increased interleukin (IL)-1beta messenger ribonucleic acid expression in beta -cells of individuals with type 2 diabetes and regulation of IL-1beta in human islets by glucose and autostimulation.

Abstract: CONTEXT: Elevated glucose levels impair islet function and survival, and it has been proposed that intraislet expression of IL-1beta contributes to glucotoxicity. OBJECTIVE: The objective was to investigate IL-1beta mRNA expression in near-pure beta-cells of patients with type 2 diabetes (T2DM) and study the regulation of IL-1beta by glucose in isolated human islets. METHODS: Laser capture microdissection was performed to isolate beta-cells from pancreas sections of 10 type 2 diabetic donors and nine controls, and IL-1beta mRNA expression was analyzed using gene arrays and PCR. Cultured human islets and fluorescence-activated cell sorter-purified human beta-cells were used to study the regulation of IL-1beta expression by glucose and IL-1beta. RESULTS: Gene array analysis of RNA from beta-cells of individuals with T2DM revealed increased expression of IL-1beta mRNA. Real-time PCR confirmed increased IL-1beta expression in six of 10 T2DM samples, with minimal or no expression in nine control samples. In cultured human islets, IL-1beta mRNA and protein expression was induced by high glucose and IL-1beta autostimulation and decreased by the IL-1 receptor antagonist IL-1Ra. The glucose response was negatively correlated with basal IL-1beta expression levels. Autostimulation was transient and nuclear factor-kappaB dependent. Glucose-induced IL-1beta was biologically active and stimulated IL-8 release. Low picogram per milliliter concentrations of IL-1beta up-regulated inflammatory factors IL-8 and IL-6. CONCLUSION: Evidence that IL-1beta mRNA expression is up-regulated in beta-cells of patients with T2DM is presented, and glucose-promoted IL-1beta autostimulation may be a possible contributor.

The role of reactive oxygen species and proinflammatory cytokines in type 1 diabetes pathogenesis

Abstract: Type 1 diabetes (T1D) is a T cell–mediated autoimmune disease characterized by the destruction of insulin-secreting pancreatic β cells. In humans with T1D and in nonobese diabetic (NOD) mice (a murine model for human T1D), autoreactive T cells cause β-cell destruction, as transfer or deletion of these cells induces or prevents disease, respectively. CD4+ and CD8+ T cells use distinct effector mechanisms and act at different stages throughout T1D to fuel pancreatic β-cell destruction and disease pathogenesis. While these adaptive immune cells employ distinct mechanisms for β-cell destruction, one central means for enhancing their autoreactivity is by the secretion of proinflammatory cytokines, such as IFN-γ, TNF-α, and IL-1. In addition to their production by diabetogenic T cells, proinflammatory cytokines are induced by reactive oxygen species (ROS) via redox-dependent signaling pathways. Highly reactive molecules, proinflammatory cytokines are produced upon lymphocyte infiltration into pancreatic islets and induce disease pathogenicity by directly killing β cells, which characteristically possess low levels of antioxidant defense enzymes. In addition to β-cell destruction, proinflammatory cytokines are necessary for efficient adaptive immune maturation, and in the context of T1D they exacerbate autoimmunity by intensifying adaptive immune responses. The first half of this review discusses the mechanisms by which autoreactive T cells induce T1D pathogenesis and the importance of ROS for efficient adaptive immune activation, which, in the context of T1D, exacerbates autoimmunity. The second half provides a comprehensive and detailed analysis of (1) the mechanisms by which cytokines such as IL-1 and IFN-γ influence islet insulin secretion and apoptosis and (2) the key free radicals and transcription factors that control these processes.

Biological and Biomaterial Approaches for Improved Islet Transplantation

Abstract: Islet transplantation may be used to treat type I diabetes. Despite tremendous progress in islet isolation, culture, and preservation, the clinical use of this modality of treatment is limited due to post-transplantation challenges to the islets such as the failure to revascularize and immune destruction of the islet graft. In addition, the need for lifelong strong immunosuppressing agents restricts the use of this option to a limited subset of patients, which is further restricted by the unmet need for large numbers of islets. Inadequate islet supply issues are being addressed by regeneration therapy and xenotransplantation. Various strategies are being tried to prevent beta-cell death, including immunoisolation using semipermeable biocompatible polymeric capsules and induction of immune tolerance. Genetic modification of islets promises to complement all these strategies toward the success of islet transplantation. Furthermore, synergistic application of more than one strategy is required for improving the success of islet transplantation. This review will critically address various insights developed in each individual strategy and for multipronged approaches, which will be helpful in achieving better outcomes.