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Cell Based Therapy for Type 1 Diabetes: Should We Take Hyperglycemia Into Account?

ABSTRACT: Diabetes mellitus is characterized by long standing hyperglycemia leading to numerous life-threatening complications. For type 1 diabetes mellitus, resulting from selective destruction of insulin producing cells by exaggerated immune reaction, the only effective therapy remains exogenous insulin administration. Despite accurate compliance to treatment of certain patients, transient episodes of hyperglycemia cannot be completely eliminated by this symptomatic treatment. Novel immunotherapeutic approaches based on tolerogenic dendritic cells, T regulatory cells and mesenchymal stem cells (MSCs) have been tested in clinical trials, endeavoring to directly modulate the autoimmune destruction process in pancreas. However, hyperglycemia itself affects the immune system and the final efficacy of cell-based immunotherapies could be affected by the different glycemic control of enrolled patients. The present review explores the impact of hyperglycemia on immune cells while providing greater insight into the molecular mechanisms of high glucose action and subsequent metabolic reprogramming of different immune cells. Furthermore, over-production of mitochondrial reactive oxygen species, formation of advanced glycation end products as a consequence of hyperglycemia and their downstream signalization in immune cells are also discussed. Since hyperglycemia in patients with type 1 diabetes mellitus might have an impact on immune-interventional treatment, the maintenance of a tight glucose control seems to be beneficial in patients considered for cell-based therapy.

SUBMITTER: Grohova A

PROVIDER: S-EPMC6370671 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Cell Based Therapy for Type 1 Diabetes: Should We Take Hyperglycemia Into Account?

Grohová Anna A Dáňová Klára K Špíšek Radek R Palová-Jelínková Lenka L

Frontiers in immunology 20190205

Diabetes mellitus is characterized by long standing hyperglycemia leading to numerous life-threatening complications. For type 1 diabetes mellitus, resulting from selective destruction of insulin producing cells by exaggerated immune reaction, the only effective therapy remains exogenous insulin administration. Despite accurate compliance to treatment of certain patients, transient episodes of hyperglycemia cannot be completely eliminated by this symptomatic treatment. Novel immunotherapeutic ap ...[more]

PMID: 30804929

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Project description:ObjectiveCalcitonin Gene-Related Peptide α (CGRPα) is a multifunctional neuropeptide found in the central and peripheral nervous system with cardiovascular, nociceptive, and gastrointestinal activities. CGRPα has been linked to obesity and insulin secretion but the role of this circulating peptide in energy metabolism remains unclear. Here, we thought to utilize a monoclonal antibody against circulating CGRPα to assess its ability to improve glucose homeostasis in mouse models of hyperglycemia and diabetes.MethodsWe examined the outcome of anti-CGRPα treatment in mouse models of diabetes and diet-induced obesity, using db/db mice, Streptozotocin (STZ) treatment to eliminate pancreatic islets, and high fat diet-fed mice. We also correlated these data with application of recombinant CGRPα peptide on cultured mature adipocytes to measure its impact on mitochondrial bioenergetics and fatty acid oxidation. Furthermore, we applied recombinant CGRPα to primary islets to measure glucose-stimulated insulin secretion (GSIS) and gene expression.ResultsBL6-db diabetic mice receiving anti-CGRPα treatment manifested weight loss, reduced adiposity, improved glucose tolerance, insulin sensitivity, GSIS and reduced pathology in adipose tissue and liver. Anti-CGRPα failed to modulate weight or glucose homeostasis in STZ-treated animals. High fat diet-fed mice showed reduced adiposity but no benefit on glucose homeostasis. Considering these findings, we postulated that CGRPα may have dual effects on adipocytes to promote lipid utilization while acting on pancreatic β-cells to modulate insulin secretion. Analysis of CGRPα in the pancreas showed that the peptide localized to insulin-positive cells and perivascular nerves surrounding islets. Ex-vivo analysis of pancreatic islets determined that CGRPα blocked GSIS and reduced insulin-2 gene expression. Mechanistical analysis revealed that recombinant CGRPα was able to reduce glycolytic capacity as well as fatty acid oxidation in primary white adipocytes.ConclusionsThese results establish a multifaceted role in energy metabolism for circulating CGRPα, with the ability to modulate thermogenic pathways in adipose tissue, as well as pancreatic β-cell dependent insulin secretion. Reducing circulating CGRPα levels with monoclonal therapy presents therapeutic potential for type 2 diabetes as shown in BL6-db/db mice but has reduced potential for models of hyperglycemia resulting from loss of β-cells (STZ treatment).

Project description:BackgroundThe Barbados Diabetes Remission Study-2 reported that a low-calorie diet for weight loss and diabetes remission implemented within the community and supported by trained community health advocates was both an acceptable implementation strategy and a clinically effective intervention. This study aimed to examine the adaptability of the face-to-face protocol into an online modality.MethodsThe Iterative Decision-making for Evaluation of Adaptations (IDEA) framework guides researchers in examining the necessity of the adaptation and the preservation of core intervention elements during the adaptation process. Adaptation outcomes were documented using the Framework for Reporting Adaptations and Modifications to Evidence-Based Implementation Strategies (FRAME-IS). Implementation outcome was determined by fidelity to core elements. Intervention effectiveness was determined from the analysis of clinical data.ResultsWe decided that an adaptation was needed as COVID-19 control measures prohibited in-person interactions. The core elements-i.e. 12-week intervention duration, daily 840-kcal allowance, and weekly monitoring of weight and blood glucose-could be preserved during the adaptation process. Adaptations were made to the following: (1) the context in which data were collected-participants self-measured at home instead of following the original implementation strategy which involved being measured by community health advocates (CHA) at a community site; (2) the context in which data were entered-participants posted their measurements to a mobile application site which was accessible by CHAs. As with the original protocol, CHAs then entered the measurements into an online database; (3) the formulation of the low-calorie diet-participants substituted the liquid formulation for a solid meal plan of equivalent caloric content. There was non-inferiority in fidelity to attendance with the online format (97.5% visit rate), as compared to the face-to-face modality (95% visit rate). One participant deviated from the calorie allowances citing difficulty in estimating non-exact portion sizes and financial difficulty in procuring meals. Weight change ranged from - 14.3 to 0.4 kg over the 12-week period, and all group members achieved induction of diabetes remission as determined by a FBG of < 7mmol/l and an A1C of < 6.5%.ConclusionThe results suggest that this adapted online protocol-which includes changes to both the implementation strategy and the evidence-based practice-is clinically effective whilst maintaining fidelity to key elements. Utilization of the IDEA and FRAME-IS adaptation frameworks add scientific rigour to the research.Trial registrationClinicalTrials.gov NCT03536377 . Registered on 24 May 2018.

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Cell Based Therapy for Type 1 Diabetes: Should We Take Hyperglycemia Into Account?

Publications

Cell Based Therapy for Type 1 Diabetes: Should We Take Hyperglycemia Into Account?

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