Current and future therapies for type 1 diabetes

AbstractIn type 1 diabetes, insulin remains the mature therapeutic cornerstone; yet, the increasing number of individuals developing type 1 diabetes (predominantly children and adolescents) still face severe complications. Fortunately, our understanding of type 1 diabetes is continuously being refined, allowing for refocused development of novel prevention and management strategies. Hitherto, attempts based on immune suppression and modulation have been only partly successful in preventing the key pathophysiological feature in type 1 diabetes: the immune-mediated derangement or destruction of beta cells in the pancreatic islets of Langerhans, leading to low or absent insulin secretion and chronic hyperglycaemia. Evidence now warrants a focus on the beta cell itself and how to avoid its dysfunction, which is putatively caused by cytokine-driven inflammation and other stress factors, leading to low insulin-secretory capacity, autoantigen presentation and immune-mediated destruction. Correspondingly, beta cell rescue strategies are being pursued, which include antigen vaccination using, for example, oral insulin or peptides, as well as agents with suggested benefits on beta cell stress, such as verapamil and glucagon-like peptide-1 receptor agonists. Whilst autoimmune-focused prevention approaches are central in type 1 diabetes and will be a requirement in the advent of stem cell-based replacement therapies, managing the primarily cardiometabolic complications of established type 1 diabetes is equally essential. In this review, we outline selected recent and suggested future attempts to address the evolving profile of the person with type 1 diabetes. Graphical abstract

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Targeting dysfunctional beta-cell signaling for the potential treatment of type 1 diabetes mellitus

Experimental Biology and Medicine ◽

10.1177/1535370218761662 ◽

2018 ◽

Vol 243 (6) ◽

pp. 586-591 ◽

Cited By ~ 3

Author(s):

Rachel J Fenske ◽

Michelle E Kimple

Keyword(s):

Diabetes Mellitus ◽

Type 1 Diabetes ◽

Beta Cell ◽

Cell Signaling ◽

Type 1 Diabetes Mellitus ◽

Therapeutic Targets ◽

Alpha Subunit ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

Since its discovery and purification by Frederick Banting in 1921, exogenous insulin has remained almost the sole therapy for type 1 diabetes mellitus. While insulin alleviates the primary dysfunction of the disease, many other aspects of the pathophysiology of type 1 diabetes mellitus are unaffected. Research aimed towards the discovery of novel type 1 diabetes mellitus therapeutics targeting different cell signaling pathways is gaining momentum. The focus of these efforts has been almost entirely on the impact of immunomodulatory drugs, particularly those that have already received FDA-approval for other autoimmune diseases. However, these drugs can often have severe side effects, while also putting already immunocompromised individuals at an increased risk for other infections. Potential therapeutic targets in the insulin-producing beta-cell have been largely ignored by the type 1 diabetes mellitus field, save the glucagon-like peptide 1 receptor. While there is preliminary evidence to support the clinical exploration of glucagon-like peptide 1 receptor-based drugs as type 1 diabetes mellitus adjuvant therapeutics, there is a vast space for other putative therapeutic targets to be explored. The alpha subunit of the heterotrimeric Gz protein (Gαz) has been shown to promote beta-cell inflammation, dysfunction, death, and failure to replicate in the context of diabetes in a number of mouse models. Genetic loss of Gαz or inhibition of the Gαz signaling pathway through dietary interventions is protective against the development of insulitis and hyperglycemia. The multifaceted effects of Gαz in regards to beta-cell health in the context of diabetes make it an ideal therapeutic target for further study. It is our belief that a low-risk, effective therapy for type 1 diabetes mellitus will involve a multidimensional approach targeting a number of regulatory systems, not the least of which is the insulin-producing beta-cell. Impact statement The expanding investigation of beta-cell therapeutic targets for the treatment and prevention of type 1 diabetes mellitus is fundamentally relevant and timely. This review summarizes the overall scope of research into novel type 1 diabetes mellitus therapeutics, highlighting weaknesses or caveats in current clinical trials as well as describing potential new targets to pursue. More specifically, signaling proteins that act as modulators of beta-cell function, survival, and replication, as well as immune infiltration may need to be targeted to develop the most efficient pharmaceutical interventions for type 1 diabetes mellitus. One such beta-cell signaling pathway, mediated by the alpha subunit of the heterotrimeric Gz protein (Gαz), is discussed in more detail. The work described here will be critical in moving the field forward as it emphasizes the central role of the beta-cell in type 1 diabetes mellitus disease pathology.

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Effect of glucagon-like peptide-1 (7–37) on beta-cell function after islet transplantation in type 1 diabetes

Diabetes Research and Clinical Practice ◽

10.1016/j.diabres.2006.03.022 ◽

2006 ◽

Vol 74 (2) ◽

pp. 189-193 ◽

Cited By ~ 18

Author(s):

Michelle Fung ◽

David Thompson ◽

R. Jean Shapiro ◽

Garth L. Warnock ◽

Dana K. Andersen ◽

...

Keyword(s):

Type 1 Diabetes ◽

Beta Cell ◽

Islet Transplantation ◽

Beta Cell Function ◽

Cell Function ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

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Stem cells for [beta] cell replacement in type 1 diabetes

Endocrine Abstracts ◽

10.1530/endoabs.49.s20.1 ◽

2017 ◽

Author(s):

Valeria Sordi

Keyword(s):

Stem Cells ◽

Type 1 Diabetes ◽

Beta Cell ◽

Cell Replacement ◽

Beta Cell Replacement

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Diabetes and osteoporosis

Orvosi Hetilap ◽

10.1556/oh.2011.29154 ◽

2011 ◽

Vol 152 (29) ◽

pp. 1161-1166 ◽

Cited By ~ 4

Author(s):

Zsuzsanna Valkusz

Keyword(s):

Vitamin D ◽

Type 1 Diabetes ◽

Bone Mass ◽

Fragility Fractures ◽

Vitamin D Supplementation ◽

Bone Collagen ◽

Skeletal Changes ◽

Glucagon Like Peptide 1 ◽

Bone Quantity

Over the last decades a considerable amount of data has accumulated to indicate that metabolic and endocrine alterations of diabetes affect bone quantity and quality. These skeletal changes may increase the risk of bone fracture. There is strong evidence that in type 1 diabetes the decreased bone mass, lack of insulin and insulin-like growth factor-1, dysregulation of adipokines, and increased levels of proinflammatory cytokines are in the background of fragility fractures. In type 2 diabetes hyperinsulinemia, insulin resistance and increased body weight may result in an increase of bone mass; however, accumulation of advanced glycation end products within the bone collagen driven by glucotoxicity may increase the cortical porosity. There is a higher incidence of falls resulting from diabetes-related co-morbidities such as diabetic retinopathy, peripheral neuropathy, hypoglycemic episodes and sometimes from the medications. Vitamin D deficiency has special impact on glucose metabolism and the prevalence of diabetes. Vitamin D supplementation in childhood can decrease incidence of type 1 diabetes by 80%. The effect of thiazolidinediones, glucagon-like peptide-1 agonists and metformin, agents for treatment of diabetes open a new connection between bone, carbohydrate and fat metabolism. Orv. Hetil., 2011, 152, 1161–1166.

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294-OR: Type 1 Diabetes Patients with Residual Beta-Cell Function Display Improved Time in Euglycemia and Less Glycaemic Fluctuation after Exercise

Diabetes ◽

10.2337/db19-294-or ◽

2019 ◽

Vol 68 (Supplement 1) ◽

pp. 294-OR

Author(s):

GUY S. TAYLOR ◽

KIERAN SMITH ◽

JADINE SCRAGG ◽

AYAT BASHIR ◽

RICHARD A. ORAM ◽

...

Keyword(s):

Type 1 Diabetes ◽

Beta Cell ◽

Beta Cell Function ◽

Cell Function ◽

Diabetes Patients

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817-P: Financial Stress Factors, Psychological Factors, and Self-Management Outcomes in Emerging Adults with Type 1 Diabetes

Diabetes ◽

10.2337/db20-817-p ◽

2020 ◽

Vol 69 (Supplement 1) ◽

pp. 817-P

Author(s):

JULIA E. BLANCHETTE ◽

VALERIE B. TOLY ◽

JAMIE R. WOOD ◽

CAROL M. MUSIL ◽

DIANA L. MORRIS ◽

...

Keyword(s):

Type 1 Diabetes ◽

Emerging Adults ◽

Psychological Factors ◽

Financial Stress ◽

Stress Factors ◽

Self Management

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Time in range for multiple technologies in type 1 diabetes: a systematic review and network meta-analysis

10.2337/figshare.12116691 ◽

2020 ◽

Author(s):

Anthony Pease ◽

Clement Lo ◽

Arul Earnest ◽

Velislava Kiriakova ◽

Danny Liew ◽

...

Keyword(s):

Systematic Review ◽

Type 1 Diabetes ◽

Closed Loop ◽

Meta Analysis ◽

Management Strategies ◽

Glucose Testing ◽

Closed Loop Systems ◽

Percent Time ◽

Time In Range

Background: Time-in-range is a key glycaemic metric, and comparisons of management technologies for this outcome are critical to guide device selection. Purpose: We conducted a systematic review and network meta-analysis to compare and rank technologies for time in glycaemic ranges. Data sources: We searched All Evidenced Based Medicine Reviews, CINAHL, EMBASE, MEDLINE, MEDLINE In-Process and other non-indexed citations, PROSPERO, PsycINFO, PubMed, and Web of Science until 24 April, 2019. Study selection: We included randomised controlled trials >2 weeks duration comparing technologies for management of type 1 diabetes in adults (>18 years of age), excluding pregnant women. Data extraction: Data were extracted using a predefined template. Outcomes were percent time with sensor glucose levels 3.9–10.0mmol/l (70–180mg/dL), >10.0mmol/L (180mg/dL), and <3.9mmol/L (70mg/dL). Data synthesis: We identified 16,772 publications, of which 14 eligible studies compared eight technologies comprising 1,043 participants. Closed loop systems lead to greater percent time-in-range than any other management strategy and was 17.85 (95% predictive interval [PrI] 7.56–28.14) higher than usual care of multiple daily injections with capillary glucose testing. Closed loop systems ranked best for percent time-in-range or above range utilising surface under the cumulative ranking curve (SUCRA–98.5 and 93.5 respectively). Closed loop systems also ranked highly for time below range (SUCRA–62.2). Limitations: Overall risk of bias ratings were moderate for all outcomes. Certainty of evidence was very low. Conclusions: In the first integrated comparison of multiple management strategies considering time-in-range, we found that the efficacy of closed loop systems appeared better than all other approaches.

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