Jamen Cannon

Background. Type 1 diabetes (T1D) is an autoimmune disorder in which the immune system attacks the β-cells of the pancreas¹. These cells are responsible for insulin production, which lowers blood glucose levels, in part, by increasing cellular glucose uptake, increasing glycogenesis, decreasing glycogenolysis and gluconeogenesis, and inhibiting Glucagon secretion by the a-cells of the pancreas^2,3. The β-cells also produce amylin, which slows gastric emptying, increases satiety after mealtimes, and inhibits the release of Glucagon⁴. The dysregulation of these hormones can lead to poor control of blood glucose, potentially causing serious comorbidities such as retinopathy, nephropathy, and polyneuropathies¹. T1D treatment has recently shifted to a system known as an ‘Artificial Pancreas,’ which uses continuous measurement of interstitial-fluid glucose and an algorithm to deliver insulin with minimal human intervention⁷. This methodology results in a better control of glucose than with traditional treatment modalities. While these systems show promise in the treatment of T1D, they fail to address deficiencies in amylin and glucagon dysregulation in patients with T1D. Addressing these deficiencies has the potential to better control glucose levels.

Methods. A literature search was performed on PubMed using keyword: “Artificial Pancreas”, “Glucagon Dual Hormone Closed Loop System”, and “Amylin Dual Hormone Closed Loop System”. These searches contributed 10 articles to this abstract. Literature was accepted from peer-reviewed journals or textbooks published within 10 years that are relevant to the subject.

Results. Multiple trials have been performed to assess DHCLs utilizing glucagon and amylin. These trials returned mixed results – trials using glucagon DHCLs found that an algorithm-controlled glucagon system helped prevent hypoglycemia following moderate exercise in adult patients, but may increase hyperglycemic events when exercise was not included ^8,9. However, another trial in adolescent patients found that using a glucagon DHCL resulted in worse glucose control, with less time in the optimal glucose range¹⁰. These differences may be explained by patient demographics, emphasis on exercise, and technical challenges in each trial. One common technical difficulty faced was clogging of glucagon lines, due to glucagon’s instability in liquid formulation. Studies utilizing amylin found that using a DHCL improved glucose control compared to insulin alone, but also produced mild GI side effects that may be a barrier to clinical adaptation⁴.

Conclusions. DHCLs show significant promise in the treatment of T1D, but several challenges must be overcome, including development of a liquid stable glucagon formulation and collection of more data on glucagon and amylin DHCL’s to develop a dosing algorithm.

Works Cited

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2. Linda S. Costanzo. Endocrine Physiology. In: Board Review Series Physiology. 8th ed. WOLTERS KLUWER business; 2023:224-268. Accessed March 23, 2024. https://brs.lwwhealthlibrary.com/content.aspx?sectionid=253004167&bookid=3207#253004355
3. Asfour, Ghaid. Human Physiology. In: Glucose Regulation. Accessed April 16, 2024. https://books.lib.uoguelph.ca/human-physiology/chapter/glucose-regulation-3/
4. Haidar A, Tsoukas MA, Bernier-Twardy S, et al. A Novel Dual-Hormone Insulin-and-Pramlintide Artificial Pancreas for Type 1 Diabetes: A Randomized Controlled Crossover Trial. Diabetes care. 2020;43(3):597-606. doi:10.2337/dc19-1922
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7. Nwokolo M, Hovorka R. The Artificial Pancreas and Type 1 Diabetes. J clin endocrinol metab. 2023;108(7):1614-1623. doi:10.1210/clinem/dgad068
8. Castle JR, El Youssef J, Wilson LM, et al. Randomized Outpatient Trial of Single- and Dual-Hormone Closed-Loop Systems That Adapt to Exercise Using Wearable Sensors. Diabetes care. 2018;41(7):1471-1477. doi:10.2337/dc18-0228
9. Wilson LM, Jacobs PG, Ramsey KL, et al. Dual-Hormone Closed-Loop System Using a Liquid Stable Glucagon Formulation Versus Insulin-Only Closed-Loop System Compared With a Predictive Low Glucose Suspend System: An Open-Label, Outpatient, Single-Center, Crossover, Randomized Controlled Trial. Diabetes care. 2020;43(11):2721-2729. doi:10.2337/dc19-2267
10. Lindkvist EB, Laugesen C, Reenberg AT, et al. Performance of a dual-hormone closed-loop system versus insulin-only closed-loop system in adolescents with type 1 diabetes. A single-blind, randomized, controlled, crossover trial. Front endocrinol. 2023;14. doi:10.3389/fendo.2023.1073388