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Biocatalyzed Synthesis of Antidiabetic Drugs
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
The pancreatic hormone amylin is co-synthesized and co-released with insulin from pancreatic beta-cells, although it is also expressed in the central nervous system, in particular in parts involved in metabolic control, such as the lateral hypo-thalamus (LH) (Boyle et al., 2018). Amylin regulates glucose homeostasis by inhibiting gastric emptying, inhibiting the release of the counter-regulatory hormone glucagon and inducing meal-ending satiety, Chemically, amylin is a polypeptide (37 aminoacid residues) belonging to the calcitonin (CT) family of peptides, which includes CT itself, the CGRPs comprising two variants (αCGRP and βCGRP), adrenomedullin (AM) and AM2 (intermedin) (Bower and Hay, 2016). Anyway, human amylin cannot be used therapeutically because of its tendency to self-associate into toxic amyloid fibrils, which are connected with beta-cell death, so that an analogue, pramlintide (Symlin®, Amylin Pharmaceuticals) was developed by exchanging the corresponding residues of human amylin (Ala-25, Ser-28 and Ser-29) for proline, to afford a more stable and soluble, non-aggregating and yet equipotent peptide in comparison with human amylin (See Fig. 11.5). Structure of human amylin and analogue pramlintide.
Diabetes Mellitus/Anti-DM Pharmacological Management
Published in Mihai V. Putz, New Frontiers in Nanochemistry, 2020
Bogdan Bumbăcilă, Corina Duda-Seiman, Daniel Duda-Seiman, Mihai V. Putz
Amylin, (islet amyloid polypeptide) or diabetes-associated peptide is co-secreted with insulin in the islet of Langerhans of diabetic patients in approximately 1:100, amylin-insulin ratio. Amylin is a small insoluble peptide with a molecular weight of only 3.9 kDa which has a relatively low tissue concentration. Amylin plays a role in glycemic regulation by slowing gastric emptying and promoting satiety. The actions of amylin analogs appear to be synergistic to that of insulin and can significantly reduce body weight, HbA1c values and even the dosage of insulin (Adeghate et al., 2011).
Closed-loop insulin delivery: update on the state of the field and emerging technologies
Published in Expert Review of Medical Devices, 2022
In addition to insulin, secretion of the hormones glucagon and amylin is impaired in people with type 1 diabetes. Glucagon is secreted in response to falling glucose levels and triggers release of glucose stored as glycogen from the liver. Amylin delays gastric emptying and reduces post-prandial hyperglycemic excursions. Dual-hormone systems aim to deliver one of these two hormones in addition to insulin, to further improve glucose control by allowing for more aggressive insulin delivery [108]. Barriers to dual-hormone systems include the need for a second or dual chamber pump, and the risk of gastrointestinal side-effects. Newer glucagon analogues are more stable at room temperature than previously available formulations, enabling continuous infusion without the need for daily set changes [109]. A 7-day study of 10 participants in the home setting using the iLet dual-hormone using dasiglucagon vs insulin-only showed higher time in range with dual-hormone (79% vs 72%), and lower time in hypoglycemia [110]. Amylin’s synthetic analogue pramlintide has been trialed in adult inpatient dual-hormone closed-loop studies, and results showed improvements in time in range compared to insulin-only systems [111]. Larger, pivotal trials of dual-hormone systems are in the pipeline.
Closed-loop control in insulin pumps for type-1 diabetes mellitus: safety and efficacy
Published in Expert Review of Medical Devices, 2020
In type 1 diabetes, insulin-producing pancreatic beta cells are destroyed by an immune-mediated process. Beta and alpha cells produce insulin, amylin, and glucagon, all of which are hormones required to maintain the body’s glucose homeostasis. Prior to insulin therapy, type 1 diabetes was universally fatal. Nowadays, insulin is either replaced with multiple daily injections (MDI) using both short- and long-acting insulins, or by continuous infusion of rapid-acting insulin via an insulin pump. Even with insulin replacement therapy and frequent self-monitoring of blood glucose levels, people with diabetes are at risk of multiple long-term complications if glucose control is suboptimal [1], as well as the immediate risks posed by dangerously low (hypoglycemia) or high (hyperglycemia) glucose levels if insulin is acutely over- or under-dosed.
Closed-loop insulin delivery: current status of diabetes technologies and future prospects
Published in Expert Review of Medical Devices, 2018
Strategies to address the immediate postprandial period by delaying carbohydrate appearance are currently being studied. Amylin is a hormone co-secreted with insulin by the pancreatic beta-cell and is deficient in people with T1D [84]. It delays gastric emptying, inhibits glucagon secretion, and plays a role in achieving satiety, thereby facilitating a reduction in postprandial glycaemic burden [85]. The effects of pramlintide, a synthetic analog of amylin, on postprandial glycaemia have recently been evaluated in small clinical research facility studies [86]. Co-administration with insulin in a CLS has shown a reduction of postprandial glycaemic excursions compared to single-hormone CLS alone [87]. Reported side effects of amylin include nausea and vomiting [88]. Larger studies are still needed to establish efficacy and tolerance in CLS.