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Biocatalyzed Synthesis of Antidiabetic Drugs
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Incretins are gut hormones that potentiate insulin secretion after meal ingestion in a glucose-dependent manner (Campbell and Drucker, 2013). The incretin effect, a term that refers to the observation that orally administered glucose results in a larger increase in plasma insulin levels and insulin-dependent decrease in blood glucose concentration when compared to the same amount of glucose given intravenously (Rondas et al., 2013), is responsible for 50%-70% insulin production. The two best studied incretins are glucose-dependent insulinotropic polypeptide (also named gastric inhibitory polypeptide, GIP), a 42 amino acid peptide synthesized in and secreted from enteroendocrine K cells located primarily in the duodenum and proximal jejunum, although CNS production of GIP has also been described);glucagon-like peptide-1 (GLP-1) a 30 amino acid residue peptide, originated from preproglucagon, synthesized in the l-cells in the distal ileum, in the pancreas and in the brain.
Diabetes and Antidiabetic Therapy: Control of Glucose
Published in Richard J. Sundberg, The Chemical Century, 2017
There are other polypeptide hormones besides insulin involved in glucose regulation. The α cells in the pancreas produce glucagon, a 29-amino acid polypeptide, which controls glucose production in the liver. In normal subjects, glucagon causes the liver to break down glucose stored as the polymer glycogen. The glucose level is kept in balance by regulation of endogenous glucose production and glucose use, especially by the brain. Ingestion of carbohydrates causes the glucose level to increase and results in increased insulin production and suppresses glucagon secretion. Under high glucose levels other organs such as the heart, muscle, and adipose tissue increase glucose use. There is another mechanism for glucose control that involves polypeptide hormones formed primarily in the small intestines. One is called glucagon-like peptide-1 (GLP-1). Another is glucose-dependent insulinotropic peptide (GIP). These and related peptides are called incretins. The incretins effect the release of insulin in response to ingested glucose. They serve to connect insulin release to eating and are more sensitive to oral glucose intake than to the level of glucose in the blood. Attempts to use incretin analogs in therapy of diabetes are discussed in Section 16.4.7. These relationships are summarized in Figure 16.4.
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
Two classes of incretin-based therapy have been developed to overcome the clinical limitations of native GLP-1: GLP-1 receptor agonists (e.g., liraglutide, and exenatide), which exhibit increased resistance to DPP-4 degradation and thus provide pharmacological levels of GLP-1, and DPP-4 inhibitors (e.g., sitagliptin, vildagliptin, saxagliptin), which reduce endogenous GLP-1 degradation, thereby providing physiological levels of GLP-1 (Garber, 2011).
Toxicological and pharmacokinetic properties of sucralose-6-acetate and its parent sucralose: in vitro screening assays
Published in Journal of Toxicology and Environmental Health, Part B, 2023
Susan S. Schiffman, Elizabeth H. Scholl, Terrence S. Furey, H. Troy Nagle
Consumption of sucralose was noted to alter glucose and/or insulin concentrations in the plasma of some human subjects when delivered in liquids or capsules (Lertrit et al. 2018; Méndez-García et al. 2022; Pepino et al. 2013; Romo-Romo et al. 2018; Schiffman and Rother 2013; Suez et al. 2022) and when accompanied by carbohydrate (Dalenberg et al. 2020) or another non-caloric sweetener (Young et al. 2017). Maternal ingestion of sucralose during pregnancy impacted the progeny’s metabolism including downregulation of hepatic detoxification mechanisms and changes in bacterial metabolites (Olivier-Van Stichelen, Rother, and Hanover 2019). Additional studies reported that sucralose might affect incretin hormones including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) as well as the sodium-dependent glucose co‑transporter‑1 (SGLT‑1) (Kreuch et al. 2018; Lertrit et al. 2018; Margolskee et al. 2007; Sun et al. 2017; Young et al. 2017). Further, sucralose was demonstrated to blunt thyroid function (Pałkowska-Goździk, Bigos, and Rosołowska-Huszcz 2018). Chronic sucralose ingestion at levels that have regulatory approval in the United States and Europe also modify the fecal metabolome (Bian et al. 2017), liver proteome (Liu et al. 2019), and induce the expression of two intestinal proteins involved in first-pass metabolism, specifically P-glycoprotein (P-gp) and cytochrome P450 (CYP3A4) (Abou-Donia et al. 2008).
Closed-loop insulin delivery: update on the state of the field and emerging technologies
Published in Expert Review of Medical Devices, 2022
Other adjunctive therapies have been introduced to optimize glycemic control. Glucagon-like peptide-1 (GLP-1) is an incretin hormone that increases satiety, slows gastric emptying and suppresses glucagon release. Initial small inpatient studies of GLP-1 use with fully closed-loop therapy seemed promising, but there have been no recent larger studies to evaluate outpatient efficacy [112]. Sodium-glucose co-transporter (SGLT2) inhibitors lower plasma glucose by blocking renal reabsorption and increasing renal excretion of glucose in an insulin-independent manner. Data on SGLT2 as an adjuvant in closed-loop therapy is limited, but results from a recent inpatient study in young adults using fully closed-loop with dapagliflozin were promising with no signs of hypoglycemia or ketosis [113]. Hybrid closed-loop with empagliflozin and simple meal announcement was non-inferior to hybrid closed-loop with carbohydrate counting (and no empagliflozin) in 30 adults on two days in another recent study [114]. Unfortunately, SGLT2s are no longer authorized for treatment of type 1 diabetes [115].
A dipyrrole derivative from Aloe vera inhibits an anti-diabetic drug target Dipeptidyl Peptidase (DPP)-IV in vitro
Published in Preparative Biochemistry & Biotechnology, 2020
C. Prasannaraja, A. S. Kamalanathan, M. A. Vijayalakshmi, Krishnan Venkataraman
Understanding the mechanism of pancreatic rejuvenation has increased considerably upon discovery of incretins such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), which helps in maintaining glucose homeostasis (i.e., incretin effect) with increased β-cell mass and function.[5] GLP-1, is a glucose-dependent insulinotropic gut hormone, secreted by the intestinal L-cells that stimulate insulin secretion.[6] However, it is rapidly degraded by the ubiquitous proteolytic enzyme DPP-IV. Patients with type 2 diabetes have increased DPP-IV enzyme activity[7] and thus, inhibition of DPP-IV, the enzyme that makes GLP-1 biologically inactive, enhances the incretin effect and is considered as one of the targets for the treatment of T2DM.[8] Oral administration of synthetic DPP-IV inhibitors to type 2 diabetic patients effectively reduced glycated hemoglobin levels.[9] The synthetic DPP-IV inhibitors currently in use have very few side effects, however, the durability and long-term safety needs to be established.[10] Several food derived peptides and small molecules have been characterized for their anti-diabetic activity[11,12] and many of them have been identified and found to act as promising DPP-IV inhibitors, potentially contributing to glycemic control.[13–16]