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Mahvash Disease
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
Glucagon is a counterregulatory hormone for insulin, which lowers the extracellular glucose (usually stored in the liver as a polymer of glucose molecules or polysaccharide glycogen), and works to raise the concentration of glucose in the bloodstream through its binding to the glucagon receptor (GCGR, a G protein-coupled receptor of 485 aa) located in the plasma membranes of the liver (hepatocytes or liver cells) as well as the kidney, pancreas, heart, brain, and smooth muscle. This activates the stimulatory G protein, and then adenylate cyclase, triggering cAMP production and converting stored polysaccharide glycogen into glucose (i.e., glycogenolysis). After exhaustion of stored glycogen, glucagon promotes synthesis of additional glucose (i.e., gluconeogenesis) in the liver and kidneys. In addition, glucagon may shut off glycolysis in the liver, turning glycolytic intermediates into gluconeogenesis.
Central and Peripheral Modulators of Appetite and Satiety
Published in Emmanuel C. Opara, Sam Dagogo-Jack, Nutrition and Diabetes, 2019
Gabrielle Page-Wilson, Sam Dagogo-Jack
Endogenous GLP-1 abundance can be augmented by inhibition of DPP4. Although oral DPP-4 inhibitors have been shown to improve glycemic control and are approved for the treatment of type 2 diabetes, their effects on body weight are neutral (Amori et al. 2007, Dicker 2011). Recently, efforts have been made to establish GLP-1 and glucagon receptor co-agonists for the treatment of obesity. These compounds harness the lipolytic and thermogenic effects of glucagon, while counteracting glucagon-induced hyperglycemia by the co-administration of GLP-1 (Sanchez-Garrido et al. 2017). In response to promising animal data, showing PEGylated GLP-1 and glucagon receptor co-agonism results in weight loss and improved glucose tolerance in diet-induced obese mice (Day et al. 2009, Clemmensen et al. 2014), early clinical trials in humans are now underway (Sanchez-Garrido et al. 2017).
Mahvash Disease
Published in Dongyou Liu, Tumors and Cancers, 2017
As a counter-regulatory hormone for insulin, which lowers the extracellular glucose (which is usually stored in the liver as a polymer of glucose molecules, or polysaccharide glycogen), glucagon works to raise the concentration of glucose in the bloodstream through its binding to the glucagon receptor (GCGR, a G protein-coupled receptor of 485 amino acids) located in the plasma membranes of hepatocytes (liver cells) as well as in the kidney, pancreas, heart, brain, and smooth muscle. This activates the stimulatory G protein and ten adenylate cyclase, triggering cAMP production and converting stored polysaccharide glycogen into glucose (so-called glycogenolysis). After the exhaustion of stored glycogen, glucagon promotes synthesis of additional glucose (called gluconeogenesis) in the liver and kidneys. In the meantime, glucagon also shuts off glycolysis in the liver, turning glycolytic intermediates into gluconeogenesis [2].
Clinical efficacy and safety of dasiglucagon in severe hypoglycemia associated with patients of type 1 diabetes mellitus: a systematic review and meta-analysis
Published in Expert Review of Clinical Pharmacology, 2023
Sagar Dholariya, Deepak Parchwani, Siddhartha Dutta, Ragini Singh
Recently, the subcutaneous form of aqueous glucagon has been introduced to manage hypoglycemia. Dasiglucagon, a new human glucagon analog peptide, is the leading glucagon medication available in a prefilled syringe or autoinjector as a liquid preparation, developed by Zealand Pharma. Dasiglucagon was approved for the first time by the United States Food and Drug Administration (USFDA) in March 2021 to treat severe hypoglycemia in pediatric and adult diabetic patients [16]. Compared to natural glucagon, dasiglucagon also has 29 amino acids. Still, seven of them with aggression propensity have been replaced (at 17th, 20th, 24th, and 27th positions in glucagon, the natural amino acids arginine, glutamine, glutamine, and methionine are replaced with Alanine, glutamate, lysine, and glutamate, respectively) [17]. Consequently, a decrease in isoelectric pH (pI) from 7.0 to 4.7 and a reduction in the tendency to form fibrils produce dasiglucagon with better solubility and chemical stability [18]. Further, dasiglucagon does not form aggregate after 14 days at 40°C under shaking conditions in accelerated stability experiments, and this stability was additionally validated in a 1-year stability analysis in which the prefilled dasiglucagon syringe was evaluated for aggregate under continuous rotating conditions at room temperature. Therefore, dasiglucagon can be stable at room temperature for up to 1 year [19,20]. In addition, like native glucagon, dasiglucagon specifically activates the liver glucagon receptor and increases blood glucose levels by stimulating liver glycogenolysis [21].
Type 1 diabetes: key drug targets and how they could influence future therapeutics
Published in Expert Opinion on Therapeutic Targets, 2023
Yoon Kook Kim, Kashif M. Munir, Stephen N. Davis
A randomized trial of 21 patients with T1DM receiving a single dose 70 mg of REMD-77, a glucagon receptor antagonist, vs placebo showed a 26% reduction in insulin dose (p = 0.02), and average daily glucose levels 27 mg/dl lower (p < 0.001) in patients treated with REMD-77 [65]. Patients were monitored with continuous glucose monitors and on post-treatment days 6–12, REMD-77 treated patients showed approximately 25% greater time in range and approximately 40% lower time in hyperglycemia, without a difference in hypoglycemia time. No adverse effects were seen with REMD-77, however, the risk of glucagonoma in the setting of long-term glucagon receptor blockade, and the risk of fasting hypoglycemia are unclear in humans. Also, studies with glucagon receptor antagonists in individuals with type 2 diabetes have demonstrated increased hepatic fat and liver enzymes raising caution with this mechanism of treatment [66].
Misrouting of glucagon and stathmin-2 towards lysosomal system of α-cells in glucagon hypersecretion of diabetes
Published in Islets, 2022
Farzad Asadi, Savita Dhanvantari
Our findings indicate that intracellular trafficking of glucagon through the endolysosomal system could be a new regulatory mechanism for glucagon secretion in pancreatic α-cells. In non-diabetic α-cells, glucagon secretion is regulated by several factors, notably by glucose, amino acids and free fatty acids;11,27,28 and the paracrine effectors insulin and somatostatin.9,29,30 Diabetes disrupts this fine regulation of glucagon secretion, resulting in glucagon hypersecretion and aggravation of hyperglycemia. Alterations in the paracrine control of glucagon secretion by insulin and somatostatin result in an abnormal α-cell response to high glucose concentrations, through insulin deficiency, α-cell insulin resistance9,31 or α-cell somatostatin resistance.32 Additionally, hepatic glucagon receptor resistance and impairment of amino acid turnover increases glucagon secretion from α-cells through the liver-α-cell axis.33,34