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Pharmacological and Surgical Interventions to Improve Brain Insulin Resistance
Published in André Kleinridders, Physiological Consequences of Brain Insulin Action, 2023
Linus Haberbosch, Lukas Maurer, Reiner Jumpertz-von Schwartzenberg
GIP is an incretin hormone stimulating insulin secretion and reducing hypoglycemia similar to GLP-1. Outside of the pancreas, GIP receptors (GIPR) are expressed in neurons of hypothalamic nuclei linked to appetite control (62). Recent evidence shows improved glucose metabolism and reduced weight gain in CNS-specific humanized GIPR knockout mice, as indicated by enhanced glucose tolerance and decreased fasting levels of glucose and insulin (63). Conversely, GIP application centrally and peripherally showed similar results in the same study. However, when applied in CNS-specific GIPR knockout mice, the effects of GIP on body weight were lost, but improvements in glucose metabolism were replicated (63). While centrally applied GIP improved glycemic control in central GIPR knockout mice, these data suggest a more important role of peripheral/pancreatic GIP effects on glucose metabolism. GIP analogues have shown some promise in reducing oxidative stress and amyloid plaque load in cortex and hippocampus, indirectly improving brain insulin sensitivity by reverting amyloid mediated receptor desensitization (64), however relevant direct effects have not been demonstrated yet.
Diabetes Mellitus, Obesity, Lipoprotein Disorders and other Metabolic Diseases
Published in John S. Axford, Chris A. O'Callaghan, Medicine for Finals and Beyond, 2023
GLP-1 is an incretin hormone which augments insulin release and inhibits glucagon release from the pancreas. GLP-1 has a short half-life because it is inactivated by proteases including dipeptidyl protease IV. A variety of drugs with GLP-1 receptor agonist activity are licensed for type 2 DM including exenatide, liraglutide, lixisenatide and semaglutide.
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.
Circulating glucagon-like peptide-1 level in patients with liver cirrhosis
Published in Archives of Physiology and Biochemistry, 2023
Masoud Nouri-Vaskeh, Neda Khalili, Amirreza Khalaji, Pouya Behnam, Leila Alizadeh, Sara Ebrahimi, Neda Gilani, Mehdi Mohammadi, Seyed Alisalar Madinehzadeh, Mohammad Zarei
Many studies have reported a higher level of incretin hormones in liver cirrhosis after glucose intake. In a study by Junker et al, GLP-1 levels were higher in cirrhotic patients compared with healthy controls during the first 60 min of oral glucose tolerance test (OGTT) but did not differ from 0 to 240 min. Despite the higher incretin hormones, however, a markedly reduced incretin effect was observed in cirrhotic patients (Junker et al.2015). Also, studies have shown increased GLP-1 serum levels in patients with other chronic inflammatory diseases, such as metabolic syndrome and coronary artery disease, in comparison to healthy individuals (Piotrowski et al.2013, Yamaoka-Tojo et al.2010). Currently, NAFLD is regarded as the hepatic manifestation of metabolic syndrome (Wainwright and Byrne, 2016). On the other hand, some studies have demonstrated a reduced production of incretin hormones in cirrhotic patients in response to glucose intake (Bernsmeier et al.2014, Bozzetto et al.2016). Collectively, no general consensus exists on the levels of GLP-1 and GIP in cirrhotic patients, both their basal plasma level and their postprandial glucose-induced level, and also their potential role in the progression of end-stage liver disease.
Recent advances in proteolytic stability for peptide, protein, and antibody drug discovery
Published in Expert Opinion on Drug Discovery, 2021
Xianyin Lai, Jason Tang, Mohamed E.H. ElSayed
Among the aminopeptidases, DPP4 gained the most attention during peptide drug SAR engineering because it is well known to cleave many biological substrates including growth factors, chemokines, neuropeptides, and vasoactive peptides, leading to loss of their activity in most cases [70]. Specially, DPP4 is responsible for the degradation of incretins such as gastric inhibitory peptide (GIP) and Glucagon-like peptide-1 (GLP-1) that are targets for novel therapies in the pharmaceutical industry [71]. GIP and GLP-1 are incretins that bind to specific receptors on pancreatic beta cells and increases insulin release before blood glucose levels are elevated, delay gastric emptying, and suppress glucagon secretion, having beneficial effects in type 2 diabetes. However, both hormones are rapidly cleared from the blood by DPP4, resulting in a shorter half-life [72].
Late gestational testosterone exposure causes glucose deregulation and elevated cardiac VCAM-1 and DPP-4 activity in rats
Published in Archives of Physiology and Biochemistry, 2021
Taofeek O. Usman, Lawrence A. Olatunji
DPP-4 is a transmembrane glycoprotein that inactivates incretins such as glucagon-like peptide (GLP)-1 and gastric inhibitory peptide (GIP) via cleavage of N-terminal dipeptides (Zhong et al.2013, Mulvihill and Drucker 2014). Both GLP-1 and GIP are rapidly inactivated by DPP-4, which results in their having a short half-life. Incretins such as GLP-1 have been shown to increase insulin secretion and suppress glucagon secretion. Glucose deregulation has been associated with reduced GLP-1 secretion while increased DPP-4 activity has been correlated with impaired glucose homeostasis in type 2 diabetes mellitus (T2DM; Mannucci et al.2005). DPP-4 is also expressed on endothelial cells and plays an important role in the regulation of vascular tone and angiogenesis (Pala and Rotella 2013), while other studies have implicated the DPP-4/incretin axis in the development of cardiovascular diseases. DPP-4 also plays a role in inflammation via activation of NF-κB pathway (Zhong et al.2013) which has also been implicated in the activation of VCAM-1 (Inoue et al.2004). Hence, DPP-4 plays an important part in the development of cardiometabolic disorders.