Insulin degludec/liraglutide (IDegLira) is a fixed-ratio combination (FRC) of basal insulin and glucagon-like protein-1 receptor agonist (GLP-1 RA) that has demonstrated glycemic and metabolic benefits in patients with type 2 diabetes mellitus (T2DM) in both randomized controlled trials and real-world studies.
A synthetic monomeric peptide triple receptor agonist, termed "Triagonist" that incorporates glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP) and glucagon (Gcg) actions, was previously developed to improve upon metabolic and glucose regulatory benefits of single and dual receptor agonists in rodent models of diet-induced obesity and type 2 diabetes.
Cardiovascular outcome trials (eg, LEADER [Liraglutide Effect and Action in Diabetes Evaluation of Cardiovascular Outcome Results], SUSTAIN-6) demonstrated that GLP-1 (glucagon-like peptide 1) analogs including liraglutide reduce the risk of cardiovascular events in type 2 diabetes mellitus.
However, GIP stimulates glucagon secretion even at hyperglycemia in people with T2D, suggesting that inappropriate GIPR activity in α-cells contributes to the pathogenesis of T2D.
Effects of sequential treatment with lixisenatide, insulin glargine, or their combination on meal-related glycaemic excursions, insulin and glucagon secretion, and gastric emptying in patients with type 2 diabetes.
Our hypothesis was that variants in CCK, GLP-1, and TCF7L2 (transcription factor 7-like 2 locus), which is associated with greatest genetic risk for development of type 2 diabetes mellitus, are associated with GE and independently with glucose tolerance.
Eight weeks after liraglutide or human umbilical cord mesenchymal stem cell administration, FPG, HbA<sub>1c</sub> , glucagon, body weight, and pancreatic ASK1, JNK, and BAX mRNA and proteins were significantly decreased, and the levels of serum C-p, INS and GLP-1, ratio of insulin positive area, and Bcl-2 expression were significantly increased in three treatment groups compared with T2DM group (P<.05).
This overview outlines and discusses the impaired insulin responses to GIP as well as the effect of GIP on glucagon secretion and the potential involvement of GIP in obesity and bone disease associated with type 2 diabetes.
Contrary to GLP-1, the development of effective GIP-based T2D treatments has been hindered by poor bioavailability and attenuation of beta cell responses to GIP in some patients with sub-optimally controlled T2D.
Whilst such effects of GIP antagonism are yet to be evaluated in humans, recent studies using combined GIP and GLP-1 agonists have shown weight reduction and improved glycaemic control in people with type 2 diabetes (T2D).
Exposure of the small and large intestine to bile acids induces GLP-1 secretion, modulates the composition of the gut microbiota, and reduces postprandial blood glucose excursions in humans with and without T2DM.
Glucagon-like peptide-1 (GLP-1) and strategies based on this blood sugar-reducing and appetite-suppressing hormone are used to treat obesity and type-2 diabetes.
In line with this, the insulinotropic effects of GIP and GLP-1 are impaired in patients with type 2 diabetes, even when administered in supraphysiological doses.
Nevertheless, prior animal and human studies on incretin mimetics, glucagon like peptide-1 receptor agonists (GLP-1 RA) approved for T2DM treatment, have provided indirect evidence that they may also ameliorate NAFLD/NASH, whereas dipeptidyl dipeptidase-4 inhibitors (DDP-4i) were not better than placebo in reducing liver fat in T2DM patients with NAFLD.
Among the gastrointestinal hormones, the incretins: glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 have attracted interest because of their importance for the development and therapy of type 2 diabetes and obesity.
Both GLP-1 and GIP are substrates of the enzyme dipeptidyl peptidase-4 (DPP-4), and DPP-4 inhibitors, which potentiate their effects on glycaemic control, are now used to treat type 2 diabetes (T2D).
Polyagonist peptides that exert agonism at GIP, GLP-1 and glucagon receptors are also under investigation as potential treatments for obese type 2 diabetes.