Major stimuli for insulin secretion include increased serum glucose and some AAs. Activation of cholinergic (muscarinic) receptors also increases insulin secretion, whereas activation of α2-adrenergic receptors inhibits insulin secretion. The gastrointestinal tract releases incretin hormones that stimulate pancreatic insulin secretion. GLP-1 is particularly potent in augmenting glucose-dependent stimulation of insulin secretion (GSIS). GLP-1 is degraded by dipeptidyl peptidase (DPP)-4. DPP-4– resistant GLP-1 analogues and inhibitors of DPP-4 are currently used to increase GSIS in patients with type 2 diabetes.
7.
Insulin binds to the insulin receptor (InsR), which is linked to multiple pathways that mediate the metabolic (Akt kinase) and growth effects (MAPK) of insulin.
8.
During the digestive phase, insulin acts on the liver to promote trapping of glucose as G6P. Insulin also increases glycogenesis, glycolysis, and de novo lipogenesis (DNL) in the liver. Insulin inhibits gluconeogenesis, glycogenolysis, and assembly of lipids into VLDL.
9.
Insulin increases GLUT4-mediated glucose uptake in muscle and adipose tissue.
10.
Insulin increases glycogenesis, glycolysis, and in the presence of caloric excess, lipogenesis in muscle.
11.
Insulin increases glycolysis and generation of G3P in adipocytes. Insulin induces expression of LPL and its transport to the luminal side of capillary endothelial cells. Insulin promotes uptake and activation of FFAs and esterification of fatty acyl CoAs to G3P to form
TG, and it decreases hormone-sensitive lipase activity in adipocytes.
12.
Insulin increases AA uptake and protein synthesis in skeletal muscle but also essentially all insulin target cells. Insulin/Akt kinase signaling activates mTORC1 and S6K to promote synthesis of ribosomal proteins and proteins involved in mRNA translation, as well as other types of proteins. Insulin inhibits proteosomal degradation of protein.
13.
Glucagon is a catabolic counterregulatory hormone. Its secretion increases during periods of food deprivation, and it acts to mobilize nutrient reserves. It also mobilizes glycogen, fat, and even protein.
14.
Glucagon is released in response to decreased serum glucose (and therefore decreased insulin) and increased serum AA levels and β-adrenergic signaling.
15.
Glucagon binds to the glucagon receptor, which is linked to PKA-dependent pathways. The primary target organ for glucagon is the liver. Glucagon increases liver glucose output by increasing glycogenolysis and gluconeogenesis. It increases β-oxidation of fatty acids and ketogenesis.
16.
Glucagon regulates hepatic metabolism both by regulation of gene expression and through posttranslational PKA-dependent pathways.
17.
The major counterregulatory factors in muscle and adipose tissue are the adrenal hormone epinephrine and the sympathetic neurotransmitter norepinephrine. These two factors act through β2-and β3-adrenergic receptors to increase cAMP levels. Epinephrine and norepinephrine enhance glycogenolysis and fatty acyl oxidation in muscle and increase hormone-sensitive lipase in adipose tissue.
18.