Insulin secretion is stimulated by increased serum glucose and certain amino acids, as well as activation of cholinergic receptors. Conversely, insulin secretion is inhibited by activation of α2-adrenergic receptors. The release of incretin hormones from the gastrointestinal tract also promotes pancreatic insulin secretion. GLP-1, a type of incretin hormone, is particularly effective in enhancing glucose-dependent stimulation of insulin secretion. However, GLP-1 is broken down by dipeptidyl peptidase-4 (DPP-4). Currently, DPP-4-resistant GLP-1 analogues and DPP-4 inhibitors are used to increase glucose-dependent stimulation of insulin secretion in patients with type 2 diabetes.

Insulin binds to the insulin receptor (InsR), which is connected to multiple pathways responsible for mediating the metabolic effects (Akt kinase) and growth effects (MAPK) of insulin.

During the digestive phase, insulin acts on the liver to facilitate the conversion of glucose into glycogen-6-phosphate (G6P). Additionally, insulin promotes glycogenesis, glycolysis, and de novo lipogenesis (DNL) in the liver. On the other hand, insulin inhibits gluconeogenesis, glycogenolysis, and the formation of very low-density lipoproteins (VLDL) from lipids.

In muscle and adipose tissue, insulin enhances glucose uptake mediated by the GLUT4 transporter.

In muscle, insulin increases glycogenesis, glycolysis, and, in the presence of excess calories, lipogenesis.

In adipocytes, insulin increases glycolysis and the production of glycerol-3-phosphate (G3P). Insulin also induces the expression of lipoprotein lipase (LPL) and its transportation to the luminal side of capillary endothelial cells. Furthermore, insulin promotes the uptake and activation of free fatty acids (FFAs) and the esterification of fatty acyl CoAs to G3P, leading to the formation of triglycerides (TG). Additionally, insulin decreases the activity of hormone-sensitive lipase in adipocytes.

Insulin enhances the uptake of amino acids (AAs) and protein synthesis, not only in skeletal muscle but also in all insulin target cells. The insulin/Akt kinase signaling pathway activates mTORC1 and S6K, promoting the synthesis of ribosomal proteins, proteins involved in mRNA translation, and other types of proteins. Insulin also inhibits the proteasomal degradation of proteins.

Glucagon, a counterregulatory hormone, functions as a catabolic hormone that is released during periods of food deprivation to mobilize nutrient reserves. It facilitates the mobilization of glycogen, fat, and even protein.

Glucagon is released in response to decreased serum glucose levels (resulting in decreased insulin) and increased serum amino acid levels, as well as β-adrenergic signaling.

Glucagon binds to the glucagon receptor, which is connected to pathways dependent on protein kinase A (PKA). The liver is the primary target organ for glucagon. Glucagon promotes the production of glucose in the liver by increasing glycogenolysis and gluconeogenesis. It also enhances the oxidation of fatty acids and ketone body synthesis (ketogenesis).

Glucagon regulates hepatic metabolism through the regulation of gene expression and posttranslational pathways that are dependent on PKA.

Epinephrine and norepinephrine, hormones released from the adrenal glands and sympathetic neurons, respectively, act as major counterregulatory factors in muscle and adipose tissue. They exert their effects through β2- and β3-adrenergic receptors, increasing cyclic adenosine monophosphate (cAMP) levels. Epinephrine and norepinephrine enhance glycogenolysis and fatty acyl oxidation in muscle, as well as increase the activity of hormone-sensitive lipase in adipose tissue.
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.