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III.3.B.a. Insulin

General effects: Insulin has a pleiotropic effect, which means that it does not act on a specified target organ.

Main effects:

Reduction of blood Glu level:

Glu uptake  ­ (­ = increase)

Glu synthesis (gluconeogenesis: endogenous Glu production - EGP)  ( = decrease),

Glu catabolism (glycolysis)  ­,

Glycogen catabolism (glycogenolysis) .

Reduction in plasma amino acid level:

Amino acid uptake ­,

Protein synthesis ­,

Protein catabolism .

Inhibition of ketone body production (ketogenesis):

FFA in the blood ; less is transported to the liver).

The level of cAMP, a second messenger, is decreased.

Proglucagon gene expression is inhibited.

Increased Na+ reabsorption in the proximal and distal tubules of the kidney.

In addition to the general effects, insulin exerts effects on 3 main target tissues: the adipose and muscle tissues and the hepatic cells.

In the adipocytes:

GLUT-4 mobilization into the plasma membrane

GLUT-4 is translocated into the cell membrane, where GLUT-1 transporters are permanently present. The GLUT-4 transporters are mobilized from intracellular membrane storage sites (vesicles) to the plasma membrane by insulin stimulation, which enhances the uptake of Glu in the adipocytes.

Reduction of FFA release:

TG synthesis ­.

Increased FFA synthesis:

fat catabolism (lipolysis) .

The enzyme protein kinase C (PKC) and inositol-3-phosphate (IP3) are second messengers of cell signaling. In the lack of insulin, their functions are impaired.

Muscle

GLUT-4 translocation into the cell membrane:

Glu uptake ­,

Glycogen synthesis (glycogenesis) ­.

In the muscle, there are insulin-independent GLUT-4 transporters, which provide the energy source (by Glu uptake) for muscle contraction. The amount of the GLUT-4 transporter in the cell membrane is increased by insulin, and the Glu uptake is therefore increased. Because of the presence of insulin-independent GLUT-4 transporters in the skeletal muscle, DM patients taking part in sports or physical activity must pay more attention to the dose of insulin. In the event of increased physical activity, it is important to decrease the dose of insulin.     

amino acid uptake ­,

muscle protein synthesis ­,

K+ uptake ­.

Liver

The Glu transport is in the liver insulin-independent (also in some neurons, the brain capillaries, the small intestine, the renal tubules and the red blood cells).

The metabolic pathways in the liver are regulated by insulin:

glycogen synthesis (glycogenesis) ­,

glycogen breakdown (glycogenolysis) ,

Glu synthesis (gluconeogenesis) ,

fatty acid synthesis from Glu (lipogenesis) ­,

ketone body synthesis (ketogenesis).

The Glu release is reduced and the Glu uptake is increased in the liver by changed metabolic pathways because of the altered Glu concentration.