Diabetes pathophysiology: insulin resistance and beta cells

Diabetes pathophysiology

Unhealthy lifestyle: Over-eating, inactivity, obesity

Intraperitoneal cavity accumulates "visceral fat" (Abdominal fat), which is an endocrine organ that secretes:

Inflammatory mediador

Adipokines

Free Fatty Acids (FFAs)

Complex, unclear actions on body tissue

Insulin resistance (liver, muscle, adipose tissue become less responsive to insulin, and thus less able to use glucose as a fuel source)

Initially, beta-cells of the pancreas work overtime to ↑ insulin secretion

Over many years, insulin resstance worsens

Beta cells "tired out"

↓ Insuline secretion (Relative insulin deficiency)

Over many more years: Beta-cells deteriorate until they finnally stop producing insulin (absolute insulin deficit)

Mobilizing triglycerides into FFAs, to be used as fuel by cells

Since cells can´t use glucose, body perceives a state of "starcation"

↓ Insulin secretion

Beta-cells do not recognize hight blood glucose

Lipotoxicity: FFAs inhibit function of GLUT2 on Beta-cells ↓ Glucose import

Genetic Susceptibility Polygenetic or monogenetic factor (MODY) can predispose insulin resistance

Aging: ↓ Beta-cells so tohse predispose insulin resistance.

Medication: Corticosteroids. anti-psychotics etc...

Glucotoxicity: Hyperglycemia is directly toxic to Beta-cells

Hyperglycemia

INSULIN

Insulin initiates its action by binding to a glycoprotein receptor on the surface of the cell. This receptor consists of an alpha-subunit, which binds the hormone, and a beta-subunit, which is an insulin-stimulated, tyrosine-specific protein kinase.

Directly stimulate release of insulin from pancreatic beta cells and thereby lower blood glucose concentrations.

Sulfonylureas and meglitinides

Work by preventing the liver from converting fats and amino-acids into glucose.

Biguanides

↑ Food intake

↓ Incretins GLP-1 GIP and DPP-4

DDP4 inhibitors

Blocking the action of DPP-4, an enzyme which destroys the hormone incretin.

GLP-1 agonist

↑ GLP, who stimulating glucose-dependent insulin release from the pancreatic islets

They bind avidly to peroxisome proliferator-activated receptor gamma in adipocytes to promote adipogenesis and fatty acid uptake

Thiazolidinediones

iSGLT2

SGLT2 inhibitors function through a novel mechanism of reducing renal tubular glucose reabsorption, producing a reduction in blood glucose without stimulating insulin release.

Christopher David Sepúlveda Labrador - Therapeutic Pharmacology

Gut carbohydrate delivery and absorption

They competitively inhibit enzymes that convert complex non-absorbable carbohydrates into simple absorbable carbohydrates.

Alpha glucosidase inhibitors

Paul Robertson, R. & Miriam, S. U. (2021, 14 diciembre). Pathogenesis of type 2 diabetes mellitus. UpToDate. https://www-uptodate-com.wdg.biblio.udg.mx:8443/contents/pathogenesis-of-type-2-diabetes-mellitus?search=fisiopatologia%20diabetes%20mellitus%20tipo%202&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1

Goodman & Gilman Manual de farmacología y terapeútica, 2a edición (2.a ed.). (2022, 9 octubre). MCGRAW HILL EDDUCATION.