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Diabetes, Universidad de Guadalajara Centro Universitario de Ciencias de…

- - - - β-cells possess glucose transporters (GLUT 2), which allow glucose to enter them.
        
        Glucokinase phosphorylates glucose and converts it to glucose-6-phosphate.
        
        Glucose-6-phosphate is oxidized to adenosine triphosphate (ATP), which inhibits the cell's ATP-sensitive potassium channels.
        
        The closure of potassium channels depolarizes the cell membrane, which opens voltage-gated calcium channels, bringing calcium into the cell.
        
        Calcium stimulates the fusion of insulin-containing vesicles with the cell membrane and secretion of the hormone into the extracellular fluid by exocytosis.
  - - - Tyrosine kinase triggers a cellular phosphorylation cascade that increases or decreases the activity of various enzymes, including insulin receptor substrates, involved in effects on glucose, lipid and protein metabolism.
  - - - It favors the uptake and muscle metabolism of glucose, because the muscle consumes a lot of glucose during moderate and intense exercise or in the 2 hours after meals.
      - Facilitates membrane transport of glucose.
      - It facilitates the uptake, storage and utilization of glucose by the liver.
        
        After a meal, insulin increases hepatic glycogen synthesis.
        
        Unused glucose is stored
    - - Insulin promotes lipid synthesis and deposition by increasing glucose utilization in almost all organ tissues and reducing fat utilization.
      - Insulin deficiency increases fat utilization for energy purposes, because insulin deficiency increases plasma concentrations of cholesterol and phospholipids, as well as because exaggerated fat consumption during insulin deficiency causes ketosis and acidosis.
    - - Insulin facilitates protein synthesis and deposition and inhibits protein degradation by stimulating the transport of many amino acids into cells, increasing the translation of messenger RNA and inhibiting protein catabolism.
      - Insulin deficiency causes protein decrease and amino acid increase in plasma, because protein deposition is almost completely interrupted, protein catabolism increases and protein synthesis ceases.
      - Insulin and growth hormone act synergistically to promote growth, since the administration of growth hormone or insulin, each separately, hardly promotes growth, however, the combination of both induces spectacular growth.
- - - - Which are:
        
        Metformin - Today it is the drug of choice to treat every patient with diabetes mellitus from the time of diagnosis.
        
        Phenformin - antidiabetic withdrawn from the market in several countries due to the diversity of toxic effects(lactic acids in bloodstream), with no evidence of long-term benefit.
        
        Proguanil - an antimalarial drug.
    - - Metformin is transported by OCT-1 receptors, inhibiting the mitochondrial respiratory chain over complex 1.
        
        Generating an energy deficit that leads to a reduction in energy consumption, which translates into less glycogenesis through several pathways.
        
        ATP decreases due to increased AMP.
        
        ATP decreases by increasing AMP, cAMP inhibits Protein Kinase A (PKA) signaling, through the suppression of Adenylate Cyclase (AC), a pathway responsible for activating nuclear transcription of gluconeogenesis.
        It allosterically activates AMPK which has regulatory activity on the lipid pathway, but also on gluconeogenesis.
        
        Suppression of gluconeogenesis
        
        The suppression of gluconeogenesis is due to the suppression of the isoform of Dihydroxyacetone Dehydrogenase (mGDP), which increases the conversion of Glycerol-3-Phosphate (G3P) to Dihydroxyacetone phosphate. This leads to a decrease in the gluconegenic pathway.
  - - - They increase insulin release by the pancreas.
        
        Insulin release from β-cells of the pancreas: Sulfonylureas bind to an ATP-sensitive potassium receptor on the β-cell making the effect of glucose metabolism more potent.
        
        Decreased serum glucagon concentrations: Long-term administration decreases serum glucagon concentrations, which may contribute to the hypoglycemic effect of the drugs.
    - - 1st Generation
        
        ▪ Acetohexamide
        
        ▪ Chlorpropamide
        
        ▪ Tolbutamide
        
        ▪ Tolazamide
      - 2nd Generation
        
        ▪ Glipizide
        
        ▪ Gliclazide
        
        ▪ Glibenclamide (glyburide)
        
        ▪ Gliquidone
        
        ▪ Glimepiride
  - - - Agonists of gamma receptors that activate peroxisome proliferation ( PPAR -y).
        
        The discrepancy between the two types of thiazolidinediones lies in their side chains, these translate into discrepancies in their metabolic action.
        
        Pioglitazone
        
        The presence of food in the stomach may delay its uptake, but does not affect its overall bioavailability.
        
        It is metabolized by CYP2C8 and CYP3A4 in the liver.
        
        It reduces triglycerides more markedly than rosiglitazone.
        
        Rosiglitazone
        
        Rapidly absorbed and protein-bound.
        
        Metabolized in the liver, by CYP2C8.
        
        Implies a higher cardiovascular risk than pioglitazone.
  - - - Miglitol
      - Acarbose
    - - Inhibits maltases, saccharases, dextrinases and glucoamylases that hydrolyze oligosaccharides to disaccharides and monosaccharides that are subsequently absorbed.
        
        Generates a delay in the absorption of complex polysaccharides.
        
        Increases the release of glucagon-like peptide (GLP-1) leading to insulin secretion.
  - - - Florizin
      - Dapagliflozin