Glycemic Control II

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Glycemic Control II
2013-04-01 02:03:26
Pharmacology II Rutgers

For Rutgers P2 students preparing for the second Pharmacology II exam
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  1. AMP-dependent Kinase "AMPK": Structure
    • Heterotrimer = α1β1γ1
    • Detects AMP/ATP in the cell
    • γ-subunit binds AMP, then gets phosphorylated ---> activation of α-subunit
  2. Effects of AMPK Activation
    • 1. Increased glucose uptake (GLUT4 to membrane)
    • 2. Excessive glycogen storage
    • 3. Increased fatty acid oxidation
    • 4. Reduced protein synthesis (Rheb w/ GDP inactivates mTOR)
    • *Senses increased AMP lvls* "Oh, we're using glucose? I guess we better collect some more and replenish our stores. And we should shut down protein synth, so we don't use too much energy."
  3. How Exercise triggers AMPK in muscle
    • Exercise increases the intracellular amount of ATP + AMP
    • ⇧ mitochondrial biogenesis, muscle glycogen, glucose uptake (via GLUT4 and hexokinase)
  4. Effects of long-term training
    • Promotes switch from Fast Glycolytic muscle fibers to Fast Oxidative Glycolytic
    • By upregulating PPARα, PGC-1, UCP-3 and cytochrome c
    • More mitochondria!
  5. Exercise and AMPK in Fat and Liver
    • Exercise increases fatty acid oxidation (AMPK activation via ghrelin required)
    • Increases carnitine palmitoyl transport into the mitochondria
    • Apparently regulates Acetyl CoA Carboxylase and Malonyl CoA Decarboxylase
    • Inhibits HMGR (key in cholesterol and mevalonic acid synthesis)
  6. Acetyl CoA Carboxylase
    • Converts acetyl-CoA to malonyl CoA, which inhibits Carnitine-palmitoyl transferase-1
    • Essentially prevents β-oxidation in Liver and Fat mitchondria
    • Promotes fatty acid synthesis
    • Inactivated by activated AMPKP
  7. Ghrelin Regulation of ACC
    • Works via PLC/IP3/DAG/Ca2+ pathway to phosphorylate (and thus activate) AMPK in liver and fat cells
    • AMPKP can then deactivate ACC, allowing oxidation of fatty acids
    • "Makes you grumble" = orexigenic signals
  8. Carnitine
    • The carrier of fatty acids in fat and liver cells
    • Carries fatty acids from cytoplasm to mitochondria to facilitate fatty acid β-oxidation and the citric acid cycle
  9. Adipokines (leptin & adiponectin)
    • Long term and short term changes to mTOR
    • Leads to inhibition of GTPase by phosphorylating TSC.  This allows Rheb-GTP to activate mTOR
    • Activation of mTOR signals satiety
    • Leptin works synergistically with insulin to regulate mTOR in Proopiomelanocortic neurons
  10. Pathophysiology of Type II DM: per organ
    • Liver: hepatic glucose production does not decrease even after a meal!
    • Skeletal muscle: insulin causes less glucose utilization than normal
    • Pancreatic islet: glucagon levels do not decrease as much as normal in response to a meal, and insulin levels do not increase as much (nor as quickly) as normally.
    • Adipose: insulin does not downregulate lipolysis as much as normal
  11. Pathophysiology of Diabetes: general
    Metabolic disorder: ⇩ carb metabolism, ⇧ protein and lipid metabolism --> hyperglycemia, glucosuria, electrolyte imbalance, sorbital-induced cataracts --> blindness, altered sensation in peripheral nerves

    • Ketosis: ⇩ insulin --> ⇧protein catabolism, nitrogen excretion, gluconeogenesis, lipid & FFA breakdown, ketone bodies
    • Electrolyte imbalance: ⇧GFR, ketone bodies, dehydration, hunger, thirst --> coma
  12. Lispro
    • Human analogue of insulin: transposed lysine and proline in B chain
    • Onset: 0.2-0.5 hours
    • Duration: 3-4 hours
    • Tx: for meals or acute hyperglycemia
  13. Ultralente
    • Human, crystalline suspension
    • Onset: 4-6 hours
    • Duration: 24-36 hours
    • Tx: provide basal insulin and overnight coverage
  14. Aspart
    • Human, switch B28 proline to aspartate
    • Ultrarapid
    • MoA: Prevents self-association --> promotes absorption
  15. Long term insulin analogs
    • Glargine and Detemir
    • MoA: alter pI of insulin = decrease solubility at low pH
    • Slow-release from SC stores
  16. Rapid Acting insulin analogs
    • Lispro, Aspart, Glulisine
    • MoA: reduce multimerization = dimer (lispro), hexamer (aspart)
  17. α-Glucosidase Inhibitors
    • MoA: carbohydrate analogs that competitively inhibit brush border α-glucosidase enzymes; prevent absorption of dietary carbs
    • Examples: Acarbose, Miglitol, Voglibose
    • Tx: postprandial hyperglycemia; mild new-onset patients
    • Monitor serum aminotransferase levels and triglycerides (increase)
    • No risk of hypoglycemia, GI distress goes away after a while 
  18. Insulin Secretagogues
    • MoA: inhibit the β-cell K+/ATP channel at the SUR1 subunit, thus stimulating insulin release
    • First Gen Sulfonylureas: Acetohexamide, Chlorpropamide, Tolazamide, Tolbutamide (risk of hypoglycemia)
    • Second Gen Sulfonylureas: Glimepiride (can cause weight gain)
    • Meglitinides: Nateglinide, Repaglinide (can cause hypoglycemia)
  19. Thiazolidinediones
    • MoA: bind and stimulate the nuclear hormone receptor peroxisome proliferator activated receptor-γ (PPARγ), thus increasing insulin sensitivity in adipose, liver and muscle
    • Examples: Pioglitazone, Rosiglitazone
    • No risk of hypoglycemia, but hepatotoxic~
  20. Biguanides
    • Metformin
    • MoA: activates AMPK to block breakdown of fatty acids and to inhibit hepatic gluconeogenesis and glycogenolysis.
    • Increase glucose uptake and usage by skeletal muscle via AMPK
  21. Peptides
    • Glucagon-like peptide-1 (GLP-1) agonist: Exenatide = enhances glucose-dependent insulin secretion, inhibits glucagon secretion, delays gastric emptying, decreases appetite
    • Glucagon: to increase blood sugar if hypoglycemic
    • Somatostatin analogs: inhibit GHRH release
    • Amylin: acts on brain to slow down glucose uptake from the gut and glycogenolysis
  22. DPP-IV Inhibitors
    MoA: alters incretins (GLP-1 and GIP-1), increasing duration and size of postprandial levels
  23. Thyroid hormone
    • ⇧ BMR, HR, CO, carb & lipid metabolism, protein synth
    • ⇩ insulin sensitivity
  24. Cortisol & Dexamethasone
    • Decrease inflammatory response to β-cells in pancreatic islets
    • Useful for Type I DM