Endocrine 1

From Iusmphysiology

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  • started here on 02/25/11 at 9AM.


  • 9:15AM


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Contents

[edit] Insulin actions

  • LIver
    • Increases lipid, glycogen, and protein syn
    • Stops glycogenolysis
    • Increases glucose uptake (glut4)
  • Muscle
    • Increases glucose uptake (glut4)
  • Adipose tissue
    • Increases fat production and storage

[edit] Insulin signaling networks

  • Insulin receptor:
    • Tetrameric: alpha, alpha, beta, beta
    • Binds, activates kinase activity
    • Autophoses to increase kinase activity
    • Phoses stuff to activate and deactivate.
    • Deactivates gene expression and growth
    • Activates glycogen synthesis, protein synthesis, anti-apop, and anti-lypolysis
  • We're looking all the way down stream to find out what's broken in insulin-resistant states.

[edit] Diabetes mellitus

  • Type 1: failure to make insulin b/c beta cells are killed by auto immune response
    • 5-10%
  • Type 2: Insulin improperly used; resistance combined with deficiency in production
  • Gestational diabetes:
  • Prediabetes: lots of people.

[edit] Type 1 daibetes

  • Beta cell mass has decreased.
  • Some event causes an immune response.
  • Average diagnosis age = 7-8
    • Because they have to lose their beta cell mass before symptoms show up.
  • At first the glucose can be normal.
  • Then c protein ...
  • So we given them insulin
    • Shots, pumps, etc.
    • Pumps are the best regulators.
  • We'd like to use transplantation
    • Mixed success

[edit] Type 2 diabetes: Resistance

  • A given amount of glucose intake requires a larger amount of insulin release to maintain blood glucose regulation.
  • Mutations of the insulin receptor are rare; think leprochonism.
  • Metabolic syndrome:
    • Hyperlipidemia
    • Cardiovascular disease
    • Glucose abnormalities
    • 3 of 4 diabetes die of a vascular complication
  • Even normal people have periods of insulin resistance; normally the pancreas compensates.
    • For example, cortisol can cause these periods.
  • In type 2, eventually the beta cells go from highly overcompensating and then die.

[edit] Diagnosis

  • Fasting plasma glucose test
    • Have them fast
    • Then have them come in and measure their plasma glucose.
    • Normal < 99 mg/dl
    • Pre = 100-125
    • T2DM > 126 mg / dl
  • YOu can also do a glucose tolerance test
    • Drink lots of glucose
    • NOrm < 139
    • Pre = 140-199
    • T2DM > 200

[edit] Pathogenesis

  • Turns out it isn't the insulin receptor.
  • In all the studies, we do see that an inflammatory response and lipid overload can wreak havoc on glucose regulation.
    • They increase some bad serine kinases that phos the receptor to arrest the kinase ability and thus the decrease.
  • Even high insulin can cause resistance to insulin.
  • Hyperglycemia increases resistance at muscle and fat.
  • Dyslipidemia occurs:
    • Decreased HDL
    • Increased TAGS
    • Increased Small, dense LDLs
  • We also see increased blood pressure and coronary artery disease.
  • Circulatory system damage, renal failure, neuropathy, retinopathy.

[edit] Scope of the problem

  • Awareness of diabetes is going up but incidence is too.
  • Obesity is a huge risk factor for diabetes.

[edit] Lifestyle intervention

  • Educate the pt so they can take care of themselves.
  • Explain why exercise works.
  • Explain why other foods are better.

[edit] Pharma

  • B/c insulin resistance can be caused by many things, we have to treat in many different ways: change the lipids, change the receptor, change signaling pathways, etc.
  • Sulfonylurea
    • Subclasses: meglitinides, nateglinides
    • Enhance insulin secretion
    • 1950s
    • Work on beta cells on a potassium channel to cause polarization to increase Ca influx to increase vescicular release.
  • Guanines
    • Work on liver
    • Favorite of physicians
    • Metformin
    • Works best...for a while
    • Increases liver sensitivity to insulin
    • Prevents glycogen breakdown by inhibiting glucagon response
  • Alpha glucosidases
    • Inhibit ?
  • Thiazolidinediones
    • Increase sensitivity of muslc eand adipose to insulin
  • GLP1 is an encrenton
    • Has a very short halflife
    • Degraded by DPP4
    • Lizard spit has a glp-like protein that isn't degraded by dpp4
    • Mimetics (byetta) is now given to pts.
  • Jenuvia
    • Dpp4 inhibitor


  • stopped here on 02/25/11 at 10AM.
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