Endocrine 1

From Iusmphysiology

• started here on 02/25/11 at 9AM.

• 9:15AM

4i7usU I think this is a real great blog.Thanks Again. Really Great.

Contents 1 Insulin actions 2 Insulin signaling networks 3 Diabetes mellitus 3.1 Type 1 daibetes 3.2 Type 2 diabetes: Resistance 3.3 Diagnosis 3.4 Pathogenesis 3.5 Scope of the problem 3.6 Lifestyle intervention 3.7 Pharma

[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.