Insulin and Diabetes Part 1 Flashcards
Criteria for diagnosing diabetes?
- A1C over 6.5%
- Fasting Plasma Glucose over 126 mg/dL
- 2h plasma glucose over 200 mg/dL during OGTT
- Random plasma glucose over 200 mg/dL
Who gets Type 1?
Early age (mean=12) usually, but can show up in adults
family history often negative
Maybe triggered by viruses, chemicals, etc. in predisposed
Two types of non insulin dependent DM? Who gets them?
Non-obese – Under 25, MODY
Obese – Over age 35 (AODM)
Three effects of hyperglycemia caused by a lack of insulin
- Low glucose uptake
- low glycogen synthesis
- More conversion of AA to Glu
Goals of diabetes treatment
HbA1c below 7 (ideally 6)
Keep blood glucose below 150 mg/dL
Prevent/Delay complications
Main studied (first slide…) method that hyperglycemia may cause damage
- Oxidation products with glu react irreversibly with proteins to form Advanced Glycation End-products. These may lack normal protein function and accelerate the aging process. Example - Crystalin + Glu –> Cataracts
Pathway proposed for why hyperglycemia damages nerves
POLYOL PATHWAY
Aldose reductase pathway depletes nerves of NADPH, increasing vulnerability to Oxygen radicals
Other than the polyol pathway, what other pathways are upregulared with hyperglycemia and may lead to increased protein modification
Hexosamine pathway
OKC Pathway
AGE Pathway
What are the parts of the Insulin receptor? What do they do?
alpha – suppresses beta till insulin binds
beta – tyrosine kinase (autophos)
How does insulin receptor upregulate Glut4
- IRS –> P13K –> PKB –> GLUT4
2. IRS –> P13K –> PDK1 –> aPKC –> GLUT4
Insulin effects on the liver
Inhibits – glycogenolysis, ketogenesis, gluconeogenesis
Stimulates – Glycogen and triglyceride synth
Insulin effects on the skeletal muscle
Stimulates glucose+AA transport
Insulin effects on adipose tissue
Stimulates triglyceride storage + glucose transport
Where does glucose go when fasting
75% non-dependent – Liver, GI, brain
25% dependent – Skeletal Musc
Where does glucose go when fed
80-85% dependent – skeletal muscle
4-5% – dependent – adipose (inhibits FFA release, low FFA enhances action on skeletal muscle)
Important details on the 4 GluTs
1 – widely expressed
2 – beta cells, liver. High Km
3 – Neurons
4 – Insulin Induced, Skeletal muscle+Adipocytes
Action of Amylin
Co-secreted with insulin
Slows gastric emptying, decreases food intake
Inhibits glucagon secretion
In secretory granules, Insulin is cleaves by…
Proconvertases
Human insulin cDNA is expressed in…
E. Coli – Humulin
Yeast – Novolin
Three main Ultra Rapid Onset/Very short action insulins
Lispro
Aspart
Glulisine
Insulin preparation with Intermediate onset and action?
NPH
Insulin preparation with slow onset and long action (basal insulins)
Glargine, Detemir, Degludec
How does NPH (Neutral Protamine Hagedorn) insulin work?
Bunch of insulin is bound to a protamine.
Over time tissue proteases chew up the protamine to release the insulin.
Only (non-regular) insulin product that is unmodified
What is Lispro?
Insulin with a reversal of P28 and K29 that decreases self association. This will decrease complex formation and make it faster acting.
