M2 - Lect 11 - Type 1 Diabetes

Question 1

Goal of Anti-Diabetic Therapies

Answer 1

to achieve glycated hemoglobin levels ≤7%

Question 2

What happens if you don’t take insulin?

Answer 2

Hyperglycemia

Diabetic ketoacidosis

Question 3

Insulin has a natural tendency

to self-associate and form

Answer 3

hexamers

Question 4

Regular Insulin (R, Toronto)

Answer 4

• Recombinant DNA technology from the human
  proinsulin gene (significantly reduced antigenicity)
  – Short acting insulin (administer ~30 min before
  having a meal)
  – Clear solution

Question 5

Neutral Protamine Hagedorn (NPH or N)

Answer 5

– Produced by adding protamine to regular insulin
– Reduces the absorption rate from an injection site
resulting in an intermediate duration of action
– Highest variability of absorption (25-50%)
– Cloudy solution

Question 6

Rapid Acting Formulations (mimic meal-time

insulin)

Answer 6

– Aspart (NovoRapid® - Novo Nordisk)
– Glulisine (Apidra® - Sanofi Aventis)
– Lispro (Humalog® - Lilly)
➢Duration of action ~4-5 hrs
➢Lowest variability of absorption (5%)

Question 7

Long Acting Formulations (mimic basalinsulin)

Answer 7

– Glargine (Lantus® - Sanofi Aventis)
– Detemir (Levemir® - Novo Nordisk)
– Degludec (Tresiba® - Novo Nordisk – Approved
Sept 2015)

Question 8

Insulin Action/Pharmacology

Answer 8

Free insulin binds to insulin receptors
– Intrinsic receptor tyrosine kinase activity
– Promotes glucose uptake, glucose metabolism, and
energy storage in muscle
– Reduces endogenous glucose production by the liver
– Anabolic hormone
▪ Glycogen storage in liver
▪ Fat storage in adipose tissue
▪ Protein synthesis in muscle

Question 9

Insulin causes glucose uptake by

Answer 9

– Activation of Akt and translocation of
GLUT4 to the plasma membrane
(muscle, fat)

Question 10

Insulin causes glycogen synthesis by

Answer 10

– Inhibition of GSK3 prevents GSK3-

mediated inhibition of GS

Question 11

Insulin reduces gluconeogenesis by

Answer 11

– Inhibition of FoxO1 reduces the
transcription of numerous genes of
gluconeogenesis (liver)

Question 12

Insulin causes protein synthesis by

Answer 12

– Activation of mTOR modifies
numerous signaling molecules that
turn on protein synthesis (muscle)

Question 13

How does insulin affect ketogenesis and lipolysis?

Answer 13

– Activation of Akt leads to
increased phosphodiesterase 3B
activity, which degrades cAMP,
and reduces lipolysis (adipose
tissue)
– Reductions in lipolysis reduce
circulating free fatty acid delivery
to the liver, which reduces rates
of ketone body production
– Insulin activates acetyl CoA
carboxylase (ACC) in the liver,
which produces malonyl CoA and:
• Inhibits fatty acid oxidation
• Promotes fatty acid biosynthesis

– All of this collectively leads to an
inhibition of ketogenesis

Question 14

What are adverse effects of Insulin?

Answer 14

– Hypoglycemia (low blood sugar levels)
– Localized lipodystrophy (either a loss or
hypertrophy of fatty tissue at the site of injection)
▪ More common with animal source insulin
– Insulin allergy is rare resulting from localized
histamine release
▪ Likely caused by non-insulin components of solution
– Insulin resistance is very rare, caused by
development of anti-insulin antibodies in circulation
– Weight gain

Question 15

How does glucagon work?

Answer 15

– Glucagon activation of the
glucagon receptor GPCR is linked
to activation of Gs proteins and
activation of AC, increasing cAMP
levels & activating PKA
– Activates glycogen phosphorylase
to mobilize liver glycogen stores
for increases hepatic glucose
output to maintain normoglycemia

Question 16

Glucagon pens (1 mg) can be
injected

Answer 16

intramuscularly or

subcutaneously