Lecture 16: Fuel Metabolism, Endocrine Pancreas

Question 1

Endocrine pancreas

Answer 1

Insulin + glucagon synth. + secretion

Question 2

Insulin

Answer 2

Anabolic protein hormone; storing energy state
Binds RTK

Question 3

Glucagon

Answer 3

Catabolic protein hormone; mobilizing energy stores
Binds GPCR

Question 4

Effects of carb meal

Answer 4

Incr. gluc -> insulin release, less glucagon:
Liver: unreg. gluc. uptake (non insulin dpdt)
Muscle, adipose: insulin dpdt gluc. uptake

Question 5

Effects of protein meal

Answer 5

Increased AAs -> insulin + glucagon release
Insulin indpt:
Brain: uses gluc. made from liver AAs

Insulin dpdt:
- Liver: AA uptake, protein synth., conversion to gluc., glycogen, TAGs
- Muscle: AA uptake
- Adipose: TAG uptake

Question 6

Effects of fatty meal

Answer 6

• TGs secreted as chylomicra
  Insulin dpdt:
• LPL takes up FAs -> adipocyte TG storage, muscle FA fuel use

Question 7

Post-absorptive state (interprandial)

Answer 7

Decr. insulin, incr. glucagon
Brain: uses gluc. from liver
Liver: glycogenolysis, gluconeogen., using FAs as fuel
Muscle: glycogenolysis, decr. gluc. use and more FA uptake
Adipose: decr. gluc. uptake/use; lipolysis freeing glycerol, FAs to blood

Question 8

Brief starvation state

Answer 8

~3 days, low insulin
- Brain: gluc. use from liver
- Liver: no glycogen left; gluc. from AAs, lactate; FAs -> ketone body formation
- Muscle: no glycogen; protein degrad. -> AA release; more ketone body use over FAs
- Adipose: incr. lipolysis

Question 9

Long term starvation state

Answer 9

~24 days, low insulin
- Liver: ketogenesis as major muscle fuel
- At day 24: brain switches to ketones; muscle switches back to FAs

Question 10

Hypoglycemia

Answer 10

• CNS v. sensitive to low blood gluc.
• Triggers stress response w/ epi; pale, sweaty, increased counterreg. hormones (cortisol, GH)

Question 11

Acute hyperglycemia

Answer 11

Acute = metabolic
- Glycosuria
- 3 P’s:
1. Polyuria (osm. diuresis)
2. Polydipsia (thirst)
3. Polyphagia (hunger; cells don’t see high blood gluc. only internal)

Question 12

Chronic hyperglycemia

Answer 12

High gluc. -> microvasc. disease -> retin-/neuropathy

Neuropathy eventually causes macrovasc. disease: coronary art. disease, stroke, decreased peripheral circulation

Question 13

Diabetes mellitus

Answer 13

Chronic hyperglycemia leading to clinical complications
Type I: absolute insulin deficit due to autoimmu. beta cell loss
Type II: relative insulin deficit and/or resist.
Gestational: during pregnancy

Question 14

Diabetic KetoAcidosis

Answer 14

Assoc. w/ Type I diabetes, not T2
- Cells use TGs, protein instead of gluc. -> ketogenesis increase
- Excess ketoacids -> metabolic acidosis, fruity acetone breath, osm. diuresis -> fluid/electrolyte loss

Question 15

Islets of Langerhans

Answer 15

Endocrine pancreas
Alpha cells -> glucagon
Beta cells -> insulin

Question 16

Insulin secretion regulation

Answer 16

Stim by:
- Serum gluc., FAs, AAs
- Incretins (GastroInhibitory Peptide, Glucagon-like Peptide-1)
- Epi to beta receptor
- Parasymp. NS

Inhib. by:
- Low serum gluc., FAs, AAs
- SST hormone
- Epi to alpha receptor
- Symp. NS

Question 17

Insulin synthesis process

Answer 17

Synth. as pre-pro-protein
- Pre: signal peptide to ER; signal peptidase cleaves
- Pro: proprotein to Golgi; stored in secretory vesicles
- Pro seq. cleaved in vesicle; Pro + protein seq. exocytosed
C peptide (Pro seq.) differentiates endo vs exo insulin

Question 18

Insulin secretion process

Answer 18

1. Unregulated gluc. influx via GLUT2
2. Metabolism -> higher ATP:ADP
3. Incr. ATP closes K+ channels -> depolar.
4. Ca++ channels open w/ depolar. -> Ca influx
5. Ca++ mediated SNARE secretory vesicle exocytosis

Question 19

How do sulfonylureas treat T2 diabetes?

Answer 19

Sulfonylureas block K+ channel -> depolar. -> increased insulin release

Question 20

Insulin half life

Answer 20

5-8 min; secreted into portal vein and 50% of action happens and is degraded in liver before circulation

Question 21

Insulin receptor

Answer 21

Constitutive dimer RTK (ready to go)
- Auto-Pi -> IRS-1/2 recruitment -> signal cascade
- Many downstream signaling mechs e.g. PPCK inhib (gluconeogen. enzyme), e.g. ACC stim. (FAS)

Question 22

GLUT transporter family

Answer 22

GLUT2: insulin indpt, low affinity, high capacity (liver, pancreas beta)
GLUT4: insulin dpdt, high affinity (muscle, adipose); insulin signal -> receptor fusion w/ membrane (no insulin = transporter recycled)

Question 23

Liver glucose uptake pathways

Answer 23

Uptake via GLUT2 + increased insulin signal:
- Glycolysis, TCA cycle upreg.
- Glycogen synthesis upreg.
- VLDL TAG secretion
- Protein synthesis upreg.

Question 24

Muscle gluc. uptake pathway

Answer 24

Via GLUT4:
- Upreg. glycolysis, TCA
- Upreg. glycogen synth.
- Upreg. protein synth.

Question 25

Adipose gluc. uptake pathway

Answer 25

Via GLUT4: - Glycolysis upreg. -> lipid synth. upreg - Protein synth. upreg. -> LPL upreg. for FA uptake from VLDLs

Question 26

Glucagon effects

Answer 26

Primary functions occur in liver: upreg. glycogenolysis, gluconeogen., ketosis - Pancreatic alpha cells secrete - GPCR -> liver catabolic enzyme Pi