Block 3 Lecture 4 -- Hormonal Regulation of Fuel Metabolism Flashcards
What tissue-specific hormone receptors are present in the liver?
1) GLUT-1
2) alpha-adrenergic
3) beta-adrenergic
4) glucagon
What tissue-specific hormone receptors are present in the muscle?
1) GLUT-4
2) beta-adrenergic
3) insulin
Typical FPG?
80-100 mg/dL
Typical post-prandial [glucose]?
120-140 mg/dL
MW of glucose?
180 g/mol
What happens if glucose < 80 mg/dL?
coma, death, hemolysis
What are the consequences of not storing fat?
1) atherosclerosis, LDL = stroke, MI
What happens if too much fat is stored?
fat-only catabolism
What are the functions of insulin?
1) promotes nutrient storage
2) anabolic for blood proteins
3) promotes utilization of glucose for fuel
What are insulin’s nutrient storage effects?
1) glycogen synthesis
2) protein synthesis
3) TG synthesis in liver
4) TG storage in adipose
How is insulin sotred?
as the Zn2+ complex
Describe the structure of insulin?
2 peptide chains connected by 2 disulfides
What is structure of proinsulin?
folded with formation of disulfide bonds
Structure of pre-proinsulin
translation product after processing removes signal sequence in the RER
Why is C-peptide a good diagnostic tool?
not cleared as rapidly as insulin
What factors stimulate insulin release?
1) parasympathetic stimulation
2) Ala/Arg
3) GIP
What factors inhibit insulin release?
insulin
How is insulin solubilized from its storage form?
Ca++ displaces Zn++
What stimulates glucagon release?
1) catecholamines
2) cortisol
3) GI hormones
4) AAs
What control glucagon release?
lack of insulin
What suppresses glucagon release?
insulin and glucose
half-life of glucagon?
4 minutes
functions of glucagon?
1) stimulates glycogenolysis and gluconeogenesis in liver
2) mobilizes FAs in adipose
What other factors affect glucagon release?
1) blood metabolite levels
2) neuronal signals
3) other insulin opponents
What percentage of islet is beta cells?
75%
What percentage of islet is alpha cells?
20%
What percent of islet is delta cells?
5%
What does the cholera toxin do?
inhibits GTP hydrolysis by Galpha
What is the reaction catalyzed by adenylate cyclase?
4 ATP –> 4 AMP –> 4 cAMP
What is the function of phosphodiesterase?
inactivates cAMP
What substances inhibit PDE?
caffeine, theophylline, theobromine
What does cAMP do?
binds regulatory dimer of PKA to allow catalytic dimer to phosphorylate shit
What is a CRE?
cAMP Response Element, a DNA promoter that encodes gluconeogenesis enzymes
How are CRE’s bound to stimulate transcription?
cAMP-PKA phosphorylates CREBs that then bind CREs
What hormones function through membrane receptors?
1) glucagon
2) epinephrine
3) beta-receptors
What hormones function through RTKs?
insulin
Describe RTK action?
1) dimerizes
2) TK autophosphorylates Tyr residues
What hormones function through PIP2 hydrolysis couplers?
epinephrine alpha receptors
What hormones function through gated ion channels?
1) angII
2) neurotransmitters
What do alpha1 receptors do?
vascular smooth muscle contraction via PIP2
What do beta1 receptors do?
myocardial increase HR & contractility
What do beta2 and 3 receptors do?
fuel metabolism
How does the insulin RTK take effect?
IRS (insulin receptor substrate) has an SH2 domain that binds Tyr-PO4s of RTK
What does IRS-1 do?
affects glucose metabolism
What does IRS-2 do?
affects fat metabolism
What are cortisol’s effects?
works synergistically with glucagon to…
1) mediate long-term changes in fuel metabolism
What is the MoA of sulfonylureas?
blocks ATP-dependent K+ channels in beta cells to increase Ca++ mobilization
What are the sulfonylureas?
1st gen: tolbutamide
2nd gen: glipizide, glimepiride, glibencalmide
What is the MoA of repaglinide?
same as Sulfonylureas
What is the MoA of metformin?
stimulates AMP-activated PK to decrease liver gluconeogenesis via expression of SHP which inhibits expression of PEPCK & G6Pase
What class of hypoglycemic agents is Metformin from?
biguanide
Where is metformin derived from?
french lilac
What is salsalate’s mechanism of action?
NSAID with blood-sugar lowering activity, decreases inflammation, increases insulin sensitivity
What drugs are DPP4 inhibitors?
sitagliptin, saxagliptin
What is the MoA of DPP4-inhibitors?
inhibits dipeptidylpeptidase-4 (involved in glucagon release); also stimulate insulin release by inhibiting inactivation of insulin-stimulating incretins
What is the MoA of exantide?
incretin mimetic
What is the MoA of Liraglutide?
GLP-1 analog with palmitate side chain that acts like incretins
How is synthetic glucagon administered?
IM or SQ
