Insulin and Diabetes Flashcards
How is fuel utilized in starvation? (i.e. explain the graph below. what happens prior to and during prolonged starvation?)
Patients starved for 40 days and 40 nights; glycogen stores utilized until they got all used up
Following glycogen depletion, pts start gluconeogenesis and using ketone bodies
In the fed state, fuel is stored. What are the 3 storage forms of fuel?
For each storage form, would you use it locally or systemically?
Glycogen, fat and protein
Glycogen: muscle glycogen - local use (muscle doesn’t have G6Pase); liver glycogen - systemic
Fat: adipose tissue - systemic use; broken down to glycerol and fatty acids
Protein: only used as last resort (mostly structural)
How is fuel mobilized during fasting? (i.e. how are following fuel sources used : muscle, adipose tissue,liver)
Fuel mobilization:
Muscle – amino acids used to make glucose
Adipose tissue – fatty acids can be oxidized to generate ATP, glycerol used for gluconeogenesis
Liver – gluconeogenesis and ketone body production
What are the energy sources for anaerobic tissues during starvation?
What are 3 energy source options for aerobic tissues (hint: keto-fatty-sugars)
Describe what’s shown in the graph
Aerobic tissues: have to use glucose
Anaerobic: ketones, fatty acids, glucose
Free fatty acids converted to ketone bodies that can cross BBB
During starvation, FFA levels go up a little bit, Acetoacetate and beta-hydroxybutyrate levels go up further once FFAs start getting converted
Brain doesn’t use free fatty acids because they don’t cross blood brain barrier (coz they’re bound to albumin in circulation) - FYI
Describe the effect of insulin secretion on the following organs following a meal:
Muscle
Adipose tissue
Liver
Brain
Adipose tissue prompted to take up glucose and decrease fatty acid and glycerol mobilization
Muscle prompted to take up glucose and decrease protein breakdown
Liver prompted to slow down ketogenesis and gluconeogenesis
Brain not really regulated by insulin; brain normally uses glucose, during starvation it uses ketone bodies
Describe the effect of insulin supppresion on the following organs during starvation:
Muscle
Adipose tissue
Liver
Brain
Describe the regulation of insulin secretion between obese and non-obese patients in the graph.
Explain the difference in the rise of insulin in obese pts
Glucose levels go up right after a meal and come back down when insulin is secreted
Glucose levels between obese and normal weight individuals track pretty closely
In obese pts, insulin levels rise significantly more because they’re insulin resistant (need more insulin to control their glucose)
Describe the post translational processing of proinsulin
Significance of C peptide
Proinsulin is cleaved into B-A chains and C peptide
B and A chains connected via disulfide bonds, C peptide is pretty much a waste product after cleavage
C peptide is secreted in equimolar amounts with insulin, so if you want to test if pancreas is making insulin (there should be making C peptide if they’re secreting insulin normally)
Historical insulins
Rapid acting insulins (and characteristics)
Long acting insulins (and characteristics)
Historical insulins: bovine and porcine insulin
Long acting insulin replaces basal insulin secretion even during fasting
Glargine: delayed absorption, precipitates at pH 7.4
Detemir: fatty acid group bound to albumin >> prolongs duration of action
Rapid acting insulin gives pts the peak of insulin right after a meal (and it goes away rapidly also);
Lispro and Aspart – don’t dimerize; monomers have ultra-rapid absorption
Enzyme responsible for glucose sensing in beta cell
Differences between GK and Hexokinase
Effect of gain of function mutation
Effect of loss of function mutation
Glucokinase
GK: Km in physiological range (sensitive to changes in glucose conc)
Glucose specific
Hexokinase: not glucose specific
fully saturated at all physiological glucose concentrations
GOF mutation - hypoglycemia
LOF mutation - diabetes
Describe how insulin secretion is mediated by ATP.
How do sulfonylureas work?
Sulfonylureas are directed against this pathway; inhibit SUR receptor on the K+ channel, shuts the K+ channel down, promotes insulin secretion
(basically works like ATP except its blocking the SUR)
Explain the graph below
Incretins (what do they do and which ones are they)
Role of DPP4
Role of DPP4 inhibitors
Giving glucose by oral route = more insulin secretion compared to giving insulin intravenously
Incretins basically increase insulin secretion; GLP1 and GIP
DPP4: Cleaves 2 most aa/s off GIP and GLP1; inactivates GLP1 and GIP;
Also decreases food intake and glucagon secretion
DPP4 doesn’t depend on glucose
DPP4 inhibition: protects incretins from degradation
Hormones that protect against hypoglycemia
Glucagon
Epinephrine
Growth hormone
Cortisol
Glucagon functions
+glycogenolysis,+gluconeogenesisn (+Glycogen phosphorylase activity)
+oxidation of lipids
promotes hepatocellular survival (whatever that means)
- Glycogen synthase activity
- Acetyl CoA carboxylase activity
Ketogenesis pathway (i.e. describe what happens in the fed state)
Molecule that regulates ketogenesis (hint: intermediate of fatty acid oxidation)
Fed state: fatty acids present >> fatty acyl coA turned into triglycerides for storage or get converted to ketone bodies
Entry of fatty acyl coA into mitochondria regulated by malonyl coA (intermediate of fatty acid oxidation)
(high malonyl coA - no ketogenesis; low malonyl coA - +ketogensis)
Definition of Type 1 diabetes
Effects of Type 1 diabetes
Autoimmune destruction of beta cells = no insulin secretion
Type 1 diabetes - basically everything that would happen when you normally have insulin suppression is amplified
Steps in insulin signlaing pathway
Insulin binding to its receptor
Receptor crosslinking/activation of tyrosine kinase activity
(auto/trans)phosphorylation of tyrosine residues in intracellular domain
phosphorylation of IRS molecules
Docking of downstream molecules (PI3K) to IRS molecules
Activation of AKT2
Downstream effects: GLUT4 translocation; FOXO1 degradation; others (cell growth and differentiation; glucose and protein synthesis)
What is the effect of insulin-mediated activation of PDE3B (phosphodiesterase 3B)?
Relationship between cAMP and Hormone-sensitive lipase
Function of HSL
cAMP upregulates HSL
Insulin upregulates PDE3B (degrades cAMP)
Hormone sensitive lipase involved in fatty acid breakdown
Describe how insulin regulates FOXO1 activity
Downstream effect of FOXO1 degradation
What happens with FOXO1 activity in fed vs fasting states?
In fed state, FOXO1 activity = high >> + PEP-CK; +G6P >> increaased gluconeogenesis
Describe the HbA1c test. What is it based on?
Aldehyde group in glucose forms Schiff base which can form an irreversible attachment to a protein; if you incubate the protein + glucose, you form a glycated protein
Hb in RBCs: rate of glycation proportional to glucose concentration (how much glycated Hb you have tells you how much glucose you’ve got)
Describe how increased levels of ectopic fat can lead to insulin resistance
Lots of ectopic fat >> increased DAG levels >> increased DAG activates PKCe >> PKCe adds P to IRS1/2 >> impairs insulin signaling >> causes resistance
Action and location of action of the following Type 2 diabetes drugs:
Metmorfin
PPARy agonists
SGLT2 inhibitors
Bromocryptine-QR
Metformin: liver: decreases glucose production
PPARy agonists: adipose tissue: increase fat storage
SGLT2 inhibitors: kidney: increase urinary glucose excretion
Bromocryptine-QR: brain: alters circadian rhythm
Action of the following insulins (can be used for both Type 1 and 2 diabetes) (hint: alpha glip, sulfur dip)
DPP4 inhibitors: decrease incretin degradation
Alpha glucosidase inhibitors: decrease starch digestion
Sulfonylureas: increase insulin secretion
GLP1R: increase glucose-dependent insulin secretion
Difference between SGLT1 and 2 (affinity for glucose, abundance)
Effects of SGLT2 inhibitors on weight and blood pressure
SGLT2 – low affinity glucose transport but there’s more of it so it carries most of the glucose transport load;
SGLT1 (in kidney and intestine) – high affinity glucose uptake (takes up whatever’s not absorbed via SGLT2)
Weight loss via loss of glucose and calories
Blood pressure lowered via loss of sodium
Describe how SGLT2 inhibitors cause increased ketogenesis
Lowered plasma glucose >> lowered insulin dose >> increased lipolysis >> increased ketogenesis
