Diabetes/Obesity Metabolism

Question 1

Lipogenic liver

Answer 1

Fed-state: insulin signaling
1) Glucose from blood stream to liver –> brain, adipose tissue and muscle, glycogen synthesis,
2) Some glucose in liver diverted to form pyruvate/acetyl-coA –> TAGs
Sent via VLDL to adipocytes and muscle (b-ox)
3) AA ingested to liver –> catabolized and converted to acetyl coA and urea
Used as energy or converted to TAGs
4) Fats via lymphatic system to muscle and liver

Question 2

Insulin target enzymes (by muscle, liver and adipose)

Answer 2

Muscle: ↑ GLUT4, ↑ glycogen synthase, ↓ glycogen phosphorylase, ↑ PFK-1 (by PFK-2), ↑ pyruvate dehydrogenase complex
Result: increased glucose uptake for glycogen synthesis and glycolysis/pyruvate oxidation

Liver: ↑ glucokinase, ↑ glycogen synthase, ↓ glycogen phosphorylase, ↑ PFK-1 (by PFK-2), ↑ pyruvate dehydrogenase complex, ↑ acetyl-coA carboxylase
Result: increased glucose uptake (glucokinase) for glycogen synthesis, glycolysis/pyruvate oxidation and fatty acid synthesis

Adipose: ↑ GLUT4 and ↑ lipoprotein lipase
Result: increased glucose uptake and TAG synthesis

Question 3

Glucogenic liver

Answer 3

Fasting state: glucagon signaling
Liver becomes main source of the glucose for the brain, ketones but not fatty acids
All about energy for the brain

1) Glycogen converted to Glu-6-phosphate –> glucose for the brain
2) TAGs broken down into fatty acids for ketone bodies and glycerol (gluconeogenesis)
3) AA broken down into ketone bodies and pyruvate (gluconeogenesis)

Question 4

Glucagon target enzymes in liver and adipocytes:

Answer 4

Liver: ↓ PFK-1, ↑ FBPase-2, ↑ PEP carboxykinase and ↓ pyruvate kinase, ↑ glycogen phosphorylase, ↓ glycogen synthase

Adipocytes: ↑ hormone sensitive lipase, ↑ PKA (to phos-Perilipin)

General Ketogenesis: ↓ acetyl-coA carboxylase

Question 5

Fuel used over the 4 hours post meal

Answer 5

Directly after: insulin induced pathways (↑ glycolysis and glycogenesis)

2 hours post prandial: blood glucose drops, glucagon released (↑ glycogenolysis)

4 hours post-prandial: TAG hydrolysis (↑ hormone sensitive lipase and PKA)

Question 6

Prolonged fasting metabolism outcome

Answer 6

Prolonged fasting is same pathways as glucogenic liver but with accumulation of ketone bodies which are toxic and acidic

Increased protein breakdown (esp. Lys-Phe-Glu-Arg-Gln sequences in liver and heart)
Non-essential AA deaminated

Ketone bodies can support minimum energy requirements but functioning won’t be the same

Question 7

During prolonged fasting these intermediates build up

Answer 7

Diversion of oxaloacetate to gluconeogenesis so acetyl-coA builds up and favors ketone synthesis
Excess ketone bodies excreted in the urine

Question 8

Plasma levels of fuel during starvation

Answer 8

Glucose declines
Beta-hydrobutyrate skyrockets
Acetoacetate and acetone slowly increase (acetone is exhaled, limited in blood and not metabolized)
FA levels remain the same as they are not metabolized by the brain

Question 9

Type I vs Type II Diabetes

Answer 9

Type I: insufficient insulin production due to autoimmune destruction of beta cells (early onset)

Type II: insulin resistance due to defective insulin signaling
IRS proteins DEphosphorylated and GLUT4 sequestered in cytoplasm

If IRS-1 is not phosphorylated, the signaling cascade falls apart and GLUT4 receptors don’t travel to membrane, no synthesis of glycogen so glucose levels remain high

Question 10

Diabetes symptoms

Answer 10

Elevated glucose, ↑ osmolarity causing thirst and urination
Glycosylation of proteins
Accelerated fat breakdown (in type II eventually turns to fat gain) producing ↑ ketone bodies
↑ acidosis
Triggered bicarbonate buffering system - alters breathing pattern
Acetone breath due to metabolism of acetoacetate –> acetone (exhaled)

Question 11

Adipokines

Answer 11

Peptide hormones - are link between adipocytes and brain in signaling
Carry info about fuel stores in adipose tissue and hunger levels
ex. leptin, adiponectin

Question 12

What is adiponectin?

Answer 12

insulin sensitizing and anti-inflammatory effects

Question 13

Anorexigenic pathway and hormones

Answer 13

Signals: leptin and insulin
1) Leptin stimulates secretion of a-Melanocyte stimulating hormone (a-MSH)
2) Insulin leptin, PYY and GLP-1 inhibits neuropeptide Y (NPY) to strengthen signal
3) a-MSH stimulates 2nd order neurons to eat less, metabolize more

Question 14

Orexigenic pathway and adipokines

Answer 14

Signal: Ghrelin
1) Ghrelin stimulates NPY
2) NPY stimulates 2nd order neurons to eat more

Question 15

Result of db gene mutation

Answer 15

Encodes for leptin receptor in the brain (hypothalamus)
Leads to continuous eating, obesity, elevated cortisol, shivering, infertility, insulin resistance, early death

In mice, leptin injection caused weight loss and temperature normality but not in humans due to higher leptin levels

Question 16

Ghrelin signaling

Answer 16

Produced in the stomach, short-term orexigenic peptide hormone
Ghrelin receptors found in the hypothalamus, heart and adipose tissue
GPCR signaling pathway to increase hunger
Injection of ghrelin immediately increases hunger

Question 17

Insulin and leptin efficacy time scale

Answer 17

long term scale, as opposed to ghrelin which is short term scale

Question 18

PYY

Answer 18

Function: appetite suppressing peptide hormone, inhibits NPY and reduces hunger
Structure: 36 AA with 2 Tyr residues
Stimuli: food entering the stomach
Location: Secreted by SI and colon in response to stimuli

Question 19

Gut microbes effect on obesity

Answer 19

Microbes produce SCFA: acetate, butyrate and propionate

Propionate acts as ligand and binds to GPCR stimulating pre-adipocyte differentiation into WAT and inhibition of lipolysis

Differences in gut microbiota between lean and obese individuals

Question 20

Lipid toxicity hypothesis

Answer 20

1) Enlarged adipocytes produce Macrophage Chemotaxis Protein (MCP-1) to attract macrophages which are pro-inflammatory
2) Macrophages produce TNF-a in adipocytes, that favors export of FA
3) FA exported to muscle and deposited as ectopic fat
4) Ectopic fat interferes with GLUT4 movement, contributing to insulin resistance
Counter hypothesis: insulin resistance leads to obesity

Question 21

What is glucokinase?

Answer 21

Same function as hexokinase but found only in the liver and pancreas beta cells
Acts as a blood sugar detector
Catalyzes glucose –> glucose-6-phosphate

Question 22

Satiety signals vs adiposity signals

Answer 22

Satiety: PYY and GLP-1 (gut) inhibit NPY

Adiposity: Leptin (adipose) and insulin (pancreas) inhibit NPY