Diabetes

Question 1

metabolic regulation modes ?

Answer 1

#substrate availability
#Allosteric
#hormonal : Acute/ long-term adaptation

Question 2

what goes on in the fasting state ?

Answer 2

it’s a catabolic period; energy is metabolized

Question 3

how does glucagon signal ? how is the signal regulated ?

Answer 3

phosphodiesterases regulate the localization, duration, and amplitude of cyclic nucleotide signaling within subcellular domains. PDEs are therefore important regulators of signal transduction mediated by these second messenger molecules.

GPCR —> G protein activates adenylyl cyclase —> cAMP —> PKA —> phosphorylation kinase

Question 4

the effet on isulin secretion on glucagon ?

Answer 4

insulin secretion inhibits glucagon secretion by alpha cells

Question 5

effect of insulin on glycogen synthesis and breakdown ?

Answer 5

promotes the more active version of synthase and the less active veersion of phosphorylase

Question 6

the effect of the rise in insulin/glucagon ratio on each of the regulatory steps of glycolysis ?

Answer 6

1. Glucokinase stimulated by glucose,

results in increase in G6P.
2. G6P increases glycogen synthase

activity (allosteric), results in an

increase glycogen.
3. Increase in F2,6P2, stimulates

PFK-1.
4. F1,6P2 stimulates Pyruvate Kinase,

increasing pyruvate.

Question 7

CPT ?

Answer 7

Question 8

Mention some of the major regulators of fatty acid metabolism in the FED state

Answer 8

citrate from beta oxidation activates ACC (regulatory hormone of fatty acid synthesis)

Question 9

role of AMPK and PKA ?

Answer 9

they stimulate beta oxidation and inhibit ACC (synthesis)

Question 10

how does insulin reverse the effect of glucagon ?

Answer 10

it activates a phosphatase that reverses the glucagon0depndent phosphorylation of pyruvate kinase. (liver needs to metabolize glucose rather than synthesize it)

Question 11

how do glucose transporters respond to insulin stimulation ?

Answer 11

when signal intensity of GLUT 4 was measured inside the cell and on the plasma membrane before and after insulin stimulation, there was a huge increase in plasma membrane transporters (recrution). —> indicates that GLUT 4 receptors are recruited from the cell’s interior in response to insulin stimulation. the complexity of the mechanism allows for exquisite control of GLUT-4

Question 12

how are fats from the gut handled in the absorptive state ?

Answer 12

fats are transported from the gut via chylomicrons into the liver where TAGs are made and transported in VLDLs into adipose and muscle

Question 13

glucose, insulin, glucagon correlation graph

Answer 13

Question 14

how does liver adjust blood glucose in a fasted state ?

Answer 14

first by depleting glycogen stores and then gluconeogenesis

Question 15

gluconeogenic substrate ?

Answer 15

amino acids (glutamate and alanine); lactate, glycerol

Question 16

extended fasting ?

Answer 16

adipose –> beta oxidation –> glycerol sent to liver for gluconeogenesis–> FA sent to muscle and tissue and other body parts and liver for ketone body synthesis

muscle–> alot of protein breakdown –> alanine and glutamine sent to liver for gluconeogenesis

Question 17

fatty acids, ketone bodies, glucose correlation chart

Answer 17

Question 18

Diabetes types: elementary comparison

Answer 18

TYPE-1 no insulin secretion (dysfunctional beta cells)

MODY2 –> glucokinase molecule that is less sensitive or less responsive to rising levels of glucose. The beta cells in MODY 2 have a normal ability to make and secrete insulin, but do so only above an abnormally high threshold

Question 19

dysfunction and death of beta cells in type-1 diabetes

Answer 19

Question 20

elaborate on type-1 diabetes

Answer 20

Type 1 diabetes —\> autoimmune attack on beta cells of the pancreas —\> gradual depletion of beta cell degradation —\> symptoms appear abruptly; at this point pancreas fails to respond adequately to ingestion of glucose.
#HYPERGLYCEMIA —\> due to high hepatic gluconeogenesis and lack of peripheral utilization by muscle and adipose that have INSULIN-DEPENDENT GLUT-4
#Ketosis —\> profuse fatty acid mobilization from adipose —\> ketone body synthesis —\> ketosis
#acetyl coA from beta oxidation is used in ketogenesis and allosterically activates pyruvate carboxylase.
#hypertriacylglycerolemia : the huge pool of FA’s trafficked into the liver isnt all oxidized or used for ketogenesis —\> trafficked out of the liver by VLVD’s and out of the gut by chylomicrons —\> BUT due to lack of lipoprotein insulin-dependent secretion, they remain in the blood causing hyperglycerolemia

Question 21

insulin resistance instances ?

Answer 21

decreased uptake of glucose in liver and adipose

gluconeogenesis in liver

Question 22

metabolic changes in T2D ?

Answer 22

Metabolic changes in T2D:
#hyperglycemia: caused by increased hepatic production of glucose, combined with diminished peripheral us. ketosis is usually minimal or absent in patients with T2B because the presence of insulin, even in the presence of resistance, restrains hepatic ketogenesis.
#Dyslipidemia: in the liver, FAs are converted to TAGs, which are packaged and secreted in VLDL. chylomicrons are synthesized from dietary lipids by the intestinal mucosal cells following a meal. because insulin-dependent, lipoprotein degradation catalyzed by lipoprotein lipase in adipose tissue is low in diabetics, the plasma chylomicron and VLDL levels are elevated, resulting in hypertriacylglycerolemia.

Question 23

T2D pathology

Answer 23

Question 24

Leptin Vs. Adiponectin

Answer 24

Leptin is a hormone secreted by adipose tissue that controls food intake and energy expenditure. Leptin resistance is associated with *obesity*.

Question 25

the effect of over-expressing adiponectin in leptin deficient mice ?

Answer 25

their metabolism is normalized; glucose, insulin, and TAG levels go down

Question 26

toxic fat and insulin resistance theory

Answer 26

Accumulation of fat in the liver and muscle promotes insulin resistance (blocks insulin receptor signal transduction) in these tissues by an unknown mechanism(s). Many theories. Early IR in one organ will over time induces IR of other organs. Fat in adipose less “toxic”.

Question 27

fructose and obesity ?

Answer 27

The majority of fructose is metabolized by the liver because it is the tissue that expresses high levels of both Glut5 and fructokinase.

Fructose promotes glucose metabolism in the liver by promoting glucokinase accumulation in the cytosol.

β-cells do not metabolize fructose efficiently; therefore, the insulin response to fructose is less than to glucose.

Question 28

Liver Steatosis ?

Answer 28

insulin resistance –> increased lipolysis and increase in transport of TAGs to the liver and more FFA’s –> FFA contribute to decreased use of glucose : hyperglycemia –> increases deposition of TAG in the liver

Question 29

fatty liver in alcoholics ?

Answer 29

NADH abundance due to ethanol oxidation –> gluconeogenesis halted since its intermediates now prefer reduction pathways (via the replete