BIOL class 23

Question 1

insulin

Answer 1

a peptide hormone secreted by the beta cells of the pancreas; the major target tissues are the liver, muscle, and adipocytes

Question 2

insulin induces..

Answer 2

• GLUT4 movement to the cell surface in FAT and MUSCLE
• helps support protein synthesis, cell division, differentiation, glycogen synthesis/storage, fatty acid synthesis

Question 3

insulin inhibits..

Answer 3

gluconeogenesis, lipolysis, glycogen catabolism

Question 4

what is “insulin sensitivity” and “insulin resistance”

Answer 4

refers to the roles of insulin in glucose homeostasis, prolonged elevated glucose levels in the serum during fasting are indications of insulin resistance and the onset of diabetes

Question 5

diabetes mellitus

Answer 5

a group of diseases that are manifested by hyperglycemia; persistence of excessive levels of glucose in serum (and urine)

Question 6

how the pancreas senses an increase of glucose in the serum

Answer 6

• an increase in serum glucose increases the production of ATP by respiration which in turn closes an ATP-gated K+ channel
• this causes membrane depolarization and Ca1+ channel opening
• Ca2+ activates secretion of insulin
• as glucose is depleted from serum, ATP levels in cells go down, channel re-opens and insulin secretion stops

Question 7

the post-meal clearance of glucose is through the RAS-independent pathway of insulin signaling

Answer 7

• insulin receptor activation in muscle and adipose tissue leads to fusion of vesicles carrying the GLUT4 glucose transporter with the plasma membrane
• this allows glucose to be dumped from the serum and into muscle and adipocytes
• these tissues then complete glycolysis

Question 8

when insulin signaling is normal…

Answer 8

• liver metabolism shifts to glucose storage and fatty acid production/packaging and transport; gluconeogenesis is inhibited

Question 9

why is gluconeogenesis inhibited when insulin signaling is normal?

Answer 9

• insulin inhibits gluconeogenesis

Question 10

decreased insulin signaling = uncontested glucagon signaling

Answer 10

• diabetes
• increased ketone and glucose production
• increased ketone and glucose in the bloodstream

Question 11

what is diabetes?

Answer 11

chronic disease which occurs when the pancreas does not produce enough insulin, or when the body cannot effectively use the insulin it produces
- this leads to an increased concentration of glucose in the blood (hyperglycemia)
- diabetes is the persistence of high glucose levels in the serum after a meal

Question 12

type 1 diabetes

Answer 12

• autoimmune disease that leads to the elimination of the beta-cells in the pancreas, resulting in NO insulin production/secretion
• treatments include daily insulin injection, candidate for stem cell therapy

Question 13

type 2 diabetes

Answer 13

• caused by increasing insulin resistance that develops over time due to defects that can occur in any part of the pathways downstream of insulin production
• treatments include diet, exercise, stimulation of insulin secretion, suppression of glucagon signaling, inhibition of glucose uptake and/or activation of glucose excretion

Question 14

why is obesity a risk factor for type II diabetes?

Answer 14

• insulin-stimulated glucose transport/uptake is impaired by obesity
• blood glucose stays high even as insulin levels increase
• the system becomes increasingly “resistant” to insulin
• excessive levels of lipids already in the system “dampens” the insulin signaling pathway through feedback inhibition of IRS-1

Question 15

IRS1 (insulin receptor subrate 1)

Answer 15

key regulator of insulin signaling
- its downstream effects are ACTIVATED by its phosphorylation on TYROSINES
- the pathway is negatively regulated by phosphorylation on IRS-1 SERINES
- unregulated phosphorylation of serines on IRS1 can lead to insulin signaling defects

Question 16

Hypothesis 1 on how obesity leads to insulin resistance

Answer 16

• excessive fat activates an inflammatory response
• enlarged adipocytes atrract macrophages, which send out inflammatory signals that then lead to phosphorylation of serines on IRS-1

Question 17

hypothesis 2 on how obesity leads to diabetes

Answer 17

• fat overload in cells is directly responsible for resistance
• an imbalance in fat metabolism leads to an increase in DAGs
• DAGs activate PKCs
• PKCs phosphorylate serines on IRS-1; dampening signaling

Question 18

hyperglycemia

Answer 18

• increased serum glucose so skeletal muscle and adipocytes are NOT clearing serum glucose via GLUT4 transporter
• passive glucose uptake occurs in the kidney, retina, and some nerves, leading to excessive levels of glucose in these tissues which leads to increased NADH/NADPH levels

Question 19

problems of hyperglycemia include

Answer 19

1) advanced glycation end products (AGE) → glycation of proteins → AGE receptor activation → increased oxidative stress
2) polyol/sorbitol pathway → increased oxidative stress
3) aberrant protein kinase C regulation → increased oxidative stress

Question 20

problem 1: protein glycation

Answer 20

• non-enzymatic addition of glucose to proteins or lipids; products can be rearranged to yield AGEs
• glucose is attached by lysine amine, creating a schiff base that can rearrange to eventually form cross-links between proteins

Question 21

AGE can cause several problems: