Insulins

Question 1

Hyperglycemia

Answer 1

-leads to covalent modification of proteins
-form Advanced Glycation End products (AGE)
-accumulation of aldehyde form of glucose = more reactive = excessive oxidation = glyoxal and methylglyoxal
-reactions with amino side chains = deoxyglucosone

Question 2

AGE (advanced glycation end products)

Answer 2

-protein + reactive glucose
-loss of normal protein function
-acceleration of aging process
-may account for lots of long term complications
-A1c (rx to hemoglobin?)

Question 3

receptor of AGE (RAGE)

Answer 3

-part of MHC complex
-immunoglobulin family
-bind peptides containing CML (methylglyoxal) and CEL (glyoxal) maybe structure
-promotes inflammation

Question 4

Mechanisms of cell damage initiated by hyperglycemia

Answer 4

-aldose reductase
-protein modification
-GFAT

Question 5

Aldose Reductase in hyperglycemia

Answer 5

-inc use of polyol pathway
-use up NADPH
-store glucose as sorbitol in neurons
-dec oxidative protection
-accumulation of sorbitol can lead to swelling of cells in nervous system

Question 6

Protein Modification in hyperglycemia

Answer 6

-Hexoamine pathway: fructose to glucosamine molecule that can affect function of proteins
-Protein Kinase C pathway: change signaling and accumulation of protein kinase (ROS)

Question 7

GFAT in hyperglycemia

Answer 7

-glutamine F-6P amidotransferase
-hexosamine pathway

Question 8

Insulin Receptor

Answer 8

-structure slide 21
-a and b subunits
-disulfide cross-linking
-only one insulin molecule can bind at a time despite being dimer
-C-terminal region contains tyrosine kinase activity

Question 9

Insulin receptor a subunits

Answer 9

-regulatory unit
-supresses catalytic activity of beta subunit
-repression relieved by insulin binding!

Question 10

insulin receptor B subunits

Answer 10

-contain tyrosine kinase catalytic domains
-autophosphorylation (bc dimerized)
-activated by insulin
-Leu, Cys, FnIII, ID

Question 11

Insulin membrane receptor in action

Answer 11

-a2B2
-inc lipogenesis (MAPK)
-inc glycolysis (PI3K to PKB)
-inc glycogen synthesis (PIP3 to PDK1 to aPKC)
-dec gluconeogenesis (aPKC activates glucose transporters)
-inc glucose uptake (glucose transporter)
-inc DNA/RNA synthesis
-liver, muscle, fat cells

Question 12

Normal insulin signaling

Answer 12

-IRS binds to phosphorylated receptor
-recruits P13K that phosphorylates PIP2 to PIP3
-PIP3 recruits PDK1 to membrane
-PDK1 phosphorylates PKB and aPKC also inc glycolysis
-aPKC stimulates glucose transporters = inc glucose uptake

-inc glycogen synthesis
-dec gluconeogenesis
-P13K and MAPK inc lipogenesis
-MAPK inc lipogenesis and cell growth and proliferation (inc DNA/RNA synthesis)
-PKB inc glycolysis

Question 13

Insulin effect on liver

Answer 13

-INHIBITS glycogenolysis, ketogenesis, gluconeogenesis
-STIMULATES glycogen and triglyceride synthesis

Question 14

Insulin effects on skeletal muscle

Answer 14

-STIMULATES:
-glucose transport
-amino acid transport

Question 15

Insulin effect on adipose

Answer 15

-triglyceride storage
-glucose transport

Question 16

Glucose disposal while fasting

Answer 16

-75% non-insulin dependent (liver, GI, brain)
-25% insulin dependent (skeletal muscle)
-Glucagon secreted to prevent hypoglycemia

Question 17

Glucose Disposal in fed state

Answer 17

-80-85% insulin dependent in muscle
-4-5% insulin dependent in adipose
-glucagon secretion inhibited
-inhibit release of FFA from adipose

Question 18

decreaced serum FFA effects

Answer 18

-enhances insulin action on skeletal muscle
-reduces hepatic glucose production

Question 19

Glucose transporters

Answer 19

-GLUT 1-3 constitutive
-1 in B cells
-2 in b cells and liver predominant
-3 in neurons
-GLUT 4 insulin induced

Question 20

GLUT 4

Answer 20

-glucose transporter
-insulin induced
-Km = 5mM
-muscle and adipocytes

Question 21

Pancreas

Answer 21

-site of insulin production and secretion
-islet of langerhans (endocrine part of pancreas)
-dif cell types = dif hormones
-A cells= glucagon
-D cells = somatostatin
-B cells = insulin, amylin

Question 22

pancreatic polypeptide hormones

Answer 22

-glucagon (A)
-somatostatin (D)
-insulin (B)
-amylin (B)

other species have more b cells

Question 23

Glucagon

Answer 23

-pancreatic hormone
-A cells
-stimulate glycogen breakdown
-inc blood glucose

Question 24

Somatostatin

Answer 24

-pancreatic hormone
-D cells
-general inhibitor of secretion of glucagon and insulin

Question 25

Insulin (pancreas)

Answer 25

-hormone
-B cells
-stimulate glucose uptake and utilization

Question 26

Amylin

Answer 26

-pancreatic hormone
-B cells
-secreted w insulin
-slow gastric emptying
-dec food intake
-inhibit glucagon secretion

Question 27

Insulin processing

Answer 27

-synthesized as single peptide and deposited in secretory granules
-cleaved to A + B chains and C (connecting) peptide in secretory granule
-cleaved by proconvertases

Question 28

Proconvertases

Answer 28

-cleave insulin peptide to A + B chains and C peptide in secretory granules

Question 29

Insulin granules?

Answer 29

-has zinc
-zinc packs insulin together in nic structure