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Endo Repro Midterm > Endocrine Pancreas > Flashcards

Endocrine Pancreas Flashcards

1
Q

Describe the organization of the islets of Langerhans in terms of cell types and
hormones secreted.

LO1

A

Hormones of endocrine cells of pancreas

  1. insulin
  2. glucagon
  3. somatostatin

Fxn: lipid, CHO, and AA metabolism

Clusters= islets of Langerhans

  • 1-2% of pancreatic mass
  • 2500 cells/islet
  • innervated by adrenergic, cholinergic, and peptidergic neurons
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2
Q

B cells of pancreas

  • %
  • secretion
A

60-65% of islet

centrally located

secrete insulin and C peptide

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3
Q

A cells of pancreas

  • %
  • secretion
A

20% of islet

peripherally located

secrete glucagon

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4
Q

D cells of pancreas

  • %
  • secretion
A

5% of islet

secrete somatostatin

neuronal in appearance and send “dendrite-like” processes to B cells

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5
Q

F cells of pancreas

A

Secrete pancreatic polypeptide

acts like a satiety signal

  • neuropeptide Y
  • peptide YY family
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6
Q

Describe the paracrine mechanisms of hormones in the pancreatic islets
- how do islets of langerhans communicate with each other? (2)

LO2

A

Ion concentration changes signal

  1. Gap junctions
    - rapid cell-to-cell communication
  2. Blood supply
    - islets receive 10% of pancreatic blood flow
    - venous blood from one cell type bathes other cell types
    - venous blood from B cells carries insulin to a and b cells
    • blood flow to center of islet & pick up insulin
    • flows through periphery on a cells to inhibit glucagon secretion

*paracrine actions work in reverse of blood flow

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7
Q

Explain the significance of the C
peptide as a diagnostic tool

Lo3

A

insulin and cleaved C peptide packaged together in secretory vesicles

  • secreted in equimolar quantities into blood

**C peptide can be used as marker of endogenous insulin secretion

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8
Q

Insulin

  • characteristic
  • secreted in response to…
  • main stimulator
A

Major anabolic hormone

secreted in response to carbohydrate and protein meal

glucose is main stimulatory factor of insulin secretion

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9
Q

Insulin synthesis

  • components
  • pathway

LO3

A

Peptide hormone- 2 chains linked by disulfide bridges

Preproinsulin-> proinsulin-> insulin and C peptide

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10
Q

Preproinsulin

A

signal peptide with A & B chains with connecting peptide (C peptide)

  • no disulfide bonds
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11
Q

Proinsulin

A

no signal peptide

  • c peptide still attached in insulin
  • packaged into secretory granules
  • proteases here cleave proinsulin
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12
Q

Explain the glucose-dependent regulation of insulin secretion/release from pancreatic β cells
- 8 steps

LO4

A
  1. Glucose enters cells via GLUT2
  2. Glucose is phosphorylated by glucokinase
  3. Glucose 6 phosphate is oxidized promoting ATP generation
  4. ATP closes the “inward-rectifying” K+ channels
  5. Plasma membrane is depolarized
  6. Activation of voltage-gated Ca2+ channels
  7. Ca2+ enter cells
  8. Initiates mobilization of insulin(and C peptide) containing vesicles to plasma membrane and exocytosis
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13
Q

Explain the glucose-dependent regulation of insulin secretion/release from pancreatic β cells
- key ideas/ concepts (sulfonylurea, c peptide)

A
  1. rises in ATP CLOSES the K+ channels ( ATP dependent K channels)
  2. Sulfonylurea receptor, associated with ATP- dependent K+ channels, increase insulin secretion
    - causes membrane depolarization to occur more easily
    - more Ca2+ entry
    - used for type 2 DM treatment
  3. C peptide secretion used as tool to measure function to b cells and endogenous insulin secretion
    - C peptide is typically secreted in urine
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14
Q

Insulin Receptor

- mechanism it undergoes

A

bound-insulin receptor autophosphorylates itself and phosphorylates other proteins

insulin-receptor complex is internalized by target cell

downregulation of receptor by insulin itself

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15
Q

Intracellular steps leading to insulin
secretion (3)

LO4a

A
  1. insulin binding to receptor
    - phosphorylation of insulin receptor substrate (IRS) and other proteins
  2. Substrate proteins phosphorylate and activate/inactivate downstream pathways
    - PI3k/AKt/ mtor
    - MAP kinases
    - these mediate metabolic and mitogenic responses
  3. Translocation of vesicles containing GLUT4 to membrane
    - Glucose enters via faciliated diffusion
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16
Q

Insulin secretion in relationship to blood glucose
- diabetics

LO4a

A

insulin secretion is PROPORTIONAL to plasma glucose changes

glucose stimulate insulin secretion in a BIPHASIC manner

  • in diabetic individuals: “first phase” or acute insulin response is lost first
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17
Q

Alternative Intracellular Pathways for Glucose Uptake Independent of Insulin

LO4a

A

activation of AMP-kinase (AMPK) results in GLUT 4 translocation to plasma membrane

muscle contractions stimulate this process

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18
Q

How does GI peptides (CCK, GLP-1, GIP), and local glucagon and somatostatin
modulate insulin release?

LO5

A

GI peptides

  • via GPCR signaling/ adenlyl cyclase/ camp
  • via GPCR signaling/ IP3/DAG/PKC

glucagon

  • via GPCR signaling
  • adenlyl cyclase

Somatostatin
via GPCR signaling
- andenylyl cylase

19
Q

Stimulatory Factors for insulin secretion

LO8

A
  • increase glucose concentration
  • increase AA concentration
  • increase FA and ketoacid concentration
  • glucagon
  • cortisol
  • glucose-dependent insulinotropic peptide (GIP)
  • potassium
  • vagal stimulation (ACH)
  • Sulfonylurea drugs
20
Q

Inhibitory Factors for insulin secretion

LO8

A
  • decreased blood glucose
  • fasting
  • exercise
  • somatostatin
  • alpha adrenergic agonist; NE
  • diazoxide
21
Q

Describe the main effects of insulin on carbohydrate, protein, and fat metabolism
- on Skeletal muscles (5)

LO6

A
  1. increased glucose uptake
    - increase GLUT4 and better translocation
  2. increase glycogen synthesis
    - increase hexokinase/glucokinase
    - activates glycogen synthase
  3. Increase glycolysis and CHO oxidation
    - increase glycolysis- hexokinase, PFK, PDH
  4. increased protein synthesis
  5. decreased protein breakdown
22
Q

Describe the main effects of insulin on carbohydrate, protein, and fat metabolism
- on liver (7)

LO6

A
  1. promote glycogen synthesis
    - glucokinase and glycogen synthase
  2. increases glycolysis and CHO oxidation
    - glucokinase, PFK, pyruvate kinase
  3. decreases gluconeogenesis
    - inhibit PEPCK, fructose 1,6 biphosphate, and G6P phosphatase
  4. increase hexose monphosphate shunt
  5. increase pyruvate oxidation
  6. increase lipid storage and decrease lipid oxidation
  7. increases protein synthesis and decrease protein breakdown
23
Q

Describe the main effects of insulin on carbohydrate, protein, and fat metabolism
- on adipose tissue (4)

LO6

A
  1. increased glucose uptake
    - increased GLUT4 and better translocation
  2. increased glycolysis
    - more production of a-glycerol phosphate for esterification and lipogenesis
  3. decreased lipolysis
    - inhibit HSL
  4. promotes uptake of fatty acids
    - LPL (lipoprotein lipase) activity/ synthesis
24
Q

Coordinated Actions of Insulin

LO8

*** MEMORIZE

A
  1. increase glucose uptake into cells
    - decrease glucose in blood levels
  2. increased glycogen formation
  3. decreased glycogenolysis
  4. decrease gluconeogenesis
  5. increase protein synthesis
    - decrease amino acids
  6. increased fat deposition
    - decreased fatty acids
  7. decrease lipolysis
    - decrease keto acids
  8. increased K+ uptake into cells
    - decreased K+
25
Q

Type 1 DM

  • general effects
  • conditions

LO10

A

Juvenile Onset diabetes

inadequate insulin secretion

destruction of B cells
- often from autoimmune disease

  1. increased blood glucose
  2. fatty acids
  3. ketoacids
  4. increased conversion of fatty acids to ketoacids

decreased utilization of ketoacids results in diabetic ketoacidosis (DKA)

26
Q

Type 1 diabetes

- effects on macromolecules (3)

A
  1. increase blood [glucose]
    - decrease uptake of glucose
    - decrease glucose utilization
    - increase gluconeogenesis
  2. increase blood [FA} and [ketoacid]
    - decrease FA synthesis
    - decrease TG synthesis
    - increase TG breakdown
    - increase level of circulating free FA
    - increased conversion of FA to ketoacids
    - decreased ketoacid utilization by tissues
    * results: Diabetic ketoacidosis= metabolic acidosis
  3. increase amino acid concentation
    - increase protein breakdown
    - decrease protein synthesis
    - increase catabolism of aa
    • loss of lean body mass (catabolic state)
      - increase ureagenesis
27
Q

Type 1 Diabetes Mellitus
- effects on ions and nutrients (2)

LO10

A
  1. hyperkalemia- shift of K+ out of cells
    - intracellular concentration is thus low
    - lack of insulin effect on Na/K Atpase
    - plasma levels may be normal, total K+ is usually low due to polyuria and dehydration
  2. Osmotic diuresis/ Glucosuria
    - increased blood glucose increases filtered load of glucose, exceeds reabsorptive capacity of proximal tubule
    - water & electrolyte reabsorption also blunter
    - Polyuria-increases excretion of Na and K even though urine concentration of electrolytes if low
    - thirst (polydipsia)
28
Q

Treatment of Type 1 DM insulin replacement

  • goal
  • drawbacks (5)

LO11

A

goal: recreate normal physiology (basal and bolus insulin)
- insulin injections right before meals

Drawbacks

  1. painful and time consumin
  2. lag between glucose measurement and insulin dosing
  3. delayed absorption of insulin following sc injections
  4. poor blood glucose control -prolonged periods of hyperglycemia
  5. insulin pumps have advantages
29
Q

Type 2 Diabetes Mellitus
- describe

LO12

A

insulin resistance

  • progressive exhaustion of active B-cells due to environmental factors (amongst others)
    • includes sedentary lifestyle, malnutrition, obesity
    • pt produce insulin, but often ned more and more

95% of diabetes cases

30
Q

Type 2 DM

  • associations
  • progression of insulin resistance (3)

LO12

A

reactive hyperinsulinemia followed by relative hypoinsulinemia

obesity-induced insulin resistance

  1. decreased GLUT 4- uptake of glucose in response to insulin (classical skeletal muscle impairment)
  2. Decreased ability of insulin to repress hepatic glucose production
  3. inability of insulin to repress adipose tissue uptake (via LPL) and lipolysis (via HSL)
31
Q

Type 2 DM pathophysiology

- effects and mechanism

A
  1. insulin resistance mechanism still not well understood
    - post-receptor signaling- ultimately results in decreased glucose transport number and mobilization
  2. increased hepatic glucose productions
  3. non-alchoholic fatty liver disease/ hepatic steatosis
  4. hyperglucagonemia
  • not as prone to ketoacidosis as T1DM

non-obese patients T2DM can occur due to decreased insulin release by pancreas independent of peripheral insulin resistance

32
Q

Treatment of Type 2 DM

LO12

A
  1. Caloric restriction, weight reduction, physical activity/exercise
  2. insulin secretagogues
    - sulfonylurea drugs
    - incretin analog of GLP-1 (exanatide);injection needed
  3. slow absorption of CHO
    - a-glucosidase inhibitors (acarbose, migitol)
    - amylin analogs (pramintide)
  4. Insulin sensitizers
    - biguanide drugs (metformin)- better insulin receptor trafficking
  5. bariatric surgery
33
Q

Glucose Tolerance Test

A

if insulin slowly rises, no biphasic first phase=> diabetics

34
Q

Incretin Hormones

  • types
  • characteristics
A

intestine derived hormones
- GLP-1, GIP (secreted in response to GI glucose and fat)

short half life

stimulate insulin secretion (glucose dependent)

inhibit glucagon secretion

slow gastric emptying

35
Q

Type 1 DM Summary

  • age of onset
  • ketosis on onset
  • family history
  • pathophysiology
  • associated conditions

LO13

A

age of onset
- peak in early childhood and adolescence

ketosis on onset
- common

family history
- 10-20%

pathophysiology
- autoimmune disease

associated conditions

  • autoimmune thyroid disease
  • Celiac Disease
  • Addison’s Disease
36
Q

Type 2 DM Summary

  • age of onset
  • ketosis on onset
  • family history
  • pathophysiology
  • associated conditions

LO13

A

age of onset
- post-pubertal

ketosis on onset
- uncommon

family history
- >50%

pathophysiology
- insulin resistance

associated conditions

  • obesity
  • lipid abnormalities
  • PCOS
  • NAFLD
37
Q

Glucagon

  • characteristics & structure
  • synthesis
  • storage
A

single straight-chain polypeptide with 29AA

member of same peptide family as secretin and GIP

synthesized as preproglucagon

stored in dense granules of a-cells

38
Q 
Secretion of Glucagon 
- stimulated by... (6)
- blood glucose 
- insulin 
- inhibitory factors
LO15
A

stimulated by

  1. **decrease blood glucose\
  2. increased AA
  3. fasting
  4. CCK
  5. b adrenergic agonists
  6. Ach

Blood glucose reflects balance between hypoglycemic actions of insulin and hyperglycemic actions of anti-insulin hormones

insulin inhibits glucagon production and secretion

other inhibitory factors include:
- somatostatin, FA, ketoacids

39
Q

Actions of Glucagon on liver

LO14

A

Glucagon increases blood glucose

  • substrates are directed toward glucose formation
  • increases gluconeogenesis (reduced productions of Fructose 2,6 biphosphate)
  • increased glucogenolysis
  • inhibit glycogen synthesis
40
Q

Glucagon actions on other organs

A

Stimulates lipolysis- both adipose tissue and skeletal muscle

ketoacids produced from fatty acids

41
Q

Stimulatory factors affecting glucagon secretion (7)

A
  • fasting
  • decrease glucose conc
  • increase aa concentration
  • increase FA and ketoacid concentration
  • CCK
  • B adrenergic agonist
  • ACh
42
Q

inhibitory factors affecting glucagon secretion (3)

A
  • insulin
  • somatostatin
  • Increase FA and ketoacid concentration
43
Q

Glucagon actions and effects of blood levels (4)

A
  1. increase glycogenolysis
    - increase blood glucose concentration
  2. increae gluconeogenesis
  3. increase lipolysis
    - increase blood FA concentration
  4. increase ketoacid formation
    - increase blood ketoacid concentration

Endo Repro Midterm (12 decks)

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