Pancreatic Peptides

Question 1

What is the function of the pancreas?

Answer 1

• Maintaining constant circulating glucose levels (preferred source of energy for all cells)
• Changes in blood glucose are frequent due to physiological and metabolic events (food digestion, muscle activity, thermogenesis, food deprivation)
• Endocrine gland
• Insulin, glucagon, somatostatin, pancreatic polypeptide (PP), amylin, and gastrin
• Maintain normal glycemia (80-110 mg/100mL)

Question 2

Insulin

Answer 2

• Anabolic reactions
• Increase energy storage

Question 3

Glucagon

Answer 3

• Catabolic reactions
• Breakdown of energy stores

Question 4

Explain the cycle of glucose homeostasis.

Answer 4

• Brain consumes the most glucose in the body
• Glucose replenishment comes from the liver: 70% glycogenolysis (liver glycogen and 30% gluconeogenesis

1. Glucose consumption
2. Brain, RBCs, WBCs, Muscle
3. When glucose is needed: RBCs and WBCs release pyruvate and lactate, Muscles release pyruvate, lactate, glycogenic AA, and alanine, and Adipose tissue releases glycerol
4. Amino acid fragments and glycerol in liver begin gluconeogenesis to produce glucose -> stored glycogen
5. Stored glycogen undergoes glycogenolysis to produce glucose

• Amino acids predominantly coming from the muscles
• Lipolysis (triglyceride hydrolysis) leads to release of glycerol and free fatty acids into the bloodstream
• Muscle glycogen (80% of body pool) is used during exercise by the muscle cells but can not be redistributed into the body

Question 5

What are the two major tissue types in the pancreas?

Answer 5

1. Acini: secrete digestive juices into duodenum
2. Islets of Langerhans: secrete hormones into the blood

• 2% of pancreatic tissue is endocrine
• 98% is exocrine

Question 6

Explain the cells in the islets of Langerhans.

Answer 6

• 1 to 2 million islets organized around small capillaries
• Three major types of cells

1. Beta cell (60-80% of all cells in islets): lie mainly in the middle of each islet and secrete insulin and amylin
2. Alpha cells (15-20% of total): secrete glucagon
3. Delta cells (10%): secrete somatostatin
   - PP cell: present in small numbers in the islets and secretes pancreatic polypeptide

Question 7

Pancreatic Polypeptide (PP)

Answer 7

• Regulation of pancreatic enzymes and secretions
• Stimulates secretion of gastric acid (HCl) by the parietal cells of the stomach

Question 8

Amylin

Answer 8

• Regulation of food intake
• Slows gastric emptying and promotes satiety

Question 9

Explain the synthesis of insulin and glucagon.

Answer 9

1. Synthesized as large preprohormones
2. ER: prohormones are formed
3. Golgi: hormone and peptide fragments
4. Packaged into secretory granules

• Beta cells: insulin and connecting (C) peptide are released into the circulating blood in equimolar amounts (C-peptide is cleaved off)
• Insulin (polypeptide) containing two amino acid chains (A-21 and B-30 amino acids) connected by disulfide bridges
• Glucagon is a straight-chain polypeptide of 29 amino acid residues
• Insulin and glucagon circulate unbound to carrier proteins and have short half-lifes (about 6 minutes0

Question 10

What enzymes are responsible for the cleavage of proinsulin into insulin?

Answer 10

Peptidase enzymes: PC1/3 and PC2

Question 11

What are the targets of insulin signaling?

Answer 11

• Insulin affects all tissues directly or indirectly
• Main targets: liver, muscle, adipose tissue
• IR: two alpha and two beta subunits with two ligand binding domains

Question 12

Explain the impacts of insulin.

Answer 12

• Released with high blood glucose (wants to decrease)
  1. Muscle: increases glucose transport (uptake), increases glycogen synthesis
  2. Liver: Suppress gluconeogenesis, increase glucose transport, increase glycogen synthesis (storage)
  3. Adipose tissue: inhibits lipolysis and increases glucose transport
• Insulin promotes fat deposition, protein synthesis and protein storage
• Insulin stimulates transport of amino acids into the cells
• Insulin increases the translation of mRNA (forming to proteins)

Question 13

What are the three pathways when insulin binds to IR?

Answer 13

1. MAPK -> cell differentiation and vascular constriction regulation (ET-1)
2. IRS1 -> P13K -> AKT -> glucose uptake, glycogen synthesis, inhibit gluconeogenesis
3. GLUT4 translocation

Question 14

What is the impact of a lack of insulin?

Answer 14

• Lack of insulin causes protein depletion and increased plasma amino acids
• Protein wasting

Question 15

Explain the correlation of insulin and the brain.

Answer 15

• Insulin has little effect on uptake or use of glucose in the brain
• Brain cells are permeable to glucose
• When glucose falls too low, hypoglycemia shock (progressive nervous irritability -> fainting, seizures, coma)

Question 16

Glucagon

Answer 16

• Glucagon and GLPs are produced from the same pro-glucagon
• Glucagon produced by pancreatic alpha cells (and EEC and brain) and GLPs are produced by EEC (L-cells)
• 29 amino acids
• N-terminal histidine is essential for biological activity
• Adenyl-cyclase activity

Question 17

Explain the impacts of glucagon.

Answer 17

• Released with low blood glucose (wants to increase)
  1. Liver: stimulates gluconeogenesis and increases glycogenolysis
  2. Adipose tissue: increases lipolysis (burns fat)
• No glucagon receptor on muscle

Question 18

Glucagon receptor

Answer 18

• GPCR
• cAMP is key secondary messenger
• Glucagon receptors expressed in: liver and kidney, smaller amounts in adipose tissue, heart, adrenals
• No expression in muscle

1. Glucagon binding -> activates adenylate kinase
2. ATP -> cAMP
3. Inactive protein kinase -> active protein kinase
4. Inactive phosphorylase b kinase -> active phosphorylase b kinase
5. Phosphorylase b -> phosphorylase a (RLS)
6. Glycogen -> glucose-6-phosphate
7. Glucose released into blood

Question 19

How is glucagon secretion regulated?

Answer 19

• Low blood glucose = glucagon secretion
• Increased blood amino acids = glucagon secretion
• Exercise = glucagon secretion
• Increased blood glucose = inhibits glucagon secretion
• Somatostatin = inhibits glucagon and insulin secretion

Question 20

Type 1 Diabetes

Answer 20

• Lack of insulin production
• Autoimmune (own immune system attacks pancreas)
• Genetic link
• Treat with insulin (insulin-dependent)
• Ligand issue
• Onset in childhood or mid-life
• Lower BMI

Question 21

Type 2 Diabetes

Answer 21

• Target cells are resistant to insulin
• Treat with diet and exercise
• May treat with oral medications
• May treat with insulin
• Receptor issue
• Onset in adulthood
• Higher BMI
• High circulating glucose and insulin levels -> insulin resistance (IR)
• Insulin resistance increases with weight gain (intra-abdominal)
• Decreased glucose disposal rate in response to insulin
• Impaired insulin action in muscle, liver, and fat

Question 22

Explain the impact of insulin resistance in different organs.

Answer 22

1. Muscle: decrease glucose transport and decrease glycogen synthesis
2. Liver: failure to suppress gluconeogenesis, intact fatty acid synthesis
3. Adipose tissue: decreased glucose transport, impaired lipolysis inhibition

• Mechanisms: excess circulating insulin -> receptor downregulation and increased negative feedback
• Cell autonomous (immune) impairment of insulin signaling
• Enlargement of adipose cells leads to IR
• Chronic inflammation