Pancreatic Hormones

Exocrine pancreas cell composition

acinar and pancreatic duct cells

Acinar cell purpose

secrete digestive enzymes

Enzymes secreted by acinar cells

Amylase, proteases, lipases and phospholipases, nucleases

Amylase function

digest carbohydrates

Protease function

hydrolyze proteins

Lipase and phospholipase function

breakdown lipases

Nuclease function

digest nucleic acids

Pancreatic duct cell secretion

bicarbonate rich fluid

Endocrine pancreas name

islets of Langerhans

What percentage of the pancreas is the islets

1-2% of mass

What innervates islet cells

SNS and PNS of ANS

How do Islet cells communicate with each other

gap junctions and hormonal regulation

Alpha cell product secreted

Glucagon

Cellular response of alpha secretion of glucagon

promote liver output of glucose

Glucagon role in glucose regulation

elevates blood glucose

Beta cell secretions

Insulin, proinsulin, c peptide, amylin

Cellular response to insulin (glucose, glycolysis, anabolic pathways)

promote glucose uptake

stimulate glycolysis

stimulate anabolic pathways

Insulin’s role in glucose regulation

Lower blood glucose + promote storage of glycogen

Proinsulin major cellular response

Weak insulin-like activity at ~ 1/20th of insulin

Proinsulin role in glucose regulation

no major role

C peptide major cellular response

Marker of insulin secretion- secreted with insulin at 1:1 ratio

C peptide role in glucose regulation

no major role

Amylin major cellular response

Co-secreted with insulin at about 100:1 (insulin:amylin)

Amylin role in glucose regulation

Slows gastric emptying, promote satiety, and prevents after meal spikes in blood glucose

Delta cell secreted product

somatostatin

Somatostatin major cellular response

Inhibit secretion of insulin and glucagon

Somatostatin role in glucose regulation

unknown

F cell secreted product

Pancreatic polypeptide

Pancreatic polypeptide major cellular response

unknown

Pancreatic polypeptide role in glucose regulation

unsure if any action on fuel homeostasis

What stimulates synthesis and secretion of insulin

Exposure of beta cell to glucose stimulates synthesis and secretion

Steps in synthesis of insulin

Synthesis occurs in ER and Golgi of beta cell

1. Insulin gene on Chr 11 transcribed to mRNA

2. mRNA translated to preproinsulin

3. Preproinsulin cleaved to proinsulin in ER

4. Proinsulin with A, B, and C domains is packaged in secretory vesicles by Golgi

5. Proteases cleave C domain (C-peptide)

6. Resultin insulin molecule has two domains, A and B, joined by disulfide bridges

What happens to secreted insulin in the first pass through the liver

60% of secreted insulin is removed in a first pass through the liver

What happens to secreted C-peptide in the first pass through the liver

C-peptide is not removed

How to measure insulin secretion

quantity of C-peptide secreted per 24 hours is a good indication of insulin released over 24-hour period

Major stimulus for insulin secretion

glucose

Incretin hormone effect

oral glucose elicits higher insulin secretory response than IV glucose

Incretin name origin

intestine + secretion + insulin → incretin from intestine secreted to stimulate insulin

Mechanism of glucose stimulated insulin secretion

1. Glucose enters beta cell through GLUT2

2. Glucose phosph by GK

3. Glucose metabolized

4. Increase ATP

5. ATP sensitive potassium channels close

6. Membrane depolarization

7. Voltage dependent calcium channels open

8. Influx of calcium

9. Fusion of insulin containing secretory vesicles to membrane and release of insulin

Insulin receptor

receptor tyrosine kinase with 2 identical alpha chains and 2 identical beta chains

Insulin receptor signal transduction

• Insulin binds to sites on the alpha chains

• Receptor phosphorylates itself and other intracellular substrates (e.g. insulin receptor substrates)

• Activation of other kinases and phosphatases

Glucose effect of Insulin receptor signal transduction

Translocation of GLUT-4 to plasma membrane allowing glucose transport into cell

Gene expression and growth effect of Insulin receptor signal transduction

increased gene expression and growth

Protein, glycogen, and triacylglycerol synthesis effect of Insulin receptor signal transduction

Increased protein, glycogen, and triacylglycerol synthesis

Effects of insulin on hepatocytes (glucose, GK, glycogen, fats, proteins)

1. Glucose enters by GLUT-2 (not insulin sensitive)

2. Promotes synth of GK- incr glycolysis and carbohydrate oxidation

3. Promotes glycogen synth by activating glycogen synthase

4. Promotes synth and storage of fats by stim acetyl CoA carboxylatse

5. Promotes protein synth

Effects of insulin on skeletal muscle

1. Glucose enters by GLUT-4

2. Translocation of GLUT-4 to plasma membrane

3. Promotes glycogen synthesis by activating hexokinase and glycogen synthase

4. Promotes protein synthesis and slows protein degradation

Overall effects of insulin on skeletal muscle and hepatocytes***

directs cellular fuel metabolism, increase oxidation of glucose preserving protein and fat stores

Major effects of insulin on adipocytes

1. Glucose enters through GLUT-4

2. Translocation of GLUT-4

3. Metabolism of glucose to alpha-glycerol to make fat

4. inihibits hormone sensitive lipase

5. promotes synthesis of lipoprotein lipase

Importance of insulin stimulation of lipoprotein lipase synthesis in adipocytes

exports LPL to the endothelial cells where it breaks down circulating TAG found in lipoproteins. The breakdown product of LPL is fatty acids which leave the circulation and enter body’s cells

Major effects of insulin on neurons

1. Glucose enters brain through GLUT-3 transporter and through GLUT-4

2. modulates peripheral metabolism

3. modulates neuronal functions

4. modulates phosphorylation of tau protein- component in development of alzheimer disease

Clinical implication of insulin effects on neurons

Insulin Resistance and Type 2 Diabetes Mellitus contribute to cognitive and mood disorders and neurodegenerative diseases

Insulin resistance

Complex metabolic disorder, insidious (develops gradually)

Insulin resistance pathogenesis

accumulation of ectopic lipid deposition

Contraction-Mediated Uptake of Glucose in Skeletal Muscle

Muscle contraction provides a non-insulin-stimulated mechanism to promote glucose entry into muscle cells- stimulates the translocation of GLUT4 transporters into the muscle membrane

Exercise effect on insulin sensitivity

Regular exercise can enhance insulin sensitivity and thus plays an important role in the prevention and treatment of type 2 diabetes mellitus

Glucose and insulin response to exercise

• Increase glucose transport during exercise

• After-exercise effect promotes insulin sensitivity and promotes glycogen storage

Mechanism for exercise stimulation of glucose uptake

1. AMP-activated Kinase (AMPK) activated by high AMP/ATP ratio

2. Exercise stimulates AMPK- exercise depletes ATP stimulating production of 2 ADP → ATP + AMP

3. AMPL stimulates phosphorylation of AS160

4. AS160 when not phosphorylated inhibits translocation of Glut-4 to the membrane

5. Phosphorylation of AS160 promotes GLUT-4 translocation

Is insulin-stimulated and contraction-stimulated glucose additive

yes

Clinical Implication of insulin-stimulated and contraction-stimulated glucose being additive

timing of insulin dosing and physical activity/exercise must be considered to prevent hypoglycemia

Stimuli for secretion of glucagon in hepatocytes

decreased plasma glucose (amino acids also stimulate secretion)

Glucagon mechanism

Glucagon binds to glucagon receptor, which is a G-protein coupled receptor. This interaction stimulates cAMP-dependent signaling pathways

Major effects of Glucagon

1. Promotes glycogenolysis and inhibits glycogen synthesis

2. Promotes gluconeogenesis

3. Promotes oxidation of fats and production of keton bodies

Absorptive State endocrine stimulus

insulin

Absorptive State characteristics

• Ingested nutrients are entering the blood

• Glucose is the major energy source

• Anabolic pathways predominate and body proteins are maintained

• Metabolic pathways promote storage of fuels (glycogen, fat)

Postabsorptive State major endocrine stimulus

GLUCAGON + cortisol, SNS

Postabsorptive State characteristics

• GI tract is empty of nutrients

• Major goal is to “spare the glucose” for the brain

• Glycogenolysis, Gluconeogenesis, and Lipolysis maintain blood glucose