You are on page 1of 70

The Endocrine Pancreas

Pancreas
A triangular gland, which has both exocrine and endocrine cells, located behind the stomach

Strategic location Acinar cells produce an enzyme-rich juice used for digestion (exocrine product) Pancreatic islets (islets of Langerhans) produce hormones involved in regulating fuel storage and use.

The Endocrine Pancreas

Islets of Langerhans
1 million islets
1-2% of the pancreatic mass Beta () cells produce insulin

Alpha () cells produce glucagon


Delta () cells produce somatostatin F cells produce pancreatic polypeptide

Islets of Langerhans

Insulin
Hormone of nutrient abundance
A protein hormone consisting of two amino acid chains linked by disulfide bonds Synthesized as part of proinsulin (86 AA) and then excised by enzymes, releasing functional insulin (51 AA) and C peptide (29 AA).

Insulin Structure
1- Large polypeptide 51 AA (MW 6000) 2- Two chains linked by disulfide bonds. A chain : (21 AA) B chain : (30 AA) 3 -Disulfide bonds.

51 amino acids
2 chains linked by disulfide bonds 5800 Dalton molecular weight

Insulin Structure

Protein and Polypeptide Synthesis and Release

Insulin Synthesis
insulin gene encodes a large precursor of insulin (preproinsulin) During translation, the signal peptide is cleaved (proinsulin) During packaging in granules by Golgi, proinsulin is cleaved into insulin and C peptide

Insulin Synthesis
DNA (chromosome 11) in cells

mRNA
Preproinsulin (signal peptide, A chain, B chain, and peptide C)

proinsulin
insulin

Insulin Synthesis

Synthesis of insulin and role of C-Peptide


Inactive Insulin Precursors
Preproinsulin and Proinsulin

C- peptide
Essential for Proper folding
Good Indicator of insulin secretion

Insulin Synthesis
Insulin synthesis is stimulated by glucose or feeding and decreased by fasting Threshold of glucose-stimulated insulin secretion is 100 mg/dl. Glucose rapidly increase the translation of the insulin mRNA and slowly increases transcription of the insulin gene

Glucose is the primary stimulator of insulin secretion

Glucose Dependent Release of Insulin into blood


Mediated through rise in Calcium Concentration in - cells

Glucose taken into cells is phosphorylated and metabolized


Resultant production of ATP ATP sensitive K- Channels closes leading to depolarization Opening of Voltage - gated calcium channels and influx of calcium into the cells Calcium causes vesicles containing insulin to be Exocytosed from cells Drugs like sulfonylureas, oral hypoglycemic agents increase insulin secretion by closing ATP sensitive K Channels

Regulation of Insulin Secretion

Regulation of Insulin Secretion


No insulin is produced when plasma glucose below 50 mg/dl Half-maximal insulin response occurs at 150 mg/dl A maximum insulin response occurs at 300 mg/dl

Insulin secretion is biphasic:


Upon glucose stimulation an initial burst of secretion (5-15 min.)

Then a second phase of gradual increment that lasts as long as blood glucose is high

Insulin secretion is biphasic

Insulin works through a tyrosine kinase (TK) receptor mechanism


Insulin from b cells of the pancreas

Figure 6-10

Insulin Signaling

Insulin regulation of glucose entry in skeletal muscle


*Overall insulin promotes storage of glucose as a fuel and a reduction of

blood glucose when elevated

Insulin regulation of glucose metabolism in the liver

Figure taken from: http://www.smbs.buffalo.edu/bch/Courses/bch404/GW_Nature_InsulinSig.pdf#search=%22GLUT4%20vesicles%20micrograph%22

Metabolic Effects of Insulin


Nearly all cells (80%) increase glucose uptake (seconds)

Active transport
Primarily affects liver and muscle

Brain tissue is excepted


Alters phosphorylation of many key intracellular metabolic enzymes (minutes)

Alters protein synthesis and gene transcription (hours)

Insulin Action on Cells:


Insulin is the hormone of abundance. The major targets for insulin are: liver Skeletal muscle

adipose tissue The net result is fuel storage as glycogen , TAG & proteins with inhibition of their mobilization

Insulin Action on Carbohydrate Metabolism:

Liver:
Stimulates glucose oxidation Promotes glucose storage as glycogen Inhibits Glycogenolysis Inhibits gluconeogenesis Muscle: Stimulates glucose uptake (GLUT4) Promotes glucose storage as glycogen

Insulin Action on Carbohydrate Metabolism : Adipose Tissue:

Stimulates glucose transport into adipocytes


Promotes the conversion of glucose into triglycerides and fatty acids

Glucose Transport
GLUT2 (liver, pancreas) GLUT4, insulin sensitive transporter (muscle, adipose tissue) GLUT3 (brain)

Glycogen Synthesis
Short term storage of glucose

Activates glycogen synthase


Inhibit glycogen phosphorylase

Glycolysis is also stimulated by insulin

Lipogenic and Antilipolytic


Insulin promotes lipogenesis and inhibits lipolysis Promotes formation of -glycerol phosphate and fatty acid synthesis

Stimulates fatty acid synthase (FAS)


Inhibits hormone sensitive lipase (HSL)

Activates lipoprotein lipase (LPL)


Expression of gene for Lipoprotein Lipase is enhanced

Protein Synthesis Increased and Reduced Degradation


Insulin promotes protein accumulation:
1. Stimulates amino acid entry into cells 2. Increases the activity of protein synthesis by activation of factors required for initiation of translation

3. Inhibits protein degradation

Action of insulin on Liver:

Action of insulin on Fat:

Action of insulin on Muscle:

Insulin: Summary

Insulin Control
Gastrointestinal hormones

Most Cells
Muscle

Protein synthesis
Glucose uptake Glycogen synthesis

amino
acids

Adipose

Amino acids

Pancreas Insulin
Beta cells

Glucose uptake Glycerol production Triglyceride breakdown Triglyceride synthesis

triglycerides

Liver
Blood glucose

Glucose uptake

Glycogen synthesis Fatty acid synthesis Glucose synthesis

glucose

Brain
No effect
Feedback

Insulin Affects Tissues Differently: Summary


Muscle
Uptake of glucose and immediate use (exercise) or storage as glycogen (Exercising muscles can take up glucose without insulin)

Liver
Uptake of glucose and storage as glycogen
Inhibits glycogen phosphorylase Activates glycogen synthase Inhibits glucose synthesis Promotes excess glucose conversion to fatty acids

Adipose Tissue
Promotes glucose uptake and conversion to glycerol for fat production

Insulin and Fat Metabolism


Liver cells store glycogen only up to 5-6%
Remaining glucose metabolized to fat Triglycerides are synthesized and release into blood

Adipose cells store fat


Inhibits breakdown of triglycerides

Stimulates uptake and use of glucose to form glycerol


Stimulates fatty acid uptake and conversion to triglycerides

Lack of insulin
Free fatty acids build up in blood
Liver metabolizes to produce phospholipids and cholesterol Can lead to excess acetoacetic acid production and buildup of acetone (acidosis, which can lead to blindness and coma)

Insulin and Protein Metabolism


Promotes
Transport of amino acids Protein synthesis Gene transcription

Inhibits protein degradation Prevents glucose synthesis in liver


Preserves amino acids

Lack of insulin causes elimination of protein stores

Glucagon
A 29-amino-acid polypeptide hormone that is a potent hyperglycemic agent

Produced by cells in the pancreas


Its major target is the liver, where it promotes:

Glycogenolysis glycogen to glucose

the breakdown of

Gluconeogenesis synthesis of glucose from lactic acid and non-carbohydrates Release of glucose to the blood from liver cells

SYNTHESIS
DNA in cells mRNA Preproglucagon

proglucagon glucagon

Glucagon Signaling

Mechanism of action for glucagon


Glucagon from a cells of pancreas

Biological Effects Produced by Glucagon


INCREASED :

Glycogenolysis
Gluconeogenesis Fatty Acid Oxidation Ketogenesis Uptake of amino acids

DECREASED : Glycogenesis

Factors Affecting Glucagon Secretion:

Glucagon Action on Cells:

Targets of Glucagon Action


Activates a phosphorylase, which cleaves off a glucose 1-phosphate molecule off of glycogen. Inactivates glycogen synthase by phosphorylation (less glycogen synthesis). Increases Phosphoenolpyruvate carboxykinase, stimulating gluconeogenesis Activates lipases, breaking down triglycerides. Inhibits acetyl CoA carboxylase, decreasing free fatty acid formation from acetyl CoA Result: more production of glucose and substrates for metabolism

Regulation of Glucagon Release Increased blood glucose levels inhibit glucagon release.

Amino acids stimulate glucagon release (high protein, low carbohydrate meal). Stress: epinephrine acts on betaadrenergic receptors on alpha cells, increasing glucagon release (increases availability of glucose for energy).
Insulin inhibits glucagon secretion.

Insulin & Glucagon Regulate Metabolism

The Regulation of Blood Glucose Concentrations

Diabetes Mellitus (DM)


A serious disorder of carbohydrate metabolism
Results from hyposecretion or hypoactivity of insulin

The three cardinal signs of DM are:


Polyuria huge urine output Polydipsia excessive thirst Polyphagia excessive hunger and food consumption

Diabetes Mellitus Type I


Age of onset : Appears during childhood or puberty beta cells destroyed Moderate genetic predisposition

Low or No insulin produced chronic fasted state, "melting flesh",


Acute complications : ketosis, acidosis, glucosurea, diuresis & coma No response to oral hypoglycemic drugs Treatment only insulin replacement

Diabetes Mellitus: Type II --a Group of Diseases


Frequently occur after the age f 35

gradual appearance of symptoms


Very strong genetic predisposition Over 15 million diabetics in USA- 10% type I, 90% type II obesity usually observed Insulin resistance with combined inability of cells to produce appropriate quantity of insulin Chronic complications: atherosclerosis, renal failure& blindness Acute complication : hyperosmolar hyperglycemic state

Type II Diabetes Mellitus


Slow to develop. Genetic factors are significant. Occurs most often in people who are overweight.

Insert fig. 19.12

Decreased sensitivity to insulin or an insulin resistance.


Obesity.

Do not usually develop ketoacidosis.


May have high blood [insulin] or normal [insulin].

Diabetes Mellitus: Type II a Group of Diseases

GTT

Oral Glucose Tolerance Test

Measurement of the ability of b cells to secrete insulin. Ability of insulin to lower blood glucose.
Normal persons rise in blood [glucose] after drinking solution is reversed to normal in 2 hrs.

Insert fig. 19.8

Symptoms of Diabetes Mellitus

Metabolic Changes in Diabetes Mellitus (DM)

Consequences of Uncorrected Deficiency in Type I Diabetes Mellitus

Insert fig. 19.11

Treatment in Diabetes Change in lifestyle:


Increase exercise:
Increases the amount of membrane GLUT-4 carriers in the skeletal muscle cells.

Weight reduction. Increased fiber in diet. Reduce saturated fat.

Hypoglycemia
Over secretion of insulin. Reactive hypoglycemia:
Caused by an exaggerated response to a rise in blood glucose. Occurs in people who are genetically predisposed to type II diabetes. Insert fig. 19.13

Metabolic Regulation
Anabolic effects of insulin are antagonized by the hormones of the adrenals, thyroid, and anterior pituitary.
Insulin, T3, and GH can act synergistically to stimulate protein synthesis.

You might also like