PHYSIOLOGY 4TH BIMO
ENDOCRINE SYSTEM- PANCREAS
DR.PALOMA
PANCREATIC HORMONES:
1. INSULIN
- Protein hormone from beta cells of the
pancreas
- Belongs to the gene family that include: insulin-
like growth factors I and II (IGF I & IGF II) and
relaxin
- Synthesized on the polyribosomes as
preproinsulin endoplasmic reticulum as
proinsulin  golgi apparatus as secretory
granules in zinc-bound crystals exocytosis
*The peptide chain of insulin’s prohormone folds back on
itself with the help of disulfide (S-S) bonds. The prohormone
cleaves to insulin and C-peptide
1 -
…INSULIN
- Is an anabolic and hypoglycemic hormone
- Facilitates glucose entry into cells except brain,
kidney tubules, intestinal mucosa, and red
blood cells
- Indirectly facilitates glucose entry into
hepatocytes by promoting glycogenesis
(reducing intracellular glucose)
- Directly facilitates glucose entry in other cells
by its action on the cell membrane
- Has a half-life of 5-8 minutes
- Degraded rapidly from the blood by
INSULINASE in the liver, kidney and other
tissues
- Because insulin is secreted into the portal vein,
it is exposed to liver insulinase before it enters
the peripheral circulation. As a consequence,
almost half the insulin is degraded before
leaving the liver. Thus peripheral tissues are
exposed to only half the serum insulin
concentration as the liver
- Insulin begins to be released a few minutes
after food intake
- If stimulus is maintained, insulin secretion falls
within 10 mins. And slowly rise again within 1
hour. These are the EARLY PHASE AND LATE
PHASE OF INSULIN RELEASE. The early phase
releases the pre-formed whereas the late
phase releases the newly formed insulin.
- GLUCOSE is the primary stimulus of insulin
secretion
- GLUT2 transporter facilitates entry of glucose
into beta cells
- GLUTOKINASE ENZYME- the “GLUCOSE
SENSOR” of beta cells. This phosphorylates
glucose to G6P once it enters the beta cells. It
has been found that the rate of glucose entry is
correlated to the rate of glucose
phosphorylation and directly related to insulin
secretion.
…INSULIN
- ATP-SENSITIVE K+ CHANNELS- closes with G6P
metabolism by beta cells. This has ATP-binding
subunit called SUR which is also activated by
sulfonylurea drugs (oral agents for
hyperglycemia)
- VOLTAGE GATED CALCIUM CHANNELS open-
activates exocytosis of insulin/proinsulin
secretory granules
OTHER FACTORS THAT INCREASE INSULIN SECRETION:
- Amino Acid
- Beta keto acids
- Glucagon
- Acetylcholine-vagal (parasympathetic)
cholinergic innervation (i.e.- in response to a
meal)
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Free fatty acids (through a G-protein coupled
reactor)
- Intestinal hormones (i.e.-glucagon-like peptide1
(GPL-1), gastric inhibitory polypeptide- GIP)- act
by raising cyclic-AMP which amplifies the effect
of calcium
- BUT THESE AGENTS DO NOT INCREASE INSULIN
SECRETION IN THE ABSENCE OF GLUCOSE
FACTORS THAT INHIBIT INSULIN SECRETION:
- ALPHA 2 ADRENERGIC RECEPTORS w/c are
activated by epinephrine from adrenal medulla
& norepinephrine from postganglionic
sympathetic fibers. This act by decreasing cyclic
AMP.
- Adrenergic inhibition of insulin serve to protect
against hypoglycemia especially during exercise
- Beta adrenergic blockers
- Thiazides
- Alloxan
- Somatostatin from D cells (unclear in humans)
THE INSULIN RECEPTOR:
- Member of the RECEPTOR TYROSINE KINASE
(RTK) family
- Composed of alpha/beta monomers. The alpha
subunit are external and contain the hormone
binding sites. The beta span the membrane and
contain the tyrosine kinase domain
- Binding of insulin to the receptor induces cross
phosphorylation of each beta subunit on 3
tyrosine residues
 - Termination of insulin/IR signaling potentially
play a role in insulin resistance and type 2
diabetes mellitus
- Insulin down-regulate its own receptor by
receptor mediated endocytosis
- Several serine/ threonine protein kinases are
activated by insulin w/c inactivate IR and IRS
proteins
- Activation of “suppressor of cytokine signaling”
(SOCS) family of protein which residues activity
levels of IR and IRS proteins
PRINCIPAL ACTIONS OF INSULIN
ADIPOSE TISSUE
- Increase glucose entry
- Increase fatty acid synthesis
- Increase glycerol phosphate synthesis
- Increase triglyceride deposition
- Activation of lipoprotein lipase
- Inhibition of hormone-sensitive lipase
- Increased potassium uptake
SKELETAL MUSCLE
- Increased glucose entry
- Increased glycogen synthesis
- Increased amino acid uptake
- Increased protein synthesis in ribosomes
- Decreased protein catabolism
- Decreased release of gluconeogenic amino
acids
- Increased ketone uptake
2 - Increased potassium uptake
LIVER
- Decreased cyclic AMP
- Decreased ketogenesis
- Increased protein synthesis
- Increased lipid synthesis
- Decreased glucose output due to decreased
gluconeogenesis and increased glycogen
synthesis
GLUCAGON
- From alpha cells
- The primary “COUNTERREGULATORY”
HORMONE that INCREASES BLOOD GLUCOSE
LEVELS through its effects on liver glucose
output
- A CATABOLIC, GLYCOGENOLYTIC,
GLUCONEOGENIC, LIPOLYTIC AND KETOGENIC
HORMONE
- A member of the secretin gene family. The
precursor preglucagon has the AA sequences
for glucagon (GPL1 and GPL2) which is cleaved
to produce the 29-amino acid peptide glucagon
- Circulates in an unbound form with a short half
life of 6 minutes
- LIVER is the primary target of glucagon with
only small effects on peripheral tissues. This is
also THE PREDOMINANT SITE OF GLUCAGON
DEGRADATION (80%). Because the glucagon
(from gut or pancreas) enters the hepatic portal
vein to the liver before reaching the systemic
circulation, a large portion of the hormone
never reach the systemic circulation.
FACTORS THAT STIMULATE GLUCAGON SECRETION
- Drop in blood glucose. A major stimulus for
glucagon secretion
- Circulating catecholamines stimulate glucagon
secretion via Beta 2 adrenergic receptors
- Serum amino acids. This means that a protein
meal will increase postprandial levels of both
insulin and glucagon which protects against
hypoglycemia; whereas a carbohydrate meal
stimulates inly insulin.
- Fasting hypoglycemia, exercise, CCK, cortisol,
stress, and cholesterol.
FACTORS THAT STIMULATE INSULIN INHIBIT GLUCAGON
SECRETION.
GLUCAGON SECRETION IS INHIBITED BY SOMATOSTATIN, FREE
FATTY ACIDS, SECRETIN, KETONES AND INSULIN
SOMATOSTATIN
- From DELTA CELLS
- 15-amino acid single chain polypeptide
- A local regulator of insulin and glucagon
secretion
- Inhibits secretion of both insulin and glucagon
- Also found in the hypothalamus (GH secretion
inhibitor)
DIABETES MELLITUS
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A.BASIC BIOCHEMICAL DEFECTS
1. Decreased glucose uptake by cells leading to:
- Hyperglycemia
- Glucosuria
- Osmotic diuresis
- Urinary loss of sodium and potassium
- Dehydration if water intake is inhibited
2. Increased protein catabolism increasing:
- Plasma amino acid conc.
- Nitrogen loss in the urine
3. Increased lipolysis leading to:
- Increased plasma free fatty acids
- Ketonemia, ketonuria, metabolic acidosis
- Respiratory compensation lowering PCO2
4. Increased glycogenolysis
5. Increased gluconeogenesis
CLINICAL SIGNS AND SYMPTOMS
- Polyuria, nocturia and polydipsia
- Polyphagia with weight loss
- Dehydration in cases of failure to drink water
- Acetone breath
- Kussmaul’s breathing
- Vomiting and abdominal pain
- Stupor coma and death