BIO 5406 Notes, 4/09/08
ENDOCRINE REGULATION OF METABOLISM
I. Introduction to Growth and Metabolism. [Hadley, pp. 264-265]a
A. Definitions.
1. Metabolism = All of the chemical reactions that occur within the cells
of the body.
2. Anabolism = Reactions that require energy and result in formation of
complex molecules.
3. Catabolism = Reactions that break down complex molecules and
release energy.
B. Energy balance.
1. During growth, anabolic processes dominate, regulated by anabolic
hormones.
2. During starvation, catabolic processes dominate, regulated by
catabolic hormones.
3. In between these two extremes, there is approximate balance
between anabolism and catabolism.
C. Growth.
1. Growth = Increase in size of an organism.
2. Two periods of rapid growth in the human.
a. Perinatal (fetus to 2 years after birth).
b. Puberty.
3. Growth involves:
a. Protein synthesis which exceeds breakdown ───> positive
nitrogen balance.
b. Cell multiplication and enlargement.
c. Increase in organ size (ex. skeletal muscle, bone).
d. Weight gain.
4. Requirements for growth.
a. Individual's growth capacity is genetically determined.
b. Environmental factors.
1. Adequate nutrition.
2. Freedom from disease.
c. Hormonal influences.
1. Growth hormone.
2. Thyroid hormones.
3. Sex hormones
4. Insulin.
5. Various growth factors.
D. Metabolism.
1. The direction of metabolic pathways shifts according to the needs of
the body.
a. Absorptive state ‑‑ just after a meal.
b. Postabsorptive (or fasting) state ‑‑ between meals.
2. Regulation of these pathways depends on the influence of hormones.
a. Insulin.
b. Glucagon.
c. Epinephrine.
d. Growth hormone.
e. Cortisol.
3. The most important metabolic disorder is diabetes mellitus.
II. Pancreas. [pp. 212, 237-239]
A. Anatomy (figurea).
1. Located behind the stomach.
2. Functions as both an exocrine and endocrine gland.
B. Histology (fig. 11.1).
1. Composed mostly of acinar cells.
a. Secrete digestive enzymes via the pancreatic duct into the duodenum.
b. Basophilic cytoplasm with many secretory granules.
2. Islets of Langerhans first described in 1867 by Paul Langerhans.
a. Endocrine portion of pancreas.
b. Make up about 1 ‑ 2% of mass of pancreas.
c. Randomly distributed.
d. Islet cells are arranged in clumps.
e. Stain light pink.
3. Islet cell types ‑‑ based on differential staining and secretory products
(fig. 11.2).
a. Beta cells ‑‑ secrete insulin.
1. Make up majority of islet cells in mammals.
2. Can be selectively destroyed by alloxan.
b. Alpha cells ‑‑ secrete glucagon.
1. Mostly on the periphery.
2. Darker nuclei and more eosinophilic cytoplasm.
c. D cells ‑‑ secrete somatostatin.
d. F cells ‑‑ secrete pancreatic polypeptide.
e. Somatostatin and pancreatic polypeptide have local roles in
regulation of insulin and glucagon secretion.
C. Embryology.
1. Exocrine and endocrine pancreas are derived from endoderm.
2. Islets are outgrowths of pancreatic ducts.
a Sherwood, L. Human Physiology: From Cells to Systems, 5th ed., 2004.
III. Diabetes and the Discovery of Insulin. [pg. 237]
A. Known since ancient times.
1. Sixth century B.C. Indian literature describes a "honey urine disease".
2. Symptoms of diabetes mellitus -- polyuria, thirst, and emaciation.
3. Some investigators recognized two types -- "thin" diabetes and
"fat" diabetes.
B. 1889 -- Joseph von Mering and Oskar Minkowski.
1. First experimental model of diabetes -- pancreatectomized dogs.
C. 1893 -- Edouard Laguesse named the islets of Langerhans and
suggested they might be a source of an internally secreted
antidiabetic substance.
D. 1894 -- Attempts to transplant pancreatic fragments under the skin of
diabetic dogs failed.
E. 1906 -- Ernest Starling suggested that human diabetes might be
relieved by injection of pancreatic extracts.
1. Several investigators made pancreatic extracts with hypoglycemic effects.
2. Problems with purity and destruction by digestive enzymes.
F. 1921 -- Discovery of insulin.
a. Read about a patient with blockage of the pancreatic duct.
1. Exocrine pancreas atrophied, but he did not develop diabetes.
b. Banting concluded that antidiabetic extracts could be made from
pancreas after duct ligation.
2. J.J.R. Macleod.
a. Carbohydrate biochemist at the Univ. of Toronto.
b. Set Banting up with some experiments and a lab to use during the
summer of 1921.
3. Charles Best.
a. Medical student.
b. Within two months, Banting and Best had demonstrated a
hypoglycemic substance extracted from pancreas.
c. Successfully reversed effects of pancreatectomy in a diabetic dog.
d. Called the substance "insulin", a name that had been proposed in
1909.
4. J.B. Collip.
a. Performed purification studies.
b. Developed a bioassay using induction of convulsions in rabbits.
G. Clinical developments.
1. 1922 -- Insulin was given to a severely diabetic 14‑year‑old
boy, Leonard Thompson.
a. Produced an immediate drop in blood glucose and miraculous
improvement in his medical condition.
2. By the end of 1922, Eli Lilly Company was producing 100,000 units of
insulin per week.
H. 1923 Nobel Prize awarded to Banting and Macleod.
I. Insulin "firsts".
1. 1953 -- First identification of primary structure of a protein --
2. 1959 -- First radioimmunoassay -- Solomon Berson and Rosalyn
3. 1963 -- First total laboratory synthesis of a protein.
4. 1971 -- First tertiary structure of a protein -- Dorothy Hodgkin.
5. 1982 -- First product of recombinant DNA technology to be
approved for clinical use by the FDA.
IV. Insulin. [pp. 241-247]
A. Chemistry.
1. Small protein (51 amino acids).
2. Two polypeptide chains joined by disulfide bonds (figure).
a. A chain ‑‑ 21 aa.
b. B chain ‑‑ 30 aa.
B. Biosynthesis.
1. Discovery of proinsulin.
a. Key experiment using slices of an insulin‑producing tumor (1967).
b. Tritiated leucine was added to the slices to observe its incorporation
into newly‑synthesized proteins.
c. 3H‑leucine was incorporated into insulin and a larger molecule
that appeared to be a precursor of insulin.
d. Structure of proinsulin was determined in 1968 by Ron Chance.
2. Biosynthetic pathway.
a. Preproinsulin synthesized on rough E.R.
b. Leader sequence is cleaved on entering the lumen of the E.R.
c. Disulfide bonds form, folding proinsulin (86 aa) into a coil.
d. C‑peptide connecting A and B chains is removed in Golgi
apparatus.
e. Insulin and C‑peptide are stored and secreted together.
3. Significance of C‑peptide.
a. Biological activity is unknown.
b. Measurement of C‑peptide by RIA can be used to determine rate
of insulin secretion (ex. in diabetic taking insulin).
C. Stimuli to insulin secretion.
1. Increased plasma glucose.
a. Trigger is probably a product of glucose metabolism within beta cell.
2. Increased plasma amino acids.
3. Anticipatory glucose regulation.
a. Occurs shortly after a meal, but before plasma glucose is elevated.
b. Gastric inhibitory peptide (GIP) secreted in response to entrance
of glucose into small intestine.
c. Parasympathetic stimulation.
D. Effects of insulin.
1. Membrane transport.
a. Promotes uptake of glucose and amino acids into cells.
1. h Facilitated diffusion of glucose into cells of target tissues
(ex. muscle, adipose tissue).
2. Does not affect transport of glucose into brain cells.
2. Metabolic effects.
a. Stimulates metabolic pathways that favor storage of nutrients.
b. Acts by activation or inhibition of specific enzymes.
c. Carbohydrate metabolism.
1. Increases formation and storage of glycogen in liver and muscle.
d. Fat metabolism.
1. Increases formation and storage of triglycerides in liver and
adipose tissue.
e. Increases protein synthesis.
f. Decreases blood glucose, amino acids, and fatty acids.
E. Mechanism of insulin action.
1. Insulin binds to membrane receptors (fig. 11.7).
a. Insulin binding to a-subunit causes activation of tyrosine kinase
(b-subunit).
b. Tyrosine kinase catalyzes phosphorylation of tyrosine residues
on intracellular proteins (ex. insulin receptor substrate, IRS).
2. Promotes insertion of vesicles containing GLUT-4 glucose transporter
into cell membrane.
a. GLUT-4 is the main insulin-sensitive glucose transporter.
b. In absence of insulin -- 90% is stored internally.
c. Insertion of GLUT-4 into membrane causes an increase in the
velocity of glucose transport into cell.
3. Metabolic signal (fig. 11.8).
a. Activates signaling pathways leading to synthesis and storage of
glycogen and fat (ex. activation of glycogen synthetase).
4. Growth signal.
a. Stimulates gene transcription, protein synthesis, and mitotic
activity.
F. Feedback control of insulin secretion.
1. Controlled variable is blood glucose concentration.
2. Beta cells act as sensor and control center.
V. Glucagon. [pp. 247-249, 252-253]
A. Piero Foa's crossed circulation experiment (1957).
1. Experimental setup.
a. Connect vein from pancreas of donor dog to femoral vein of
recipient dog.
b. Return blood to donor dog by another route.
c. Any hormone secreted by the donor's pancreas goes to the
recipient's blood supply.
2. Inject glucose into donor dog.
a. Donor's blood glucose increased.
b. Recipient's blood glucose fell.
c. Explanation:
3. Inject insulin into donor dog.
a. Donor's blood glucose fell.
b. Recipient's blood glucose was elevated.
c. Explanation:
B. History.
1. Hyperglycemic hormone of the pancreas was discovered in 1923
and named glucagon in 1929.
2. It took about 20 years to purify the substance and identify its structure.
C. Single-chain 29-amino acid peptide (fig. 11.11, p. 247).
D. Secreted by alpha cells of islets of Langerhans.
E. Stimuli to glucagon secretion.
1. Decreased plasma glucose.
2. Increased plasma amino acids (same as insulin).
3. Activation of sympathetic nerves.
F. Effects of glucagon.
1. Effects are opposite to insulin in most respects.
2. Stimulates metabolic pathways that favor breakdown and release
of stored nutrients.
3. Carbohydrate metabolism.
a. h Glycogenolysis and gluconeogenesis in liver.
b. Release of glucose from liver into blood.
c. h Blood glucose.
4. Fat metabolism.
a. h Lipolysis in adipose tissue.
b. Release of fatty acids into blood.
5. No effect on protein metabolism.
G. Mechanism of action.
1. Target tissues ‑‑ liver and adipose tissue.
2. Binds to membrane receptors.
3. Activates adenylyl cyclase ───> h cyclic AMP.
4. Activation of protein kinase leads to phosphorylation of various
enzymes (fig. 11.2, p. 249).
a. Activates enzymes involved in catabolic pathways
(ex. glycogen phosphorylase).
b. Inactivates enzymes involved in anabolic pathways
(ex. glycogen synthetase).
H. Feedback control of glucagon secretion.
1. Controlled variable is blood glucose concentration.
2. Alpha cells act as sensor and control center.
I. Combined effects of insulin and glucagon.
1. Fasting state.
2. After a typical meal (absorptive state).
a. Blood glucose is elevated (fig. 11.14, p. 252).
3. After a high‑protein meal.
a. Plasma amino acids are elevated, but blood glucose is not.
b. If only insulin was secreted ───>
VI. Diabetes Mellitus. [pp. 255-261]
A. Hyperglycemia = Abnormally high blood glucose concentration.
B. Affects 15 million Americans.
C. Type 1 ‑‑ insulin‑dependent diabetes mellitus (IDDM).
1. Beta cells are destroyed.
2. Low levels of insulin in blood.
3. High blood glucose.
4. Juvenile onset.
D. Type 2 ‑‑ noninsulin‑dependent diabetes mellitus (NIDDM).
1. Normal or elevated plasma insulin levels, but blood glucose levels
are high.
2. Target cells are resistant to insulin.
3. Adult onset -- diagnosed in middle-aged or older adults.
4. 90% of diabetics in U.S.
5. Most Type 2 diabetics are overweight and lack exercise.
D. Diagnosis.
1. Symptoms.
a. Unexplained weight loss.
b. Excessive thirst, urination.
c. Visual difficulties.
2. Tests.
a. Fasting blood glucose > 126 mg/dl (normal is 90-100 mg/dl).
b. Glucose tolerance test.
1. Drink cola containing glucose.
2. Blood glucose should return to normal after 2 hr.
F. Effects of severe, uncontrolled diabetes mellitus.
1. Metabolic effects.
a. Hyperglycemia.
b. Weight loss, resembling starvation.
1. Decreased uptake of glucose and amino acids.
2. Breakdown of stored nutrients.
c. Accelerated oxidation of fatty acids.
1. Excess acetyl CoA forms acetoacetic acid, b‑hydroxybutyric
acid, and acetone ‑‑ ketone bodies.
2. Ketone bodies release H+ -----> metabolic acidosis (diabetic
ketoacidosis).
2. Respiratory effects.
a. Acidsosis stimulates breathing -----> h respiratory rate.
b. Acetone breath.
3. Kidneys and body water balance.
a. Filtered glucose load exceeds Tm for tubular reabsorption
-----> glucosuria.
b. Excess ketones are excreted in urine -----> ketonuria.
c. Excess solutes take water with them -----> excess urination.
d. Dehydration, thirst.
4. Cardiovascular system.
a. i Plasma volume -----> hypotension.
5. Brain.
a. Damaged by dehydration, hypotension, and acidosis.
b. Confusion, lethargy.
c. Diabetic coma -----> death.
6. Emergency treatment.
a. Insulin.
b. Support CV system.
c. Correct acidosis.
7. Mortality.
a. Prior to 1922, most diabetics died from ketoacidosis.
b. Insulin reduced deaths from ketoacidosis to less than 10% of
diabetics.
c. Modern emergency techniques have reduced deaths to 2%.
G. Treatment of diabetes.
1. Controlled diet.
2. Exercise ‑‑ increases insulin sensitivity.
3. Insulin by injection ‑‑ Type 1.
a. Source ‑‑ recombinant DNA.
b. Insulin overdose -----> hypoglycemia -----> insulin shock.
4. Oral hypoglycemic drugs ‑‑ type 2.
a. Stimulate insulin production.
b. Increase insulin sensitivity.
H. Long‑term complications of diabetes.
1. Severity appears to be related to:
a. Number of years one is diabetic.
b. Degree of control of blood glucose.
2. Atherosclerosis and heart disease.
a. Responsible for 78% of diabetic deaths.
b. Diabetics have high LDL and low HDL cholesterol.
c. May be due to excess insulin levels.
3. Microvascular disease.
a. Thickened capillary basement membrane.
b. Poor circulation to extremities.
4. Nephropathy.
a. Renal failure due to damaged glomerular capillaries.
b. Diabetes is the leading cause of renal failure.
5. Blindness.
a. Retinopathy.
1. Proliferation of retinal capillaries.
2. Affects almost 100% of diabetics.
b. Cataracts.
c. Diabetes is the 2nd leading cause of blindness in U.S.
6. Increased susceptibility to infection.
a. Leukocytes placed in hyperglycemic solution show i phagocytosis.
b. Mucormycosis ‑‑ fungal infection of nose.
7. Neuropathy.
a. Pain or numbness of limbs.
8. Amputation.
a. Leading cause of limb amputations.
9. Diabetes is the 6th leading cause of death in the U.S.
10. Average life expectancy of a 20‑year‑old diabetic is 16 years less
than a nondiabetic).
I. Gestational diabetes.
1. Definition: Woman without a history of diabetes exhibiting
hyperglycemia during pregnancy.
2. Insulin resistance usually develops during second trimester.
a. Hormones of pregnancy cause increased insulin resistance.
3. Affects about 5% of pregnant women in U.S.
4. Risk factors.
a. Older than 25 years.
b. Family history of type 2 diabetes.
c. Overweight.
d. Race (non-white).
5. Complications.
a. Excess growth of fetus (macrosomia).
b. Hypoglycemia after birth.
c. Increased risk of type 2 diabetes in mother and baby.
6. Treatment (controversial).
a. Control blood glucose levels with insulin.
b. Insulin treatment reduced incidence of macrosomia, intrauterine
death, and birth complications.
VII. Epinephrine. [pp. 254, 330-331]
A. Effects on pancreas.
1. Inhibits insulin secretion.
2. Stimulates glucagon secretion.
B. Direct effects on metabolism.
1. Effects are similar to glucagon.
2. Stimulates metabolic pathways that favor breakdown and release
of stored nutrients.
3. Carbohydrate metabolism.
a. h Glycogenolysis and gluconeogenesis in liver.
b. Release of glucose from liver into blood.
c. h Plasma glucose.
4. Fat metabolism.
a. h Lipolysis in adipose tissue.
b. Release of fatty acids into blood.
C. Stimuli to epinephrine secretion.
1. Activation of sympathetic nervous system.
2. Hypoglycemia.
VIII. Cortisol. [pp. 351-352]
A. Essential for adaptation to fasting.
1. Cortisol secretion does not increase during fasting.
2. Small amounts of cortisol must be present for metabolic response to
glucagon and epinephrine (permissive effect).
B. Rsponse to stress.
1. Large amounts secreted during stress.
2. Catabolic effects mobilize energy stores.
a. h Lipolysis.
b. h Protein breakdown.
c. Amino acids and fatty acids are converted to glucose by liver
(gluconeogenesis).
d. h Release of glucose into blood.
e. h Blood glucose.
IX. Growth Hormone. [pp. 268-269]
A. Primary effect is to promote growth (fig. 12.6).
1. Stimulates growth of bone and cartilage.
2. Growth of all soft tissues.
a. h Uptake of amino acids into cells.
b. h Protein synthesis.
B. Large doses have a diabetogenic effect.
a. h Glycogenolysis.
b. h Lipolysis and gluconeogenesis.
c. h Blood glucose.
