Endocrinology Review: Complete Guide to Thyroid
Hormone Synthesis, Insulin and Glucagon
Physiology, Pituitary and Hypothalamic Hormones,
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Steps involved in the synthesis of thyroid hormones
(1) iodide (I-) trapped by the thyroid follicular cells;
(2) diffusion of iodide to the apex of the cells;
(3) transport of iodide into the colloid;
(4) oxidation of inorganic iodide to iodine and incorporation of iodine into tyrosine residues
within thyroglobulin molecules in the colloid;
(5) combination of two DIT molecules to form tetraiodothyronine (T4) or of MIT with DIT to
form T3;
(6) uptake of thyroglobulin from the colloid into the follicular cell by endocytosis, fusion of the
thyroglobulin with a lysosome, and proteolysis and release of T4, T3, DIT, and MIT;
(7) release of T4 and T3 into the circulation; and
(8) deiodination of DIT and MIT to yield tyrosine. T3 is also formed from monodeiodination of
T4 in the thyroid and in peripheral tissues.
Insulin Definition
the storage and anabolic hormone of the body
,General characteristics of Insulin
- small protein that contains 51 amino acids arranged in 2 chains (A & B) linked by disulfide
bridges.
- stored in beta cells of pancreas in form of hexameric crystals
1. Entire human pancreas stores up to 8mg (200 units) of insulin.
- Insulin is released from pancreatic beta cells at a low BASAL rate --> plus with stimulation
releases at a much higher rate
Insulin synthesis
Insulin is synthesized as preproinsulin and processed to proinsulin. Proinsulin is then converted
to insulin and C-peptide and stored in secretary granules awaiting release on demand. Insulin
synthesis is regulated at both the transcriptional and translational level.
insulin Stimulates release
glucose, sugars (eg. Mannose), amino acids (esp. glyconeogenic amino acids like leucine,
arginine), hormones like glucagon-like polypeptide 1 (GLP-1), glucose-dependent insulinotropic
polypeptide (GIP), glucagon, cholecystokinin, high concentrations of fatty acids, and B-
adrenergic sympathetic activity
Stimulatory drugs of insulin
sulfonylureas, meglitinides, D-phenylalanine derivatives, isoproterenol, and acetylcholine
Insulin Inhibitory hormones:
insulin, islet amyloid polypeptide, somatostatin, and leptin; alpha-adrenergic sympathetic
activity; chronically elevated glucose; low concentrations of fatty acids
Insulin Inhibitory drugs:
diazoxide, phenytoin, vinblastine, clonidine, verapamil, and colchicine
One mechanism of stimulated insulin release
1. in resting cell: normal (low) ATP levels→ K+ diffuses down its concentration gradient through
ATP-gated K+ channels, maintaining the intracellular potential @fully polarized, negative level→
insulin release is minimal
2. if glucose concentration rises → ATP production increases → K+ channels close -->
depolarization results → in muscle/nerve voltage-gated Ca2+ channels open in response to
depolarization --> allows more Ca2+ to enter cell --> increased intracellular Ca2+ results in
increased insulin secretion → insulin secretagugues close the ATP-dependent K+ channel→
depolarizes membrane→ increased insulin release by same mechanism
,Effects of insulin
- Promotes the storage of fat as well as glucose (both sources of energy) within specialized
target cells & influences cell growth and the metabolic functions of a wide range of tissues
-Promotes synthesis and storage of glycogen, triglycerides, and protein in its major target
tissues: liver, fat, and muscle. Release of insulin from pancreas is stimulated by increased blood
glucose, incretins, vagal nerve stimulation, and other factors.
Endocrine Effects of Insulin
LIVER:
-Reversal of Catabolic features of insulin deficiency:
1. inhibits glycogenolysis
2. inhibits conversion of fatty acids & amino acids to keto acids
3. inhibits conversion of amino acids to glucose
-Anabolic action:
1. promotes glucose storage as glycogen (induces glucokinase & glycogen synthase, inhibits
phosphorylase)
2. increases triglyceride synthesis & very-low-density lipoprotein formation
MUSCLE:
- Increased protein synthesis
1. increases amino acid transport
2. Increases ribosomal protein synthesis
- Increased glycogen synthesis
1. increases glucose transport
2. induces glycogen synthase & inhibits phosphorylase
ADIPOSE TISSUE:
- Increased triglyceride storage
1. Lipoprotein lipase is induced & activated by insulin to hydrolyze triglycerides from
lipoproteins
2. Glucose transport into cell provides glycerol phosphate to permit esterification of fatty acids
supplied by lipoprotein transport
3. Intracellular lipase is inhibited by insulin
glucagon definition
the hyperglycemic factor that mobilizes glycogen stores
Glucagon synthesis
in the alpha cells of the pancreatic islets of Langerhans
, Glucagon characteristics
-Peptide (identical in ALL mammals) consisting of single chain of 29 amino acids
- Degraded in the liver and kidney as well as in plasma and at its tissue receptor
-half-life is between 3-6 months
Effects of Glucagon
1. 1st six amino acids at the amino terminal of glucagon molecule bind to Gs protein-coupled
receptors on liver cells -->leads to increase in cAMP --> facilitates catabolism of stored glycogen
--> increases gluconeogenesis and ketogenesis
2. Immediate pharmacological result of glucagon infusion -->raise blood glucose by using stored
hepatic glycogen
3. NO effect on skeletal muscle glycogen because of lack of receptors
4. Pharmacological amounts of glucagon cause release of insulin from normal pancreatic beta
cells, catecholamines from pheochromocytoma, and calcitonin from medullary carcinoma cells
5. Has potent inotropic and chronotropic effect on heart, mediated by the cAMP mechanism →
produces effect similar to B-adrenergic agonists without requiring functioning B-receptors
6. LARGE doses of glucagon produce profound relaxation of the intestine
Uses of Glucagon
1. Emergency treatment of severe hypoglycemic reactions due to insulin therapy when pt is
unable to self-administer oral glucose and IV glucose treatment is not possible
2. IV, IM, sub Q, or nasal powder
3. Main adverse effect is nausea/vomiting so place unconscious pt on side after administration
4. Beta blocker overdose to increase cAMP
5. In endoscopic procedure to relax sphincter of Oddi
Contraindications of Glucagon
a. Pheochromocytoma → can cause release of catecholamines and increase BP
b. Patients with insulinoma→ can cause rebound hypoglycemia
Different types of insulin
Short-acting: Regular insulin and rapidly acting insulin analog
Long-Acting Insulin: NPH, Insulin Glargine, Insulin Detemir, insulin degludec, and mixture insulin
Short-Acting insulin
1. Regular: short-acting, soluble crystalline zinc insulin. Hypoglycemic effect appears within 30
mins after SubQ injection
-Peak @ 2hrs