Parathyroid, Calcitonin, and Insulin

• The graph shows the normal relationship between serum levels of two hormones in response to serum calcium levels.
• Parathyroid hormone and calcitonin are the two hormones.
• Option C is the correct answer: hormone A is parathyroid hormone, and hormone B is calcitonin.

Endocrine Function of the Pancreas

• The exocrine pancreas secretes pancreatic juice into the duodenum.
• The endocrine pancreas includes Islets of Langerhans, which make up 2% of pancreatic mass and have a rich blood supply.
• A (α) cells secrete glucagon, which is involved in carbohydrates, fats, and protein metabolism.
• B (β) cells secrete insulin, which is critical for protein metabolism.
• D (δ) cells secrete somatostatin, which inhibits secretion.
• F cells secrete pancreatic polypeptide, which regulates gastrointestinal tract functions.

Insulin Synthesis and Processing

• Insulin is synthesized as preproinsulin in ribosomes.
• Signal peptide cleavage and folding in the endoplasmic reticulum (ER) results in proinsulin.
• Proinsulin is then transported to the Golgi apparatus.
• Proinsulin is processed into insulin by excising the C chain.
• The resulting insulin consists of two chains (A and B) connected by disulfide bridges.

Insulin Characteristics

• Insulin is a polypeptide with two amino acid chains linked by disulfide bridges.
• Release occurs via exocytosis with 90% of the released product being Insulin.
• C-peptide is released during insulin production and indicates the endocrine function of the pancreas, and is measured in diabetes treated artificially
• Proinsulin is released with no function.
• Transport happens in plasma in its free form with a half life of 5 minutes.
• Degradation happens in the liver and kidneys by insulinases.

Insulin Receptor

• The insulin receptor is a catalytic receptor with enzymatic activity.
• It is a tetramer of 2 alpha and 2 beta subunits.
• The alpha subunit is extracellular and binds insulin.
• The beta subunit is integral and intracellular and has tyrosine kinase activity.

Insulin Mechanism of Action

• Insulin's binding to receptor alpha subunits requires both subunits to be occupied.
• Stimulation of tyrosine kinase and autophosphorylation of the beta subunits occurs upon insulin binding.
• Binding of IRS1-4 to beta subunits (insulin–receptor substrates), followed by phosphorylation of IRS.
• This activates intracellular signal systems, leading to various effects.

Insulin Effects

• Storage of carbohydrate, fat, and protein makes insulin a hormone of abundance.
• Insulin rapidly increases the transport of glucose, amino acids, and K+ into insulin-sensitive cells.
• Insulin intermediately increases protein synthesis, reduces protein degradation and activates glycolytic enzymes, glycogen synthesis and inhibits phosphorylase and gluconeogenic enzymes.
• Insulin later causes translation of mRNA for new protein enzymes.

Membrane Glucose Transport

• Glucose transport occurs by facilitated diffusion, and includes GLUT 1-14, which transport glucose.
• GLUT 1 is found in brain BBB and placenta.
• GLUT 2 is a B cell glucose sensor in pancreas, and is in kindey and intestine, for basolateral membrane trasnport
• GLUT 4 is in skeletal, cardiac and adipose tissue, and is insulin stimulated.
• Secondary active transport with Na occurs via SGLT 1 and 2 in kidney and intestine for luminal membrane transport.

Insulin and Carbohydrates

• Meal increases blood glucose, which stimulates secretion of insulin
• Increased secretion then uptake, storage in liver muscles and adipose
• Utilizes more glucose and less fat
• In the liver, there is uptake and storage of glucose converted to glycogen via glycogen synthase.
• Conversion of excess glucose to fats, with inhibition of gluconeogenesis.
• Insulin reduces amino acid release from muscles and reduces inhibition of enzymes in the liver

Insulin and Carbohydrates - Muscles

• Insulin absence decreases permeability making the muscle use FA
• Insulin after a meal causes more GLUT 4 and entry of the glucose to be stored in glycogen

Insulin and Carbohydrates - Adipose Tissue & Brain

• In adipose tissue, it is used to take more glucose from GLUT 4 and store as FA.
• In the Brain there is decreased function due to insulin levels
• The brain relies on GLUT 1 and 3. Glucose is the only energy source so blood glucose decreases causing hypoglycemic shock, and coma

Insulin and Fats

• Insulin leads to fat storage in adipose tissue, synthesizing FA in the liver.
• Glucose is converted into glycogen, then pyruvate, then acetylCOA, and creates FA that become lipoproteins which can be degraded using lipoprotine lipase.

Adipose Tissue and Insulin

• Inhibits hormone sensitive lipase to lower FA release.
• There is uptake of glucose, converting FA (less than liver), and leads to the product of alpa-glycerol phosphate, glycerol, and TAG to store.

Insulin And Proteins

• There is increased protein synthesis and storage.
• Higher transmission of AA to the cells.
• It affects DNA trancription and translation by ribosomes for an increased protein formation
• Decreases protein catabolism, and converts saving AA via decreased gluconeogensis in the liver.

Insulin for Growth

• Essential for synthesis of proteins and has synergy with growth hormone

Control of insulin secretion

• Negative feedback includes blood glucose.
• A higher glucose results ina higher insulin secretion, and lower is vice versa
• Higher glucose in GLUT 2 causes more glucokinase.
• Glucose converted to Glu6P and ATP, causes depolarization.
• Calcium channels, K channels.
• Biphasic secretion

Control of insulin secretion - More details

• AA arginine lysine are stimulating agents
• Gatrins, secretin, Cholecystokinin, glucose dependent peptid stimulate insluin
• Parasympathetic response
• Increases cAMP w 2 adrenergics agonists

Control of insulin secretion - Inhibitors

• Somatostatin, sympathetic with alpha receptors, hypokalemia

Diabetes Melitus

• Main condition is an insulin deficiency
• Type 1 dependent on Insulin and autoimmune destruction of cells, which causes decreased plasma. 10%
• Non insulin cases come from maturity, there is less sensitivity that lowers plasma. Risk is from obesity, hypertension, 90%

Complications of a lacking insulin

1. Lower intake of glucose in the cells which makes hyperglycemia
2. Releases fat and can deposit fats in vessels
3. Increase proteocatalbolism releasing AAs and gicing hyperglycemia
4. More ketones leads to hypercemia, glycosuriaa osmotic and diaresis

Diabetic Coma

• Insulin deficiency can lead to diabetic coma through several pathways.
• Decreased glucose uptake leads to hyperglycemia, glycosuria, and osmotic diuresis.
• Increased proteocatabolism results in elevated plasma amino acids and nitrogen loss in urine.
• Lipolysis increases plasma free fatty acids, causes ketogenesis, ketonemia, and ketonuria.
• All pathways can cause dehydration and acidosis and ultimately leads to coma and death.

Diabetic Complications

• Concerns in microvascular diseases that cause eye and kindey illness
• Macroavascular disease leads to acceleration of stroke
• Neuropathy of motor

What happens when there is too much Insulin

• Adenoma of Insulin in excess
• Hypoglycemia affects nervous system
• Anxiety, nervousness, sweating, confusion, lethargy, unconsciousness, coma and death

Plasma Glucose

• Various levels of glucose and symptoms
• Inhibition with high, and glucagon with low, with Irreversible brain damage at 0.6 mol

Regulation of blood glucose

• The use of antagonistic hormones that are glycogen related or liver related

Glucagon

• Polypepitde with half time, and effects glycogenolysis
• Degradations happen in the liver
• Causes glycogen activation for glycogen breakdown

How does Glucagon and Insulin Affect Blood Glucose

• Insulin and Glucagon work to maintain glucose haemostasis.
• Insulin promotes the storage of energy and is glycogenic, inhibits gluconeogenesis, is anti-lipolytic, and anti-ketogenic.
• Glucagon causes the release of energy, by glycogneolysis, gluconeogenesis, ketogenesis and is lipolytic,

Gluconeogenesis

• It stimulates liver cell glycogen syntehsis and causes release of energy

Exercise

• There are many benefits of stimulation

Other hormones

• Somatostatin is in both the hypothatlamus and pancreatic cells. It inhibits pancreatic and petuitary function. It decreases stomach gallbladder motility and secretions
• It causes anorexia. It releases GH and TSH from cells.
• Polypeptide is from cells and reduces pancreatic sections. It reduces GIT
• It releases AA into the blood.

What else can affect the regulation of glucose

• Glycogenesis, glucociticoids, T cell activity, growth, Exercise