BICD 150 Sp 14 Fortes 9 5 27 14 1 of 10 Treatment of Diabetes Type I Insulin is not being made or secreted Provide insulin via injections or pumps The dosage must be matched with the individual s diet and level of exercise Pancreatic Islet transplant o Main cause of diabetes is autoimmune antibodies of the beta cells Transplanting new beta cells may not solve the problem o Current experimental studies involve islet cells encased in a protective layer that allows small nutrients through but not antibodies Type II Increased Insulin Resistance Diet Exercise o Limit the consumption of carbohydrates especially simple sugars o Lose weight many diabetics become normal after losing weight Metformin o A drug that activates AMPK in order to inhibit Gluconeogenesis in the liver thereby helping to treat hyperglycemia PPAR agonists thiazolidinediones o PPARs are nuclear receptors that regulate the expression of a variety of adipokines that affect insulin resistance o PPARG agonists decrease Resistin Leptin TNF a and IL 6 o Increase Adiponectin o All of these actions decrease insulin resistance and increase insulin sensitivity to lower blood glucose Drugs that increase Insulin secretion o Oldest drugs act to block the ATP gated K channels This will cause depolarization in the beta cells and stimulate insulin secretion o Incretin GLP and GIP analogs stimulate beta cells to secrete insulin o DPP4 Inhibitors DPP4 is a protease enzyme that degrades the incretins Calcium Homeostasis Ca2 is an important signaling molecule and is involved in the clotting of blood Hydroxyapatite CaOH Pi crystals form the hard parts of bone and are made of calcium There is a lot of calcium in the body however the free ionized form is highly regulated A small fraction of total calcium that enters the body is actually taken up and absorbed by the gut This requires hormones as we will see ECF Ca2 is in equilibrium w bone hydroxyapatite Bone is very dynamic and is constantly being deposited and resorbed Almost all Ca2 that is filtered by the kidneys is reabsorbed in the proximal tubule Ca2 excretion and reabsorption in the kidneys is also mediated by hormones Only half of the Ca in the body is in its ionized form in the ECF The rest is either protein bound or complexed into hydroxyapatite Ionized Ca2 is 10 000x more concentrated in the ECF than in the cell Ca2 will enter cells if channels are opened Parathyroid Glands 4 spherical glands located behind the thyroid Discovered when they were removed along with the thyroid gland Patients developed tetany or sustained contractions when extracellular Ca2 is too low increasing the excitability of muscles Parathyroid hormone PTH acts to increase extracellular Ca2 levels in the blood Increase Ca2 release from bone Increase Ca2 absorption in the intestines Increase Ca2 reabsorption in the nephron The secretion of PTH increases when ionized Ca2 is low PTH functions to raise Ca2 which shuts off its own release A classic negative feedback loop Release of PTH Parathyroid cells respond to a decrease in Ca2 to stimulate the release of PTH Ca2 binds to a GPCR in the parathyroid cells When Ca2 increases the secretion of PTH is shut off Increase in Ca out Ca binds to a GPCR Increase Gaq Increase PLC Hydrolyzes PIP2 into IP3 and DAG IP3 increases Ca in from the ER Decreases the release of PTH This is counterintuitive usually Ca stimulates exocytosis not inhibits it Exocytosis of PTH is regulated by Mg2 Ca2 competes with Mg2 for this mechanism When Ca out is low there will be less stimulation of Gaq and less Ca in Mg will stimulate the release of PTH When Ca out is high Ca in will be increased and outcompete Mg2 PTH release will be inhibited Increased Ca in will inhibit both the secretion and transcription of PTH As mentioned previously one of the effects of PTH is to raise Ca2 by increasing its release from bones by breaking them down It does this by stimulating osteoblasts the cells that build bone which will then stimulate osteoclasts the cells that break down bone We will learn more about this mechanism later Osteoclasts break down bones by acidifying them promoting the release of Ca2 and Phosphate However free Ca2 released in the blood can form unwanted complexes with anions like phosphate and can form kidney stones This is lessened by another effect of PTH which is to increase reabsorption of Ca2 in the distal tubule of the nephron as well as increase excretion of phosphate and inhibiting its reabsorption Abnormal levels of Ca Hypocalcemia Most common cause is lack of PTH Results in tetany by increasing the excitability of skeletal muscles and neurons It may reduce amplitude of action potentials and strength of contraction in the heart Hypercalcemia Excess PTH Decreases excitability of skeletal muscle and neurons Increases the dissolution of bone and formation of kidney stones Stones Bones Groans Moans Lack of vitamin D results in weakening of bones Vitamin D is a precursor for a hormone known as Calcitriol or 1 25 OH 2 Vitamin D Vitamin D is formed from derivatives of cholesterol in the skin via exposure to UV light Vitamin D3 is the animal form of the vitamin and also known as Cholecalciferol Vitamin D3 can either be formed in the skin via exposure to UV light or ingested D3 is hydroxylated in the liver The kidney upon stimulation of PTH or a decrease in Ca will hydroxylate to give rise to Calcitriol Calcitriol Receptor Lipid soluble hormone intracellular nuclear receptor Increases transcription of proteins after binding of hormone to receptor Ca2 is poorly absorbed in the intestine as stated earlier There is a Ca channel in the brush border of the SI whose activity will be increased when Vitamin D increases Vitamin D stimulates Ca absorption Ca2 is absorbed from the lumen of SI cells via a Ca2 channel at the apical membrane Calbindin is a protein in the cells of the SI that binds Ca and can move to the basolateral membrane Calcitriol increase Ca ATPases that pump Ca from the basolateral membrane into the blood Increase Ca channel Increase Ca in increase calbindin Increase Ca atpase increase Ca out Calcitriol Increases Ca reabsorption in the kidney Increase deposition formation of bone Increase dissolution of bone BICD 150 Sp 14 Fortes 9 5 29 14 7 of 10 Bone formation continues throughout life and is constantly formed and resorbed Osteons have haversian canals which contain the circulation for nutrients In resting bone they contain osteocytes Compact Bone is strong and subject to the