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 problemo Current experimental studies involve islet cells encased in a protective layer that allows small nutrients through but not antibodiesType II: Increased Insulin Resistance - Diet & Exerciseo Limit the consumption of carbohydrates, especially simple sugarso Lose weight; many diabetics become normal after losing weight - Metformino A drug that activates AMPK in order to inhibit Gluconeogenesis in the liver, thereby helping to treat hyperglycemia - PPAR-γ 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-6o Increase Adiponectin o All of these actions decrease insulin resistance and increase insulin sensitivity to lower blood glucose - Drugs that increase Insulin secretiono 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 insulino DPP4 Inhibitors; DPP4 is a protease enzyme that degrades the incretins.BICD 150Sp’14Fortes95/27/141 of 10Calcium 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. Thisrequires 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 openedParathyroid 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 PTHCa2+ 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 PTHAs 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 DVitamin D is formed from derivatives of cholesterol in the skin via exposure to UV lightVitamin 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 receptorCa2+ 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 outCalcitriol:- Increases Ca reabsorption in the kidney- Increase deposition/formation of bone- Increase dissolution of bone Bone formation continues throughout life and is constantly formed and resorbed Osteons