Presentation Outline: Merci Chalvir, Session I Name: Parth Shah Date: March 22, 2012 My Research Question: How

can diabetes cause acute pre-renal injury and acute renal injury? Learning Objectives: The learning objectives of my presentation are as follows: 1. To describe the process by which diabetes can directly cause renal injury. 2. To describe how diabetes can indirectly cause renal injury by first damaging other organs and systems. Presentation: Two types of diabetes mellitus- both have symptom of hyperglycemia o Type 1 DM- result of complete or almost complete insulin deficiency o Type 2 DM- insulin resistance, increased glucose production, impaired insulin secretion Diabetes and acute renal injury o Problems with Renin-Angiotensin system Studies have shown increased activity of RAS in the kidney (intrarenal RAS) Angiotensin II leads to increased levels of GLUT1 (receptors for glucose), which leads to increased synthesis of extracellular matrix proteins Can lead to greater collagen accumulation in mesangial cells Ang II increases TGF-B1 levels, which increases levels of GLUT1 as well- this then leads to increased synthesis of ECM proteins Increased angiotensin II stimulates NADPH oxidase activityincreased activity leads to oxidative stress that damages the kidneys o Problems with renal microvascular function Oxidative stress due to angiotensin II can lead to changes in K+ channels that regulate afferent arteriolar tone K+ channels can be activated, resulting in hyperpolarization and decreased calcium influx, leading to afferent arteriolar dilation and hyperfiltration Hyperfiltration can lead to kidney damage o Interstitial disease Thickening of glomerulus in diabetic patients leads to leakage of proteins, such as albumin Glomerular ultrafiltrate in diabetic patients contains many cytokines, including TGF-B and IGF-1, which can lead to modest secretions of extracellular proteins

Macrophages are attracted to interstitium and they release more TGF-B (transforming growth factor-Beta) TGF-B and other molecules lead to increased proliferation of residential fibroblasts Impairs ability of kidney to secrete and absorb molecules

Diabetes and pre-renal acute injury o Diabetic Ketoacidosis Symptoms: nausea, vomiting, abdominal pain, tachycardia, hypotension, glucosuria Insulin deficiency with glucagon excess Changes in amounts of hormones leads to glucose synthesis Ketosis results from reduced insulin levels and increased levels of catecholamines and growth hormone- this leads to increased fatty acid release a shift toward ketone synthesis by the liver At physiologic pH, ketone bodies exist as ketoacids and are neutralized by bicarbonate, which eventually becomes depletedacidsosis results o Association between diabetes and pancreatitis and pancreatic cancer Pancreatitis can result in acute ketoacidosis Reasons for association are not clear according to recent studies o Many GI issues are due to effects of hyperglycemia and autonomic neuropathy that are associated with diabetes o Colonic ischemia Reduced flow due to dehydration (diabetes) can cause ischemia within the colon. Symptoms: bloody stool, nausea, vomiting, abdominal pain o Mesenteric ischemia Higher incidence of macrovascular atherosclerosis Abdominal pain Less blood flow to colon, GI organs, kidneys Summary of Presentation: In review, the main learning points of my presentation are: 1. Diabetes has a major effect not just directly on the kidneys, but also on gastrointestinal organs and blood vessels, which can eventually lead to kidney damage Review of Resources: Longo, Dan L., and Anthony S. Fauci, eds. Harrison's Principles of Internal Medicine. 18th ed. McGraw Hill. Access Medicine. Web. <http://www.accessmedicine.com.ezproxy.bu.edu/resourceTOC.aspx?resour ceID=4>. I found this resource to be very helpful in introducing me to diabetes and its effects on various organs. It was a good foundation for my future research.

Poretsky, Leonid. Principles of Diabetes Mellitus. Springer US, 2010. SpringerLink. Web. <http://www.springerlink.com.ezproxy.bu.edu/content/h56152/#section=6 55153 &page=3&locus=30>. This website was very useful in finding information about diabetic nephropathy. It was very dense and sifting through it took some time. Cortes, Pedro. The Diabetic Kidney. Humana, 2006. SpringerLink. Web. <http://www.springerlink.com.ezproxy.bu.edu/content/978-1-58829-6245/contents/>. This book was as useful as the previous one. However, the same issue came up with its denseness and the difficulty in extracting relevant information.