Anatomy and physiology of t2d Lesson Five Today we will… Make a human body poster that shows how t2d affects organs and body systems Look at treatment options for different symptoms of t2d Evaluate costs of prevention and treatment options for t2d

“If current trends continue, 1 in 3 Lesson 5 “If current trends continue, 1 in 3 U.S. adults will have diabetes by 2050.” Center for Disease Control and Prevention http://www.cdc.gov/chronicdisease/resources/publications/aag/ddt.htm

Many body organs are affected by type 2 diabetes. Today’s lesson focuses on: Heart Kidneys Brain Eyes Feet (limbs) Image: Wikimedia Commons

Three mechanisms Three ways type 2 diabetes damages cells and organs: Polyol Pathway Advanced Glycation End Products (AGEs) Atherosclerosis

Polyol Pathway Cells in the kidney, eye, and nerves take up glucose in the absence of insulin Inside the cell, glucose is converted to a substance (sorbitol) which builds up because it cannot get out. Water flows into the cell and can cause the cell to burst (think of a water balloon). Research has focused on inhibiting the enzyme, aldose reductase, which converts glucose to sorbitol. Currently, there are no AR inhibitors approved for clinical use in the United States (Schemmel et al., 2010). Best treatment to date is to lower blood sugar through diet (weight loss), exercise, and drugs (metformin and insulin). Connection to Worm unit: In the dialysis activity in the worm unit, water moved out of the dialysis tubing containing low glycerol into the salt. In the polyol pathway, the sorbitol cannot move out of the cell, so in order to achieve balance on both sides of the cell membrane, water moves into the cell. This is a key mechanism for nerve and retina damage

AGEs AGEs 2. Advanced Glycation End Products (AGEs) AGEs cross-link proteins and contribute to tissue stiffness in heart, bone and muscle. protein Glucose attaches to proteins protein glucose AGEs Drugs that inhibit AGE formation have been tested in clinical trials, but none have yet to be shown to reduce kidney disease. http://www.medscape.com/viewarticle/758475_8 AGE damage can also make small blood vessels leaky This is a key mechanism for eye and kidney damage.

3. Atherosclerosis Large blood vessels also become leaky due to AGEs Layers of fat and cholesterol start to accumulate along the vessel walls. Prevention of peripheral arterial disease and cardiovascular disease includes: quit smoking, reduce blood glucose, lower blood pressure to less than 140/80 mmHg, lower LDL cholesterol below 100 mg/dl, possibly take aspirin or other antiplatelet meds, exercise, changing diet Treatment: Balloon angioplasty; artery bypass http://www.diabetes.org/living-with-diabetes/complications/heart-disease/ This makes the blood vessel stiff and narrows the channel. Atherosclerosis leads to high blood pressure, causing the heart to work harder. This is a key mechanism for heart failure and stroke. It also contributes to kidney failure.

Polyol Pathway TREATMENT Cells in the kidney, eye, and nerves take up glucose in the absence of insulin Inside the cell, glucose is converted to a substance (sorbitol) which builds up because it cannot get out. Water flows into the cell and can cause the cell to burst (think of a water balloon). Can the enzyme that converts glucose into sorbitol be inhibited? Research has focused on inhibiting the enzyme, aldose reductase, which converts glucose to sorbitol. Currently, there are no AR inhibitors approved for clinical use in the United States (Schemmel et al., 2010). Best treatment to date is to lower blood sugar through diet (weight loss), exercise, and drugs (metformin and insulin). Connection to Worm unit: In the dialysis activity in the worm unit, water moved out of the dialysis tubing containing low glycerol into the salt. In the polyol pathway, the sorbitol cannot move out of the cell, so in order to achieve balance on both sides of the cell membrane, water moves into the cell. Still working on it… This is a key mechanism for nerve and retina damage

AGEs AGEs TREATMENT 2. Advanced Glycation End Products (AGEs) AGEs cross-link proteins and contribute to tissue stiffness in heart, bone and muscle. protein Glucose attaches to proteins protein glucose AGEs AGE damage can also make small blood vessels leaky Drugs that inhibit AGE formation have been tested in clinical trials, but none have yet to be shown to reduce kidney disease. http://www.medscape.com/viewarticle/758475_8 Currently, there are no AR inhibitors approved for clinical use in the United States (Schemmel et al., 2010). Best treatment to date is to lower blood sugar through diet (weight loss), exercise, and drugs (metformin and insulin). Drugs that inhibit the formation of AGEs have been tested, but…none have been shown to reduce kidney damage. Yet. This is a key mechanism for eye and kidney damage.

3. Atherosclerosis TREATMENT Large blood vessels also become leaky due to AGEs Layers of fat and cholesterol start to accumulate along the vessel walls. Balloon angioplasty can help to open narrow vessels Prevention of peripheral arterial disease and cardiovascular disease includes: quit smoking, reduce blood glucose, lower blood pressure to less than 140/80 mmHg, lower LDL cholesterol below 100 mg/dl, possibly take aspirin or other antiplatelet meds, exercise, changing diet Treatment: Balloon angioplasty; artery bypass http://www.diabetes.org/living-with-diabetes/complications/heart-disease/ This makes the blood vessel stiff and narrows the channel. Atherosclerosis leads to high blood pressure, causing the heart to work harder. This is a key mechanism for heart failure and stroke. It also contributes to kidney failure.

Chronic Elevated Blood Glucose Pathways to organ damage Chronic Elevated Blood Glucose Nerve damage Capillary damage Large blood vessel damage EYES LIMBS KIDNEYS HEART BRAIN

Where should money for treatment and/or prevention be spent? Pathways to organ damage Where should money for treatment and/or prevention be spent? Chronic Elevated Blood Glucose Nerve damage Capillary damage Large blood vessel damage EYES LIMBS KIDNEYS HEART BRAIN

TYPE 2 DIABETES Elevated Blood Glucose = PREDIABETES Prevention and Treatment $$ Normal Blood Glucose Levels Elevated Blood Glucose = PREDIABETES More Reversible Point out for students that the first arrows are bi-directional—a person can work to control elevated blood sugar and prediabetes Fix pancreas animation TYPE 2 DIABETES with severe complications such as organ damage $$$$$ Less Reversible