Q: What is the primary cause of Type I diabetes? A: Autoimmune-mediated destruction of pancreatic Beta-cell islets. Q: What is the primary cause of Type II diabetes? A: Obesity Q: Which type of diabetes is globally more prevalent? A: Type 2 -- accounts for over 90% of cases Q: T/F Type 2 Diabetes is characterized by insulin resistance and/or abnormal insulin secretion. A: True Q: By 2025, the global count of diabetics will be how many? A: 300 million, double the present 150 million. Q: Which type of diabetes is often a manifestation of a much broader underlying disorder? A: Type II Q: Define Metabolic Disorder (aka Syndrome X) and give four of the possible risk factors involved? A: It's a cluster of cardiovascular disease risk factors that include 1. glucose intolerance (which gives symptoms like Type II diabetes), 2. dyslipidemia, 3. hypertension, and 4. hypercoagulability Q: What two characteristic patterns of dyslipidemia are consistently observed in Type II diabetes? A: Increased triglyceride and decreased HDL. Q: What are the (2) supposed causes of the increased triglycerides in the dyslipidemia which often accompanies Type II Diabetes? A: High TAG levels are thought to result from 1. increased hepatic release of triglyceride-rich VLDL particles and 2. the fact that lipoprotein lipase, which is stimulated by insulin, is reduced in Type II Diabetes. Q: What action of insulin is thought to eventually lead to hypertension in an individual who is insulin resistant? A: Insulin is a potent vasodilator. Q: Does insulin increase or decrease platelet aggregation in patients that are insulin sensitive? A: Platelet aggregation is inhibited. Q: Does insulin increase or decrease platelet aggregation in obese patients? A: Platelet aggregation is enhanced. Q: What are two characteristics of all forms of diabetes? A: 1. Chronic hyperglycemia and 2. microvascular pathology (in the retina, renal glomerulus, and peripheral nerve). Q: What 3 areas of the body is microvascular pathology often seen in diabetics? A: In the retina, renal glomerulus, and peripheral nerve. Q: Early in the course of diabetes, INTRAcellular hyperglycemia causes abnormalities in blood flow AND increased vascular permeability. Why/how (3)? A: 1. DECREASED activity of vasodilators such as nitric oxide, 2. INCREASED activity of vasoconstrictors such as angiotensis II and endothelin-1 3. elaboration of permeability factors such as vascular endothelial growth factors (VEGF). Q: What are the specific results of microvascular pathology as seen (in 3 areas) in diabetics? A: 1. blindness due to retinal edema, ischemia, and hypoxia-induced neovascularization 2. axonal degeneration 3. proteinuria (renal failure) Q: T/F With time (in diabetics), microvascular cell loss occurs, in part due to programmed cell death. A: True Q: What is the cause of progressive capillary occlusion seen in microvascular pathology as seen in diabetics? A: Overproduction of extracellular matrix Q: What are 3 increased risks resulting from progressive capillary occlusion ("diabetes-accelerated atherosclerosis") as seen in diabetics? A: Increased risk of 1. myocardial infection, 2. stroke, and 3. limb amputation Q: What are the four main molecular mechanisms implicated in glucose-mediated vascular damage? A: 1. Increased polyol pathway flux 2. Advanced glycation end-product 3. Activation of Protein Kinase C 4. Increased hexosamine pathway flux Q: What is the single hyperglycemia-induced process reflected in the four main molecular mechanisms in glucose-mediated vascular damage? A: Overproduction of superoxide by the ETChain in the mitochondria. Q: How is sorbitol produced? (substrate, enzyme, cofactor, type of rxn) A: Glucose, aldose reductase, NADPH, reduction Q: Why is sorbitol (a polyol) build up a problem? A: "Sorbitol oxidation results in NADH inhibiting GAPDH promoting G3P which in turn increases DAG synthesis." DAG then activates PKC whose Beta isoform mediates retinal and renal bloodflow (details on another card). Q: What is an AGE and where are they found in INCREASED amounts in dibetics? A: An advanced glycation end-product. Found in diabetic retinal vessels and renal glomeruli. Q: How are advanced glycation end-products formed (2 steps)? A: 1. intracellular auto-oxidation of glucose to glyoxal 2. Then such reactive dicarbonyls (glyoxal, methylglyoxal, and 3-deoxyglucosone) react with amino groups on intra- and extracellular proteins to form AGEs. Q: What lipid second messenger activates PKC? A: DAG Q: Does intracellular hyperglycemia increase or decrease the amount of DAG? A: Increase Q: Activation of PKC-beta has been shown to mediate blood flow abnormalities in what 2 tissues by what (probable) mechanism? A: Retinal and renal blood flow abnormalities, perhaps by depressing nitric oxide production and/or endothelin-1 activity. Q: Modification of ____ (by ______ in the hexosamine pathway) may regulate _______-responsive genes. A: Modification of Sp1 (by GlcNAc) may regulate glucose-responsive genes. Q: Hyperglycemic shunting of excess intracellular glucose into the hexosamine pathway in aortic endothelium resulted in increased ___ __-linked ______ and a 70-80% decrease in ___ __-linked __________ and ___________. A: Increased Sp1 O-linked GlcNAc and decrease in Sp1 O-linked phosphothreonine and phosphoserine. (Sorry for the fill in the blank; none of this text was bolded, but Sp1 modification may regulate glucose-responsive elements.) Q: What is the basic goal of most current drugs used in treating type II diabetes? A: Reduce hyperglycemia Q: What are the 3 main groups of drugs used to reduce hyperglycemia in type II diabetes patients? A: 1. Sulfonylureas 2. Peroxisome proliferator-activated receptor gamma (PPARgamma) agonists 3. Alpha-glucosidase inhibitors Q: How do sulfonylureas reduce hyperglycemia in type II diabetes patients? A: They increase insulin release from metformin, which acts to reduce hepatic glucose production. Q: How do PPARgamma agonists (glitazones) reduce hyperglycemia as used in type II diabetes patients? A: They enhance insulin action Q: How do alpha-glucosidase inhibitors reduce hyperglycemia (as used in type II diabetes patients)? A: The interfere with gut glucose absorption. Q: What are (4) concerns/troubles with using the 3 main groups of drugs used to reduce hyperglycemia in type II diabetes patients? A: These therapies have 1. limited efficacy, 2. limited tolerability, 3. significant mechanism-based side effects and 4. tend to enhance weight gain Q: What is the concern/trouble of treatments to lower hyperglycemia in type II diabetics that is "of particular concern"? A: The tendency for most treatments to enhance weight gain. Q: T/F Given the critical role of obesity in the development of insulin resistance, successful approaches to attenuating appetite and/or enhancing energy expenditure will prove of great benefit in preventing and treating type 1 diabetes. A: False, in Type II Diabetes. Q: Agonists of what receptor offer the prospect of ameliorating obesity and type 2 diabetes? A: The melanocortin-4 receptor (MCR-4) Q: Abnormalities in fatty acid metabolism are increasingly recognized as key components in the pathogenesis of what syndrome and what disease? A: Metabolic syndrome (Syndrome X) and Type II Diabetes Q: T/F Fat-feeding and raised levels of circulating free fatty acids are clearly sufficient to induce BOTH peripheral and hepatic insulin resistance. A: True Q: What is the result of lipid accumulation within pancreatic islet cells? A: It has been proposed to impair insulin secretion. Q: Accumulation of lipids inside liver and muscle cells and specific increases in muscle long-chain fatty-acyl-CoA content have been implicated in causing ______ __________. A: Insulin resistance Q: How might leptin prevent diet-induced diabetes (as shown in rodents)? A: By reducing fat accumulation or "steatosis" in the liver and muscle, which accumulation would otherwise cause insulin resistance to develop. Q: What are 3 therapeutic targets that may help avoid insulin resistance as induced by lipotoxicity? A: 1. AMP-activated protein kinase (AMPK), 2. acetyl-CoA carboxylase (ACC) 3. Peroxisome proliferator-activated receptor gamma (PPARgamma) Q: What city was voted the fattest in the USA and what do officials patrolling the streets carry in an effort to persuade locals to lose weight? A: Philadelphia; bathroom scales (if this is on the test, Goates has to buy everyone a drink -- diet soda of course) Q: What are some sociocultural perspectives/questions of type II diabetes (and other non-communicable disease) prevention? A: Is health really determined largely (no pun intended) by individual choice? How do decreased labor and increased transportation, computerization etc. impact human health? How does the ready availability of tasty calorie-laden foods impacted human health? Can we turn the clock back?