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PathoConceptMAP
- 1. GROUP #3 CONCEPT MAP by Lynne Bielska, Kyounghee Han, Helen Onwudinanti & Michael Seeley
- 2. OBESITY INSULIN RESISTANCE NON FUNCTIONING PANCERATIC BETA CELLS DIABETES MELLITIS TYPE II causes causes Diagnosis of Diagnosis of OVERVIEW Increased demand for insulin synthesis
- 3. InflammationHyperglycemia Physiologic stress Inc Visceral Adipose tissue OBESITY causes causes Diabetes Type II Insulin Resistance Decreased function of Beta Cells Diagnosis: A1C, FPG>126mg/dl, CPG >200mg/d,l, OGTT causes Alterations in insulin secretion Genetic factors Diet high in carbohydrate and fat Increased demand for insulin synthesis Increased free fatty acids Addition of causation factors in RED
- 4. Hyperglycemia Insulin Resistance Increased demand for insulin from Beta cells Near constant increase of blood insulin Down-regulation of insulin receptor sites Hyperglycemia Leads to Insulin has less binding receptors; blood glucose remains high Decreased beta cell mass and function Increased demand for insulin synthesis Decrease hepatic sensitivity to insulin Gluconeogenisis in liver Diet Decreased insulin
- 5. Increased visceral adipose tissue. Waist circumference >40” in men, 35”women Adipose tissue, especially around the waist, acts as endocrine tissue. Inflammatory cytokines TNF-a, IL-6 Leptin, risitin, Decrease levels adiponectin Macrophage infiltration inflammation Increased visceral adipose tissue Adipokines, produced by adipose tissue Post-receptor mechanism Insulin resistanc e Decreased insulin synthesis in beta cellToxicity to beta cells Pancreatic Beta Cell dysfunction
- 6. Increased free fatty acids Diet Glucolipotoxic conditions hyperglycemia Increased free fatty acids Beta cell apoptosis Decreased beta cell mass and function Alteration in insulin secretion in beta cell
- 7. Inflammation Inflammation Oxidative Stress (O.S) DNA Damage Mitochondria Beta cell injury & dysfunction Impaired insulin production Inflammatory cytokines; TNFa and IL-6 Hyperglycemia
- 8. Stress In Liver: Increased gluconeogenesis decreased glycogen synthesis anti-insulin effect Stress Hormones: Cotisol, Growth hormone, Catecholamine, dopamine, histamine In muscle & adipose tissue: Decreased glucose uptake lipogenesis in abdomen & trunk Pancreatic Beta Cell death, dysfunction Hyperglycemia Pro-inflammatory transcription factor activation Activation of inflammatory mediators: tumor necrosis factor-a (TNFa) & interleukin-6 (IL-6) Cortisol Increased fatty acids Obesity T Helper Cells suppressed Physiologic Stress
- 9. Genetic Factors Obesity Diabetes type II The Genetic Link Variant in FTO gene Adipokines & inflammatory cytokines Increased free fatty acids Regulation of ghrelin. Variant cases decrease See next slide
- 10. The Genetic Link Continued Genetic Factors Diabetes type II Genetic Loci Maturity Onset Diabetes of the Young (MODY) MODY 1 – HNF4A MODY 2 – GCK MODY 3 – HNF1A MODY 4 – IPF1 MODY 5 – HNF1G MODY 6 – NEUROD1 MODY7 – KLF11 MODY 8 – CEL MODY 9 – PAX4 MODY 10 – INS MODY 11 - BLK Higher genetic risk: African American Native American Pima Indians Hispanic Americans Genetic Loci for insulin secretion ADRA2A – Polymorphism of the Human Alpha – Adrenergic Receptor gene is associated with decreased insulin secretion Genetic Loci for Pancreatic and Beta Cell Function: TCF7L2 SLC30A8 HHEXIIDE KCNJ11 Genetic Loci for Insulin post receptor defects GYS1 – Defect in post receptor enzyme for glucose synthesis If one twin develops Type II DM the other has a 90 % risk of developing it First Degree Relatives of patients with Type II DM have impaired non- oxidative metabolism before developing DM Genetic Loci for Hepatic Nuclear Factors (HNF) MODY 1 – HNF4A MODY 3 – HNF1A MODY 5 – HNF1G Alterations in specific genes Independent genetic risk factors
- 11. References: Bjorck, L., Giang, K., Heden-Stahl, C., Novak, M., Rosengren, A. & Wilhelmsen, L. (2013). Perceived stress and incidence of type 2 diabetes: a 35- year follow-up study of middle-aged Swedish men. Diabetic Medicine. 30: pe8-e16. Bjorkelund, C., Gedda, B., Marklund, B. & Svenningsson, I. (2012). Anxiety and depression in obese and normal weight individuals with diabetes type 2: A gender perspective. Scandinavian Journal of Caring Sciences. 26: 349-354. Chaturvedi, N. The burden of diabetes and its complications: trends and its complications for intervention. Diabetes Res Clin Pract 2007; 76 (1): p3-12 ( PubMed) Cariello, A. New insight on oxidative stress and diabetes complications. Nature 2001; 414: 813-820 (PubMed) Chu, X., Erdman, R., Gerst, H., Derr, K., Al-Agha, M., Blosky, M. & Carey, D. et al (2008). Association of morbid obesity with FTO and INSIG2 allelic variants. Arch Surg 143: 235–40. Flier, J. & Kahn, B. (2000). Obesity and insulin resistance. Journal of Clinical Investigation. 106:473-481. http://www.jci.org/articles/view/10842 Hastty, A., Guterrez, D. & Puglisi, M. (2009). Impact of increased adipose tissue mass on inflammation, insulin resistance, and dyslipidemia. Current Diabetic Rep. 9: 526-532. Herrero, L.Naaz, A. & Shoelson, S. (2007). Obesity, inflammation and insulin resistance. Gastroenterology. 132:2169-2180. Juge, N., Mithen, R.F., Traka, M. Molecular basis for chemoprevention by Sulforaphane: A comprehensive review. Cell Mo Life Sci 2007; 64: 1105-1127 ( PubMed) Karra, E., O’Daly, O., Choudhury, A., Yousseif, A., illership, S., Neary, M. & Batterham, R. (2013). A link between FTO, ghrelin, and impaired brain food-cue responsitivity. Journal of Clinical Investigation. McCance, K.L. & Huether, S.E. (2009). Pathophysiology, the Biological Basis for Disease in Adults and Children. (6th ed.) Mosby: Maryland Heights, Missouri. Thorleifsson, G., Walters, G., Gudbjartsson, D., Steinthorsdottir, V., Sulem, P. & Helgadottir, A. et al. (2009). Genome-wide association yields new sequence variants at seven loci that associate with measures of obesity. Nat. Genet. 41: 18–24. Whitmore, C. (2010). Obesity and diabetes in adults. British Journal of Nursing. 19: 880-887.
Editor's Notes
- Our focus question for our concept map is: How is obesity related to development of diabetes type 2?” In the United States, type 2 diabetes mellitus affects 10.5% of those ages 45-64 years, and 18.4% of those ages 65-74. The incidence of diabetes has doubled in all adult age groups in the past two decades. Type 2 diabetes mellitus is characterized by insulin resistance and impaired insulin secretion. As approximately 90% of people with type 2 diabetes are overweight or obese, obesity is seen as a significant contributory factor in its development.
- This slide shows a more detailed overview of concepts, and how the major concepts are linked. An arrow indicates causative factor. The red boxes are major factors that cause or contribute to insulin resistance and decreased function of pancreatic beta cells, which are shown in orange. In the following slides, we will elaborate on these major concepts in detail, and show relationships between them. Diabetes Mellitus type II is diagnosed by …..
- Hyperglycemia is defined as… Due to the elevated levels of blood glucose in an overweight individual, the β-cells in the pancreas must release more insulin than normal to meet the demand and return the blood to homeostatic levels. The near-constant increase in blood insulin levels results from an effort to match the increase in blood glucose, which will cause receptor sites on the liver cells to downregulate and decrease the number of receptors for insulin, increasing the subject’s resistance by decreasing sensitivity to this hormone. There is also a hepatic decrease in sensitivity to insulin. This can be seen in the continuing gluconeogenesis in the liver even when blood glucose levels are elevated. Gluconeogenesis increases blood glucose in compound the problem. This is the more common process of insulin resistance, which leads to adult-onset diabetes. (need citation).
- Increased visceral adipose tissue, or “central obesity” is associated with DM II more so than generalized obesity. It is defined as having a waist circumference >40” in men and >35” for women. Adipose tissue, especially centrally, acts as endocrine tissue in that it secretes hormones. Adipokines are hormones produced in adipose tissue, which increase serum levels of leptin, resistin and decreased levels of adiponectin. Leptin decreases insulin synthesis in the beta cell. A varity o;f infalmmatory cytokines are shown to be toxic to beta cells. These changes are associated with decreased insulin sensitivity, or insulin resistance which is the down regulation of insulin receptors on cells. Adipokines also release inflammatory cytokines and induce insulin resistance through a post-receptor mechanism.
- Pancreatic beta cells are extremely sensitive to high levels of glucose and free fatty acids, and under these glucoliptoxic conditions, beta cells undergo apoptotic cell death. The adipokin leptin decreases insulin synthesis in the beta cell. Elevated free fatty acids and intracellular deposits of triglycerides and cholesterol are also found in obese people. Increase in free fatty acids cause alterations in insulin secretion within the beta cell.
- Long lasting effect of hyperglycemia ( Inflammation) is known to damage cells as a result of oxidative stress. (Carcello, 2001) Oxidative stress accounts for the complications of type two diabetes such as cardiovascular disease (CVD), retinopathy, nephropathy, neuropathy ( Chaturvedi, 2007) Oxidative stress from inflammation also causes beta cell injury and dysfunction.
- Stress stimulates anterior and posterior pituitary gland to release a variety of hormones including adrenocorticotropic hormone (ACTH), growth hormone, and antidiuretic hormone. ACTH stimulates the cortex of the adrenal gland to release glucocorticoid hormone (mainly cortisol). One of the primary effects of cortisol is the stimulation of gluconeogenesis or the formation of glucose from amino acids or free fatty acids in the liver, resulting in pancreatic beta-cell destruction and type 2 diabetes. In muscle and adipose tissue, cortisol decreases glucose uptake, causing hyperglycemia and increases lipogenesis in abdomen and trunk, resulting in central obesity. Stress also activates inflammatory mediators such as tumor-necrosis factor-a and interleukin-6, and causes insulin-resistance, pancreatic cell death, resulting in Type 2 diabetes. It is interesting that self-perceived permanent stress is an important long-term predictor of diagnosed diabetes, independently of socio-economic status, BMI and other conventional Type 2 diabetes risk factors” according to researchers.
- Many genes have been identified that are associated with type 2 diabetes, including those that code for beta cell mass, beta cell function (ability to sense blood glucose levels, insulin synthesis, and insulin secretion), insulin receptors, glucagon synthesis, cellular responsiveness to insulin stimulation and others. These genetic abnormalities combined with environmental influences, such as obesity, result in the basic mechanisms of diabetes: insulin resistance and decreased insulin secretion by beta cells. Although many individuals with risk factors for type 2 diabetes are insulin resistant, only those individuals who are genetically predisposed to beta cell dysfunction will develop DM II. Genetic predisposition involved in increased ad-lib food intake, particularly fat consumption and impaired satiety. Increased exposure to high fat diet leads to up-regulation of the fat mass and obesity-associated gene (FTO) leads to more fat intake. Variant on FTO gene predisposes to DM2 through the effect on BMI, this variant is though to cause 22% of common obesity. FTO regulates ghrelin, a hormone secreted in the gut that alters appetite and food intake. Ghrelin is also associated with insulin resistance
- Genetic Loci: is a specific position along a chromosome composed of different nucleotide sequences (McCance, Huether, Brashers, & Rote, 2010, p. 144-145)