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ueda2011 pathophysiology of dm-d.adel
- 1. Review Of The Pathophysiology Of Type 2 Diabetes And The Key Role Of Incretin Hormones
- 2. Major Pathophysiologic Defects in Type 2 Diabetes Kahn CR, Saltiel AR. In: Kahn CR et al, eds. Joslin’s Diabetes Mellitus. 14th ed. Lippincott Williams & Wilkins; 2005:145–168. Hepatic glucose output Insulin resistance Glucose uptake Glucagon (α cell) Insulin (β cell) LiverLiver Hyperglycemia Islet-Cell Dysfunction MuscleMuscle AdiposeAdipose tissuetissue PancreasPancreas LiverLiver
- 3. Reprinted from Primary Care, 26, Ramlo-Halsted BA, Edelman SV, The natural history of type 2 diabetes. Implications for clinical practice, 771–789, © 1999, with permission from Elsevier. Development and Progression of Type 2 Diabetes and Related Complicationsa a Conceptual representation. Insulin levelInsulin level Insulin resistanceInsulin resistance Hepatic glucoseHepatic glucose productionproduction PostprandialPostprandial glucoseglucose Fasting plasmaFasting plasma glucoseglucose BBetaeta-cell function-cell function Progression of Type 2 Diabetes Mellitus Impaired Glucose Tolerance Diabetes Diagnosis Frank Diabetes 4–7 years Development of Macrovascular Complications Development of Microvascular Complications
- 4. Relative Contribution of FPG and PPG to Overall Hyperglycemia Depending on HbA1c Quintiles n = 58 n = 58 n = 58 n = 58n = 58 0 20 40 60 80 100 <7.3 7.3–8.4 8.5–9.2 9.3–10.2 >10.2 Postprandial glucose Fasting glucose HbA1c Contribution,% Monnier L et al. Diabetes Care. 2003;26:881–885. Copyright 2003 American Diabetes Association from Diabetes Care, Vol. 26, 2003; 881-885. Reprinted with permission from The American Diabetes Association.
- 5. Incretins Modulate Insulin and Glucagon to Decrease Blood Glucose During Hyperglycemia GLP-1=glucagon-like peptide-1; GIP=glucose-dependent insulinotropic polypeptide. Brubaker PL et al. Endocrinology 2004;145:2653–2659; Zander M et al. Lancet 2002;359:824–930; Ahren B. Curr Diab Rep 2003;3:365–372; Buse JB et al. In: Williams Textbook of Endocrinology,11th ed. Philadelphia: Saunders; 2008:1329–1389; Drucker DJ. Diabetes Care 2003;26:2929–2940. Incretin hormones GLP-1 and GIP are released by the intestine throughout the day; their levels increase in response to a meal. Release of active incretins GLP-1 and GIPa Blood glucose in fasting and postprandial states Ingestion of food Glucagon from alpha cells (GLP-1) Hepatic glucose production GI tract DPP-4 enzyme Inactive GLP-1 Insulin from beta cells (GLP-1 and GIP) Glucose-dependent Glucose-dependent Pancreas Inactive GIP Beta cellsBeta cells Alpha cellsAlpha cells Peripheral glucose uptake
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Editor's Notes
- Initiating Early and Appropriate Therapy: Considerations for Type 2 Diabetes
- Major Pathophysiologic Defects in Type 2 Diabetes This diagram depicts the impact of type 2 diabetes on the feedback loop that regulates glucose homeostasis.1 In type 2 diabetes, insulin resistance is increased and insulin secretion is impaired.2 Most patients with type 2 diabetes have insulin resistance. Normally, pancreatic β cells increase insulin secretion to compensate for insulin resistance. However, when β-cell function is impaired, hyperglycemia develops.2 By the time diabetes is diagnosed, β-cell function has already decreased substantially and continues to decline over time.2 Once insulin secretion is impaired, an imbalance between insulin and glucagon can develop. Elevated glucagon levels lead to an increase in hepatic glucose production, which leads to an increase in blood glucose.2 Likewise, with decreased secretion of insulin, less glucose is taken up by muscle, adipose tissue, and liver.3
- Development and Progression of Type 2 Diabetes This conceptual diagram shows a proposed paradigm on the development and progression of pathophysiology in type 2 diabetes.1 The horizontal axis in the figure shows the years before and after diagnosis of diabetes. Insulin resistance begins years before diagnosis.1 Insulin resistance rises during disease development and continues to rise during impaired glucose tolerance (IGT). Over time, insulin resistance remains stable during the progression of type 2 diabetes.1 The insulin secretion rate increases to compensate for the decrease in insulin effectiveness due to insulin resistance. β-cell function can decrease even as insulin secretion increases. At the time of diagnosis of type 2 diabetes and 6 years afterwards about 50% and 73% of β-cell function has been lost, respectively.2 Over time, β-cell compensatory function deteriorates and insulin secretion decreases. β-cell function progressively fails.1,2 Initially, fasting glucose is maintained in near-normal ranges. The pancreatic β cells compensate by increasing insulin levels, leading to hyperinsulinemia. This compensation keeps glucose levels normalized for a time, but as β cells begin to fail, IGT develops with mild postprandial hyperglycemia. As the disease progresses, the β cells continue to fail, resulting in higher PPG levels. With continued loss of insulin secretory capacity, fasting glucose and hepatic glucose production increase.1 Once β cells cannot secrete sufficient insulin to maintain normal glycemia at the fasting or postprandial stage, type 2 diabetes (hyperglycemia) becomes evident. Insulin resistance and β-cell dysfunction are established well before type 2 diabetes is diagnosed.1
- Relative Contribution of FPG and PPG to Overall Hyperglycemia Depending on HbA1c Quintiles This study evaluated the relative contributions of FPG and PPG to overall hyperglycemia in 290 non–insulin-, non–acarbose-using patients with type 2 diabetes. The analysis suggested that both FPG and PPG contribute to overall hyperglycemia.1 The relative contribution of PPG levels decreased progressively from the lowest to the highest quintile of HbA1c.1 In contrast, the relative contribution of FPG showed a gradual increase with increasing levels of HbA1c.1 Thus, targeting both FPG and PPG may be required to optimize blood glucose levels.1
- Incretins Modulate Insulin and Glucagon to Decrease Blood Glucose During Hyperglycemia This schematic summarizes the pathways related to the observed effects of glucagon-like peptide-1(GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) on insulin and GLP-1 on glucagon. Following a meal, the release of incretins is stimulated: GLP-1 from L cells located primarily in the distal gut (ileum and colon) and GIP from K cells in the proximal gut (duodenum).1,2 Together, these incretins enhance the insulin response of the pancreatic β cells to an oral glycemic challenge.2 GLP-1 helps suppress glucagon secretion from pancreatic α cells when glucose levels are elevated.2-5 The subsequent insulin-induced increase in glucose uptake by muscles and other tissues and the reduced glucose output (the result of increased insulin and decreased glucagon) from the liver result in better physiologic control of glucose levels.2-5