Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Insulin and the regulation of plasma glucose Guo Xiaosun [email protected] Shandong University Part 1 Introduction Circulating glucose level are maintained within tight limits, which requires a complex control system. Importance of Glucose Regulation • Too little – Brain problems • Too much – Osmotic water loss (cellular and systemic) – Damages blood vessels fluorodeoxyglucose-positron-emission tomography, FDG-PET Glucose in urine Anatomy of the pancreas The functions of pancreas • 1. Exocrine function: pancreatic juice • 2. Endocrine function: hormones The endocrine pancreas Hormones of endocrine pancreas 胰岛激素与血糖 (+) (-) Part 2 Insulin and the response to high blood glucose levels • Insulin discovered by Frederick Banting and Charles Best in 1921. Leonard Thompson first patient successfully treated. 1965/9/17 it is the first protein synthesized by Chinese scientists . Leonard Thompson (1908–1935) Before and after receiving insulin (McCormick) • 51 amino acids • 2 chains linked by disulfide bonds • 5800 Dalton molecular weight Synthesis and secretion Insulin in blood • • • • 1. No specific carrier 2. Half life:3-5 min 3. Normal fasting level is within a tight range 4. Changed in response to food intake. Effects of Insulin • Nearly all cells (80%) increase glucose uptake (seconds) – Active transport – Primarily affects liver and muscle – Brain tissue is excepted • Alters phosphorylation of many key intracellular metabolic enzymes (minutes) • Alters protein synthesis and gene transcription (hours) Insulin Affects Tissues Differently • Muscle – Uptake of glucose and immediate use (exercise) or storage as glycogen (Exercising muscles can take up glucose without insulin) – Inhibits glycogen breakdown • Liver – Uptake of glucose and storage as glycogen. – Inhibits glycogen breakdown – Inhibits gluconeogenesis. • Adipose Tissue – Promotes glucose uptake and conversion to glycerol for fat production Insulin and Fat Metabolism • Liver cells store glycogen only up to 5-6% – Remaining glucose metabolized to fat – Triglycerides are synthesized and release into blood – Inhibits breakdown of fatty acids to ketones. • Adipose cells store fat – Inhibits breakdown of triglycerides – Stimulates uptake and use of glucose to form glycerol – Stimulates fatty acid uptake and conversion to triglycerides • Lack of insulin – Free fatty acids build up in blood – Liver metabolizes to produce phospholipids and cholesterol – Can lead to excess acetoacetic acid production and buildup of acetone (acidosis, which can lead to blindness and coma) Insulin and Protein Metabolism • Promotes – Transport of amino acids – Protein synthesis – Gene transcription • Inhibits protein degradation • Prevents glucose synthesis in liver – Inhibits breakdown of amino acids to form glucose. – Decreases urea formation • Lack of insulin causes elimination of protein stores Most Cells Insulin Control Protein synthesis Muscle Glucose uptake Glycogen synthesis Gastrointestinal hormones Adipose Amino acids Pancreas amino acids Insulin triglycerides Glucose uptake Glycerol production Triglyceride breakdown Triglyceride synthesis Beta cells Liver Blood glucose Glucose uptake Glycogen synthesis Fatty acid synthesis Glucose synthesis Brain No effect Feedback glucose Regulation of insulin secretion • 1. Plasma glucose concentration • 2. Others: Ach, bombesin, GLP1 Part 3 Hormones that act to raise blood glucose levels Glucagon Other hormones Glucagon 1. α cell 2. 29-amino-acid peptide 3. Response to low glucose levels 4. Effects: on liver, blood glucose↑ (1)Increase glycogenolysis (2)Stimulate gluconeogenesis (3)stimulate lipolysis (4)cell uptake Glu and amino ↓ Glycolysis ↓ Glucagon Control Triglyceride breakdown Triglyceride storage Exercise Amino acids Adipose Fatty acids Pancreas Alpha cells Epinephrine (stress) Liver Glycogen breakdown Glucose synthesis Glucose release Brain No effect Feedback Blood glucose Other hormones that act to raise blood glucose 1. Growth hormone 2. Glucocorticiods 3. Catecholamine Regulation of hormones on blood glucose Importance of Glucose Regulation • Too little – Brain problems • Too much – Osmotic water loss (cellular and systemic) – Damages blood vessels Part 4 Disorders of bloodglucose regulation: Diabetes mellitus case • Robert ,male,18y. • tired, large volume of urine, thirst, losing weight, his breath smelled ketotic. • PE: W 60kg, H 1.75m, pulse 90b.p.m, BP 115/75mmHg • Lab: Urine: glucose +++, ketones++ DM (diabetes mellitus) Characteristics: Chronic hyperglycemia Metabolism disturbance Main symptoms: • • • • Polydipsia Continuous hunger Polyuria Weight loss Cause: inadequate production and/or action of insulin 全球糖尿病流行趋势2000--2025 Classification of Diabetes Mellitus( ADA 1997) • Type 1 diabetes – A. Immune mediated – B. Idiopathic • Type 2 diabetes • Other specific types • Gestational diabetes mellitus Oral glucose tolerance test Aim: to confirm DM. Method: to measure how the body deals with glucose load. FPG (mmol/l) CH IFH 7.0 I-IFG IFG+IGT 6.1 5.6 IPH I-IGT 2hr PPG(mmol/l) 7.8 11.1 • IFG(impaired fasting glucose) • IGT(impaired glucose tolerance) Type1 diabetes: insulin deficiency Cause of type1 diabetes • Β cell destruction • (1) Genetic predisposition: HLA gene • (2) Environmental challenge: inflammation of B cell and attacked by immune system Results of type1 diatebes • Hyperglycemia • The body response as hypoglycemia • Glycosuria • Ketone bodies↑ • Kussmaul’s respiration • May lead to ketoacidosis • Growth Failure in children 胰 岛 素↓ 葡 萄 糖 利 用↓ 蛋白质分解↑ 糖氧化↓ 脂肪分解↑ 血 糖↑ 酮体生成↑ 能量不足 >肾糖阈 饥饿感 高渗性利尿 多食 多尿 (尿糖) 酮血症 脱水 口渴 多饮 体重↓ 酮 尿 酸中毒 昏 迷 Complications of type1 diatebes Diabetic ketoacidosis Complications of type1 diatebes Hypoglycemic coma • Cause • Prevention • Treatment Laboratory Examinations • Urine – glucose – ketone body – trace protein blood Glucose ketone body HbA1c FIM Insulin、C peptide、 insulin autoantibody Oral glucose tolerance test , IVGTT C peptide release test Comprehensive Diabetes Management Plan • • • • • Diet Exercise Pharmacologic therapy Monitoring of Blood Glucese Patient Education Management of type1 diatebes Appropriate diet • (1) several small regular meal than one large meal • (2) low in fat and simple carbohydrates • carbohydrates 50-60%, fat 20-25%,protein15-20% • (3) high vegetables and fruits • (4) avoid alcohol Appropriate Exercise • Walk is safe. Management of type1 diatebes Insulin therapy: 1.DM: (1) IDDM : the only effective drug (2) NIDDM (3) DM associated with acute or serious complications: Ketoacidosis, hyperosmolar nonketotic coma (4) DM patients under stress conditions Management of type1 diatebes Insulin therapy: 2.Other uses (1) Hyperkalemia and intracellular hypokalemia GIK(极化液): iv. drip 10%GS 1000ml Insulin 20u KCl 3g (2) Some psychotic disorders (3) Adjunctive therapy for some diseases Pharmacokinetics of insulin 1.Absorption: subcutaneous injection (S.C.). Inhalation 2.Metabolism: Half life:3-5 min 3.Preparations Insulin type Onset Long-acting Detemir (Levemir) 3 to 4 hours Glargine (Lantus) 90 minutes Intermediate-acting NPH (Humulin N) 1 to 2 hours Short-acting Aspart (Novolog) 15 minutes Glulisine (Apidra) 15 to 30 minutes Lispro (Humalog) 15 minutes Regular 30 to 60 minutes Mixed* NPH/lispro or 15 to 30 minutes aspart NPH/regular 30 to 60 minutes Peak Duration 6 to 8 hours None 6 to 23 hours 24 hours 4 to 10 hours 14 or more hours 1 to 3 hours 30 to 60 minutes 30 to 90 minutes 2 to 4 hours 3 to 5 hours 4 hours 3 to 5 hours 5 to 8 hours Dual 14 to 24 hours Dual 14 to 24 hours *—NPH/regular: Humulin 70/30, Novolin 70/30, Humulin 50/50; NPH/lispro or aspart: Humalog 75/25, Novolog 70/30, Humalog 50/50. Onset of action, peak, and duration of exogenous insulin preparations. Adapted from Hirsch IB. Insulin analogues. N Engl J Med. 2005;352(2):177. 1型糖尿病胰岛素治疗方案(1) 基础—餐前加強疗法,每日注射4次 胰岛素 R 胰岛素 N R 20-45% 早餐前30分钟 R 20-30% 午餐前30分钟 R 20-30% 晚餐前30分钟 N 20-30% 睡前注射 每天总剂量减去胰岛素N量作为100%来分配早餐前,午餐前和晚餐前胰岛素用量的百分数 1型糖尿病胰岛素治疗方案(2) 预混型人胰岛素每日注射两次 Adverse reactions of insulin 1.Hypoglycemia: most common Prevention and treatment 2.Insulin allergy 3.Insulin Resistance Acute resistance: stress( anti-insulin substance↑ free fatty acids↑pH↓ ) Chronic resistance: 1) anti-insulin autoantibody 2) down regulation of receptor 3) dysfunction of glucose transfer 4. Others Type2 diatebes: relative insulin deficiency Cause and risk factors of type2 DM • Age greater than 40 years • ethnic groups, including African Americans, Hispanic Americans, Asian Americans, and Native Americans, have a higher risk for diabetes. • Family history of diabetes • Diabetes during a previous pregnancy • Excess body weight (especially around the waist) • Given birth to a baby weighing more than 9 pounds • Low activity level (exercising less than 3 times a week) • City dwelling Metabolic syndrome 61 Complications of type2 diatebes • 1. Hyperosmolar non-ketotic coma Dehydrateion More likely to clot: stroke, AMI • 2. Hypoglycaemia Long-term consequences of poor glycemic control 1992年糖尿病日 1993年糖尿病日 1994年糖尿病日 1995年糖尿病日 1996年糖尿病日 1997年糖尿病日 1998年糖尿病日 一个与所有国家所 有人有关的健康问 题 糖尿病儿童与成长 糖尿病与老年 糖尿病和教育,降 低无知的代价 2002年糖尿病日 糖尿病与您的眼 睛:不可忽视的 危险因素 2003年糖尿病日 糖尿病损害肾脏 2004年糖尿病日 糖尿病与肥胖 2005年糖尿病日 2006年糖尿病日 胰岛素与生命 全球的觉醒:改善 生命的关键 2007年糖尿病日 2008年糖尿病日 糖尿病人的权利 2009年糖尿病日 1999年糖尿病日 糖尿病的代价 2000年糖尿病日 新千年糖尿病和生 活方式 2010年糖尿病日 2001年糖尿病日 糖尿病心血管疾病 与社会负担 2011年糖尿病日 2012年糖尿病日 糖尿病与足部护 理 糖尿病与脆弱人 群 关心儿童和青少 年糖尿病 青少年儿童的糖 尿病 糖尿病预防与教 育 糖尿病教育与预 防 应对糖尿病,立 即行动 糖尿病,保护我 们的未来 Nodular glomerulosclerosis 65 Aneurysm Hemorrhage and Exudates 66 67 • Bullosis diabeticorum 68 69 Results of type 2 DM • Need higher levels of insulin secretion • May require insulin in the end. Management of type 2 DM • Dietary control • Body weight control • Increase physical activity – at least walk for 30 min. per days • Medications (hypoglycemic agents; insulin ) 新的治疗药物层出不穷 1920s 动物胰岛 素 1950s 1960s 1970s 纯化胰岛 素 1980s 人胰岛素 1990s 和半合成 胰岛素 Lispro 2000s Glargine Aspart 磺脲类 甲磺丁脲 氯磺丙脲 醋磺己脲 格列本脲 格列吡嗪 格列美脲 双胍类 氯茴苯酸类(苯 二甲双胍 甲酸衍生物) 瑞格列奈 那格列奈 α-糖苷酶 噻唑烷二酮类 胰高血糖 抑制剂 素样肽1 罗格列酮 72 阿卡波唐 (GLP1 匹格列酮 米格列醇 ) Oral Antidiabetic agents Hypoglycemic agents Sulfonylureas Non-Sulfonylureas Antihyperglycemic agents Biguanides Insulin sensitizers Inhibitor of α-glycosidase 73 各类抗糖尿病药物的作用部位 胰腺 磺脲类 瑞格列奈 那格列奈 胰岛素分泌受损 葡 萄 糖 肠 高血糖 道 ↓葡萄糖苷 酶抑制剂 肝脏 ↑HGP 二甲双胍 胰岛素增敏剂 ↓葡萄糖摄取 ↑胰岛素增敏剂 ↑二甲双胍 肌肉 74 Orally hypoglycemic agents Sulfonylureas (磺酰脲类) The first generation: tolbutamide(甲苯磺丁脲) chlorpropamide(氯磺丙脲) The second generation: glyburide (格列本脲, 优降糖 ) glipizide (格列吡嗪, 美吡哒) gliquidone (格列喹酮, 糖肾平) glimepiride (格列美脲) The third generation: gliclazide (格列齐特,达美康) Pharmacological effects of sulfonylureas 1. Hypoglycemic action: weaker than Insulin (1) Increasing insulin release from β cell : KATP blockadge→Ca2+ (2) Enhancing sensitivity of target cell to insulin Increasing the number and affinity of insulin receptors (3) Decreasing glucagons release from α cell Pharmacological effects of sulfonylureas 2.Other effects (1)Antidiuretic action: chlorpropamide, glyburide pathway: reinforcing the role of ADH (2) blood platelets aggregation and adhesion ↓ gliclazide Adverse reactions of sulfonylureas 1. Hypoglycemia reactions 2. Gastrointestinal tract reactions 3. Anaphylactic reaction 4. Hepatic damage Orally Hypoglycemic agents • Non-Sulfonylureas Repaglinide(瑞格列奈) Nateglinide(那格列奈) 可模拟正常人生理性胰岛素分泌,口服 给药后迅速起效,半衰期仅1小时左右,4小 时后基本代谢清除,两餐之间不刺激胰岛 素释放。 发生低血糖的机会较低 Orally Antihyperglycemic agents Biguanides (双胍类) Metformin (甲福明,二甲双胍) Phenformin(苯乙福明,苯乙双胍) Pharmacological effects of biguanides 1. Antihyperglycemic action (1) Postponing glucose absorption (2) Promoting glucose usilization: anaerobic glycolysis (3) Inhibiting release of glucagon 2.Other effects (1) Regulating blood lipid (2) Antiplatelet effects Adverse reactions of biguanides 1.Gastrointestinal irritation 2. Lactic acidosis:phenformin Orally Antihyperglycemic agents Insulin sensitizer Thiazolidinediones (TZD,噻唑烷二酮类) Rosiglitazone(罗格列酮) Englitazone (恩格列酮) Pioglitazone (吡格列酮) Troglitazone (曲格列酮) Ciglitazone (环格列酮) Pharmacological effects of insulin sensitizer • 1.Improving insulin resistance • 2.Regulating blood lipid • 3.Improving vessel complication of NIDDM • 4.Improving β-cell function Adverse reactions of insulin sensitizer Low incidence of hypoglycemia Heptic toxicity: Troglitazone (曲格列酮) 水肿、水储留,部分患者的体重增加。 可引起贫血和红细胞减少 Orally Antihyperglycemic agents α-glycosidase inhibitors • Acarbose(阿卡波糖) Mechanism of action : Inhibiting α-Glycosidase • (1) decreasing the formation of glucose • (2) slowing the absorption of glucose Effects of α-glycosidase inhibitors When Medications Fail • • • • • • • Acute infections or other serious illnesses Pregnancy Major surgery Congestive heart failure Kidney disease Liver disease Use of other drugs (prednisone and some psychiatric medications) • Overeating or excessive weight gain • Antibodies that destroy beta cells (in people with type 1, misdiagnosed as type 2) • Progressive loss of beta cell function over many years Starting Insulin Indications for Starting Insulin Absolute •All patients with type 1 diabetes •Ketoacidosis or severe hyperglycemia (blood sugars over 500) •Presence of serious infection (for example, pneumonia) •Concurrent illness (such as heart attack) •During and after major surgery •During pregnancy •Failure to achieve ideal glycemic control with two or three oral agents • A1c over 10% • A1c over 7.5 % plus fasting glucose over 250 Relative •Patients who are underweight or losing weight without dieting •Patients who have symptoms from blood sugars over 200 •Any patient who is hospitalized •Patients requiring steroids (such as prednisone) for other disorders •Onset of diabetes prior to age thirty, or a duration over fifteen years •Complications such as painful diabetic neuropathy 91 Gestational diabetes • Women without previously diagnosed diabetes are found to have inappropriately high blood sugar levels during pregnancy. The metabolic syndrome • Diagnosis • Treatment Metabolic Syndrome 94 THANK YOU