Insulin and the regulation of plasma glucose

Guo Xiaosunguoxiaosun@126.comShandong 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

胰岛激素与血糖

（＋）

（－）

Hormones of endocrine pancreas

Part 2 Insulin and the response to high blood glucose levels

• Insulin discovered byFrederick Banting and Charles Best in 1921.

Leonard Thompson first patient successfully treated.

1965/9/17 it is the first protein synthesized by Chinese scientists .

Before and after receiving insulin (McCormick)

Leonard Thompson (1908–1935)

• 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

Insulin Control Muscle

Glucose uptake Glycogen synthesis

Liver Glucose uptake Glycogen synthesis Fatty acid synthesis Glucose synthesis

BrainNo effect

PancreasBeta cells

Gastrointestinalhormones

Feedback

amino acids

glucose

triglyceridesAdipose Glucose uptake Glycerol production Triglyceride breakdown Triglyceride synthesis Insulin

Most Cells Protein synthesis

Amino acids

Bloodglucose

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

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

Glucagon Control

Liver Glycogen breakdown Glucose synthesis Glucose release

BrainNo effect

PancreasAlpha cells

Exercise

Feedback

Adipose Triglyceride breakdown Triglyceride storage

Blood glucose

Fatty acids

Epinephrine(stress)

Amino acids

1. Growth hormone

2. Glucocorticiods

3. Catecholamine

Other hormones that act to raise blood glucose

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 hyperglycemiaMetabolism 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.

IFH CH

I-IFG IFG+IGT

IPHI-IGT

FPG (mmol/l)

2hr PPG(mmol/l)

7.0

6.1

7.8 11.1

5.6

• 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↓

蛋白质分解↑蛋白质分解↑ 脂肪分解↑脂肪分解↑

酮体生成↑酮体生成↑

酮血症酮血症

酮 尿酸中毒昏 迷

酮 尿酸中毒昏 迷

脱水脱水

体重↓体重↓口渴口渴

多饮多饮

高渗性利尿高渗性利尿

多尿( 尿糖 )

多尿( 尿糖 )

多食多食

血 糖↑血 糖↑

饥饿感饥饿感

能量不足能量不足

糖氧化↓糖氧化↓

葡 萄 糖 利 用↓葡 萄 糖 利 用↓

＞肾糖阈＞肾糖阈

Complications of type1 diatebes

Diabetic ketoacidosis

Complications of type1 diatebes

Hypoglycemic coma

• Cause

• Prevention

• Treatment

• Urine – glucose– ketone body– trace protein

Laboratory Examinations

bloodGlucoseketone bodyHbA1cFIMInsulin 、 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.

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

Management of type1 diatebes

Insulin therapy:

Pharmacokinetics of insulin

1.Absorption: subcutaneous injection (S.C.).

Inhalation

2.Metabolism:

Half life:3-5 min

3.Preparations

Insulin type Onset Peak DurationLong-actingDetemir (Levemir) 3 to 4 hours 6 to 8 hours 6 to 23 hoursGlargine (Lantus) 90 minutes None 24 hoursIntermediate-actingNPH (Humulin N) 1 to 2 hours 4 to 10 hours 14 or more hoursShort-actingAspart (Novolog) 15 minutes 1 to 3 hours 3 to 5 hoursGlulisine (Apidra) 15 to 30 minutes 30 to 60 minutes 4 hoursLispro (Humalog) 15 minutes 30 to 90 minutes 3 to 5 hoursRegular 30 to 60 minutes 2 to 4 hours 5 to 8 hoursMixed*NPH/lispro or aspart

15 to 30 minutes Dual 14 to 24 hours

NPH/regular 30 to 60 minutes 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

预混型人胰岛素每日注射两次

1 型糖尿病胰岛素治疗方案 (2)

Adverse reactions of insulin

1.Hypoglycemia: most commonPrevention and treatment2.Insulin allergy3.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 transfer4. 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 年糖尿病日一个与所有国家所有人有关的健康问题

1993 年糖尿病日 糖尿病儿童与成长

1994 年糖尿病日 糖尿病与老年

1995 年糖尿病日 糖尿病和教育，降低无知的代价

1996 年糖尿病日 胰岛素与生命

1997 年糖尿病日 全球的觉醒：改善生命的关键

1998 年糖尿病日 糖尿病人的权利

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

2001 年糖尿病日 糖尿病心血管疾病与社会负担

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 糖尿病与足部护理

2006 年糖尿病日 糖尿病与脆弱人群

2007 年糖尿病日 关心儿童和青少年糖尿病

2008 年糖尿病日 青少年儿童的糖尿病

2009 年糖尿病日 糖尿病预防与教育

2010 年糖尿病日 糖尿病教育与预防

2011 年糖尿病日 应对糖尿病，立即行动

2012 年糖尿病日 糖尿病，保护我们的未来

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Nodular glomerulosclerosis

66

Aneurysm Hemorrhage and Exudates

67

68

• Bullosis diabeticorum

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 )

72

新的治疗药物层出不穷

双胍类

动物胰岛素

纯化胰岛素

人胰岛素和半合成胰岛素

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

LisproGlargineAspart

α- 糖苷酶抑制剂阿卡波唐 米格列醇

噻唑烷二酮类罗格列酮匹格列酮

胰高血糖素样肽 1（ GLP

1 ）

氯茴苯酸类（苯甲酸衍生物）瑞格列奈那格列奈

二甲双胍

1920s

1950s

1960s

1970s

1980s

1990s

2000s

73

Oral Antidiabetic agents

Hypoglycemic agents Sulfonylureas

Non-Sulfonylureas

Antihyperglycemic agents Biguanides

Insulin sensitizers

Inhibitor of α-glycosidase

74

各类抗糖尿病药物的作用部位各类抗糖尿病药物的作用部位

磺脲类 瑞格列奈　　那格列奈

胰腺

胰岛素分泌受损 葡萄糖

↓葡萄糖苷 酶抑制剂

肠道

高血糖

↑HGP

肝脏

↓葡萄糖摄取 肌肉　二甲双胍　胰岛素增敏剂

↑胰岛素增敏剂↑二甲双胍

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 )

Orally hypoglycemic agents

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

2.Other effects(1)Antidiuretic action:

chlorpropamide, glyburide

pathway: reinforcing the role of ADH

(2) blood platelets aggregation and adhesion ↓

gliclazide

Pharmacological effects

of sulfonylureas

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

Biguanides ( 双胍类 )

Orally Antihyperglycemic agents

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

Insulin sensitizer

Orally Antihyperglycemic agents

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

α-glycosidase inhibitors

Orally Antihyperglycemic agents

• 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

• 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

When Medications Fail

91

Absolute Relative

•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

•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

Indications for Starting Insulin

Starting Insulin

Gestational diabetes

• Women without previously diagnosed diabetes are found to have inappropriately high blood sugar levels during pregnancy.

The metabolic syndrome

• Diagnosis

• Treatment

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Metabolic Syndrome

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