Insulin and the regulation of plasma glucose
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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

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Insulin and the regulation of plasma glucose

Insulin and the regulation of plasma glucose

Guo Xiaosun

[email protected]

Shandong University


Part 1 introduction

Part 1 Introduction

Circulating glucose level are maintained

within tight limits, which requires a complex control system.


Importance of glucose regulation

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

Glucose in urine


Anatomy of the pancreas

Anatomy of the pancreas


The functions of pancreas

The functions of pancreas

  • 1.Exocrine function: pancreatic juice

  • 2. Endocrine function: hormones


The endocrine pancreas

The endocrine pancreas


Insulin and the regulation of plasma glucose

Hormones of endocrine pancreas

胰岛激素与血糖

(+)

(-)


Part 2 insulin and the response to high blood glucose levels

Part 2 Insulin and the response to high blood glucose levels


Insulin and the regulation of plasma glucose

  • Insulin discovered byFrederick Banting and Charles Best in 1921.

Leonard Thompson first patient successfully treated.

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

Leonard Thompson (1908–1935)

Before and after receiving insulin (McCormick)


Insulin and the regulation of plasma glucose

  • 51 amino acids

  • 2 chains linked by disulfide bonds

  • 5800 Dalton molecular weight


Synthesis and secretion

Synthesis and secretion


Insulin in blood

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

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

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

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

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

Most Cells

 Protein synthesis

Insulin Control

 amino

acids

Muscle

 Glucose uptake

 Glycogen synthesis

Gastrointestinal

hormones

  • Adipose

  • Glucose uptake

  • Glycerol production

  • Triglyceride breakdown

  •  Triglyceride synthesis

 triglycerides

Amino acids

Pancreas

Beta cells

 Insulin

  • Liver

  •  Glucose uptake

  • Glycogen synthesis

  • Fatty acid synthesis

  • Glucose synthesis

Bloodglucose

 glucose

Brain

No effect

Feedback


Regulation of insulin secretion

Regulation of insulin secretion

1. Plasma glucose concentration

2. Others: Ach, bombesin, GLP1


Part 3 hormones that act to raise blood glucose levels

Part 3 Hormones that act to raise blood glucose levels

Glucagon

Other hormones


Glucagon

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

Glucagon Control

  • Adipose

  • Triglyceride breakdown

  • Triglyceride storage

 Fatty acids

Exercise

Amino acids

Pancreas

Alpha cells

  • Liver

  •  Glycogen breakdown

  • Glucose synthesis

  •  Glucose release

 Blood glucose

Epinephrine

(stress)

Brain

No effect

Feedback


Other hormones that act to raise blood glucose

Other hormones that act to raise blood glucose

1. Growth hormone

2. Glucocorticiods

3. Catecholamine


Regulation of hormones on blood glucose

Regulation of hormones on blood glucose


Importance of glucose regulation1

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

Part 4 Disorders of bloodglucose regulation:

Diabetes mellitus


Insulin and the regulation of plasma glucose

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

DM (diabetes mellitus)

Characteristics:

Chronic hyperglycemia

Metabolism disturbance

Main symptoms:

  • Polydipsia

  • Continuous hunger

  • Polyuria

  • Weight loss

    Cause: inadequate production

    and/or action of insulin


Insulin and the regulation of plasma glucose

全球糖尿病流行趋势2000--2025


Classification of diabetes mellitus ada 1997

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

Oral glucose tolerance test

Aim: to confirm DM.

Method: to measure how the body deals with glucose load.


Insulin and the regulation of plasma glucose

7.0

6.1

5.6

7.8 11.1

FPG (mmol/l)

CH

IFH

I-IFG

IFG+IGT

IPH

I-IGT

2hr PPG(mmol/l)


Insulin and the regulation of plasma glucose

  • IFG(impaired fasting glucose)

  • IGT(impaired glucose tolerance)


Type1 diabetes insulin deficiency

Type1 diabetes: insulin deficiency


Cause of type1 diabetes

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

Results of type1 diatebes

  • Hyperglycemia

  • The body response as hypoglycemia

  • Glycosuria

  • Ketone bodies↑

  • Kussmaul’s respiration

  • May lead to ketoacidosis

  • Growth Failure in children


Insulin and the regulation of plasma glucose

胰 岛 素↓

葡 萄 糖 利 用↓

蛋白质分解↑

脂肪分解↑

糖氧化↓

血 糖↑

酮体生成↑

能量不足

>肾糖阈

脱水

酮血症

饥饿感

高渗性利尿

酮 尿

酸中毒

昏 迷

多尿

(尿糖)

口渴

体重↓

多食

多饮


Complications of type1 diatebes

Complications of type1 diatebes

Diabetic ketoacidosis


Complications of type1 diatebes1

Complications of type1 diatebes

Hypoglycemic coma

  • Cause

  • Prevention

  • Treatment


Insulin and the regulation of plasma glucose

Laboratory Examinations

  • blood

    • Glucose

    • ketone body

    • HbA1c

    • FIM

    • Insulin、Cpeptide、insulin autoantibody

    • Oral glucose tolerance test ,

    • IVGTT

    • C peptide release test

  • Urine

    • glucose

    • ketone body

    • trace protein


Comprehensive diabetes management plan

Comprehensive Diabetes Management Plan

  • Diet

  • Exercise

  • Pharmacologic therapy

  • Monitoring of Blood Glucese

  • Patient Education


Management of type1 diatebes

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 diatebes1

    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


    Insulin and the regulation of plasma glucose

    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

    Pharmacokinetics of insulin

    1.Absorption:

    subcutaneous injection (S.C.).

    Inhalation

    2.Metabolism:

    Half life:3-5 min

    3.Preparations


    Insulin and the regulation of plasma glucose

    *—NPH/regular: Humulin 70/30, Novolin 70/30, Humulin 50/50; NPH/lispro or aspart: Humalog 75/25, Novolog 70/30, Humalog 50/50.


    Insulin and the regulation of plasma glucose

    Onset of action, peak, and duration of exogenous insulin preparations.

    Adapted from Hirsch IB. Insulin analogues. N Engl J Med. 2005;352(2):177.


    Insulin and the regulation of plasma glucose

    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


    Insulin and the regulation of plasma glucose

    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

    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

    Type2 diatebes: relative insulin deficiency


    Cause and risk factors of type2 dm

    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


    Complications of type2 diatebes

    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

    Long-term consequences of poor glycemic control


    Nodular glomerulosclerosis

    Nodular glomerulosclerosis


    Aneurysm hemorrhage and exudates

    Aneurysm Hemorrhage and Exudates


    Insulin and the regulation of plasma glucose

    • Bullosis diabeticorum


    Results of type 2 dm

    Results of type 2 DM

    • Need higher levels of insulin secretion

    • May require insulin in the end.


    Management of type 2 dm

    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 )


    Insulin and the regulation of plasma glucose

    动物胰岛素

    纯化胰岛素

    新的治疗药物层出不穷

    1920s

    1950s

    1960s

    1970s

    1980s

    1990s

    2000s

    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

    人胰岛素和半合成胰岛素

    二甲双胍

    氯茴苯酸类(苯甲酸衍生物)

    瑞格列奈

    那格列奈

    胰高血糖素样肽1(GLP1)

    Lispro

    Glargine

    Aspart

    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


    Oral antidiabetic agents

    Oral Antidiabetic agents

    • Hypoglycemic agents

      • Sulfonylureas

      • Non-Sulfonylureas

    • Antihyperglycemic agents

      • Biguanides

      • Insulin sensitizers

      • Inhibitor of α-glycosidase


    Insulin and the regulation of plasma glucose

    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

    肠道

    ↓葡萄糖苷 酶抑制剂

    高血糖

    肝脏

    ↑HGP

    ↓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

    Sulfonylureas (磺酰脲类)

    Orally hypoglycemic agents

    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

    Pharmacological effects of sulfonylureas

    1. Hypoglycemic action:weaker than Insulin

    • 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


    Insulin and the regulation of plasma glucose

    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

    Adverse reactions of sulfonylureas

    1. Hypoglycemia reactions

    2. Gastrointestinal tract reactions

    3. Anaphylactic reaction

    4. Hepatic damage


    Orally hypoglycemic agents

    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

    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

    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

    Adverse reactions of biguanides

    1.Gastrointestinalirritation

    2. Lactic acidosis:phenformin


    Insulin sensitizer

    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)


    Insulin and the regulation of plasma glucose

    Pharmacological effects of insulin sensitizer

    • 1.Improving insulin resistance

    • 2.Regulating blood lipid

    • 3.Improving vessel complication of NIDDM

    • 4.Improving β-cell function


    Insulin and the regulation of plasma glucose

    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


    Glycosidase inhibitors

    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 glycosidase inhibitors

    Effects of α-glycosidase inhibitors


    Insulin and the regulation of plasma glucose

    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


    Insulin and the regulation of plasma glucose

    Starting Insulin

    Indications for Starting Insulin


    Gestational diabetes

    Gestational diabetes

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


    The metabolic syndrome

    The metabolic syndrome

    • Diagnosis

    • Treatment


    Metabolic syndrome

    Metabolic Syndrome


    Insulin and the regulation of plasma glucose

    THANK YOU


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