Download Chapter 36 Insulin and oral hypoglycemic agents

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
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