单击此处编辑母版副标题样式 diabetes mellitus endocrinology department, renji hospital...
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Diabetes Mellitus
Endocrinology Department, Renji Hospital
陶 弢
Definition
Diabetes mellitus is a heterogeneous primary disorder of
carbohydrate metabolism with multiple etiologic factors that
generally involve absolute or relative insulin deficiency or
both. All causes of diabetes ultimately lead to hyperglycemia,
and it can causes the late complications involving the eyes,
kidneys, nerves and blood vessels.
Environmental-Genetic interactions
Absolute or relative insulin deficiency
Disorder of carbohydrate, protein and fat metabolism
hyperglycemia
Complications involving the eyes,kidneys,nerves and blood vessels
病因
发病机制
病理生理
共同特征
最终结局
Epidemiology
Global prevalence of diabetes
1.942.2
3.3
0
0.5
1
1.5
2
2.5
3
3.5DM
全球
患者
总数
(亿
)
2004 year 2010 year 2025 year
1
2
3
4
5
6
7
8
9
10
Total
印度中国美国俄联邦日本巴西印度尼西亚巴基斯坦墨西哥Ukraine
所有其他国家
19.4
16.0
13.9
8.9
6.3
4.9
4.5
4.3
3.8
3.6
49.7
135.3
印度中国美国巴基斯坦印度尼西亚俄联邦墨西哥巴西埃及日本所有其他国家
57.2
37.6
21.9
14.5
12.4
12.2
11.7
11.6
8.8
8.5
103.6
300.0
糖尿病患者前糖尿病患者前 1010 位的国家位的国家排名 国家国家 1995
( 百万 )2025
( 百万 )
King H, et al. Diabetes Care 1998;21:1414–31.
Epidemiology
Classification
Etiologic classification of diabetes mellitus(1997 ADA 1999 WHO)
Type 1 diabetes (T1DM)
Other specific types
Type 2 diabetes(T2DM)
Gestation diabetes mellitus(GDM)
βcell destruction, usually leading to absolute insulin deficiency
A. Immune mediated
1) being rapid, mainly in infants and children
2) being slow, mainly in adults-----latent autoimmune diabetes in
adults, LADA
B. Idiopathic clinical feature
obviously family history , early onset, at the beginning having ketosis, need
a small quantity insulin therapy;
βcell destruction slowly progressing , after onset several months or years not
need insulin therapy
一 . Type 1 diabetes (T1DM)
LADA– Clinical feature
1. Called type 1.5 DM or slowly progressing insulin-dependent diabetes
2. T cell mediated autoimmune disease
3. Adult age at diagnosis (range 30-70year)
4. Lean or non-obesity
5. The presence of diabetes-associated autoantibodies(IA2, ICA, GAD )
6. Delay (at least half year )from diagnosis in the need for insulin therapy t
o manage hyperglycemia
7. Having type 1 DM’s predisposing genes( such as HLA-DR3,HLA-DR4,
BW54, DQ-131-57-NON-ASP etal)
8. Often accompany thyroid and gastric parietal cells organ specific antibod
y
may range from predominantly insulin resistance with relative
insulin deficiency to a predominantly secretory defect with insulin
resistance
The risk of developing this form of diabetes increases with age, obesity and lack of p
hysical activity
It is often associated with a strong genetic predisposition, more than is the type 1 diabetes
higher prevalence
二 . Type 2 diabetes (T2DM)
5%
90%
5%
1型糖尿病2型糖尿病其他类型糖尿病
三 . Other specific types
Divided into 8 subgroups according to the etiology
and pathogenesis, including all the secondary diabetes
and specific etiologic diabetes
Genetic defects of B cell function
Maturity-onset diabetes of the young (MODY)
1). Chromosome 20,HNF-4a (MODY1)
2). Chromosome 7p,glucokinase (MODY2)
3). Chromosome 12,HNF-1a (MODY3)
4). Insulin promoter factor 1,IPF-1((MODY4)
5). Chromosome 17 cen-q , HNF-1ß (MODY5)
6 ). Chromosome 2q,NEUROD4 (MODY6)
7). Mitochondrial DNA
Other specific types
MODY Clinical feature
Early onset, at least one patient develops Diabetes before the
age of 25
Autosomal Dominant Inheritance , disease deliver fit Mendeli
an inheritance ; having three generation or above family const
ellation heredity history
Diabetes may be treated by diet or tablets and does not always
need insulin treatment
Mitochondrial maternal inheritance diabetes clinical feature
Maternal inheritance; means children of female patient possible w
ith disease, children of male patient not with disease
Early onset, Lean or non-obesity
Diabetes may be treated by diet or tablets and does not always ne
ed insulin treatment at initial stage, no prone to ketosis; but in the
long run, need for insulin therapy to manage hyperglycemia
Often accompany dysaudia in prediabetes or afterdiabetes
Minority having manifestation damaged by (nerve, muscle, retina
hematopoietic system, et al) or serum lactic acid raising up
Other specific typesGenetic defects of insulin action
Type A insulin resistance( ovarian hyperandrogen insulin resistant acanthosis nigrican
HAIR-AN )
Rabson-Mendenhall syndrome
Leprechaunism
Lipoatrophic diabetes
Disease of exocrine pancreas
Endocrinopathies
Drug or chemical-induced
Infections
Uncommon forms of immune-mediated diabetes
Other genetic syndromes sometimes associated with diabetes
四 . Gestation diabetes mellitus(GDM)
Diabetes and IGR be diagnosed during the gestation
Screening the GDM during gestation 24—28 weeks through OGTT• 50g glucose test -----screen test• 100g glucose test -----diagnostic test• High-risk group, age>25y or age<25y but obesity, direct relative of DM
6 weeks after parturition, OGTT be given again
Etiology and pathogenesis
Type 1 DM
Prone to ketoacidosis
Absolute insulin deficiency(ID)
(Low C-peptide level)
β-cell destructionidiopathy
Genetic susceptibility
Enviromental factors initiate
GADA,IAA,ICAIA2 and IA-2β
HLA-DR/DQ
autoimmune
(Virus infection, chemical, diet)
HLA and autoantibodies
HLA (histocompatibility locus antigen)---major effective gene
• HLA –DR3,-DR4-----background condition
• HLA –DQ-B57-Asp---- resistance gene
• HLA –DQ-B57-Val/Ala/Ser;DQ-A52-Arg---predisposing genes
• TNFβ and hsp70(heat shock protein 70) gene polymorphism
Autoantibody :
• GADA (antibody to glutamic acid decarboxylase)--- β-cell destruction early mark
er
• ICA (islet cell autoantibody)—specificity low
• IAA (autoantibody to insulin) —specificity low
• IA-2 ( autoantibody to tyrosine phosphatases IA-2 andIA-2β)---specificity high
Type 2 DM
Genetic susceptibility Enviromental factors( obese, rich diet ,oldLess physical activity )
Insulin deficiency(ID) Insulin resistance(IR)
IGR (IGT, IFG)
T2DM
Low born weight
Insulin resistance : definition
• Insulin sensitivity
The ability of insulin to degrade dissociation glucose concentration
stimulate to utilize glucose: muscle and fat
inhibit to generate glucose: liver
• Insulin resistance Lossing insulin sensitivity lead to hyperinsulinemia
insulin resistance
endodermis functional disturbanc
e
Accelerate to generate
atherosclerosis
cardiovascular disease
Type 2 DType 2 DMM
IGTIGTHyperinsulinemia
-cell decompensatio-cell decompensationn
Microvascularcomplication
Central obesity
hypertension
hypertriglyceridemia HDL cholesterol
plasminogen System dysfunctionpolycystic ovarian
syndrome
Cusi K, Cusi K, Diabetes Care, 2000Diabetes Care, 2000
mechanism of action
Relation gene
• Insulin resistance insulin receptor substance 1 and 2 di-allelic mutation glucose transporter -4(GLUT-4) genetic mutation
insulin receptor already detected fifty mutable site
uncoupling protein (UCP) genetic mutation
• Insulin deficiency glucokinase (GCK)
glucose transporter -2(GLUT-2) mitochondria defect proinsulin processing disorder insulin structural abnomalities
islet amyloid polypeptide( IAPP)
Pathophysiology of DM
Insulin deficiencyIR
Characterized by hyperglycemia
Accompanied by disruption of protein , lipid , water and electrocytes metabolism
Glucogen synthesis
Glucose oxidation
Glucogen catabolism
Hepatic glucose production
Adipocytes uptake TG
Lipid synthesis (lipoproteinesterase activity )Lipid mobilization (Hormone sensitive lipase )
ketone (acetone, acetoacetic acid,
beta-hydroxybutyric acid)
Clinical feature of DM
Stage
Type
Eugly-
caemia Hyperglycemia
normal
regula-tion IGT
IFG
Diabetes mellitusdon’t need need insulin
insulin insulin sustained
Type 1
Type 2
Specific
GDM
Etiological factor type of diabetes clinical stage
Insulin deficiency Insulin resistance
hyperglycemiadisruption of protein , lipid , water and electrocytes metabolism
Chronic impairment : Macrovascular (CHD, CVD, PVD)
Microvascular (kidney, reticular, nerve)
osmotic diuresis
polyuria( 多尿 ),
Thirst( 口渴 ),
Polydipsia( 多饮 )
Polyphagia( 多食 )
Weight loss( 消瘦 )
Visiual blurring
Vulvovagitis and pruritus( 瘙痒 )
Insulin deficiency Insulin resistance
hyperglycemia
OGTT+
C-peptide/insulin
Urine glucose ( for monitoring)
blood glucose ( for diagnosis and monitoring)
HbA1c ( for monitoring)
Urine/blood ketone
Lab test
hypoinsulinemia hyperinsulinemia
HbA1c
Glucose sticks to the haemoglobin to make a'glycosylated hae
moglobin' molecule, called haemoglobin A1C or HbA1C.
By measuring the HbA1C it can tell you how high your blood
glucose has been on average over the last 8-12 weeks.
Measuring the HbA1C by affinity chromatography and high
efficiency liquid chromatography
Normal range :4%--6%
Diagnostic criteria (1999, WHO)
Plasma glucose (mmol/L)
FPG RPG OGTT 2h
Normal range < 6.1 and < 7.8
Diabetes mellitus ≥7.0 or ≥ 11.1 or ≥ 11.1
IGR
IFG ≥6.1---< 7.0 <7.8
IGT <7.0 ≥7.8 ---< 11.1
1. Classic symptom plus casual plasma glucose ≥ 11.1mmol/L, casual is defined as any time of day without regard to time since last meal
or2. An overnight fasting glucose(FPG) ≥ 7.0mmol/L ,Fasting is defined as no caloric intake for at least 8 hours or3. 2 h PG ≥ 11.1mmol/L during an OGTT. If without classic symptom,each must be confirmed,on a subsequent day, by any one of the three methods given as above
The diagnostic criteria for diabetes mellitus
To differentiate type 1DM and type2DM
type1DM tpye2DM
Onset mode acute Chronic and delitescence
onset age Young(<25 y,12-14y) >40 years old(60-65y)
Clinical feature typical and severity Light or asymptoms
ketoacidosis spontaneously Usually having remote cause(infection etal)
Insulin or C-peptide release test
Low or Deficiency peak value delay or absence
Onset body weight Normal or tabification Overweight or obesity
Chronic impairment Nephropathy(35%-40%----mainly death cause)
Cardiovascular Disease(>70%--- mainly death cause)
treament insulin Oral hypoglycemia agents/insulin
LADA diagnose keypoint
1. Onset after 20y,clinical symptom(polyurine, polydipsia, polyphagia, weight loss) obviously,BMI<25kg/m2, FBG>16.5mmol/l
2. Fasting Cpeptid≤0.4nmol/l ,OGTT1h and/or 2h Cpeptid≤0.8nmol/l ,curve low and equal
3. GADA( + )
4. HLA-DQ B57 non-Asp homozygote
1 add 2/3/4------LADA?
Chronic complication
Macrovascular (CHD, CVD, PVD) -metabolic syndrome-IR
Microvascular (kidney, reticular, nerve) -thickening of the capillary basement membr
ane
Macrovascular
• morbidity rate high
• young age of onset
• pathogenetic condition progress quickly
• Multiorgan to be involved in
• mainly death cause in type2 DM
• intermittent lameness ( 间歇性跛行 )
Microvascular
• Markable change: microcirculation disturbance microangioma to shape micrangium basal membrane thickening• Centre component element: Hyperglycemia
• Pathogenesis
Diabetic retinopathy
• Non-proliferation If evidence of mild nonproliferation retinopathy is present,the current recom
mended approach is frequent evaluation through repeated ophthalmic exam
inations • Proliferation If the retinopathy is extensive or is preproliferative or preliferative,the patient
should be evaluated for treatment by photocogulation
Diabetic Retinopathy( China : 1984 )
• backgroundI microaneurysms and/ or dot hemorrhagesII hard exudates and/ or dot hemorrhagesIII soft exudates and/ or dot hemorrhages
• proliferative I growth of abnormal blood vessels and/ or vitreous hemorrhages
II growth of abnormal blood vessels and fibrous tissue
III growth of abnormal blood vessels and fibrous tissue, detaqchment of the
retina
Background Diabetic Retinopathy
Hard exdates
Dot hemorrhages
Proliferative Diabetic Retinopathy
Diabetic nephropathy
• I: hypertrophy, hyperfiltration
• II: microalbuminura after exercise(UAER: 20-200ug/min or UA 30-300 mg/24h)
• III: continuity microalbuminura
• IV: macroalbuminura (UAER>200ug/min or UA> 300 mg/24h) edema and hypertension
• V: ESRD
Diabetic neuropathy
• Peripheral polyneuropathy (symmetry /multiple/slowly pro
gressing/lower limb severity)
• Mononeuropathy (oculomotor nerve/ abducent nerve)• Autonomic neuropathy (stomach intestine/ urinary system/
sexual organ/ cardiovascular system)
Skininfection
Acute complication
• Diabetic Ketone acidosis (DKA)
• Non-ketone diabetic-hyperosmal coma ( NKDC)
• Lactate acidosis
• Hypoglycemic coma
treatment
• Early, long term, integrated, individualized
Diet control
Physical activity
Drug therapy
education
Self-monitoring
Target(2002, Asia-Pacific area)
ideal acceptable badFVPG < 6.1mmol/L ≤7.0mmol/L >7 mmol/L2hVPG < 8.0mmol/L ≤10mmol/L >10mmol/LHbA1c < 6.5% 6.5-7.5% >7.5%TG <1.5 mmol/L <2.2mmol/L > 2.2 mmol/L TC < 4.5mmol/L >4.5 mmol/L > 6.0 mmol/L LDL-C < 2.5 mmol/L < 4.4mmol/L > 4.4 mmol/L HDL-C > 1.1 mmol/L 0.9-1.1mmol/L < 0.9 mmol/LBP < 130/80mmHg >130/80-<140/90 > 140/90BMI M < 25 <27 ≥ 27 F < 24 <26 ≥26
Diet
• Total calorie control (ideal bodyweight)
• Carbohydrate (50-60%)
Protein(15-20%)
Lipid(20-25%)
• Distribution ( eg. 1/5, 2/5,2/5)
Lifestyle modificationLifestyle modification
生活方式干预生活方式干预 ---- eat less, walk more---- eat less, walk more
1.1. 30 minutes, moderate exercise, 5/7days30 minutes, moderate exercise, 5/7days
2.2. Health dietHealth diet
3.3. Weight lossWeight loss
Lifestyle modification (Finland)Lifestyle modification (Finland)Weight loss 2.4kg in 5 years, T2DM decreased 58%Weight loss 2.4kg in 5 years, T2DM decreased 58%
DPPDPPWeight loss 4.3kg in 3 years, T2DM decreased 58%Weight loss 4.3kg in 3 years, T2DM decreased 58%
Oral hypoglycemic agents
• Sulfonylureas —— glyburide, glipizide, glimeperide • Glinides —— retaglinide , nateglinid • Biguanides —— metformin
glucosidase inhibitor —— acarbose, miglitol ,voglibose
• Thiazolidiones —— rosiglitazone, pioglitazone
Mechanism of action-SU
nategliniderepaglinide (36 kD)
SUR
depolarization
ATPglimipiride ( 65 kD )
glyburide ( 140 kD )
Kir 6.2
SUR
Mechanism of action-MF
↓Insulin secretion burden
↓Hepatic output
控制血糖
↑Glucose uptake
muscle
pancrease
liver
American Diabetes Association.Medical Management of Non-Insulin-Dependent(Type2) Diabetes.3rd et.Alexandria,VA: American Diabetes Association:1994
Mechanism of action- acarbose
Acarbose
Oligosaccharide
Acarbose
Small intestinemucosa
Reversible inhibition of oligosaccharide breakdown by -glucosidases
Mechanism of action-TZD
•Agonists of PPARγ (peroxisome proliferator activated receptorγ,)
Indication of insulin therapy
1. T1DM2. T2DM:• Acute complication: NHDC, DKA, LA• End stage of chronic complication• Stress• Pregnancy• SU Failure• Severe weight loss• Cortisol therapy
Insulin therapy
Fasting hyperglycemia• insulin deficiency (waning of circulating in
sulin levels)• Somogyi phenomena• Dawn phenomena
hyperglycemia
Insulin level Insulin sensitivity
β-cell
SU(AC 30’)
Benzoic acid derivatives(AC 0-5’)
insulinBiguanides
Thiazolidinediones
hepatic
Muscle,adipocyte
-glucosidase inhibitor
STEP-WISE STRATIGE
Matthaei S, et al. Endocr Rev 21:585,2000
EDUCATIONDIET
EXERCISEMF
TZDSU
insulin
80 120 160 200
FPG (mg/dl)
100
80
60
40
20
0
mean insulin during OGTT (mU/l)
pregnancy
• Diet• Exercise• Insulin therapy
Insulin deficiency
Rapid mobilization of energy from stores in muscle and fat depots.
Ketone production
Insulin-antagonistic hormone
Utilization is reduced
Ketone is accumulated
acidosisDisturbance of electrocyte
Nausea vomiting
Rapid and deep respiration
osmotic diuresis
Hyperglycemia
polyuria
DKA
depletion of intravascular volume
Precipitating factors:infection , diet, surgery, trauma, pregnancy
Precipitating factors
• Most common: infection• Cerebrovascular accident• Alcohol abuse• Pancreatitis• Myocardial infarction• Trauma• Drugs (corticosteroids, thiazides,sympathomimet
ic agents)
Insulin deficiency
Rapid mobilization of energy from stores in muscle and fat depots
Ketone is accumulated
Insulin-antagonistic hormone
acidosisDisturbance of electrocytes
Hyperglycemia
Lab test
depletion of intravascular volume
acetoacetate, B-hydroxybutyrate,acetone
HCO3 - , PH K, Na, Cl
Bun Cr
Precipitating factors:blood count,X-ray,ECG
Insulin deficiency Insulin-antagonistic hormone
Ketone is accumulated
acidosis
Disturbance of electrocyte
Hyperglycemia
treatment
depletion of intravascular volume
Insulin supplement
(0.1U/kg/h)
Liquid supplement
Insulin therapy-Exclude hypokalemia(K<3.3 mEq/l)
• Intravenous bolus of RI at 0.15 units/kg• Followed by continuous infusion 0.1U/kg/h• Target: 1st h BG2.8-4.2mmol/l
or check hydration, if acceptableDoubled insulin fusion
• BG<14mmol/l, insulin 0.05-0.1U/kg/h+5-10%GS• Keep BG-14mmo/l,until acidosis in DKA or mental obtu
ndation and hyperosmolarity in HHS are resolved.• When pt can eat,0.5-1.0U/kg/d H(2/3 in AM, 1/3 in PM)
Fluid therapy -Adult patients• Aim: expansion of the intravascular and extravasc
ular volume and restoration of renal perfusion.• 1st h: 0.9% NS 15-20ml/kg/h—1-1.5l• Then 4-14 ml/kg/h — 200-700ml
0.9%NS—serum Na low0.45%NS —serum Na high/normal
• Judged by hemodynamic monitoring(Bp), measurement of fluid output and input, and clinical examination.
• Avoid iatrogenic fluid overload
•<50ml/kg over first 4h
•Replace fluid deficit evenly over 48h
•Osmolality decreased less than 3mOsm/kg.H2O.h
POTASSIUM
• <3.3mM,avoid insulin therapy• <5.5mM, start Ka supplement20-30mEq/l• 10% KCl 20ml/l• Aim 4-5mEq/l
Partial Insulin deficiency Insulin-antagonistic hormone
Serum sodium
osmotic diuresis
Hyperglycemia
polyuria
NHDC
dehydration
Precipitating factors:infection , diet, cerebrovascular accident, MI
Lethargy,confusion
hyperosmotality
Absence of significant ketosis
Coma
Consideration question
• How to diagnose and treat Diabetes mellitus ?
• How to differentiate type 1DM and type2DM ?
谢谢!