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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！