Download Diabetes mellitus

Diabetes Mellitus
Endocrinology Department, Renji Hospital
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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.
病因
Environmental-Genetic interactions
发病机制
Absolute or relative insulin deficiency
病理生理
Disorder of carbohydrate, protein and fat metabolism
共同特征
hyperglycemia
最终结局
Complications involving the eyes,kidneys,nerves
and blood vessels
Epidemiology
3.3
全球DM患者总数（亿）
3.5
3
2.5
2.2
1.94
2
1.5
1
0.5
0
2004 year
2010 year
2025 year
Global prevalence of diabetes
Epidemiology
糖尿病患者前10位的国家
国家
1995
1
2
3
印度
中国
美国
(百万)
19.4
16.0
13.9
4
5
6
7
8
俄联邦
日本
巴西
印度尼西亚
排名
9
10
巴基斯坦
墨西哥
Ukraine
所有其他国家
Total
8.9
6.3
4.9
4.5
4.3
3.8
3.6
49.7
135.3
国家
2025
印度
中国
美国
(百万)
57.2
37.6
21.9
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
14.5
12.4
12.2
11.7
11.6
8.8
8.5
103.6
300.0
King H, et al. Diabetes Care 1998;21:1414–31.
Classification
Etiologic classification of diabetes mellitus
(1997 ADA
1999 WHO)
Type 1 diabetes (T1DM)
Type 2 diabetes(T2DM)
Other specific types
Gestation diabetes mellitus(GDM)
一 . Type 1 diabetes (T1DM)
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
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 to
manage hyperglycemia
7.
Having type 1 DM’s predisposing genes( such as HLA-DR3,HLADR4,BW54, DQ-131-57-NON-ASP etal)
8.
Often accompany thyroid and gastric parietal cells organ specific
antibody
二. Type 2 diabetes (T2DM)
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 physical activity
It is often
associated with a strong genetic predisposition, more than is the
type 1 diabetes
 higher prevalence
5%
5%
1型糖尿病
2型糖尿病
其他类型糖尿病
90%
三. Other specific types
Divided into 8 subgroups according to the etiology
and pathogenesis, including all the secondary diabetes
and specific etiologic diabetes
Other specific types
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
MODY Clinical feature
 Early onset, at least one patient develops Diabetes before the
age of 25
 Autosomal Dominant Inheritance , disease deliver fit
Mendelian inheritance ; having three generation or above
family constellation 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
with 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
need 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 types
Genetic 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
HLA-DR/DQ
Type 1 DM
Genetic susceptibility
Enviromental factors initiate
(Virus infection, chemical, diet)
idiopathy
GADA,
IAA,
autoimmune
ICA
IA2 and
IA-2β
β-cell destruction
Absolute insulin deficiency(ID)
(Low C-peptide level)
Prone to ketoacidosis
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
marker
• 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
Low born weight
Genetic susceptibility
Enviromental factors
( obese, rich diet ,old
Less physical activity )
Insulin resistance(IR)
Insulin deficiency(ID)
IGR (IGT, IFG)
T2DM
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
mechanism of action
b-cell decompensation
IGT
Type 2
DM
Microvascular
complication
Cusi K,
Diabetes Care, 2000
insulin resistance
Hyperinsulinemia
endodermis
functional
disturbance
Accelerate to
generate
atherosclerosis
Central obesity
hypertension
hypertriglyceridemia
HDL cholesterol
plasminogen
System dysfunction
polycystic ovarian
syndrome
cardiovascular disease
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
IR
Insulin deficiency
Characterized by
hyperglycemia
Accompanied by
disruption of protein ,
lipid , water and
electrocytes metabolism
Adipocytes uptake TG 
Glucogen synthesis 
Glucose oxidation 
Glucogen catabolism 
Hepatic glucose production
Lipid synthesis 
(lipoproteinesterase activity )
Lipid mobilization (Hormone
sensitive lipase )
ketone (acetone, acetoacetic acid,
beta-hydroxybutyric acid)
Clinical feature of DM
Etiological factor type of diabetes clinical stage
EuglyHyperglycemia
Stage caemia
normal
Diabetes mellitus
need
need insulin
regula-tion IGT don’t
insulin
sustained
IFG insulin
Type
Type 1
Type 2
Specific
GDM
Insulin deficiency
hyperglycemia
Insulin resistance
disruption of protein ,
lipid , water and
electrocytes metabolism
osmotic diuresis
polyuria(多尿),
Thirst(口渴),
Polydipsia(多饮)
Visiual blurring
Vulvovagitis and
pruritus(瘙痒)
Polyphagia(多食)
Chronic impairment :
Weight loss(消瘦)
Macrovascular (CHD, CVD, PVD)
Microvascular (kidney, reticular, nerve)
Lab test
Insulin deficiency
Insulin resistance
hypoinsulinemia
hyperinsulinemia
OGTT
+
C-peptide/insulin
hyperglycemia
Urine glucose ( for monitoring)
blood glucose ( for diagnosis and monitoring)
HbA1c
( for monitoring)
Urine/blood ketone
HbA1c

Glucose sticks to the haemoglobin to make a'glycosylated
haemoglobin' 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
Diabetes mellitus
< 6.1
≥7.0
and
or ≥ 11.1
< 7.8
or ≥ 11.1
IGR
IFG
IGT
≥6.1---< 7.0
<7.0
<7.8
≥7.8 ---< 11.1
The diagnostic criteria for diabetes
mellitus
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
or
2. An overnight fasting glucose(FPG) ≥
7.0mmol/L ,Fasting is defined as no caloric intake for
at least 8 hours
or
3.
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
To differentiate type 1DM and type2DM
type1DM
tpye2DM
acute
Chronic and delitescence
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
Onset mode
onset age
LADA diagnose keypoint
1.
2.
3.
4.
Onset after 20y,clinical symptom(polyurine, polydipsia,
polyphagia, weight loss) obviously,BMI<25kg/m2,
FBG>16.5mmol/l
Fasting Cpeptid≤0.4nmol/l ,OGTT1h and/or 2h
Cpeptid≤0.8nmol/l ,curve low and equal
GADA(＋)
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)
membrane
-thickening of the capillary basement
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
recommended approach is frequent evaluation through repeated ophthalmic
examinations
• Proliferation
If the retinopathy is extensive or is preproliferative or preliferative,the
patient should be evaluated for treatment by photocogulation
Diabetic Retinopathy
（China：1984）
• background
I
II
III
microaneurysms and/ or dot hemorrhages
hard exudates and/ or dot hemorrhages
soft exudates and/ or dot hemorrhages
• proliferative
I
growth of abnormal blood vessels and/ or
vitreous hemorrhages
growth of abnormal blood vessels and
fibrous tissue
growth of abnormal blood vessels and
fibrous tissue, detaqchment of the retina
II
III
Background Diabetic Retinopathy
Hard exdates
Dot hemorrhages
Proliferative Diabetic Retinopathy
Diabetic nephropathy
• I: hypertrophy, hyperfiltration
• II: microalbuminura after exercise(UAER: 20200ug/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
progressing/lower limb severity)
• Mononeuropathy (oculomotor nerve/ abducent nerve)
• Autonomic neuropathy (stomach intestine/ urinary system/
sexual organ/ cardiovascular system)
Skin
infection
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
education
Drug
therapy
Selfmonitoring
Target(2002, Asia-Pacific area)
ideal
acceptable
bad
FVPG
< 6.1mmol/L
≤7.0mmol/L
>7 mmol/L
2hVPG
< 8.0mmol/L
≤10mmol/L
>10mmol/L
>7.5%
HbA1c
< 6.5%
6.5-7.5%
TG
<1.5 mmol/L
<2.2mmol/L
TC
< 4.5mmol/L
>4.5 mmol/L
LDL-C
< 2.5 mmol/L
HDL-C
> 1.1 mmol/L
0.9-1.1mmol/L
BP
BMI
< 130/80mmHg
M < 25
F < 24
>130/80-<140/90
<27
<26
< 4.4mmol/L
> 2.2 mmol/L
> 6.0 mmol/L
> 4.4 mmol/L
< 0.9 mmol/L
> 140/90
≥ 27
≥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 modification
生活方式干预---- eat less, walk more
1. 30 minutes, moderate exercise, 5/7days
2. Health diet
3. Weight loss
Lifestyle modification (Finland)
Weight loss 2.4kg in 5 years, T2DM decreased 58%
DPP
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
repaglinide (36 kD)
Kir 6.2
nateglinide
SUR
depolarization
SUR
ATP
glimipiride（65 kD）
glyburide（140 kD）
Mechanism of action-MF
pancrease
↓Insulin secretion burden
控制血糖
↓Hepatic output
liver
↑Glucose uptake
muscle
American Diabetes Association.Medical Management of Non-Insulin-Dependent(Type2)
Diabetes.3rd et.Alexandria,VA: American Diabetes Association:1994
Mechanism of action- acarbose
Reversible inhibition of oligosaccharide breakdown by -glucosidases
Acarbose
Acarbose
Oligosaccharide
Small intestine
mucosa
Mechanism of action-TZD
•Agonists of PPARγ (peroxisome
proliferator activated receptorγ,)
Indication of insulin therapy
1.
2.
•
•
•
•
•
•
•
T1DM
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
insulin levels)
• Somogyi phenomena
• Dawn phenomena
hyperglycemia
-glucosidase inhibitor
SU(AC 30’)
Benzoic acid derivatives(AC 0-5’)
Thiazolidinediones
Muscle,adipocyte
insulin
β-cell
Insulin level
Biguanides
hepatic
Insulin sensitivity
STEP-WISE STRATIGE
100
mean insulin
during OGTT
(mU/l)
80
60
40
20
0
FPG (mg/dl)
80
EDUCATION
DIET
EXERCISE
120
160
MF
TZD
SU
insulin
Matthaei S, et al. Endocr Rev 21:585,2000
200
pregnancy
• Diet
• Exercise
• Insulin therapy
Precipitating factors:
infection , diet, surgery, trauma, pregnancy
Insulin-antagonistic hormone
Insulin deficiency
Hyperglycemia
Rapid mobilization of
energy from stores in
muscle and fat depots.
osmotic diuresis
polyuria
DKA
Utilization is reduced
depletion of
intravascular volume
Disturbance of electrocyte
Ketone production 
Ketone is accumulated
Nausea
vomiting
acidosis Rapid and deep
respiration
Precipitating factors
•
•
•
•
•
•
•
Most common: infection
Cerebrovascular accident
Alcohol abuse
Pancreatitis
Myocardial infarction
Trauma
Drugs (corticosteroids,
thiazides,sympathomimetic agents)
Precipitating factors:blood count,X-ray,ECG
Insulin deficiency
Hyperglycemia
depletion of
intravascular volume
Bun  Cr 
Lab test
Insulin-antagonistic hormone
Rapid mobilization of
energy from stores in
muscle and fat depots
Ketone is accumulated
acetoacetate,
B-hydroxybutyrate,
acetone
Disturbance of electrocytes
K, Na, Cl
acidosis
HCO3 - , PH 
treatment
Insulin-antagonistic hormone
Insulin deficiency
Hyperglycemia
Insulin
supplement
Ketone is accumulated
(0.1U/kg/h)
depletion of
intravascular volume
acidosis
Disturbance of electrocyte
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 BG2.8-4.2mmol/l
or check hydration, if acceptable
Doubled 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
obtundation 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
extravascular volume and restoration of renal
perfusion.
•<50ml/kg
• 1st h: 0.9% NS 15-20ml/kg/h—1-1.5l
over first 4h
• Then 4-14 ml/kg/h — 200-700ml
•Replace fluid
0.9%NS—serum Na low
deficit evenly
0.45%NS —serum Na high/normal
over 48h
• Judged by hemodynamic monitoring(Bp),
•Osmolality
measurement of fluid output and input, and decreased less
clinical examination.
than
• Avoid iatrogenic fluid overload
3mOsm/kg.H2
O.h
POTASSIUM
•
•
•
•
<3.3mM,avoid insulin therapy
<5.5mM, start Ka supplement20-30mEq/l
10% KCl 20ml/l
Aim 4-5mEq/l
NHDC
Precipitating factors:
infection , diet, cerebrovascular accident, MI
Partial Insulin deficiency
Insulin-antagonistic hormone
Hyperglycemia
osmotic diuresis
Absence of significant
ketosis
hyperosmotality
polyuria
dehydration
Lethargy,confusion
Serum sodium 
Coma
Consideration question
• How to diagnose and treat Diabetes
mellitus ？
• How to differentiate type 1DM and
type2DM ?
谢谢！