Diabetes Mellitus
Renming Hu M.D,PhD
Department of Endocrinology
Huashan Hospital
Institute of Endocrinology and
Diabetes at Fudan University
Classification of
diabetes(ADA-1997)
Type 1
? (beta-cell destruction,usually leading to absolute insulin
deficiency)
? Autoimmune
? Idiopathic
? Type 2
– (may range from predominantly insulin resistance with relative
insulin deficiency to a predominantly secretory defect with or without
insulin resistance)
? Other specific types
? Gestational diabetes**
Other specific types
? Genetic defects of beta-cell function
? Genetic defects in insulin action
? Diseases of the exocrine pancreas
? Endocrinopathies
? Drug- or chemical-induced
? Infections
? Uncommon forms of immune-mediated
diabetes
? Other genetic syndromes sometimes
associated with diabetes
Pathogenesis
Pathology
? Type 1 DM,inflammation of pancreas
? Type 2 DM,amyloidosis of pancreas
? Large vessel, atherosclerosis
? Kidney, diffuse or nodular glomerular
sclerosis
? Retina,arteriolar sclerosis、
microaneurysm,exudates,new vessel
formation
? Nerve,axon degeneration,
myelinolysis
0
10
20
30
40
50
60
70
80
90
season
1
season
2
season
3
season
4
east
west
north
Pathophysiology
Abnormalities in metabolism
? Carbohydrate, anabolism?, catabolism?,
utilization
? Lipid, anabolism?, catabolism?,
ketoplasia
? protein,anabolism?, catabolism?,
glyconeogenesis
Insulin secretion curve,normal and
diabetics
0
200
400
600
800
1000
1200
1400
1600
0 30 60 90 120
clock time(hours)
insulin(
μ
U/ml）
type2
normal
obese
type 1
Clinical Presentation
Natural history of type 2 DM
After the diagnosis of type 2 diabetes,
IR constantly exists
Insulin secretion ability gradually declines,
When FPG reachs the diagnostic criteria,insulin
secretion ability has already declined by 50%
When FPG≥ 7.0mmol/L,?-cell insulin secretion
ability
When FPG≥10?11.0mmol/L,?-C insulin
secretion ability has already neared absolute deficiency
Models of the onset of two phrases
of type 2 DM
NGT IGR(IFG,IGT) DM
?cell exhaustion
Insulin resistance Insulin resistance
WHO plasma glucose guideline
IG
T
IFG
NGT
DM
75gOGTT
2hPG
(mmol/L)
FPG
(mmol/L)
7.0
6.1
FPG
7.8 11.1
IGT
Comparison of type 1 and type 2 DM
type1 DM type2 DM
Usual age of onset <30 years >40years
Mode of onset acute chronic
weight normal overweight or obesity
or weight loss
symptoms polyuria,polydipsia,similar but usually
weight loss less severe presentation
Acute complications often few
Chronic complications
Large vessel disease less then type 2 DM leading cause of death
Renal disease leading cause of death 5%?10%
Insulin and c-peptide low or lack peak value delayed,high or deficiency
Immune marker usually + usually -
Therapy insulin dependence oral antidiabetic agents are available
Chronic complications
? Macrovascular disease
? Microangiopathy
– Diabetic retinopathy
– Diabetic renal disease
– Diabetic neuropathy
? Diabetic dermatopathy
? Infection
Mechanism of complications
?Activation of polyol （ or sorbitol） pathway
?Formation of non-enzyme saccharification
products
?Change of hemodynamics
? Activation of PKC
?Microangiopathy theory
Hyperglycemia is the essential
reason for diabetic complications
? DCCT
Diabetes Control and Complications Trial
? UKPDS
United Kingdom Prospective Diabetes
Study
UKPTS,results
? HbA1c 0,9%，（ intensive therapy vs routine therapy）
? Intensive therapy group,diabetis associated complications
12%,and the fatalness of microvascular complications 25%。
? It cannot evidently reduce the incidence of great vessel
disease,such as miocardial infarction and strock,
? Most stimulating findings,Biguanides can prevent or slow
the onset and/or progression of diabetic complications in
overweight patients
? Tight control of hypertension can prevent or slow the onset
and/or progression of diabetic complications by 24%
（ 144/82mmHg vs 154/87mmHg）, stroke by 44%，
microvascular complications by 37%。
Epidemiology of diabetes
Macrovascular disease
? Diabetics are easy to get atherosclerosis
– Monckeberg?s sclerosis 41.5％
– Intimal arteriosteogenesis 29.3％
? Coronary heart disease,cerebrovascular disease,24
times
– Risk of miocardial infarction,10 times
– Risk of stroke, 3.8 times,especially in women
? Risk of lower limb amputation,15times, fatalness
Hypertension in DM
?Morbidity rate
?diabetes,20%?40%
?Diabetes in EU(35-54years),30%?50%
?Diabetes in China,29.2%
?pathogenesis
?aortosclerosis
?Arteriola resistance
?Hypertension associated with DN
?Renal hypertension caused by stenosis of
renal artery
? Diabetic retinopathy－ leading course of new cases of blindness
? Pathogeny,state of illness, course of disease,age of onset
? <5 years, eyeground disease is not common
? <10 years, 50％ eyeground disease
? <20 years, 80?90％ eyeground disease
Diabetic Retinopathy
Classifications (China)
? Background retinopathy
Ⅰ microaneurysms, dots of hemorrhages
Ⅱ yellow and white hard exudates,haemorrhages
Ⅲ white soft exudates,haemorrhages spots
? Proliferative retinopathy
Ⅳ new vessel formation, haemorrhage into the
vitreous
Ⅴ new vessel formation and fibrosis
Ⅵ retinal detachment
Diabetic nephropathy
? DN is the leading cause of ESRD (end-stage renal
disease)
– Almost 40％ of Type 1 DM died of uremia
– Incidence of DN in type 2 DM is about 20％
– In EU,DN accounts for 1/3 of dialysis and kidney
transplantation cases
– In China,DN also accounts for quite a lot of dialyses
and kidney transplantations
Stages of diabetic nephropathy(1)
stage I increased kidney DM already
filtration diagnosised GFR↑↑ enlarged kidneys(B- ultrasonic)
GFR>130ml/min
Stage II clinically silent phase DM 2?5year GFR ↑20?40％ renal enlargement,
with continued glomerular hypertrophy,
hyperfiltration and hypertrophy expansion of the mesangial matrix
thickening of the glomerular
basement membrane resulting in
glomerulosclerosis
Stage III concealed DN
microalbuminuria DM5?10year microalbuminuria 1/5 patients with hypertension
(20-200μg/min retinopothy↑
,or30?300mg/24h)
proteinuria 0.15?0.5g/24h
GFR> or =normal
Stages of diabetic nephropathy(2)
Stage IV Overt Nephropathy DM10?25year albuminuria>300mg/d 60?70％ patients
proteinuria>0.5g/d, with hypertentio
GFR↓(when UAER=100 and edema
mg/24h,GER begin to decrease,
about 1ml/min/month) retinopathy ↑↑
Stage V end-stage renal
disease,ESRD DM15?30 year albuminuria azotemic→
uremia
GFR< 1/3 of normal
Classification of diabetes neuropathy
（ 1）
Peripheral neuropathy
symmetric multiple peripheral neuropathy
sensibility multiple neuropathy
numbness type
pain type
numbness-pain type
sensomotor multiple neuropathy
acute or sub-acute motor multiple
neuropathy
asymmetricsingle or multiple periphearal
neuropathy
member or torso mononeural
cranial nerves disease
radiculopathy
proximal motor neuropathy
autonomic neuropathy
Autonomic neuropathy
diabetic myelopathy
diabetic spinal ataxia
spinal muscular atrophy
Cerebropathy
Hypoglycemia cerebropathy
diabetic coma
cerebrovascular disease
Diabetic sensability multiple
neuropathy
? more common in female
? Average age of onset is 58.7year
? Course of DM> 15years
? Symptoms of sense
– Numbness type,large medullated fibers
– Pain type,little medullated fibers and
nonmedullated fibers
– Numbness-pain type
? Nervous symptom examination
– parasthesia
– Lower limbs pallesthetic disturbance or dissapear
– Tendon reflex low or dissappear
– Sensory staxia
– Paratrophy symptoms
– Charcot arthropathy,ischemic gangrenosis and
foot ulcer
Diabetic autonomic
neuropathy
? Pupil disease
? Cardiovascular parafunction
– Fixed heart rate
– Postural hypertension
– Sudden cardiac death
? Gestrophageal,diarrhea
? Neuropathic bladder,erectile failure
? Abnormal sweating
?Glucosuria,associated with renal
threshold of sugar (only for clue)
?Ketonuria
?Blood sugar,plasma glucose,POD
?HBA1c,2?3 months blood sugar level
?Fructosamine,2?3 weeks blood sugar
level
?OGTT,2 hour specimen
?Insulin and C-peptide release test
Laboratory tests
Diagnosis
Criteria for diagnosing diabetes
FPG Random OGTT
plasma glucose 2hPG
mmol/L mmol/L mmol/L
DM ≥7.0 ≥11.1 ≥11.1
IGR
IFG 6.1≤FPG<7.0
IGT 7.8≤FPG<11.1
Normal <6.1 <7.8
Characteristics of new diabetic
diagnostic criteria
? FPG<6.1mmol/L is normal fasting glucose,OGTT
2hPG<7.8mmol/L is normal glucose tolerance；
? Impaired fasting glucose corresponding with impaired
glucose tolerance (IFG),6.1mmol/L ≤FPG<7.0 mmol/L ；
? The cutoff value of FPG decline from 7.8mmol/L to
7.0mol/L.the cutoff values of OGTT2hrPG and random
plasma glucose level are still 11.1mmol/L；
? FPG is the initial screening test of diabetes, OGTT is
not recommended for routine diagnostic use,
? The diagnoses of Gestational diabetes is not changed
Practical problems in diagnosis
? Symptoms ＋ random plasma glucose ≥11.1
mmol/L
? FPG,≥7.0 mmol/L
? OGTT,2hPG≥ 11.1 mmol/L
? Asymtomatic persons tests should be
repeated the once
latent autoimmune diabetes mellitus
in adults （ LADA）
? Adult onset
? Symptoms are evident
? Secretion function of ?cell is low
? GADA positive
? HLA-DQ B chain is non aspartate homozygote
Management
Goals
? Good metabolism control（ blood sugar,blood lipid、
HBA1C etc）
? Relieve symptoms
? Keeping good physiologic state and a social life
? Good quality of live
? Prevent the development of acute complications of
diabetes（ hypoglycemia,DKA,hyperosmolar
nonketotic syndrome,lactic acidosis）
? Preventing the development or delaying the
progression of the chronic complications of diabetes
Principle of treatment
? Early
? Life-long
? synthesis
? individual
Goals of control
good average bad
PBG(mmol/L)
fasting 4.4 - 6.1 ?7.0 >7.0
non-fasting 4.4 - 8.0 ?10.0 >10.0
HBA1c(％ ) <6.5 6.5-7.5 >7.5
BP(mmHg) <130/80 >130/80- <140/90 >140/90
BMI (Kg/m2)
M <25 M<27 ?27
F <24 F<26 F?26
TC (mmol/L) <4.5 ?4.5 ?6.0
HDL-c (mmol/L) >1.1 1.1-0.9 <0.9
TG (mmol/L) <1.5 <2.2 ?2.2
LDL-C (mmol/L) <2.5 2.6-4.40 >4.0
Control actuality of DM in China
? 26 centers,3965 patients
? 28％ patients measure HbA1c,8.1?2.6%，
52％ >7.5％
? FPG,9.2 ? 3.7mmol/L,55%>7.8
mmol/L
? Determing rate of microalbumin in urine,
20％
Diabetes Management Plan
? Patient education
? Health nutrition therapy
? Exercise therapy
? Drug therapy
? Monitoring of blood glucose
Phases therapy of DM
? Early reaction
? Patient therapy
? Medical nutrition therapy
? Exercise therapy
? Single drug therapy
? decline of curative effect
Combined drug therapy
? Secondary failure,distinct insufficiency
of insulin
Insulin therapy
Principles of medical nutrition theraphy
? rational control of total calorific value
? Goal,
– Keep ideal body weight
– Loss weight for obese patient
– Add weight for lean patient
? Standard body weight＝
– height（ cm）－ 105
– male,（ height－ 100 ） × 0.9
– female,（ height－ 100 ） × 0.85
? Body mass index（ BMI）, weight（ kg） /height2
（ m2）
Adult-onset diabetes thermal
energy supply per day
（ therm/kg standard weight ）
work intension
Bodily form in bed light physical middle heavy
labor physical physical
labor labor
lean 20 ? 25 35 40 >40
normal 15 ? 20 30 35 40
obesity 15 20 ? 25 30 35
Nutrition principles of diabetics
Moderate weight control
The distribution of total calorfic value,
carbohydrate 55 %?60%
fat 20%?25% 1/5,2/5,2/5
protein 15 %?20%
Drink limitation
Avoiding ?diabetic? foods (which contain sorbitol or frucotose)
Aspartame is an acceptable calorie-free sweetener
salt<10g/d,(<3g/day if hypertensive)
Calculation
?protein,0.8 ?1.2/kg standard weight
?fat,0.6 ?1.0/kg standard weight
?carbohydrate,total calorific value －
calories of protein and fat
Exercise therapy
? Benefits
– Glycaemic control
– Increase βcell sensitivity to glucose
– Blood lipid
– Weight reduction
? Estimation of quantity of exercise,heart
rate<170－ age (year)
Drug therapy
? Sulfonylureas
? Biguanides
? α-glucosidase inhibitors
? Tniazolidinediones
? Meglitinides
? Insulin
? Dry-combination therapy
Sulfonylureas,mode of action
? The principal action of these drugs is to stimulate
endogenous insulin secretion from the pancreatic β-cells
? Not to increase synthesis of insulin
? Also to increase β-cells sensitivity to glucose and exert
some influence in diminishing insulin resistance,
Sulfonylureas （ SU）,
first choice of non-
obesity T2DM
General name duration of action potency merits main site
of
excretion
Tolbutamide (D860) short weak cheap renal
Glyburide (micronase) long strong affirmed
hypoglycemia
effects in lowering
blood glucose levels
cheap renal
Gliclazide (diamicvon) medium strong prevent and renal
glipizide (minidiab) shot strong affirmed effects renal
Gliquidone (glurenorm ) shot week not renal(only5%)
Glipizide (tonbac) long strong good compliance low
incidence
Therapeutic effects of SU
? Primary failure to respond to SU occurs in 20% to
25% of patients
? FPG and 2hPG
? HbA1c 1% ? 2％
? As the period of treatment progresses,effects
decline,
– Secondary failure occurs at the rate of 10% to 15% per
year
– After 5 years, only half of the patients can keep ideal
blood glucose control,
– UKPDS,first year,blood glucose, insulin
– then, blood glucose insulin
– the 6th year,returned to the state before therapy
Indications and
contraindications of SU
? Indications
– Poor control of T2DM by weight control and physical
activity
– Poor control of T2DM by biguanides and ?-
– Combined with insulin
? Contraindications
– T1DM
– Acute or chronic diabetic complications
– Emergency
– Dysfunction of liver or kidney
– Pregnant or bleeding women
Side effects of SU
? Hypoglycemia,most common in
– Old patients
– Long-term pharmaceutics
– Symptoms of digestive tract
? Liver dysfunction
? Tetter
? Change of hematology
Biguanides, first choice of obesity
type 2 DM
Generic name dosage merits NB
phenformin <75mg/d cheap lactic acidosis
（ 降糖灵 ） restrain
oxygenic metabolism
lower energy of
oxygenic metabolism
dimethylbiguanide <1.5g/d low gastrointestinal
side-effects reaction
（ 降糖片 ）
Mechanisms of action of
biguanides
? Increasing β cell sensitivity to glucose
? Enhancing glucose uptake and utilization by muscle
? Reducing HGP by inhibiting gluconeogenesis,
? Decreasing intestinal glucose absorption
? Do Not stimulating endogenous insulin secretion from β
cell
? Do Not causing hypoglycemia when used singly
indications and contraindications
of Biguanides
? Indications
– Obesity T2DM
– Poor control by SU
– Poor control by insulin,including T1DM
– Simple obesity
– Polycystic ovary syndrome
? Contraindications
– Allergic reactions
– Renal dysfunction,serum creatinine>1.4mg/dl
– Acute or chronic acidosis
– Heart,lung disease,hypoxia,acidosis inclination
– Hypohepatia
– Severe gastroenteropathy
– Pregnancy
Side effects of Biguanides
? Diarrhea
? Anaphylaxis
? Overt macies, common in elderly patients
? Lactic acidosis
? Inhibiting ?-glucosidase
? Delaying the digestion of
glucose
? 2hPG
? Not stimulating the secretion of
Insulin
α-glucosidase inhibitors,mode of action
Therapeutic effects of Acarbose
? 2hPG
? FPG
? HbA1c about 1％,When used in combination with
SU,HbA1c, about2％
? Serum insulin slightly declined
? Weight not a few patients
? When used as monotherapy,it do not cause hypoglycemia
? When used in combination with other oral antidiabetic
agents,it may cause hypoglyceia
If hypoglycemia happens,patient should be treated by
glucose,Other kinds of sugar are ineffective
Indications and contraindications of
α-glucosidase inhibitors
? Indications
– Light cases
– using drug separately or combined
– IGT intervention,security
? Contraindications
– Allergic reactions
– Severe gastroenteropathy
– Dysfunction of renal and liver
– Acute complications
– Emergency
– Pregnant and breast feeding women
thiazolidinedion（ TZD）,insulin sensitizers
? Insulin sensitizers; agonist at the peroxisome
proliferator-activated receptor ? （ PPAR?） ;increase
glucose utilization in peripheral tissues,
? Reducing insulin resistance,hyperglycemia and
hyperlipaemia and hypertension can be improved at
varies degrees
? For T2DM:used as monotherapy or in combination
with SU,insulin,
? When used in combination with SU or insulin
,hyperglycemia
? Without insulin,it cannot reduce hyperglycemia
? Liver function should be monitored frequently,Stop
using it in case liver dysfunction is found,
? Incidence of edema:4?5%
? It may cause Hb slightly↓
Meglitinides, repaglinide
? Stimulate Pancreatic insulin secretion（ similar
with SU）,specific combinition with 36KDa
protein K pathway close
? Stimulating the first phrase secretion of insulin
? Action,rapid onset, short duration，
suppressing postload hyperglycemia quickly
? Sites of excretion, kidney 8%,fecal 92%
? Used as monotherapy or in combination with
biguanides, α-glucosidase inhibitors
? Incidence of hypoglycemia is low
Factors in choosing oral
antidiabetic agents
? age
? weight
? Blood glucose level
? Function of liver and kidney
? Characteristic of drug
? costs
Choose of oral antihyperglucemic
agents
? Older patients,short term SU
? Obesity or hyperinsulinism patients,biguanides or
acarbose
? 2hPG, α－ glucosidase
? Concentration of plasma glucose,>270 ? 300mg/dl,
the symptoms of hypertension are evident,Insulin
therapy is available
? Impaired liver and kidney function,avoid using
OHA
? Lean, fasting and after-excitation insulin all,
insulin
Drug-Combined therapy
? Reasonable diet and poor plasma
glucose control by monotherapy
? SU, biguanides, TZD and α-
glucosidase inhibitors all can be used in
combination with each other
? Small dosage combined with of all kinds
of drugs ;enhancing effects of reduce
glucaemia ;side effects of single agents
? Oral agents with insulin
? Drugs of the same class cannot be used
in a combined way,
Insulin therapy
Indications of insulin
?Type 1 DM
?Type 2 DM
?Acute complications
?Severe chronic complications of diabetes
?Emergency
?Severe dysfunction of liver or kidney
?Gestation and bleeding women
?Without tolerance OHA,curative effect of OHA, SU
invalidation
?Distinct lean
?With diseases treated by glucocorticoid
?Some specific types of DM,secondary pancreas
disease, endocrinopathies,genetic diabetes
Obstacles to using Ins in T2DM
? old notion,NIDDM
?The doctor uses OHA only and does not see
the need to use Ins,
?The patient does not want to use In for fear
of developing insulin dependence after useing
it,
?Hyperinsulinism can lead AS to CVD？
?hypoglycemia,BW↑
国内常用胰岛素一览表
产品名 生产厂家 种属来源 包装 (U/瓶 )
短效胰岛素
普通胰岛素 (RI) 上海生物制药厂 猪 400 U/瓶
优泌林 R 礼来 基因重组 400 U/瓶
诺和灵 -R 诺和诺德 基因重组 400 U/瓶
Lispro 礼来 基因重组 400 U/瓶
中效胰岛素
优泌林 N 礼来 基因重组 400 U/瓶
诺和灵 -N 诺和诺德 基因重组 400 U/瓶
NPH 徐州生化制药厂 猪 400 U/瓶
混合胰岛素
优泌林 70/30 礼来 基因重组 400 U/瓶
(人工合成 )
诺和灵 -30R 诺和诺德 基因重组 400 U/瓶
诺和灵 -30R 诺和诺德 基因重组 300 U/瓶
长效胰岛素
PZI 上海生物制药厂 猪 400 U/瓶
Differences between human and animal
insulin
? Difference in pharmacodynamic,
– Close action intensity
– Human insulin, absorption is fast, time of onset of effect is
early
? Difference in immunogenicity,
– Antigenicit of human insulin is weaker than animal insulin
– After use human insulin,antibody titer of blood insulin is
lower
? Synthesized insulin, lispro（ 28proline?29 proline ）
– Quick absorption,short effect time
Shot-term intensive insulin
therapy for T2DM
? Indications,monotherapy or combination therapy of oral
antihyperglycemia therapy fail to achieve glucose targets，
overt hyperglycemia,fasting and postprandial C-peptide
? Method,use insulin 2 times per day,NPH/R 70/30
prebreakfast and presupper, adjust the dosage with the
monitoring results of blood sugar,use insulin 4 times per
day, RI premeal,NPH before sleep
? Period of treatment,several weeks or monthes
Shot-term intensive insulin
therapy for T2DM
? Estimation of initial dosage,0.2 ? 0.4U/Kg weight per day
?Mode of therapy
? RI before meals,RI— RI— RI— O,before breakfast＞ before
supper＞ before diner
? RI before three meals + RI before supper,RI— RI— RI— RI
? RI before three meals + NPH before supper,RI— RI— RI/NPH
? RI before three meals + NPH before sleep,RI— RI— RI— NPH
? mixed insulin（ RI/NPH） before three meals（ 2/3before
breakfast, 1/3before supper）,the proportion,10R— 50R
? NPH/R 70/30before breakfast and supper
Secondary failure of OHA,combination
with insulin
?FPG? oral anti-hyperglycemia agents+ NPH before sleep
?PPG? NPH before breakfast+oral anti-hyperglycemia
agents
?FPG? PPG? oral anti-hyperglycemia agents + NPH
before sleep and before breakfast
?Insulin, adjust per 3~4 days,
? one phrase each time
up for 2~4U every time
?Before you add insulin,hypoglycemia reaction should
be excluded
Combination of OHA and NPH
before sleep
? Indication,
– OHA is invalid or has low effect
– FPG not exceeding 250 ? 300 mg/dl
– Non-lean
– LADA
– Still having some function of insulin
secretion
C-peptide,
fasting≥0.2 mmol/L
postload > 0.4 mmol/L
The effect of supplying one injection of
intermediate-acting insulin before sleep
? HGP, lipolysis
? antagonize the somogyi effects and the dawn
phenomenon caused by glucagon
?FPG returning to normal
?Helping SU to effect in daytime
?24hour PG, HbA1c
?Supplying the deficiency of act time of former OHA
?The patients needs to be supplied with one injection each
night and doesn’t need to be hospitalized,It’s easy for the
patient to accept,
difference of complementary therapy
and subtitution therapy of insulin
Complementary therapy
OHA are basic therapy,combination with insulin
NPH before sleep,FPG↓, daytime postprandial
hyperglycemia can be improved evidently
NPH perbreakfast with OHA for postprandial
hyperglycemia (often used)
Substitution therapy
Stop using OHA;substituted by insulin
Mixed insulin before breakfast and supper
Three injections perday R,R,R+N
Four injections perday R,R,R,R or R,R,R,N
Side effects of insulin
?hypoglycemia
local reaction
?Anaphylaxis systemic reaction
insulin drug resistance
?Lipid dystrophia, atrophy and fleshy
Artificial factors in influencing
curative effect of insulin
? Inject position
abdomen wall >the upper
arm>thigh>buttocks
? Inject depth
hypodermatic,not muscle
? Preservation
cold storage,not freeze
NB (1)
? Need to increase the quantity of insulin,
– Hyperpyrexia
– Hyperthyrea
– Pachyacria
– Ketoacidosis
– Severe infection or trauma
– Serious surgery
– Pregnant woman, especially in metaphase or
anaphase of pregnancy
– Adolescent children
NB (2)
? need to cut down the quantity of insulin,
– Metabolize and excretion of insulin in kidney,
hypohepatia, kidney dysfunction,thyroid
insufficiency
– Diseases which can lead to hypoglycemia,hypadrenia、
diarrhea, gastroanesthesia, intestinal obstruction、
vomit, absorption of food
– Elderly patients (easy to get hypoglycemia)
NB (3)
? Combined drugs（ glucemia ）
– Agents which increase plasma glucose,glucocorticoid,ACTH、
glucagon,estradiol,oral prophylactic,thyroxin,adrenalin,
thiazide diuretic, dilantin
– Carbohydrate metabolism abnormality,PG, felodipine、可乐定、
二氮嗪,GH,heparin,α-blocker,大麻,morphin,nicoltin、
β-blocker(普萘洛尔可阻止肾上腺素升高血糖的反应 )
NB (4)
? Combination drug therapy（ help lower plasma
glucose ）
– Slow degradation of insulin
chloroquine, quinidine, quinin
– Insulin combine globulin competely,dissociated insulin
anticoagulative agents,salicylate, sulfanilamide,
anti-tumor agents can help lowering glucemia, OHA、
assimilation steroid androgenic hormones,monoamine
oxidase inhibitor, NSAID
– Lower glucemia
ACEI,溴隐停、氯贝特、酮康唑,lithium,甲苯咪
唑,theophylline,alcohol、奥曲肽
Monitor of DM
Glucosuria,associated with renal
threshold of glucose(only for clue)
FPG
HBA1c,2?3 months blood sugar level
Fructosamine,2?3 weeks blood sugar
level
OGTT,2 hour specimen
Diabetic Ketoacidosis
（ DKA）
summarize(1)
? One of the acute metabolic complications of
diabetes
? Can be initial symptoms of diabetes
? One of the important emergency of internal
medicine
? Need rapid,reasonable treatment
? Full-scale examination of specialty knowledge of
internist or general practitioner
? Need doctors and nurses to take concerted action
Summarize (2)
? Ketosis
? DKA
? Hypoglycaemic keto-
acidotic coma
Composition and
characteristics of ketone body
? Acetoacetic acid is the first product,strong organic
acid ;can reacted with ketone powder strongly
? Dimethylketone, least quantity, neutral,no
renal reabsorption threshold ;can be excreted from
respiratory tract
? β－ oxybutyric acid, strong organic acid, biggest
quantity（ 70％）
Pathophysiology
glucagon↓↓
↑↑
Abnormalities in
carbohydrate
metabolism
lipolysis↑
Acidosis
Abnormal nervous
system
Circulation faliure
携氧系统异常
Electrolyte
disturbance
Acetone
body
Plasma
glucose
Severe dehydration
Inducement of DKA (1)
? Interrupted drug
therapy
? Improper diet
? Fatigue
? infection
? Trauma
?operation
?pregnancy,delivery
?drinking
?miocardial infarction
?else
Clinical presentations of DKA
? Intensive thirsty,diuresis
? Extremely tired,nausea, vomiting
? Varied degrees of disorder of
consciousness
? Circulation failure
? Presentations of precipitating factors
Special presentations of DKA
? Abdominal pain
? Hypothermy and abnormal
,normal body temperature”
?Number of leucocyte↑
Laboratory tests
? Urine tests
– glucosuria
– ketourine
? Blood tests
– Blood sugar
– Blood ketone
– CO2CP
– electrolyte
Examination of ketone
? Acetoacetic acid ＋ acetone body powder
rose purple
– When ketosis fades away, β-hydroxy-butyric
acid turn to acetoacetic acid, the color test of
the latter with acetone body power is evidently
better than the former
– In case of lack of oxygen, more acetoacetic
acid turns to β-hydroxy-butyric
Therapeutic goals of DKA
? Correcting acute metabolic turbulence
? Preventing and curing complications
? Reducing the case fatality rate
Transfusion is the chief therapeutic
measurement of DKA
? Restoration of circulating plasma volume
? Rebuild ERPF
? Helping insulin to exert its effect
? Reducing blood sugar
? Removing blood ketone
? Reducing the concentration of insulin
counterregulatory hormone
Transfusion
? Why, blood sugar 14mmol/L is the cutoff value
? How, double vein channels
? Reference index,--age
--vital signs
--function of heart and kidney
--shock or not
--urine quantity per hour
--CVP
Insulin is the key of therapy
? Insulin in small dosage is a simple,efficient,
safe therapy(0.1u/kg/h)
– NS 250ml+RI 25U/ iv,15 drops/min
– Blood sugar 5 ? 6mmol/L/hr
– ingnition？,RI 20U/ iv
? route
– Presistent venous inflow (other approach)
– intermittent intervenous injection
– Intermittent intramuscular injection
Correct acidosis (1)
Influence of DKA,
? Blood pH<7.0, restain contractility of cardiac
muscle
? The relationship of Blood pH and ventilatory
– pH<7.2, hyperventilation, Kussmaul?s respiration
– pH<7.0, restrain expiratory center
? Insulin sensitivity
Correct acidosis (2)
? Bad results of excessive alkali
supplementary treatment,
– Blood pH↑,CSFpH still low; easy to get
hydrocephalus
– Not good for oxidized hemoglobin to release
oxygen, and cause anoxemia of tissue
– Easy to get hypocalcemia
Correct acidosis (3)
? Usually after transfusion, blood CO2,BP
? If blood pH<7.1,HCO3-<5mmol/L
isosmotic sodium bicarbonate, 5％ NaHCO3
84ml,
or inject water to 200ml equal to
1.25%NaHCO3
? Sodium lactate is not recommended
Correct electrolyte disturbance
? Reason of low plasma potassium
– Restoration of circulating plasma volume
– Acidosis has been corrected
– Urine
– Glucose Hepatin
? Principle of potassium replacement
Considering urine volume, renal function and
concentration of blood potassium,moderately
adding potassium to intravenous fluid
Other measures
? Nurse
? Prevention and cure complications
– infection
– hydrocephalus
– Heart failure
– Kidney failure
? Removing precipitating factors
Keystone
? Criteria of diagnosis of diabetes
? Methods of diagnosis
? Principle of treatment
? Type,characteristics,indications,contrai
ndications,side effects of oral
antidiabetic agents
? Principle of treatment of DKA
胡仁明 医学博士
? 华山医院内分泌科 62489999x6622
? 复旦大学内分泌糖尿病研究所
? 62489999x6458
? E-mail Renminghu@Fuda.edu.cn
Renming Hu M.D,PhD
Department of Endocrinology
Huashan Hospital
Institute of Endocrinology and
Diabetes at Fudan University
Classification of
diabetes(ADA-1997)
Type 1
? (beta-cell destruction,usually leading to absolute insulin
deficiency)
? Autoimmune
? Idiopathic
? Type 2
– (may range from predominantly insulin resistance with relative
insulin deficiency to a predominantly secretory defect with or without
insulin resistance)
? Other specific types
? Gestational diabetes**
Other specific types
? Genetic defects of beta-cell function
? Genetic defects in insulin action
? Diseases of the exocrine pancreas
? Endocrinopathies
? Drug- or chemical-induced
? Infections
? Uncommon forms of immune-mediated
diabetes
? Other genetic syndromes sometimes
associated with diabetes
Pathogenesis
Pathology
? Type 1 DM,inflammation of pancreas
? Type 2 DM,amyloidosis of pancreas
? Large vessel, atherosclerosis
? Kidney, diffuse or nodular glomerular
sclerosis
? Retina,arteriolar sclerosis、
microaneurysm,exudates,new vessel
formation
? Nerve,axon degeneration,
myelinolysis
0
10
20
30
40
50
60
70
80
90
season
1
season
2
season
3
season
4
east
west
north
Pathophysiology
Abnormalities in metabolism
? Carbohydrate, anabolism?, catabolism?,
utilization
? Lipid, anabolism?, catabolism?,
ketoplasia
? protein,anabolism?, catabolism?,
glyconeogenesis
Insulin secretion curve,normal and
diabetics
0
200
400
600
800
1000
1200
1400
1600
0 30 60 90 120
clock time(hours)
insulin(
μ
U/ml）
type2
normal
obese
type 1
Clinical Presentation
Natural history of type 2 DM
After the diagnosis of type 2 diabetes,
IR constantly exists
Insulin secretion ability gradually declines,
When FPG reachs the diagnostic criteria,insulin
secretion ability has already declined by 50%
When FPG≥ 7.0mmol/L,?-cell insulin secretion
ability
When FPG≥10?11.0mmol/L,?-C insulin
secretion ability has already neared absolute deficiency
Models of the onset of two phrases
of type 2 DM
NGT IGR(IFG,IGT) DM
?cell exhaustion
Insulin resistance Insulin resistance
WHO plasma glucose guideline
IG
T
IFG
NGT
DM
75gOGTT
2hPG
(mmol/L)
FPG
(mmol/L)
7.0
6.1
FPG
7.8 11.1
IGT
Comparison of type 1 and type 2 DM
type1 DM type2 DM
Usual age of onset <30 years >40years
Mode of onset acute chronic
weight normal overweight or obesity
or weight loss
symptoms polyuria,polydipsia,similar but usually
weight loss less severe presentation
Acute complications often few
Chronic complications
Large vessel disease less then type 2 DM leading cause of death
Renal disease leading cause of death 5%?10%
Insulin and c-peptide low or lack peak value delayed,high or deficiency
Immune marker usually + usually -
Therapy insulin dependence oral antidiabetic agents are available
Chronic complications
? Macrovascular disease
? Microangiopathy
– Diabetic retinopathy
– Diabetic renal disease
– Diabetic neuropathy
? Diabetic dermatopathy
? Infection
Mechanism of complications
?Activation of polyol （ or sorbitol） pathway
?Formation of non-enzyme saccharification
products
?Change of hemodynamics
? Activation of PKC
?Microangiopathy theory
Hyperglycemia is the essential
reason for diabetic complications
? DCCT
Diabetes Control and Complications Trial
? UKPDS
United Kingdom Prospective Diabetes
Study
UKPTS,results
? HbA1c 0,9%，（ intensive therapy vs routine therapy）
? Intensive therapy group,diabetis associated complications
12%,and the fatalness of microvascular complications 25%。
? It cannot evidently reduce the incidence of great vessel
disease,such as miocardial infarction and strock,
? Most stimulating findings,Biguanides can prevent or slow
the onset and/or progression of diabetic complications in
overweight patients
? Tight control of hypertension can prevent or slow the onset
and/or progression of diabetic complications by 24%
（ 144/82mmHg vs 154/87mmHg）, stroke by 44%，
microvascular complications by 37%。
Epidemiology of diabetes
Macrovascular disease
? Diabetics are easy to get atherosclerosis
– Monckeberg?s sclerosis 41.5％
– Intimal arteriosteogenesis 29.3％
? Coronary heart disease,cerebrovascular disease,24
times
– Risk of miocardial infarction,10 times
– Risk of stroke, 3.8 times,especially in women
? Risk of lower limb amputation,15times, fatalness
Hypertension in DM
?Morbidity rate
?diabetes,20%?40%
?Diabetes in EU(35-54years),30%?50%
?Diabetes in China,29.2%
?pathogenesis
?aortosclerosis
?Arteriola resistance
?Hypertension associated with DN
?Renal hypertension caused by stenosis of
renal artery
? Diabetic retinopathy－ leading course of new cases of blindness
? Pathogeny,state of illness, course of disease,age of onset
? <5 years, eyeground disease is not common
? <10 years, 50％ eyeground disease
? <20 years, 80?90％ eyeground disease
Diabetic Retinopathy
Classifications (China)
? Background retinopathy
Ⅰ microaneurysms, dots of hemorrhages
Ⅱ yellow and white hard exudates,haemorrhages
Ⅲ white soft exudates,haemorrhages spots
? Proliferative retinopathy
Ⅳ new vessel formation, haemorrhage into the
vitreous
Ⅴ new vessel formation and fibrosis
Ⅵ retinal detachment
Diabetic nephropathy
? DN is the leading cause of ESRD (end-stage renal
disease)
– Almost 40％ of Type 1 DM died of uremia
– Incidence of DN in type 2 DM is about 20％
– In EU,DN accounts for 1/3 of dialysis and kidney
transplantation cases
– In China,DN also accounts for quite a lot of dialyses
and kidney transplantations
Stages of diabetic nephropathy(1)
stage I increased kidney DM already
filtration diagnosised GFR↑↑ enlarged kidneys(B- ultrasonic)
GFR>130ml/min
Stage II clinically silent phase DM 2?5year GFR ↑20?40％ renal enlargement,
with continued glomerular hypertrophy,
hyperfiltration and hypertrophy expansion of the mesangial matrix
thickening of the glomerular
basement membrane resulting in
glomerulosclerosis
Stage III concealed DN
microalbuminuria DM5?10year microalbuminuria 1/5 patients with hypertension
(20-200μg/min retinopothy↑
,or30?300mg/24h)
proteinuria 0.15?0.5g/24h
GFR> or =normal
Stages of diabetic nephropathy(2)
Stage IV Overt Nephropathy DM10?25year albuminuria>300mg/d 60?70％ patients
proteinuria>0.5g/d, with hypertentio
GFR↓(when UAER=100 and edema
mg/24h,GER begin to decrease,
about 1ml/min/month) retinopathy ↑↑
Stage V end-stage renal
disease,ESRD DM15?30 year albuminuria azotemic→
uremia
GFR< 1/3 of normal
Classification of diabetes neuropathy
（ 1）
Peripheral neuropathy
symmetric multiple peripheral neuropathy
sensibility multiple neuropathy
numbness type
pain type
numbness-pain type
sensomotor multiple neuropathy
acute or sub-acute motor multiple
neuropathy
asymmetricsingle or multiple periphearal
neuropathy
member or torso mononeural
cranial nerves disease
radiculopathy
proximal motor neuropathy
autonomic neuropathy
Autonomic neuropathy
diabetic myelopathy
diabetic spinal ataxia
spinal muscular atrophy
Cerebropathy
Hypoglycemia cerebropathy
diabetic coma
cerebrovascular disease
Diabetic sensability multiple
neuropathy
? more common in female
? Average age of onset is 58.7year
? Course of DM> 15years
? Symptoms of sense
– Numbness type,large medullated fibers
– Pain type,little medullated fibers and
nonmedullated fibers
– Numbness-pain type
? Nervous symptom examination
– parasthesia
– Lower limbs pallesthetic disturbance or dissapear
– Tendon reflex low or dissappear
– Sensory staxia
– Paratrophy symptoms
– Charcot arthropathy,ischemic gangrenosis and
foot ulcer
Diabetic autonomic
neuropathy
? Pupil disease
? Cardiovascular parafunction
– Fixed heart rate
– Postural hypertension
– Sudden cardiac death
? Gestrophageal,diarrhea
? Neuropathic bladder,erectile failure
? Abnormal sweating
?Glucosuria,associated with renal
threshold of sugar (only for clue)
?Ketonuria
?Blood sugar,plasma glucose,POD
?HBA1c,2?3 months blood sugar level
?Fructosamine,2?3 weeks blood sugar
level
?OGTT,2 hour specimen
?Insulin and C-peptide release test
Laboratory tests
Diagnosis
Criteria for diagnosing diabetes
FPG Random OGTT
plasma glucose 2hPG
mmol/L mmol/L mmol/L
DM ≥7.0 ≥11.1 ≥11.1
IGR
IFG 6.1≤FPG<7.0
IGT 7.8≤FPG<11.1
Normal <6.1 <7.8
Characteristics of new diabetic
diagnostic criteria
? FPG<6.1mmol/L is normal fasting glucose,OGTT
2hPG<7.8mmol/L is normal glucose tolerance；
? Impaired fasting glucose corresponding with impaired
glucose tolerance (IFG),6.1mmol/L ≤FPG<7.0 mmol/L ；
? The cutoff value of FPG decline from 7.8mmol/L to
7.0mol/L.the cutoff values of OGTT2hrPG and random
plasma glucose level are still 11.1mmol/L；
? FPG is the initial screening test of diabetes, OGTT is
not recommended for routine diagnostic use,
? The diagnoses of Gestational diabetes is not changed
Practical problems in diagnosis
? Symptoms ＋ random plasma glucose ≥11.1
mmol/L
? FPG,≥7.0 mmol/L
? OGTT,2hPG≥ 11.1 mmol/L
? Asymtomatic persons tests should be
repeated the once
latent autoimmune diabetes mellitus
in adults （ LADA）
? Adult onset
? Symptoms are evident
? Secretion function of ?cell is low
? GADA positive
? HLA-DQ B chain is non aspartate homozygote
Management
Goals
? Good metabolism control（ blood sugar,blood lipid、
HBA1C etc）
? Relieve symptoms
? Keeping good physiologic state and a social life
? Good quality of live
? Prevent the development of acute complications of
diabetes（ hypoglycemia,DKA,hyperosmolar
nonketotic syndrome,lactic acidosis）
? Preventing the development or delaying the
progression of the chronic complications of diabetes
Principle of treatment
? Early
? Life-long
? synthesis
? individual
Goals of control
good average bad
PBG(mmol/L)
fasting 4.4 - 6.1 ?7.0 >7.0
non-fasting 4.4 - 8.0 ?10.0 >10.0
HBA1c(％ ) <6.5 6.5-7.5 >7.5
BP(mmHg) <130/80 >130/80- <140/90 >140/90
BMI (Kg/m2)
M <25 M<27 ?27
F <24 F<26 F?26
TC (mmol/L) <4.5 ?4.5 ?6.0
HDL-c (mmol/L) >1.1 1.1-0.9 <0.9
TG (mmol/L) <1.5 <2.2 ?2.2
LDL-C (mmol/L) <2.5 2.6-4.40 >4.0
Control actuality of DM in China
? 26 centers,3965 patients
? 28％ patients measure HbA1c,8.1?2.6%，
52％ >7.5％
? FPG,9.2 ? 3.7mmol/L,55%>7.8
mmol/L
? Determing rate of microalbumin in urine,
20％
Diabetes Management Plan
? Patient education
? Health nutrition therapy
? Exercise therapy
? Drug therapy
? Monitoring of blood glucose
Phases therapy of DM
? Early reaction
? Patient therapy
? Medical nutrition therapy
? Exercise therapy
? Single drug therapy
? decline of curative effect
Combined drug therapy
? Secondary failure,distinct insufficiency
of insulin
Insulin therapy
Principles of medical nutrition theraphy
? rational control of total calorific value
? Goal,
– Keep ideal body weight
– Loss weight for obese patient
– Add weight for lean patient
? Standard body weight＝
– height（ cm）－ 105
– male,（ height－ 100 ） × 0.9
– female,（ height－ 100 ） × 0.85
? Body mass index（ BMI）, weight（ kg） /height2
（ m2）
Adult-onset diabetes thermal
energy supply per day
（ therm/kg standard weight ）
work intension
Bodily form in bed light physical middle heavy
labor physical physical
labor labor
lean 20 ? 25 35 40 >40
normal 15 ? 20 30 35 40
obesity 15 20 ? 25 30 35
Nutrition principles of diabetics
Moderate weight control
The distribution of total calorfic value,
carbohydrate 55 %?60%
fat 20%?25% 1/5,2/5,2/5
protein 15 %?20%
Drink limitation
Avoiding ?diabetic? foods (which contain sorbitol or frucotose)
Aspartame is an acceptable calorie-free sweetener
salt<10g/d,(<3g/day if hypertensive)
Calculation
?protein,0.8 ?1.2/kg standard weight
?fat,0.6 ?1.0/kg standard weight
?carbohydrate,total calorific value －
calories of protein and fat
Exercise therapy
? Benefits
– Glycaemic control
– Increase βcell sensitivity to glucose
– Blood lipid
– Weight reduction
? Estimation of quantity of exercise,heart
rate<170－ age (year)
Drug therapy
? Sulfonylureas
? Biguanides
? α-glucosidase inhibitors
? Tniazolidinediones
? Meglitinides
? Insulin
? Dry-combination therapy
Sulfonylureas,mode of action
? The principal action of these drugs is to stimulate
endogenous insulin secretion from the pancreatic β-cells
? Not to increase synthesis of insulin
? Also to increase β-cells sensitivity to glucose and exert
some influence in diminishing insulin resistance,
Sulfonylureas （ SU）,
first choice of non-
obesity T2DM
General name duration of action potency merits main site
of
excretion
Tolbutamide (D860) short weak cheap renal
Glyburide (micronase) long strong affirmed
hypoglycemia
effects in lowering
blood glucose levels
cheap renal
Gliclazide (diamicvon) medium strong prevent and renal
glipizide (minidiab) shot strong affirmed effects renal
Gliquidone (glurenorm ) shot week not renal(only5%)
Glipizide (tonbac) long strong good compliance low
incidence
Therapeutic effects of SU
? Primary failure to respond to SU occurs in 20% to
25% of patients
? FPG and 2hPG
? HbA1c 1% ? 2％
? As the period of treatment progresses,effects
decline,
– Secondary failure occurs at the rate of 10% to 15% per
year
– After 5 years, only half of the patients can keep ideal
blood glucose control,
– UKPDS,first year,blood glucose, insulin
– then, blood glucose insulin
– the 6th year,returned to the state before therapy
Indications and
contraindications of SU
? Indications
– Poor control of T2DM by weight control and physical
activity
– Poor control of T2DM by biguanides and ?-
– Combined with insulin
? Contraindications
– T1DM
– Acute or chronic diabetic complications
– Emergency
– Dysfunction of liver or kidney
– Pregnant or bleeding women
Side effects of SU
? Hypoglycemia,most common in
– Old patients
– Long-term pharmaceutics
– Symptoms of digestive tract
? Liver dysfunction
? Tetter
? Change of hematology
Biguanides, first choice of obesity
type 2 DM
Generic name dosage merits NB
phenformin <75mg/d cheap lactic acidosis
（ 降糖灵 ） restrain
oxygenic metabolism
lower energy of
oxygenic metabolism
dimethylbiguanide <1.5g/d low gastrointestinal
side-effects reaction
（ 降糖片 ）
Mechanisms of action of
biguanides
? Increasing β cell sensitivity to glucose
? Enhancing glucose uptake and utilization by muscle
? Reducing HGP by inhibiting gluconeogenesis,
? Decreasing intestinal glucose absorption
? Do Not stimulating endogenous insulin secretion from β
cell
? Do Not causing hypoglycemia when used singly
indications and contraindications
of Biguanides
? Indications
– Obesity T2DM
– Poor control by SU
– Poor control by insulin,including T1DM
– Simple obesity
– Polycystic ovary syndrome
? Contraindications
– Allergic reactions
– Renal dysfunction,serum creatinine>1.4mg/dl
– Acute or chronic acidosis
– Heart,lung disease,hypoxia,acidosis inclination
– Hypohepatia
– Severe gastroenteropathy
– Pregnancy
Side effects of Biguanides
? Diarrhea
? Anaphylaxis
? Overt macies, common in elderly patients
? Lactic acidosis
? Inhibiting ?-glucosidase
? Delaying the digestion of
glucose
? 2hPG
? Not stimulating the secretion of
Insulin
α-glucosidase inhibitors,mode of action
Therapeutic effects of Acarbose
? 2hPG
? FPG
? HbA1c about 1％,When used in combination with
SU,HbA1c, about2％
? Serum insulin slightly declined
? Weight not a few patients
? When used as monotherapy,it do not cause hypoglycemia
? When used in combination with other oral antidiabetic
agents,it may cause hypoglyceia
If hypoglycemia happens,patient should be treated by
glucose,Other kinds of sugar are ineffective
Indications and contraindications of
α-glucosidase inhibitors
? Indications
– Light cases
– using drug separately or combined
– IGT intervention,security
? Contraindications
– Allergic reactions
– Severe gastroenteropathy
– Dysfunction of renal and liver
– Acute complications
– Emergency
– Pregnant and breast feeding women
thiazolidinedion（ TZD）,insulin sensitizers
? Insulin sensitizers; agonist at the peroxisome
proliferator-activated receptor ? （ PPAR?） ;increase
glucose utilization in peripheral tissues,
? Reducing insulin resistance,hyperglycemia and
hyperlipaemia and hypertension can be improved at
varies degrees
? For T2DM:used as monotherapy or in combination
with SU,insulin,
? When used in combination with SU or insulin
,hyperglycemia
? Without insulin,it cannot reduce hyperglycemia
? Liver function should be monitored frequently,Stop
using it in case liver dysfunction is found,
? Incidence of edema:4?5%
? It may cause Hb slightly↓
Meglitinides, repaglinide
? Stimulate Pancreatic insulin secretion（ similar
with SU）,specific combinition with 36KDa
protein K pathway close
? Stimulating the first phrase secretion of insulin
? Action,rapid onset, short duration，
suppressing postload hyperglycemia quickly
? Sites of excretion, kidney 8%,fecal 92%
? Used as monotherapy or in combination with
biguanides, α-glucosidase inhibitors
? Incidence of hypoglycemia is low
Factors in choosing oral
antidiabetic agents
? age
? weight
? Blood glucose level
? Function of liver and kidney
? Characteristic of drug
? costs
Choose of oral antihyperglucemic
agents
? Older patients,short term SU
? Obesity or hyperinsulinism patients,biguanides or
acarbose
? 2hPG, α－ glucosidase
? Concentration of plasma glucose,>270 ? 300mg/dl,
the symptoms of hypertension are evident,Insulin
therapy is available
? Impaired liver and kidney function,avoid using
OHA
? Lean, fasting and after-excitation insulin all,
insulin
Drug-Combined therapy
? Reasonable diet and poor plasma
glucose control by monotherapy
? SU, biguanides, TZD and α-
glucosidase inhibitors all can be used in
combination with each other
? Small dosage combined with of all kinds
of drugs ;enhancing effects of reduce
glucaemia ;side effects of single agents
? Oral agents with insulin
? Drugs of the same class cannot be used
in a combined way,
Insulin therapy
Indications of insulin
?Type 1 DM
?Type 2 DM
?Acute complications
?Severe chronic complications of diabetes
?Emergency
?Severe dysfunction of liver or kidney
?Gestation and bleeding women
?Without tolerance OHA,curative effect of OHA, SU
invalidation
?Distinct lean
?With diseases treated by glucocorticoid
?Some specific types of DM,secondary pancreas
disease, endocrinopathies,genetic diabetes
Obstacles to using Ins in T2DM
? old notion,NIDDM
?The doctor uses OHA only and does not see
the need to use Ins,
?The patient does not want to use In for fear
of developing insulin dependence after useing
it,
?Hyperinsulinism can lead AS to CVD？
?hypoglycemia,BW↑
国内常用胰岛素一览表
产品名 生产厂家 种属来源 包装 (U/瓶 )
短效胰岛素
普通胰岛素 (RI) 上海生物制药厂 猪 400 U/瓶
优泌林 R 礼来 基因重组 400 U/瓶
诺和灵 -R 诺和诺德 基因重组 400 U/瓶
Lispro 礼来 基因重组 400 U/瓶
中效胰岛素
优泌林 N 礼来 基因重组 400 U/瓶
诺和灵 -N 诺和诺德 基因重组 400 U/瓶
NPH 徐州生化制药厂 猪 400 U/瓶
混合胰岛素
优泌林 70/30 礼来 基因重组 400 U/瓶
(人工合成 )
诺和灵 -30R 诺和诺德 基因重组 400 U/瓶
诺和灵 -30R 诺和诺德 基因重组 300 U/瓶
长效胰岛素
PZI 上海生物制药厂 猪 400 U/瓶
Differences between human and animal
insulin
? Difference in pharmacodynamic,
– Close action intensity
– Human insulin, absorption is fast, time of onset of effect is
early
? Difference in immunogenicity,
– Antigenicit of human insulin is weaker than animal insulin
– After use human insulin,antibody titer of blood insulin is
lower
? Synthesized insulin, lispro（ 28proline?29 proline ）
– Quick absorption,short effect time
Shot-term intensive insulin
therapy for T2DM
? Indications,monotherapy or combination therapy of oral
antihyperglycemia therapy fail to achieve glucose targets，
overt hyperglycemia,fasting and postprandial C-peptide
? Method,use insulin 2 times per day,NPH/R 70/30
prebreakfast and presupper, adjust the dosage with the
monitoring results of blood sugar,use insulin 4 times per
day, RI premeal,NPH before sleep
? Period of treatment,several weeks or monthes
Shot-term intensive insulin
therapy for T2DM
? Estimation of initial dosage,0.2 ? 0.4U/Kg weight per day
?Mode of therapy
? RI before meals,RI— RI— RI— O,before breakfast＞ before
supper＞ before diner
? RI before three meals + RI before supper,RI— RI— RI— RI
? RI before three meals + NPH before supper,RI— RI— RI/NPH
? RI before three meals + NPH before sleep,RI— RI— RI— NPH
? mixed insulin（ RI/NPH） before three meals（ 2/3before
breakfast, 1/3before supper）,the proportion,10R— 50R
? NPH/R 70/30before breakfast and supper
Secondary failure of OHA,combination
with insulin
?FPG? oral anti-hyperglycemia agents+ NPH before sleep
?PPG? NPH before breakfast+oral anti-hyperglycemia
agents
?FPG? PPG? oral anti-hyperglycemia agents + NPH
before sleep and before breakfast
?Insulin, adjust per 3~4 days,
? one phrase each time
up for 2~4U every time
?Before you add insulin,hypoglycemia reaction should
be excluded
Combination of OHA and NPH
before sleep
? Indication,
– OHA is invalid or has low effect
– FPG not exceeding 250 ? 300 mg/dl
– Non-lean
– LADA
– Still having some function of insulin
secretion
C-peptide,
fasting≥0.2 mmol/L
postload > 0.4 mmol/L
The effect of supplying one injection of
intermediate-acting insulin before sleep
? HGP, lipolysis
? antagonize the somogyi effects and the dawn
phenomenon caused by glucagon
?FPG returning to normal
?Helping SU to effect in daytime
?24hour PG, HbA1c
?Supplying the deficiency of act time of former OHA
?The patients needs to be supplied with one injection each
night and doesn’t need to be hospitalized,It’s easy for the
patient to accept,
difference of complementary therapy
and subtitution therapy of insulin
Complementary therapy
OHA are basic therapy,combination with insulin
NPH before sleep,FPG↓, daytime postprandial
hyperglycemia can be improved evidently
NPH perbreakfast with OHA for postprandial
hyperglycemia (often used)
Substitution therapy
Stop using OHA;substituted by insulin
Mixed insulin before breakfast and supper
Three injections perday R,R,R+N
Four injections perday R,R,R,R or R,R,R,N
Side effects of insulin
?hypoglycemia
local reaction
?Anaphylaxis systemic reaction
insulin drug resistance
?Lipid dystrophia, atrophy and fleshy
Artificial factors in influencing
curative effect of insulin
? Inject position
abdomen wall >the upper
arm>thigh>buttocks
? Inject depth
hypodermatic,not muscle
? Preservation
cold storage,not freeze
NB (1)
? Need to increase the quantity of insulin,
– Hyperpyrexia
– Hyperthyrea
– Pachyacria
– Ketoacidosis
– Severe infection or trauma
– Serious surgery
– Pregnant woman, especially in metaphase or
anaphase of pregnancy
– Adolescent children
NB (2)
? need to cut down the quantity of insulin,
– Metabolize and excretion of insulin in kidney,
hypohepatia, kidney dysfunction,thyroid
insufficiency
– Diseases which can lead to hypoglycemia,hypadrenia、
diarrhea, gastroanesthesia, intestinal obstruction、
vomit, absorption of food
– Elderly patients (easy to get hypoglycemia)
NB (3)
? Combined drugs（ glucemia ）
– Agents which increase plasma glucose,glucocorticoid,ACTH、
glucagon,estradiol,oral prophylactic,thyroxin,adrenalin,
thiazide diuretic, dilantin
– Carbohydrate metabolism abnormality,PG, felodipine、可乐定、
二氮嗪,GH,heparin,α-blocker,大麻,morphin,nicoltin、
β-blocker(普萘洛尔可阻止肾上腺素升高血糖的反应 )
NB (4)
? Combination drug therapy（ help lower plasma
glucose ）
– Slow degradation of insulin
chloroquine, quinidine, quinin
– Insulin combine globulin competely,dissociated insulin
anticoagulative agents,salicylate, sulfanilamide,
anti-tumor agents can help lowering glucemia, OHA、
assimilation steroid androgenic hormones,monoamine
oxidase inhibitor, NSAID
– Lower glucemia
ACEI,溴隐停、氯贝特、酮康唑,lithium,甲苯咪
唑,theophylline,alcohol、奥曲肽
Monitor of DM
Glucosuria,associated with renal
threshold of glucose(only for clue)
FPG
HBA1c,2?3 months blood sugar level
Fructosamine,2?3 weeks blood sugar
level
OGTT,2 hour specimen
Diabetic Ketoacidosis
（ DKA）
summarize(1)
? One of the acute metabolic complications of
diabetes
? Can be initial symptoms of diabetes
? One of the important emergency of internal
medicine
? Need rapid,reasonable treatment
? Full-scale examination of specialty knowledge of
internist or general practitioner
? Need doctors and nurses to take concerted action
Summarize (2)
? Ketosis
? DKA
? Hypoglycaemic keto-
acidotic coma
Composition and
characteristics of ketone body
? Acetoacetic acid is the first product,strong organic
acid ;can reacted with ketone powder strongly
? Dimethylketone, least quantity, neutral,no
renal reabsorption threshold ;can be excreted from
respiratory tract
? β－ oxybutyric acid, strong organic acid, biggest
quantity（ 70％）
Pathophysiology
glucagon↓↓
↑↑
Abnormalities in
carbohydrate
metabolism
lipolysis↑
Acidosis
Abnormal nervous
system
Circulation faliure
携氧系统异常
Electrolyte
disturbance
Acetone
body
Plasma
glucose
Severe dehydration
Inducement of DKA (1)
? Interrupted drug
therapy
? Improper diet
? Fatigue
? infection
? Trauma
?operation
?pregnancy,delivery
?drinking
?miocardial infarction
?else
Clinical presentations of DKA
? Intensive thirsty,diuresis
? Extremely tired,nausea, vomiting
? Varied degrees of disorder of
consciousness
? Circulation failure
? Presentations of precipitating factors
Special presentations of DKA
? Abdominal pain
? Hypothermy and abnormal
,normal body temperature”
?Number of leucocyte↑
Laboratory tests
? Urine tests
– glucosuria
– ketourine
? Blood tests
– Blood sugar
– Blood ketone
– CO2CP
– electrolyte
Examination of ketone
? Acetoacetic acid ＋ acetone body powder
rose purple
– When ketosis fades away, β-hydroxy-butyric
acid turn to acetoacetic acid, the color test of
the latter with acetone body power is evidently
better than the former
– In case of lack of oxygen, more acetoacetic
acid turns to β-hydroxy-butyric
Therapeutic goals of DKA
? Correcting acute metabolic turbulence
? Preventing and curing complications
? Reducing the case fatality rate
Transfusion is the chief therapeutic
measurement of DKA
? Restoration of circulating plasma volume
? Rebuild ERPF
? Helping insulin to exert its effect
? Reducing blood sugar
? Removing blood ketone
? Reducing the concentration of insulin
counterregulatory hormone
Transfusion
? Why, blood sugar 14mmol/L is the cutoff value
? How, double vein channels
? Reference index,--age
--vital signs
--function of heart and kidney
--shock or not
--urine quantity per hour
--CVP
Insulin is the key of therapy
? Insulin in small dosage is a simple,efficient,
safe therapy(0.1u/kg/h)
– NS 250ml+RI 25U/ iv,15 drops/min
– Blood sugar 5 ? 6mmol/L/hr
– ingnition？,RI 20U/ iv
? route
– Presistent venous inflow (other approach)
– intermittent intervenous injection
– Intermittent intramuscular injection
Correct acidosis (1)
Influence of DKA,
? Blood pH<7.0, restain contractility of cardiac
muscle
? The relationship of Blood pH and ventilatory
– pH<7.2, hyperventilation, Kussmaul?s respiration
– pH<7.0, restrain expiratory center
? Insulin sensitivity
Correct acidosis (2)
? Bad results of excessive alkali
supplementary treatment,
– Blood pH↑,CSFpH still low; easy to get
hydrocephalus
– Not good for oxidized hemoglobin to release
oxygen, and cause anoxemia of tissue
– Easy to get hypocalcemia
Correct acidosis (3)
? Usually after transfusion, blood CO2,BP
? If blood pH<7.1,HCO3-<5mmol/L
isosmotic sodium bicarbonate, 5％ NaHCO3
84ml,
or inject water to 200ml equal to
1.25%NaHCO3
? Sodium lactate is not recommended
Correct electrolyte disturbance
? Reason of low plasma potassium
– Restoration of circulating plasma volume
– Acidosis has been corrected
– Urine
– Glucose Hepatin
? Principle of potassium replacement
Considering urine volume, renal function and
concentration of blood potassium,moderately
adding potassium to intravenous fluid
Other measures
? Nurse
? Prevention and cure complications
– infection
– hydrocephalus
– Heart failure
– Kidney failure
? Removing precipitating factors
Keystone
? Criteria of diagnosis of diabetes
? Methods of diagnosis
? Principle of treatment
? Type,characteristics,indications,contrai
ndications,side effects of oral
antidiabetic agents
? Principle of treatment of DKA
胡仁明 医学博士
? 华山医院内分泌科 62489999x6622
? 复旦大学内分泌糖尿病研究所
? 62489999x6458
? E-mail Renminghu@Fuda.edu.cn
