c:\documents and settings\administrator\桌面\35 ndiabetes mellitus

Diabetes Mellitus

Dr. CAI MengyinDepartment of Endocrinology

3rd Affiliated HospitalSun Yat-sen University

•Populous country with westernized lifestyle

•Limited resources for healthcare expenditure

•Increasing prevalence of obesity

The official mascots of the Beijing 2008 Olympic Games

Populous country with obesity pandemic

Asia countries are facing challenge from Diabetes

Economy taking-off like a rocket with dramatic lifestyle change

State “on Bicycle”

Traffic jam in Beijing

Coupon for food in Guangzhou

One week’s food for a family in Beijing

Exercise less Eat More

Prevalence rate of Diabetes

Throughout the world: 150 millions

? 2%

USA: 15 millions

China: 9.7% -- N Engl J Med 2010;362:1090-101.

Canton: 1980

0.411% in 42788

China: 1980

0.609% in 304537

What is Diabetes Mellitus?

Definition:

Syndrome

Metabolic disorder of multiple etiology (causes) characterized by hyperglycemia with carbohydrates, fat, and protein metabolic alterations, which result in defects in the secretion or action of insulin, or both.

HyperglycemiaX or Metabolic Syndrome

Metabolic abnormalities and by long-term complications involving eyes, kidneys, nerves, and blood vessels

Acute complications: diabetic ketoacidosis, hyperosmolar nonketotic diabetic coma.

homogenous Heterogeneous

Genetic factorsGenetic factors Environmental factorsEnvironmental factors

Chinese population9%

MonogenicMonogenic

PolygenicPolygenic

AgingAging

LifestyleLifestyle

InfectionsInfections

Diabetes

Type IType I<10%<10%

Type IIType II>90%>90%

Etiology and Development

Defect of β Cell in Insulin Secretion & Action

Non-diabetes Pre-diabetes

Diabetes

IGT/IF

G

Fasting plasma glucose

Insulin requirement

Insulin production

<6.1mmol/L

>7.0 mmol/L

Derangements are due to relative or absolute

insulin deficiency and glucagon excessiveness.

Normally, it is a rise in the molar ratio of glucagon to

insulin which leads to diabetic decompensation.

Why does metabolic derangement happen?

Spectrum of Diabetes Mellitus

Insulin receptor gene mutations Insulin receptor gene mutations (<1%)(<1%) Insulin gene mutations (<1%)Insulin gene mutations (<1%)

Mitochondrial gene mutations (2%)Mitochondrial gene mutations (2%)

Type 2 (70%)Type 2 (70%)

Type 1 (10%)Type 1 (10%)

LADA (10-12% ?)LADA (10-12% ?)

MODY (2-4% ?)MODY (2-4% ?)

1 yr 10 yr 21 yr 32 yr 45 yr 60 yr Age at diagnosis

TYPE1TYPE2

MODY LADAMIDDDIDMOAD?

Variable Faces of Diabetes Mellitus

Type 1 diabetes mellitus

Usually onset before age of 40.

In USA, peak incidence is around 14 years old.

Onset of symptoms may be abrupt, with thirst, excessive urination, increased appetite and weight loss developing over a several-day period.

In some cases, the disease is heralded by the appearance of DKA during and intercurrent illness or following surgery.

Type 2 Diabetes Mellitus

Usually starts in middle age or older.

Symptoms begin more gradually than in type 1 diabetes, and diagnosis is frequently made when an asymptomatic person is found to have an elevated plasma glucose on routine lab. Exam..

Type 1 vs. Type 2

Type 1 Type 2

Age of onsetChildhood, young

adultAdulthood, elder

people

Body cells Responsive to insulin Resistant to insulin

Autoantibodies Positive Negative

Body fatness Low to average High

Endogenous insulin Little or none Normal or too much

Pancreatic functionBeta cells not

functionalBeta cell normal

Severity of symptoms Severe; liable to DKAMild; few or none, not liable to DKA

Insulin shots? Yes, indispensableNot during early and

middle stage

Drugs? Not solely Yes

Maturity-onset diabetes of the young (MODY)

45

33 22

1216 17

10

INS

OHA

OHA DIET

DIET

DIET

INS

Classical MODY-criteria:1. Two patients diagnosed

with diabetes before the

age 25 years.

2. Autosomal dominant

inheritance of diabetes

( 3 generations)

Note: Yellow figures indicating ages at on-set.

History of MODY genesHistory of MODY genes

MODY2MODY2GCKGCK

MODY1MODY1LinkageLinkageto chr20to chr20

1991 1992 1993 1994 1995 1996 1997 1998 1999 2000

MODY2MODY2LinkageLinkageto chr7to chr7

MODY3MODY3LinkageLinkageto chr12to chr12

MODY3MODY3HNF-1HNF-1

MODY1MODY1HNF-4HNF-4

MODY5MODY5HNF-1HNF-1

MODY4MODY4IPF1IPF1

Severe insulin resistance syndrome

Insulin signaling associated mutation

Lypodystrophy syndrome linked

mutation

Other gene

IR gene

AKT2 gene

BSCL FPLD MAD CaR gene

AGPAT2 gene

Seipin gene

LMNA PPARγ gene

LMNA ZMPSTE24 gene

Type A insulin resistance syndrome

• Autosomal recessive inheritance

• Autosomal dominant inheritance

• Penetrance is not constant

Sequencing of IR exon20

Black Arrow ：P1174W

Green Arrow ：P1178P

Weng J. Clin Endocrinol (Oxf). 2009 Nov; 71(5):659-65. Epub 2009 Jan 19.

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Glucose(2003) Glucose(2005) Insulin(2003) Insulin(2005)

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Glucose

Weng J. Clin Endocrinol (Oxf). 2009 Nov; 71(5):659-65. Epub 2009 Jan 19.

HGPS, RDthe “most” complicated and lethal type of laminopathies

HGPSRD

Hum Mol Genet, 2004, 13: 2493-2503.N Engl Med, 2008,358: 552-555.

In some other secondary identifiable condition, a diabetic syndrome can develop

• Pancreatic diseases, pancreatitis • Hormonal causes: pheochromocytoma, acromegaly,

Cushing syndrome and therapeutic administration

• Stress hyperglycemia: severe burns, acute myocardial

infarctions and other life-threatening illnesses

Mechanism of Stress of Hyperglycemia

• Endogenous release of glucagon and catecholamines

• Combinations of impairment of insulin release and induction

of insulin resistance

Gestational Diabetes Mellitus

◆ ◆ Definition:Definition:

Carbohydrates intolerance of variable severity with Carbohydrates intolerance of variable severity with onset or first recognition during pregnancyonset or first recognition during pregnancy

◆◆ Screening:

American Diabetic Association(ADA) Recommend screening all pregnant women at 24-26 wks using 50g oral glucose test with 1 hour blood glucose value of 140mg or more as an indication for standard oral glucose tolerance test. No stipulations as to the time of last meal.

Clinical manifestation

The manifestations of symptomatic diabetes

mellitus vary from patient to patient.

Most often medical help is sought because of

symptoms related to hyperglycemia: polyuria,

polydipsia, polyphagia.

But, the first event may be an acute

metabolic decompensation resulting in

diabetic coma. More occasionally, the

initial expression can be a degenerative

complication such as neuropathy in the

absence of symptomatic hyperglycemia.

Classifications of Diabetic Vascular Disease

A. Macrovascular disease: an accelerated form of athersclerosis,

accounts for the increased incidence of myocardial infarction,

stroke and peripheral gangrene .

B. Microvascular disease: basement membrane thickening of the

small blood vessles, the capillary and the precapillary arteriols,

involving the retina leads to diabetic retinopathy, the kindney

causes diabetic nephropathy, also the heart, resulting in the

cardiomegaly with heart failure in diabetic patients.

Increased coagulability

Platelet hypersensitivity

Increased blood viscosity

Impaired microvascular flow

Increased microvascular pressure and flow

Microvascular sclerosis

Limitation of maximum perfusion

Failure of autoregulation

Raised capillary pressure

Tissue damage

Hypothesis for Diabetic Microangiopathy

Microaneurysms

Scattered exudates

Haemorrhages

•Flame-shaped

•Dot and blot

Cotton-wool spots(<5)

Venous dilatation

Background

•Rapid increase in microaneurysm count

•Multiple haemorrhages

•Cotton-wool spots(>5)

•Venous beading, looping and duplication

Preproliferative

New vessels• On disc (NVD)•Elsewhere (NVE)Fibrous proliferation• On disc (FPD)• Elsewhere (FPE)Haemorrhages• Preretinal•Vitreous

Proliferative

•Retinal

detachment

•Rubeosis

iridis

•Neovascular

glaucoma

Advanced diabetic eye

disease

Macular oedema

• Focal

• Diffuse

Ischaemic maculopathy

Maculopathy

Stages of Diabetic Retinopathy

Background Proliferative

Diabetic Retinopathy

Diabetic Nephropathy

※Mechanism: thickening of capillary basement membranes and of the mesangium of renal glomeruli, produces varying degrees of glomerulosclerosis and renal insufficiency. Proteinurea is the initial manifestation.

※Natural history:

• Initial stage of normoalbuminuria: enlargement of the kidney with increased filtration rate, but the urinary albumin excretion rate (AER) is within the normal range (<15 ug/min).

• Microalbuminuria: 20 ug/min <AER<200 ug/min.

• Clinical proteinuria: AER>200 ug/min (or 300 mg/24hr), dip-stick-positive proteinuria.

• End-stage renal disease: renal dysfunction with increased serum creatine level, edema, hypertension, etc.

Diabetic NeuropathyPeripheral neuropathy

Distal, symmetric sensory loss

Motor neuropathy

Foot drop, wrist drop

Mononeuropathy multiplex (diabetic amyotrophy)

Cranial nerves III, IV, VI, VII

Autonomic neuropathy

Postural hypotension

Resting tachycardia

Loss of sweating

Gastrointestinal neuropathy

Gastroparesis

Diabetic diarrhea

Urinary bladder atony

Erectile dysfunction

Limited joint mobility

Motor damage Sensory damage Autonomic damageMicrocirculatory

diseaseMacrovascular

disease

Diabetic neuropathy

Diabetes• Smoking•Hypertension• Dyslipidaemia

Abnormal foot posture

Reduced pain and proprioception A-V shunting

• Orthopaedic problems• Charcot arthropathy

Increased foot pressures

Reduced tissue nutrition

Callus formation

Ischaemia

Ulceration

Infection

Pathways to Diabetic Foot

Foot ulceration Charcot arthropathy

Diabetic Foot

Laboratory Findings

◇ Analysis of urine glucose :

Factors affecting the result:

• kidney threshold for glucose excretion

• glomerulosclerosis

◇ Other substances in the urine :

• ketonuria

• proteinuria

• microaluminuria

urine albumin excretion rate (AER)

－ ± + ++ +++ ++++

◇ Blood glucose testing:

• venous blood sample for diagnosis

• capillary blood sample for self monitoring

◇ Glycosylated hemoglobin assay:

• GHbA1C comprised major form of GHb.

• reflects the state of glycemia over the past 2~3 months.

◇ Glucose tolerance test :

• OGTT:

• IVGTT

6

8

10

12

14

16

18

20

0 10 20 30 40 50 60

control

PATIENT

0.693K (glucose)= × 100

t 1/2

Insu

lin (m

U/L

)

30 60 90 120 150 180 210 min

T2DMNormal

T1DM

◇ Serum insulin concentration:

• fasting.

• challenged with glucose.

Reflection of insulin storage and sensitivity

C peptide

A chain

B chain

◇ Serum C peptide concentration:

• in equimolar amounts with insulin

during cleavage from proinsulin

• reflection of insulin secretion

• fasting and post-load indicating basal and storage of insulin

◇ Lipid profile:

• dependent on normal level and action of insulin

• dyslipidemia characteristic of a high level of serum triglyceride,

with low HDL-C but increased LDL-C concentration

• sufficient insulin supplement in T1DM, or improvement in

insulin sensitivity in T2DM may rectify the disorder

Diagnosis of Diabetes Mellitus

1) Symptoms of diabetes plus a random plasma

glucose concetration >11.1 mmol/L.

2) Fasting plasma glucose >7.0 mmol/L after an

overnight (at least 8-hour) fast.

3) Two-hour plasma glucose > 11.1 mmol/L during a

standard 75 g oral glucose tolerance test.

4) Impaired fasting glucose (IFG): plasma glucose

after an overnight fast that is >6.1 mmol/L but less

than 7.0 mmol/L.

Treatment of Diabetes Mellitus

Management Goals

– Obtain optimal glycemic control– Prevent and retard microvascular complications– Reduce macrovascular complications– Avoid acute diabetic complications– Better quality and lengthen span of life

Strategies

• Earlier diagnosis and treatment

• Acting on results of SMBG and GHbA1c

• Combination therapy• Education for healthy life style and self management

Good Moderate PoorFPG mmol/L 4.4-6.1 ≤ 7.0 >7.0PBS mmol/L 4.4-8.0 ≤ 10.0 >10.0 HbA1c ★ % <6.2 6.2-8.0 >8.0BMI Kg/m2 M<25

F<24M<27F<26

M ≥ 27F ≥ 26

Tch mmol/L <4.5 ≥ 4.5 6.0HDL-c mmol/L >1.1 1.1-0.9 <0.9TG mmol/L <1.5 <2.2 ≥ 2.2LDL-c mmol/L <2.5 2.5-4.4 >4.5

★According to UKPDS data.

Targets for Diabetic Control

Major Therapeutic Trials 1Major Therapeutic Trials 1DCCT (Diabetes Control & Complications Trial) 1983-1993

1441 Type 1 patients (726 no retinopathy or microalbuminuria; 715 non-prolif. retinopathy and microalbuminuria)

•Randomised to INTENSE or CONVENTIONAL Rx *

•Average follow-up 6.5 years

•INTENSE Rx reduced by approx. 60% the risk of retinopathy, nephropathy and neuropathy.

•3-fold increase in risk of hypoglycemia in INTENSE group.

* INTENSE = tid INS or pump frequently adjusted by at least qds BG

CONVENTIONAL = qd/bid INS and single daily BG or urine check

Major Therapeutic Trials 2Major Therapeutic Trials 2UKPDS (UK Prospective Diabetes Study) 1977-1997

•5102 newly diagnosed Type 2 patients from 23 centres

•Median follow up of 11 years

•Randomised to diet or Rx (INS, SU or Meformin)

•All Rx showed similar efficacy over diet

•Good glycaemic reduced risk of microvasculopathy

•Approx. 35% reduction for each 1% fall in HbA1c

•Macrovascular disease risk not affected *

function deteriorated steadily during the study regardless of Rx

* Only reduced by anti-hypertensive Rx in a sub study where the impact of aggressive BP control mirrored HOT trial.

◆◆ Set total calorie IntakeSet total calorie Intake

according to ideal body weight (IBW) and working strengthaccording to ideal body weight (IBW) and working strength

◆◆ Sample calorie distribution

◆◆ Set total calorie IntakeSet total calorie Intake

according to ideal body weight (IBW) and working strengthaccording to ideal body weight (IBW) and working strength

◆◆ Sample calorie distribution

• 50-60 % CHO• 15-20 % Protein• 20-30 % Fat

◆ ◆ About sweetenersAbout sweetenersFDA approves 4 sugar substitutes which have no CHO:FDA approves 4 sugar substitutes which have no CHO:

aspartame, saccharin, acesulfame-K, sucraloseaspartame, saccharin, acesulfame-K, sucralose

◆ ◆ Limitative drinkingLimitative drinking

◆ ◆ Reduce Sodium Intake

Diet

Food PyramidFood Pyramid

• Food Group/Servings• starch 6 -

11 • vegetable 3 -

5 • fruit 3 - 4 • milk 2 - 3• meat/protein 2 -

3– use fats, sweets,

and alcohol sparingly

Physical Activities

◇Benefits:

※Lowers glucose levels in blood

※Improves blood circulation in the entire body

※Contributes to weight loss

※Improves physical and mental wellbeing

※Helps the body to utilize insulin more efficiently

Exercise Guidelines

※※ Monitor BG before and after exercise.Monitor BG before and after exercise.

※※Avoid exercise if BG >250 mg/dl, ketones present.Avoid exercise if BG >250 mg/dl, ketones present.

※※ Use caution with exercise if BG>300 mg/dl, without ketones.Use caution with exercise if BG>300 mg/dl, without ketones.

※※ Eat CHO if BG < 100 mg/dlEat CHO if BG < 100 mg/dl

※※ If exercise is planned for just after a meal, consider reducingIf exercise is planned for just after a meal, consider reducing

the short acting insulin that covers that meal.the short acting insulin that covers that meal.

※※ If exercise is planned for 3-4 hours after a meal, consider reducingIf exercise is planned for 3-4 hours after a meal, consider reducing

the long-acting insulin.the long-acting insulin.

※※ For unplanned exercise, consider adding carbohydrate.For unplanned exercise, consider adding carbohydrate.

※※ Consume CHO before, during, or after exercise to prevent Consume CHO before, during, or after exercise to prevent

hypoglycemia.hypoglycemia.

※※ Always keep CHO foods readily available during exercise.Always keep CHO foods readily available during exercise.

Oral Hypoglycemic Agents

Sulphonylureas

Mode of action:

• Increase pancreatic insulin secretion

• May improve insulin sensitivity in peripheral tissue and decrease hepatic glucose output

Sulfonylurea Activates Insulin Secretion

Small figure shows the site of action.

◇Contra-indications :

pregnancy, surgery, severe renal failure, type 1diabetes, hypersensitivity

◇Side effects:

hypoglycaemia weight gain

◇Administer: before meal

Secondary Failure

• Secondary failure rate 5% to 10% a year(UKPDS 7% a year)

– Decreasing β-cell function– Obesity– Non-adherence to treatment– Lack of exercise– Intercurrent illness

Biguanides (Metformin)

Mode of action:

◇reduces hepatic glucose production

◇decreased intestinal absorption of glucose

◇increases peripheral utalisation of glucose in muscle &

fat tissue

◇decreased insulin requirements for glucose disposal

Precautions: ●chronic renal or cardiac failure

●hepatic impairment ●elderly ●excessive alcohol intake

Side effects: ◆gastrointestinal disturbances ◆metallic taste◆malabsorption of B12

Administer: with or after meals

Alpha Glucosidase Inhibitor (Acarbose)

Mode of action:Delays breakdown of CHO such as starch & sucrose

Contra-indications:Pregnancy, renal impairment, gastrointestinal disorders

Side effects:Gastrointestinal, rash, erythema

Administer:With the first few spoons of the meal

Thiazolidinedione

Mode of action:• Peroxisome proliferator-activated receptor gamma agonist (PPAR-Peroxisome proliferator-activated receptor gamma agonist (PPAR-))• Improves sensitivity to insulin in skeletal muscle and adipose tissue• Enhances peripheral glucose uptake, reduces hepatic glucose Enhances peripheral glucose uptake, reduces hepatic glucose

productionproduction• Preserves pancreatic functionPreserves pancreatic function• Optimum effect seen in 12 weeksOptimum effect seen in 12 weeks

Contra-indications: Heart failure, moderate to severe hepatic impairment.

Insulin Indications:

1) Type 1 diabetes

2) Type 2 diabetes whose hyperglycemia does not respond to diet therapy and oral hypoglycemic drugs

3) Pregnancy and delivery

4) Acute diabetic complications

5) Severe chronic complications

6) Severe infections, major surgery, stress etc

7) Secondary insulin insufficiency: pancreaectomy

Insulin preparations and time of reaching peak and duration

Lipoatrophy due to long term injection of ‘impure’ insulin preparations.

Novopen

Inhaled insulin

Insulin pump

Oral Agents + Insulin in Type 2 Diabetes

• Simplifies insulin regimen

• Improves glycemic control

• Better patient acceptance

• Compliance

• Convenience

• Lower doses of exogenous insulin

• Less weight gain

Rationale:

Diabetic Ketoacidosis

Presentation

Physical examination Laboratory results

Polyuria, polydipsia

Nausea, vomiting

Diarrhea, abd. Pain

Evolution for a few days

Stupor or coma in Loss of skin turgor

Kussmaul breathing

Acetone odor

Cerebral edema

PH <7.3, HCO3 <15 Eq/L

Glucose > 250 mg/dl

Elevated anion gap

High serum ketones

High uric acid

Normal osmolality

Precipitating Factors of DKA

• Noncompliance with medication

• Infection • myocardial infarction • Cerebrovascular accident • Trauma• Pancreatitis

• Emotional stress• Insulin pump dysfunction• Pregnancy

Treatment of DKA – IV fluid

Normal saline 1 liter/hr until not orthostatic hypotensive, then NS at 500 ml/hr

Electrolytes every 2 hrs initially, then every 4 hours

Glucose <250 mg/dl, change to Dextrose with 1:4 regular insulin at 250-500 ml/hr

When anion gap normal, bicarbonate >15 mEq/L, taking PO fluid, give meal and SC insulin

Treatment of DKA – Insulin

IV insulin at 5-10 u/hr in adult, 0.1 u/kg/hr in child

Check glucose hourly, if no change in 2 hrs double the insulin infusion

Glucose <250 mg/dl, slow insulin to 2-4 u/hr

Discontinue IV insulin 2-3 hrs after SC insulin dose

Treatment of DKA – Potassium

Potassium repletion if initial K is normal or low at 10-40 mEq/hr

Check potassium every 2- 4 hrs

Replete total body potassium stores over 2- 3 days

Treatment of DKA – Bicarbonate, Phosphorus

Bicarbonate replacement if pH less than 6.90

Check phosphorus 12 hrs into treatment. Replace if < 1 mEq/L