dm kuliah terbaru 2009 lengkap

11

Diabetes MellitusDiabetes Mellitus

dr. Yunus Tanggo Sp.PD, Ph.D

Bagian Ilmu Penyakit Dalam FK UKI

22

Definition of diabetes

Characterized by hyperglycaemia

• Defects in insulin production

• Autoimmune or other destruction of beta cells

• Insulin insensitivity

• Impaired action of insulin on target tissues

33

Definition of diabetesDefinition of diabetes

Chronic hyperglycaemia Chronic hyperglycaemia associated with long-term associated with long-term damage to:damage to:• EyesEyes• KidneysKidneys• NervesNerves• Heart and blood vesselsHeart and blood vessels

44

The diabetes epidemicThe diabetes epidemic

230 million affected in 2006230 million affected in 2006 350 million within 20 years350 million within 20 years Most rapid in Indian and Asian Most rapid in Indian and Asian

subcontinents subcontinents

55

Classification

1. Type 1 diabetes

–autoimmune

–LADA

–idiopathic

2. Type 2 diabetes

•Insulin resistance

•Deficiency of insulin

66

3. Other specific types3. Other specific types MODYMODY Defects in insulin actionDefects in insulin action Diseases of the pancreasDiseases of the pancreas Endocrine disordersEndocrine disorders Drug- or chemical-inducedDrug- or chemical-induced InfectionsInfections

ClassificationClassification

77

• Uncommon forms of immune-Uncommon forms of immune-mediated diabetesmediated diabetes

• Other genetic syndromesOther genetic syndromes

4. Gestational diabetes4. Gestational diabetes

ClassificationClassification

88

Insulin

GluconeogenesisGlycogenolysisGlycogen synthesis

Glucose uptakeGlycogen synthesis

Blood glucose

Insulin and glucose disposalInsulin and glucose disposal

Free fatty acid release

99

Glucose uptake Glycogenolysis Gluconeogenesis (amino acids) Ketone production (fatty acids)

Glucose uptake Protein degradation amino acids

Blood glucose

Insulin deficiency in type 1 diabetesInsulin deficiency in type 1 diabetes

Triglyceride degradation fatty acids

1010

Glucose uptake

Glycolysis

Gluconeogenesis (amino acids)


Blood glucose

Insulin insensitivity in ttype 2 diabetes

1111

Blood glucose

Glucose uptake

Insensitivity to insulin inttype 2 diabetes

Glucose uptake

Glycolysis



1212

Blood glucoseConverted to triglycerides

Effect of insulin resistance in ttype 2 diabetes

Glucose uptake

Glycolysis



Glucose uptake

1313

Pathogenesis of type 1 diabetes

• Immunological activation

• Progressive beta-cell destruction

• Insufficient beta-cell function

• Dependent on exogenous insulin

• Risk of ketoacidosis

1414


• Genetic susceptibility

• Immune factors– other autoimmune disease– antigen-specific antibodies

• Environmental trigger– viruses– bovine serum albumin– nitrosamines: cured meats– chemicals: vacor (rat poison),

streptozotin

1515

Beta-cell mass

Pathogenesis of type 1 Pathogenesis of type 1 diabetesdiabetes

Time (months - years)

Trigger

Genetic

Pre-diabetes ‘Honeymoon’

Chronic phase

Clinical diabetes

Immunological abnormalities

1616

Idiopathic type 1 diabetesIdiopathic type 1 diabetes

Non-autoimmune type 1 diabetesNon-autoimmune type 1 diabetes

No autoimmune markersNo autoimmune markers

Permanent insulinopeniaPermanent insulinopenia

KetoacidosisKetoacidosis

People of African and Asian originPeople of African and Asian origin

1717

Epidemiology of type 1 diabetes

• Increasing in recent years

• Geographic variation

• Relative affluence

• Lack of treatment

IDF Diabetes Atlas

1818

Age of onset peaksAge of onset peaks• preschoolpreschool• pubertypuberty

Autumn/winter peaksAutumn/winter peaks

Epidemiology of type 1 diabetesEpidemiology of type 1 diabetes

1919

Type 2 diabetes

• 90%-95% of people with diabetes

• Insulin insensitivity and relative insulin deficiency

• Obesity or overweight

• Complications often present at diagnosis

2020


• Multiple genes involved

• Hyperinsulinaemia

• Poor fetal nutrition beta-cell formation

• Low birth weight/weight change

• “Thrifty gene”

• 7% beta-cell loss

2121

Age (years)

Endogenous insulin

Insulin requirements

Beta-cell loss

The natural history of type 2 diabetesThe natural history of type 2 diabetes

Insulin requirements with age

Primary failure

2222

Age (years)

Endogenous insulin


Beta-cell loss

Insulin insensitivity

Hyper-insulinaemia



2323

Age (years)

Endogenous insulin


Secondary failure


Effect of oral drugs


Beta-cell loss

Hyper-insulinaemia

Insulin insensitivity

2424

Epidemiology of type 2 diabetesEpidemiology of type 2 diabetes

• Dramatic increase

• Aging population

• Disturbing trends parallel obesity epidemic

• Especially in adolescents and minority groups

• Increasing in young people

2525

Risk factors for type 2 diabetes

• Age > 40 years

• First-degree relative with diabetes

• Member of high risk population

• History of impaired glucose tolerance, impaired fasting glucose

• Vascular disease

• History of gestational diabetes

• History of delivery of macrosomic baby

CDA 2003

2626

HypertensionHypertension DyslipidaemiaDyslipidaemia Abdominal obesityAbdominal obesity OverweightOverweight Polycystic ovary diseasePolycystic ovary disease Acanthosis nigricansAcanthosis nigricans SchizophreniaSchizophrenia

Risk factors for type 2 diabetesRisk factors for type 2 diabetes

2727

• Polydipsia Polydipsia • PolyuriaPolyuria• NocturiaNocturia• Visual disturbanceVisual disturbance• FatigueFatigue• Weight lossWeight loss• InfectionsInfections

Signs and symptoms

2828

Diagnosing diabetesDiagnosing diabetes

NormalNormal Impaired fasting glucose*Impaired fasting glucose*

Impaired glucose Impaired glucose tolerance**tolerance**

DiabetesDiabetes

FPG <6.1mmol/LFPG <6.1mmol/L

<110mg/dL<110mg/dL6.1 to 6.9mmol/L*6.1 to 6.9mmol/L*

110 to 126mg/dL110 to 126mg/dL≥≥7.0mmol/L7.0mmol/L

≥≥126mg/dL126mg/dL

2hr PG <7.8mmol/L2hr PG <7.8mmol/L

<126mg/dL<126mg/dL7.8 to 11mmol/L**7.8 to 11mmol/L**

126 to 200mg/dL126 to 200mg/dL≥≥11.1mmol/L11.1mmol/L

≥≥200mg/dL200mg/dL

CDA 2003, ADA 2004, WHO 2002

2929

Impaired glucose toleranceImpaired glucose toleranceImpaired fasting glucoseImpaired fasting glucose

Intermediate statesIntermediate states Increased risk of developing Increased risk of developing

diabetes diabetes Prevention strategies to prevent Prevention strategies to prevent

or delay progressionor delay progression Increased risk of cardiovascular Increased risk of cardiovascular

diseasedisease

3030

Uncertain diagnosis:Uncertain diagnosis:Oral glucose tolerance testOral glucose tolerance test

75 g glucose load after 8 hours 75 g glucose load after 8 hours

fastingfasting Readings taken in fasting state and at Readings taken in fasting state and at

1 and 2 hours1 and 2 hours Possible problemsPossible problems

3131

Urinary ketonesUrinary ketones

AntibodiesAntibodies

C-peptideC-peptide

Tests for differential diagnosisTests for differential diagnosis

3232

SummarySummary

Type 1 diabetes Type 1 diabetes Results from progressive Results from progressive

beta-beta-cell destructioncell destruction People with type 1 People with type 1

diabetes need insulin diabetes need insulin therapy to live therapy to live

3333

Type 2 diabetes Type 2 diabetes Often characterized by insulin Often characterized by insulin

insensitivity and insensitivity and relative rather relative rather than absolute insulin deficiencythan absolute insulin deficiency

A progressive conditionA progressive condition Most people with type 2 diabetes Most people with type 2 diabetes

will need insulin within 5 to 10 will need insulin within 5 to 10 years of diagnosisyears of diagnosis

SummarySummary

Nutrition - Aims and principles

Composition of food and drinks

Macro-nutrients

• protein

• carbohydrates

• fats Micro-nutrients

• vitamins

• minerals

Nutrition recommendations for people with diabetes - a historical perspective

Distribution of calories (%)

Year Carbohydrate Protein Fat

Before 1921

Starvation diets

1921 20 10 70

1950 40 20 40

1971 45 20 35

1986 <60 12-20 <30

2004 45-65* 10-20 20-35†

* Based on individual assessment and treatment goals † <10% saturated fat

American Diabetes Association

Dietary recommendations for adults with diabetes

Carbohydrates: 45-65% (mostly starch) Dietary fibre: minimum 20g/1000 kcal Fats: 20-35% Protein: 10-20% (0.8 g/kg/day) Sodium: <3000 mg/day Vitamins and minerals: supplements not

necessary with balanced diet

Fluids

Essential for all body functions

40-60% of body weight is water

Important to drink adequate

amounts of fluid

Energy

Produced by utilizing food in the body Measurements of energy:

- usually measured in kilojoules (kJ)- calories or kilocalories (kcal)- 1 kcal = 4.2 kJ

Energy recommendations

Appropriate intake for acceptable body weight

Lower-calorie diets recommended for overweight people with diabetes

Increased-energy diets recommended - during pregnancy and lactation - during recovery from severe and prolonged illness

Proteins

Provide amino acids Help to build muscle mass Animal sources Plant sources

1 g of protein gives 4 kcal energy

Protein recommendations

0.8 g protein per kg bodyweight per day 10-20% of total energy per day Higher amounts not encouraged for

people with diabetes Animal protein often high in fat,

especially saturated Vegetable protein sources should be

encouraged – lower in fat

Carbohydrates

Should provide main source of energy for the body (>50%)

Nutrient that most influences blood glucose levels

Source of simple sugars – glucose, fructose

1 g of carbohydrate provides 4 kcal

Carbohydrates and meal planning

• Amount and source of carbohydrates should be considered when planning meals

• Carbohydrates should mainly come from

- whole grains: wheat, rice, pasta, etc- potatoes- legumes, beans, pulses - fruit and vegetables- milk

Carbohydrate recommendations

Sucrose – white sugar• Permissible source for up to 10% of

total daily energy needs• Does not increase glycaemia more than

starch• Part of a balanced meal• High sucrose contributes to obesity and

dental caries

American Diabetes Association; Canadian Diabetes Association

Carbohydrate content of common foods

Food Amount (g)

Serving Carbohydrate (g)

Bread 25 1 slice 12.4

Rice (cooked) 52 0.3 cup 14.7

Pasta 43 0.3 cup 12.6

Chappati 35 1 small 17.0

Corn meal 26 3 tablespoons 20.2

Potato 85 1 small 17.0

Couscous 52 0.3 cup 12.1

Lentils 99 0.5 cup 19.9

Banana 72 1 small 16.9

Benefits of fibre

High-fibre diet is healthy Mixture of soluble and insoluble fibre

- slows absorption of glucose- reduces absorption of dietary fats- retains water to soften stool- may reduce the risk of colon cancer- may reduce the risk of heart disease

Fats

• The most concentrated source of energy

• Foods may contain fat naturally or have it added during cooking1 g fat provides 9 kcal

Fat recommendations

• High in monounsaturated fats (>10%)

• Low in saturated fats (<10%)

• Low in polyunsaturated fats (up to 10%)

• Low in hydrogenated fat

Fats

Common sources of different fats• Saturated – red meats, butter, cheese,

margarine, ghee (clarified butter), whole milk, cream, lard

• Polyunsaturated – safflower oil, sunflower oil, corn oil

• Monounsaturated – olive oil, canola oil, rape seed oil, groundnut oil, mustard oil, sesame oil

• Trans fats – baked products, biscuits, cakes

Trans fats

Formed when liquid fats, such as oils, are chemically hydrogenated

Raise LDL cholesterol and lower HDL cholesterol

Fats and oilsFat distribution in commonly used oils

Fatty acid (grams/100grams)Saturated fatty acids

MUFA PUFA (ω-6) PUFA (ω-3)

Olive oil 13 76 10 1

Peanut oil 18 48 34 <0.5

Canola oil 6 58 26 10

Rapeseed oil 8 70 12 10

Sesame oil 15 42 42 1

Corn oil 12 32 55 1

Cottonseed oil 22 25 52 1

Soya bean oil 15 27 53 5

Sunflower oil 13 27 60 <0.5

Safflower oil 13 17 70 <0.5

Coconut 90 7 2 <0.5

Hydrogenated oil 24 19 3 <0.5

Ghee/butter oil 65 32 2 <1.0

Ghafoorrunissa et al, NIN 1994

Fish oils Balance of omega-3 and omega-6 fatty

acids part of a healthy diet Fish oils good source of omega-3 fatty acids Two or three portions of fish are

recommended per week Fish-oil supplements not recommended

Foods rich in omega-3/alpha linolenic acid

Food group Food source

Cereals and millets Wheat, bajra

Pulses and legumes

Blackgram, cowpea, rajmah, soya

Vegetables Green leafy

Spices Fenugreek, mustard

Nuts and seeds Walnut, flaxseed

Oils Mustard, soya bean oil, canola oil

a Long chain n3 PUFA (omega-3) – biologically active product of alpha linolenic acid

Ghafoorrunissa et al, NIN 1994

Cholesterol

Intake of cholesterol should be restricted

People with diabetes should consume less than 300 mg of cholesterol a day

Minimizing consumption of saturated fat will help decrease cholesterol

Vitamins Organic substances present in

very small amounts in food Essential to good health A balanced meal

automatically provides all necessary vitamins

Either fat-soluble or water-soluble

Antioxidants and flavonoids

Antioxidants help protect against heart disease and other health complications

Good sources of antioxidants – including fruit and vegetables – should be eaten daily

Recommended daily intake five portions

A properly balanced diet will supply all the vitamins and antioxidants necessary; supplements are not necessaryMultivitamin supplements are needed for people in certain circumstances

Vitamins and antioxidants -recommendations

Minerals and trace elements

A balanced diet supplies minerals and trace elements

Inorganic - regulate vital body processes In blood, enzymes, hormones, bones,

skeleton, teeth and tissue fluids Supplements not required for most; calcium

and vitamin supplementation may be desirable for elderly people

Minerals Minerals present in bones, teeth, soft tissue,

muscle, blood and nerve cells Help maintain physiological processes,

strengthen skeletal structures, preserve heart and brain function and muscle and nerve systems

Act as a catalyst to essential enzymatic reactions

Low levels of minerals puts stress on essential life functions

Sodium recommendations

Most people consume too much salt Daily intake should not exceed 6000 mg Daily sodium intake should not exceed

2400 mg Salt intake should be restricted in

hypertension, heart disease, kidney failure Diet should be based on fresh foods

Summary of dietary recommendations

Carbohydrates: 45-65% (mostly starch) Dietary fibre: min 20 g/1000 kcal Fats: 20-35%

-saturated <10%-polyunsaturated <10%-monounsaturated >10%-cholesterol <300 mg/day

Protein: 10-20% (0.8 g/kg/day) Sodium: <2400 mg/day Vitamins and minerals: with a balanced

diet, supplements not needed

Physical activity

Health benefits of physical activity /1

• Reduces total cholesterol levels

• Increases HDL levels

• Reduces blood pressure levels

• Reduces joint pain and stiffness in osteoarthritis

• Reduces the risk of coagulation abnormalities


• Reduces obesity

• Reduces risk of colon and other cancers

• Improves intermittent claudication

• Improves cardiovascular health

• Reduces coronary artery disease


Improves work, recreational and sports performance

Decreases number of ‘sick’ days

Decreases fatigue in daily activities, improves mood and self-esteem

Improves quality of sleep

Decreases stress

Encourages social interaction

Enhances quality of life

Health benefits of physical activity in type 2 diabetes

• Improved insulin sensitivity and therefore better blood glucose control

• Increased glucose utilization

• Decreased glucose production from the liver

• Decrease in circulating insulin levels during exercise

Physical activity in the prevention of type 2 diabetes

Study Characteristics & duration

Intervention

Results

Da Qing Study(China) 1997

577 persons >25 yearsRandom selection from clinics6 years follow-up

DietExerciseDiet + exercise

68% cumulative incidence 44% (reduction of 31%)41% (reduction of 46%)46% (reduction of 42%)

Finnish Diabetes Prevention Study (Finland)2001

522 persons, 40-64 yearsBMI >25 Random selection by persons3.2 years follow-up

Diet + exercise

58% decreased incidence in the ‘diet + exercise’ group

Physical activity and food

Exercise combined with caloric restriction

Modifies visceral fat and distribution of body fat

Increases muscle mass

Apple shape Pear shape

Types of exercise

Aerobic exercise uses large muscle groups and requires oxygen for sustained periods

Anaerobic (resistance) exercise uses large muscles which do not require oxygen for short periods of exercise

Recommendations

People with type 2 diabetes should accumulate 150 minutes of moderate-intense aerobic exercise each week, spread over 3 non-consecutive days

People with diabetes should be encouraged to perform resistance exercise 3 times a week

CDA 2003

Recommendations

The American College of Sports Medicine recommends 20 to 60 minutes of exercise most days a week

Aerobic exercise, such as walking, jogging, swimming, skipping, bike riding, should be sufficient to raise the pulse or increase respiration

In resistance training, it is better to use repetitive light weights than heavy weights

Tips to help start physical activity

Identify an activity that will be enjoyed Start slowly, perhaps 5-10 minutes at a time Increase duration and intensity slowly Consider doing exercise in a group or with a

partner Prevent boredom by varying the activities Set realistic goals Encourage people to reward themselves

when goals are met

Summary

Physical activity should be encouraged in all people with diabetes

People need to be educated about prevention and treatment of hypoglycaemia

People should be taught to plan for periods of physical activity

Pharmacological management

Blood glucose-lowering medicines

Aims of treatment Reduce the symptoms of hyperglycaemia

Limit adverse effects of treatment

Maintain quality of life and psychological well-being

Prevent or delay vascular complications of diabetes

Natural history of type 2 diabetes

Normal Impaired glucosetolerance

Type 2 diabetes

Time

Insulin resistance

Insulinproduction

Glucoselevel

Beta-celldysfunction

Henry 1998

Mechanisms of action

Insulin secretagogues: sulphonylureas and meglitinides increase insulin production

Biguanides and thiazolidinedionesreduce glucose production

Thiazolidinediones and biguanides reduce insulin resistance

Alpha-glucosidase inhibitors slow absorption of sucrose and starch

GLP-1 (incretins) improve response to glucose level

The principles of combination therapy

Two (or more) oral blood glucose-lowering medicines that have different mechanisms of action

Two medications rather than increase in initial medicine to maximum dosage

Fewer side effects than mono-therapy at higher doses

Expected effect of blood glucose-lowering medicines

Class of medicine Expected decrease in HbA1C in mono-therapy

Alpha-glucosidase inhibitor

0.5-0.8%

Biguanide

Insulin sensitisers

Most insulin secretagogues

Nateglinide

1.0-1.5%

1.0-1.5%

1.0-1.5%0.5%

Canadian Diabetes Association 2003

HbA1C Pre-meal 2 hours post-meal

Target for people who can achieve it (without too much hypoglycemia)1

< 6% 4-6 mmol/L 5-8 mmol/L

Target for most people with diabetes

<7% 4-7mmol/L1

90-130mg/dl*2

5-10mmol/L1

<180mg/dl2

IDF Global guideline for Type 2 diabetes3

<6.5% <6.0mmol/L<110mg/dl

<8.0mmol/L<145mg/dl

Targets for blood glucose

1CDA 2003, 2ADA 2004, 3 IDF 2005

Suggested starting medicine

HbA1c BMI Suggested medicine

<9%>25 Biguanide – alone or in

combination

<25 1 or 2 agents from different classes

>9% 2 medicines from different classes or insulin

CDA 2003

Increasing or adding

If goals have not been reached within 2-3 months, medication should be increased or medication from a different class added

Target levels should be reached within 6 months

Insulin should be added if necessary to reach target levels

Biguanides Action not fully understood Decreases glucose production in liver Mild and variable effect on muscle sensitivity

to insulin

Side effects Gastrointestinal (nausea, abdominal

discomfort or diarrhea and occasional constipation)

Lactic acidosis

BiguanidesContraindications• Renal insufficiency• Liver failure• Heart failure • Severe gastrointestinal disease

Advantages• Do not cause hypoglycaemia when used as mono-

therapy• Do not cause weight gain; may contribute to weight

loss

Biguanides

First-line treatment in overweight or obese people• Do not cause weight gain

• Have some effect on resistance at the periphery

Biguanides

Caution

• Should be discontinued 24 hours before procedures requiring intravenous contrast dye

• Can be restarted 48 hours after the procedure if renal function is not compromised

Sulphonylureas

• Increase insulin secretion regardless of blood glucose levels

• Many different medicines in this class

Side effects• Hypoglycaemia• Stimulate appetite and provoke weight gain• Nausea, fullness, heartburn• Occasional rash• Swelling

Sulphonylureas

Short-acting secretagoguesMeglitinides – increase insulin secretion in response to increasing blood glucose levels (i.e. after eating)

Side effects Hypoglycaemia (probably less than sulphonylureas) Weight gain

Sulphonylureas

Contraindications• Type 1 diabetes• Pregnancy• Breastfeeding

Sulphonylureas - Use cautiously with liver or kidney diseaseMeglitinides - Severe impairment of liver function

Thiazolidinediones

Improve sensitivity to insulin in muscle, adipose tissue and liver

Reduce glucose output from liver Changes fat distribution by decreasing

visceral fat and increasing peripheral fat

Side effects Weight gain, fluid retention Upper respiratory infection and headache Decrease in haemoglobin

Alpha glucosidase inhibitors

Slow digestion of sucrose and starch and therefore delay absorption

Slow post-meal rise in blood glucose

Side effects Flatulence, abdominal discomfort , diarrhoea As mono-therapy will not cause

hypoglycaemia Hypoglycaemia when used with other

medicine (e.g. a sulphonylurea)

Alpha glucosidase inhibitors

Contraindications• Intestinal diseases, such as Crohn’s• Autonomic neuropathy affecting the

gastro-intestinal tractMust be taken just before a meal

GLP-1 (incretin mimetic agent)

Improves beta-cell responsiveness to increasing glucose levels

Decreases glucagon secretion Slows gastric emptying Results in a feeling of fullness Must be injected subcutaneously twice a day, within 30-

60 minutes before a meal Reduces HbA1c by ~1%

Side effects Nausea Weight loss Diarrhoea Risk of hypoglycaemia when used with a sulphonylurea

GLP-1 (incretin mimetic agent)

Contraindications• End-stage kidney disease or renal

impairment• Pregnancy• Severe gastrointestinal disease

Summary

Lifestyle changes first Start medicine as soon as

needed Add a different kind No delay starting insulin

Pharmacological management

Insulin

Insulin A hormone secreted by the beta cells

Secreted in response to glucose or other stimuli, such as amino acids

Normal response characterized by low basal levels of insulin, with surges of insulin triggered by a rise in blood glucose

Insu

lin

60

0

20

40

Breakfast Lunch Supper

Insulin action1. Increases glucose uptake, particularly in

muscle, liver and adipose tissue

2. Suppresses glucose output from the liver

3. Increases formation of fat

4. Inhibits breakdown of fats

5. Promotes amino-acid uptake and prevents protein breakdown

Indications for insulin therapy

Type 1 diabetes Women with diabetes who become pregnant or

are breastfeeding Transiently in type 2 diabetes in special situations In type 2 diabetes, inadequately controlled on

glucose-lowering medicines (secondary failure)

Insulin therapy Insulin therapy aims to replicate the normal physiological insulin response Insulin regimens should be individualized

– type of diabetes

– willingness to inject

– lifestyle

– blood glucose monitoring

– age

– dexterity

– glycaemic targets

Insulin types and action

Onset (hrs) Peak (hrs) Duration (hrs)

Rapid

lispro aspart

<¼ ¾-2½ 3½-4½

Short

solubleregular

½-1 2-4 6-8

Intermediate

NPHlente

1-21-3

6-12 6-12

18-24 18-24

Long acting

ultralente glarginedetemir

4-63-41-2

8-20 3-243-8

24 or more≥24 or more 12-24 (dose-dependent)

Factors affecting absorption

Lipohypertrophy Dose of injection Site and depth of injection Exercise Ambient and body temperature Insulin type Incomplete re-suspension

Insulin regimens: once a day insulin

Soluble insulin

Intermediate-acting insulin

Insu

lin

60

0

20

40


Endogenous insulin

Twice a day insulin

Soluble insulin

Intermediate-acting insulinIn

sulin

60

0

20

40Endogenous insulin


Three times a day insulin

Soluble insulin


Insu

lin

60

0

20

40 Endogenous insulin


Rapid-acting insulin analogue


Basal-bolus regimenIn

sulin

60

0

20



Long-acting insulin analogue

Long-acting insulin analogues

Rapid-acting insulin analogue

Insu

lin

60

0

20



HbA1C Pre-meal 2 hours post-meal

Target for most people with diabetes

<7% 4-7mmol/L*

90-130mg/dl*1

5-10mmol/L*

<180mg/dl *1

IDF Global guideline for Type 2 diabetes*2

<6.5% <6.0mmol/L<110mg/dl

<8.0mmol/L<145mg/dl

Adjusting insulin – what are the targets?

*CDA 2003, *1ADA 2004, *2 IDF 2005

• Treatment targets should be individualized, especially for very young and very old

• Absence of hypoglycaemia

Starting insulin in type 2 diabetes

FINFAT: start small dose intermediate- acting insulin at night

• Aim for target fasting levels first

• Adjust by 2-4 units or 10%

• Second injection only added once fasting targets reached

Adjusting insulin

Pattern management

• Watch levels for 2-3 days

• Address hypoglycaemia first

• Aim for target fasting levels next

• Adjust by 2-4 units or 10%

• Wait 2-3 days

Adjusting insulin

• Flexible dose guideline

• Eating more

• Exercising more

• Insulin to carbohydrate ratio

• Evaluate with next blood glucose

• Tailored to individual needs

Side effects

Hypoglycaemia

Weight gain

Lipohypertrophy

Lipoatrophy

Insulin oedema

Allergic reaction

Summary All people with type 1 diabetes must be

treated with insulin The majority of people with type 2 diabetes

will need insulin within 5 to 10 years of diagnosis

Insulin therapy should not be used as a threat

Insulin regimens should be individualized Insulin should be adjusted to achieve blood

glucose as close to target range as possible

Macrovascular disease


Coronary heart disease

Cerebrovascular disease

Peripheral vascular disease

What is an “event”?


Major cause of increased morbidity and mortality in diabetes

Underlying abnormality: atherosclerosis

Williams 1999

What is atherosclerosis? Process in which deposits of fatty substances,

cholesterol, cellular waste products and calcium build up in the wall of an artery. This build up is called plaque

Plaques can grow large enough to significantly reduce the blood flow through an artery. An acute event occurs when they become fragile and rupture

Plaques that rupture cause blood clots that can block blood flow or break off and travel to another part of the body causing a heart attack and stroke

Diabetic neuropathy

Autonomic neuropathy

Postural hypotension

Arrhythmia

Silent ischaemia

Gastroparesis

Constipation

Diarrhea

Urine retention

Erectile dysfunction

Autonomic Neuropathy

Cranial nerves

Seventh nerve - Bell’s palsy: risk of corneal ulcer

Third nerve – closed eye

Sixth nerve – pupil directed nasally

Carpal tunnel

Nerve Entrapment

Mononeuropathy

Amyotrophy Radiculopathy

Peripheral Neuropathy – Sensory Motor

Most common form of neuropathy Affects approximately 50% after

15 years Affects long nerves (feet and legs)

first

• glove and stocking distribution Bilateral Equal symptoms

Diabetic foot disease –the high-risk foot

Peripheral vasculardisease

Peripheral neuropathy

Peripheral neuropathy andperipheral vascular disease

Diabetic peripheral neuropathy – risk factors

Poor glycaemic control

Long duration

Age

Height

Excessive alcohol

Nerve damage – neuropathy

Symptoms:•burning•pins and needles•pain

No symptoms

Painless nature of diabetic foot disease

Sensory nerve damage

Diabetic nephropathy

Risk factors

Poor glycaemic control Hyperlipidaemia Hypertension Genetic predisposition Glomerular hyper-filtration during early

period Ethnicity Long disease duration Smoking


About 20% to 30% of people with diabetes

In type 2 diabetes, a smaller fraction of these progress to CKD

People with type 2 diabetes – over half of those with diabetes starting on dialysis

Type 1 diabetes Decreasing incidence over past 35

years

Overall incidence

• 2.2% at 20 years duration

• 7.8% at 30 years duration

Finne 2005

Microalbuminuria(incipient diabetic nephropathy)

Acute renal hypertrophy-hyperfunction

Normoalbuminuria

Proteinuria(clinical overt diabetic nephropathy)

Chronic renal failure

10 to 15 years

Natural history of diabetic nephropathy

Protein

Albumin Albumin Excretion Rate

Microalbuminuria:

30-300 mg/24 hr 20-200 µg/min 2.5-25mg/mmol (men)3.5-35mg/mmol (women)

Macroalbuminuria:>300 mg/24 hr or>200 µg/min >25 mg/mmol (men)>35 mg/mmol (women)

Protein, microalbuminuria and Macroalbuminuria

Transient increases in albumin excretion

• Exercise• Menstruation• Pregnancy• Poor glycaemic control• Urinary tract infection• Hypertension• Cardiac failure

Factors affecting albumin excretion

Transient microalbuminuria

2/8

7

4/8

7

9/8

71

/88

2/8

8

4/8

85

/88

8/8

8

2/8

97

/89

10

/89

1/9

05

/90

7/9

01

0/9

02

/92

6/9

11

0/9

14

/921

2

5

10

50

100

200

1

2

5

10

20

50

100

200

20 µg/min

15 µg/min

AER (µg/min x 1,73m²)

Age: 15 yearsdiabetes duration: 5 years

Girl

>2 consecutive measurements >20 µg/min therafter 3 measurements normal

Example:

Permanent microalbuminuria

8/8

71

0/8

81

1/8

81

2/8

84

/89

1/9

07

/90

9/9

01

0/9

01

2/9

0

9/9

1

11

/92

12

/93

6/9

4

7/9

5

1

2

5

10

50

100

200

1

2

5

10

20

50

100

200

20 µg/min

15 µg/min

Age: 21 yearsdiabetes duration:10 years

Girl

AER (µg/min x 1,73m²) 278253

3 consecutive measurements >20 µg/min

Example:

Diabetic renal assessment Urinalysis for proteinuria Spot urine for microalbuminuria

• morning and resting or• preferably with albumin/creatinine ratio

(normal <2.5mg/mmol in men and <3.5mg/mmol in women)

Serum creatinine; preferably with adjustment of body size

Calculated glomerular filtration rate Repeat the tests at about yearly intervals if

normal If GFR <60ml/min test 3-6 monthly

Microalbuminuria

Type 1 diabetes• indicates incipient nephropathy

Type 2 diabetes• marker of increased cardiovascular

morbidity and mortality

Presence of microalbuminuria is an indication for screening of vascular disease and intensive intervention

Interventions: glycaemic control Diabetes Control and Complications Trial

(DCCT) occurrence of microalbuminuria by 40% occurrence of macroalbuminuria by

50%

United Kingdom Prospective Diabetes Study (UKPDS) overall microvascular complication rate

by 25%

Institution of tight metabolic control after onset of overt

proteinuria or renal insufficiency is important for

general health but not all that helpful in preventing chronic kidney disease


Treatment

•intensive treatment of blood pressure

target <130/80mmHg

•reduce salt in diet

•reduce alcohol

Sacks, 2001

Hypoglycaemia

Definition of hypoglycaemia

When the level of glucose falls in the

blood so that the cells in the periphery,

and eventually the brain cells, do not get

adequate glucose to function

The body’s response

● Endogenous insulin secretion suppressed

Release of glucagon, epinephrine, cortisol, growth hormone

Autonomic response

The body’s response

• Brain lacks glucose

• Temporary cognitive impairment

• Wide variation in symptoms

GlucagonHypoglycaemia stimulates release

It acts in the liver to increase glucose production

– releasing stored glycogen

– activating production of new glucose

– stimulating production of ketones

Epinephrine

Releases stored glycogen

Activates production of glucose from protein

Reduces uptake of glucose

Reduces production of insulin

Cortisol and growth hormone

• Reduce cellular uptake of glucose

• Stimulate breakdown of proteins to make glucose

• Stimulate breakdown of body fats

Hypoglycaemia

Symptoms Low blood glucose Relief of symptoms when

blood glucose raised

Symptoms of hypoglycaemia

Mild Moderate Severe

Capable of self-treating

May require prompting

Not capable of self-treatment

Tremors, palpitation, sweating,

hunger, fatigue

Headache, mood changes, low attentiveness

Conscious or unconscious

Adrenergic Neuroglycopenic Neuroglycopenic

Consequences of hypoglycaemia

Mild-moderate• fear• anxiety• affects self-

care• social stigma• prejudice

Severe• injury• seizures• transient

paralysis• cognitive

impairment• death

People at risk of hypoglycaemiaOnly those taking glucose-lowering medicines or insulin

Increased risk:• too little or wrong type of

carbohydrate• late or missed meal • fasting or malnourishment• too much insulin or insulin

secretagogues• prolonged or unplanned activity

People at risk of hypoglycaemia

Increased risk:• Recent severe hypoglycaemia

• Gastroparesis

• Liver disease or kidney failure

• Pregnancy

• Injection-related

• Over-correction of high BGL

How would you advise people to treat the following?

• Mild hypoglycaemia• Moderate hypoglycaemia• Severe hypoglycaemia

Management

Mild or moderate•Test if possible•15 g glucose; re-test•Glucose tablets•Fruit juice •Soft drink•Sugar•Re-treat if level remains low

CDA 2003

Management

Severe•20 g glucose•glucagon •intravenous dextrose•Manage seizure – place person on their side if not too agitated

Diabetic retinopathy

Diabetic eye disease

Diabetic retinopathy Diabetic cataract:

•early senile•true diabetic

(Snowflake) Recurrent iritis

Diabetic retinopathy

A silent complication with no initial symptoms

When symptoms occur, treatment is more complicated and often impossible

Screening for retinopathy is of the utmost importance

When to screen for retinopathy

Type 1 diabetes: within 5 years of diagnosis

Type 2 diabetes: at time of diagnosisThereafter, every 1 to 2 years, depending on the status of the retina

Diabetic eye disease

Blurred vision: common symptom of hyperglycaemia

Epidemiology:• any retinopathy: 21-36%• vision-threatening

retinopathy: 6-13%

Normal retina

Macula

Optic disc

Non-proliferative diabetic retinopathy

Hard exudates

Severe non-proliferative retinopathy

Haemorrhage

Cotton wool spot

Proliferative retinopathy

New vessels

Pre-retinal haemorrhage

Advanced proliferative retinopathy

Scar tissue

Early macular oedema

Fluorescein leakage

Dot haemorrhage

Blot haemorrhage

Fluorescein leakage

Pan-retinal laser bombing

Diabetic ketoacidosis andhyperosmolar hyperglycaemic

state

What is DKA?

Absolute or relative insulin deficiency Increase in counter-regulatory

hormones Breakdown of fat and muscle Biochemical triad

• hyperglycaemia• ketoacids• metabolic acidosis

High blood glucose, ketones, acidosis and dehydration

Incidence of DKA

Varies

Death mainly from cerebral oedema

Most common at onset in type 1 diabetes

Recurrent episodes

Can occur in type 2 diabetes

Kitabchi et al 2001, Joslin 2005

DKA – cause or trigger

Incidence

New-onset diabetes 5-40%

Acute illness 10-20%

Insulin omission/non-adherence

33%

Infection 20-38%

Heart attack, stroke, pancreatitis

<10%

Booth 2001, Joslin 2005

Insulin deficiency

Glucose uptake Lipolysis

Hyperglycaemia Gluconeogenesis

Glycerol Free fatty acids

Ketogenesis

Ketonemia

KetonuriaOsmotic diuresis

Urinary water losses

Electrolyte depletion

Dehydration

Acidosis

Diabetic ketoacidosis

Adapted from Davidson 2001

Glucosuria

DKA – investigations

Immediate for diagnosis Capillary blood glucose, urinary

glucose and ketones

Urgent for assessment and treatment Blood glucose Blood gases Electrolytes, urea, creatinine WBC

Consider Cardiac monitor Blood culture, urine culture Chest X-ray

DKA – laboratory findingsBlood glucose >14mmol/L (252mg/dL)

Ketones Urine: moderate to large

Blood: >3mmol/L

Osmolality Increased – high blood glucose and urea/creatinine, dehydration

Electrolytes Low/normal Na+ and Cl-

Low/normal/high K+ (often misleading)

Low HCO3 (normal 23-31)

Anion gap >10 mild

>12 moderate to severe

Blood gases pH <7.30, HCO3 <15 (mild)pH <7.00, HCO3 <10 (severe)

DKA – treatmentRehydration 1. Correct shock with bolus saline

2. Rehydration rate depends on clinical status, age and kidney function

Normal saline (0.9%) for resuscitation and rehydration initially

Glucose/saline solution when glucose around 14 mmol/L (252mg/dL)

Rehydrate steadily over 48 hours

3. Consider NG tube

Potassium Essential after resuscitation and when urine output confirmed

Kitabchi et al 1976

DKA – treatment

Insulin Infusion: 0.1 units/kg/hour after resuscitation, saline established and BG falling

Rate should be increased by 10-20% if glucose not fallen by 2-3 mmol/L (45-54mg/dL) over first hour

Monitoring BG, BP, urine output and hourly neurological status

Blood gases and electrolytes 2-hourly initially

What is HHS?

Ketosis may be present

• Coma not always present

Primarily in older people with/without history of type 2 diabetes

Always associated with severe dehydration and hyperosmolar state

Develops over weeks Kitabchi et al 2001

HHS – incidence and features

0.5% of primary diabetes hospital admissions

~15% mortality rate Can occur in type 1 diabetes

and younger people

Kitabchi et al 2001

HHS – key features

Marked hyperglycaemia Hyperosmolarity Absence of severe ketosis Altered mental awareness

Joslin 2005

HHS – causes or triggers

Booth 2001

Incidence

Infection 40-60%

New-onset diabetes 33%

Acute illness 10-15%

Medicines, steroids <10%

Insulin omission 5-15%

Signs and symptoms of HHS

Initially polyuria and polydipsia

Altered mental status

Profound dehydration

Precipitating factors

HHS – biochemical findings

Jones 2001

Blood glucose >33mmol/L (600mg/dl)

Ketones Urine: negative – small

Blood: <0.6 mmol/L

Osmolality >320mOsm/kg - (raised Na, BG, urea)

Electrolytes Raised Na, BG, urea creatinine

Anion gap <12

Blood gases pH >7.30

normal or raised HCO3

Treatment

Rehydration Caution!

Normal saline 1 l per hour initially

Consider ½ strength normal saline

Potassium Only if hypokalaemic and renal function adequate – give before insulin

Insulin May be needed as slow infusion0.1 unit/kg/hour to be increased with care if BG is slow to fall

Monitoring BG, BP, neurological function hourly until stableElectrolytes 2-hourlyCardiac or CVP monitoring

HHS – complications Complication Prevention

Hypoglycaemia Prevent by adding glucose infusion when glucose <14mmol/L (250 mg/dL)

Hypokalaemia Early potassium replacement and monitoring

Fluid overload Careful clinical monitoring and central line as needed

Vomiting/aspiration NG tube and may be nursed on side

Cerebral oedema Avoid fast blood glucose falls (should be <4mmol/L (72mg/dL) per hour; aggressive Mannitol treatment if any early signs of cerebral oedema

Meltzer 2004

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Documents

age endogenous

risk factors

natural history

insulin insensitivity

insulin requirements

blood glucose

type 2 diabetes

type 1 diabetes