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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)
Glucose uptake Protein degradation amino acids
Blood glucose
Insulin insensitivity in ttype 2 diabetes
1111
Blood glucose
Glucose uptake
Insensitivity to insulin inttype 2 diabetes
Glucose uptake
Glycolysis
Gluconeogenesis (amino acids)
Glucose uptake Protein degradation amino acids
1212
Blood glucoseConverted to triglycerides
Effect of insulin resistance in ttype 2 diabetes
Glucose uptake
Glycolysis
Gluconeogenesis (amino acids)
Glucose uptake Protein degradation amino acids
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
Pathogenesis of type 1 diabetes
• 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
Pathogenesis of type 2 diabetes
• 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
Insulin requirements
Beta-cell loss
Insulin insensitivity
Hyper-insulinaemia
The natural history of type 2 diabetesThe natural history of type 2 diabetes
Insulin requirements with age
2323
Age (years)
Endogenous insulin
Insulin requirements
Secondary failure
The natural history of type 2 diabetesThe natural history of type 2 diabetes
Effect of oral drugs
Insulin requirements with age
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
Health benefits of physical activity /2
• Reduces obesity
• Reduces risk of colon and other cancers
• Improves intermittent claudication
• Improves cardiovascular health
• Reduces coronary artery disease
Health benefits of physical activity /3
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
Breakfast Lunch Supper
Endogenous insulin
Twice a day insulin
Soluble insulin
Intermediate-acting insulinIn
sulin
60
0
20
40Endogenous insulin
Breakfast Lunch Supper
Three times a day insulin
Soluble insulin
Intermediate-acting insulin
Insu
lin
60
0
20
40 Endogenous insulin
Breakfast Lunch Supper
Rapid-acting insulin analogue
Intermediate-acting insulin
Basal-bolus regimenIn
sulin
60
0
20
40 Endogenous insulin
Breakfast Lunch Supper
Long-acting insulin analogue
Long-acting insulin analogues
Rapid-acting insulin analogue
Insu
lin
60
0
20
40 Endogenous insulin
Breakfast Lunch Supper
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
Macrovascular disease
Coronary heart disease
Cerebrovascular disease
Peripheral vascular disease
What is an “event”?
Macrovascular disease
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
Diabetic nephropathy
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
Diabetic nephropathy
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