Diabetes Mellitus

dr. Yunus Tanggo Sp.PD, Ph.D

Bagian Ilmu Penyakit Dalam FK UKI

1

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

2

Definition of diabetes
Chronic hyperglycaemia associated with long-term damage to:
Eyes Kidneys Nerves Heart and blood vessels
3

The diabetes epidemic

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

Classification
1. Type 1 diabetes

autoimmune
LADA idiopathic 2. Type 2 diabetes Insulin resistance Deficiency of insulin
5

Classification
3. Other specific types MODY Defects in insulin action Diseases of the pancreas Endocrine disorders Drug- or chemical-induced Infections

Classification
Uncommon forms of immunemediated diabetes Other genetic syndromes 4. Gestational diabetes

Insulin and glucose disposal

Gluconeogenesis Glycogenolysis Glycogen synthesis Insulin

Blood glucose

Glycogen synthesis

Glucose uptake Free fatty acid release

8

Insulin deficiency in type 1 diabetes

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

Glucose uptake Protein degradation amino acids

Triglyceride degradation fatty acids
9

Insulin insensitivity in type 2 diabetes

Glucose uptake

Glycolysis
Gluconeogenesis (amino acids)

Blood glucose

Glucose uptake Protein degradation amino acids

10

Insensitivity to insulin in type 2 diabetes

Glucose uptake Glycolysis Gluconeogenesis (amino acids)

Blood glucose

Glucose uptake Protein degradation amino acids Glucose uptake

11

Effect of insulin resistance in type 2 diabetes

Glucose uptake Glycolysis Gluconeogenesis (amino acids)

Blood glucose

Converted to triglycerides

Glucose uptake Protein degradation amino acids Glucose uptake

12

Pathogenesis of type 1 diabetes Immunological activation

Progressive beta-cell destruction Insufficient beta-cell function Dependent on exogenous insulin Risk of ketoacidosis
13

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
14

Pathogenesis of type 1 diabetes

Trigger Immunological abnormalities

Genetic Beta-cell mass

Clinical diabetes
Pre-diabetes Honeymoon Chronic phase Time (months - years)
15

Idiopathic type 1 diabetes

Non-autoimmune type 1 diabetes

No autoimmune markers

Permanent insulinopenia
Ketoacidosis People of African and Asian origin
16

Epidemiology of type 1 diabetes

Increasing in recent years Geographic variation Relative affluence

Lack of treatment

17 IDF Diabetes Atlas

Epidemiology of type 1 diabetes

Age of onset peaks
preschool puberty

Autumn/winter peaks

18

Type 2 diabetes
90%-95% of people with diabetes Insulin insensitivity and relative insulin deficiency Obesity or overweight Complications often present at diagnosis
19

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
20

The natural history of type 2 diabetes

Beta-cell loss Insulin requirements Primary failure

Insulin requirements with age Endogenous insulin

Age (years)
21

The natural history of type 2 diabetes

Beta-cell loss
Hyperinsulinaemia Insulin requirements with age Endogenous insulin

Insulin requirements

Insulin insensitivity

Age (years)
22

The natural history of type 2 diabetes

Beta-cell loss Hyperinsulinaemia Secondary failure Effect of oral drugs Insulin requirements with age Endogenous insulin

Insulin requirements

Insulin insensitivity

Age (years)
23

Epidemiology of type 2 diabetes

Dramatic increase Aging population

Disturbing trends parallel obesity epidemic

Especially in adolescents and minority groups Increasing in young people
24

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 25

Risk factors for type 2 diabetes

Hypertension Dyslipidaemia Abdominal obesity Overweight Polycystic ovary disease Acanthosis nigricans Schizophrenia

26

Signs and symptoms

Polydipsia Polyuria Nocturia Visual disturbance Fatigue Weight loss Infections

27

Diagnosing diabetes
Normal Impaired fasting glucose* Impaired glucose tolerance** <6.1mmol/L <110mg/dL 6.1 to 6.9mmol/L* 110 to 126mg/dL 7.8 to 11mmol/L** 126 to 200mg/dL Diabetes

FPG

7.0mmol/L 126mg/dL 11.1mmol/L 200mg/dL

2hr PG <7.8mmol/L <126mg/dL

CDA 2003, ADA 2004, WHO 2002

28

Impaired glucose tolerance Impaired fasting glucose

Intermediate states Increased risk of developing diabetes Prevention strategies to prevent or delay progression Increased risk of cardiovascular disease
29

Uncertain diagnosis: Oral glucose tolerance test

75 g glucose load after 8 hours fasting

Readings taken in fasting state and at 1 and 2 hours

Possible problems

30

Tests for differential diagnosis

Urinary ketones

Antibodies
C-peptide

31

Summary
Type 1 diabetes Results from progressive beta-cell destruction People with type 1 diabetes need insulin therapy to live
32

Summary
Type 2 diabetes Often characterized by insulin insensitivity and relative rather than absolute insulin deficiency A progressive condition Most people with type 2 diabetes will need insulin within 5 to 10 years of diagnosis
33

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 Before 1921 1921 1950 1971 20 40 45 Carbohydrate Protein Fat Starvation diets 10 20 20 70 40 35

1986 2004

<60 45-65*

12-20 10-20

<30 20-35
<10% saturated fat

* Based on individual assessment and treatment goals

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 Bread Rice (cooked) Pasta Chappati Corn meal Potato Amount (g) 25 52 43 35 26 85 Serving 1 slice 0.3 cup 0.3 cup 1 small 3 tablespoons 1 small Carbohydrate (g) 12.4 14.7 12.6 17.0 20.2 17.0

Couscous
Lentils Banana

52
99 72

0.3 cup
0.5 cup 1 small

12.1
19.9 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 cooking 1 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

Formed when liquid fats, such as oils, are chemically hydrogenated Raise LDL cholesterol and lower HDL cholesterol

Fats and oils

Fat distribution in commonly used oils
Fatty acid (grams/100grams)
Saturated fatty acids Olive oil Peanut oil Canola oil Rapeseed oil Sesame oil Corn oil Cottonseed oil Soya bean oil Sunflower oil Safflower oil Coconut Hydrogenated oil Ghee/butter oil 13 18 6 8 15 12 22 15 13 13 90 24 65 MUFA 76 48 58 70 42 32 25 27 27 17 7 19 32 PUFA (-6) 10 34 26 12 42 55 52 53 60 70 2 3 2 PUFA (-3) 1 <0.5 10 10 1 1 1 5 <0.5 <0.5 <0.5 <0.5 <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 Vegetables Spices Nuts and seeds Oils
a

Blackgram, cowpea, rajmah, soya Green leafy Fenugreek, mustard Walnut, flaxseed Mustard, soya bean oil, canola oil

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 watersoluble

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

Vitamins and antioxidants recommendations

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

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

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 Interventi Results on

Da Qing Study (China) 1997

577 persons >25 years Random selection from clinics 6 years follow-up

Diet Exercise Diet + exercise

68% cumulative incidence 44% (reduction of 31%) 41% (reduction of 46%) 46% (reduction of 42%) 58% decreased incidence in the diet + exercise group

Finnish Diabetes Preventio n Study (Finland) 2001

522 persons, 40-64 years BMI >25 Random selection by persons 3.2 years follow-up

Diet + exercise

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 moderateintense 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

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 wellbeing Prevent or delay vascular complications of diabetes

Natural history of type 2 diabetes

Insulin resistance Glucose level

Beta-cell dysfunction

Insulin production

Time Normal Impaired glucose tolerance Type 2 diabetes

Henry 1998

Mechanisms of action
GLP-1 (incretins) improve response to glucose level

Biguanides and thiazolidinediones reduce glucose production

Insulin secretagogues: sulphonylureas and meglitinides increase insulin production

Alpha-glucosidase inhibitors slow absorption of sucrose and starch Thiazolidinediones and biguanides reduce insulin resistance

The principles of combination therapy

Two (or more) oral blood glucoselowering medicines that have different mechanisms of action Two medications rather than increase in initial medicine to maximum dosage Fewer side effects than monotherapy at higher doses

Expected effect of blood glucoselowering medicines

Class of medicine Expected decrease in HbA1C in monotherapy 0.5-0.8% 1.0-1.5% 1.0-1.5% 1.0-1.5% 0.5%
Canadian Diabetes Association 2003

Alpha-glucosidase inhibitor Biguanide Insulin sensitisers Most insulin secretagogues Nateglinide

Targets for blood glucose

HbA1C Pre-meal 2 hours postmeal

Target for people who can achieve it (without too much hypoglycemia)1
Target for most people with diabetes IDF Global guideline for Type 2 diabetes3

< 6%

4-6 mmol/L

5-8 mmol/L

<7%

4-7mmol/L1 90-130mg/dl*2 <6.0mmol/L <110mg/dl

5-10mmol/L1 <180mg/dl2 <8.0mmol/L <145mg/dl

<6.5%

1CDA

2003, 2ADA 2004,

IDF 2005

Suggested starting medicine

HbA1c BMI >25 Suggested medicine Biguanide alone or in combination 1 or 2 agents from different classes

<9%
<25

>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

Biguanides
Contraindications
Renal insufficiency Liver failure Heart failure Severe gastrointestinal disease

Advantages
Do not cause hypoglycaemia when used as monotherapy 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 secretagogues Meglitinides 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 disease Meglitinides - 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 Crohns Autonomic neuropathy affecting the gastro-intestinal tract Must 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 3060 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
60 40 20 0

Insulin

Breakfast Lunch

Supper

Insulin action
1.

Increases glucose uptake, particularly in muscle, liver and adipose tissue

2.
3. 4. 5.

Suppresses glucose output from the liver

Increases formation of fat

Inhibits breakdown of fats

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) -2 Duration (hrs) 3-4

Rapid
lispro aspart Short soluble regular Intermediate NPH lente 1-2 1-3 4-6 3-4 1-2 6-12 6-12 8-20 3-24 3-8 18-24 18-24 24 or more 24 or more 12-24 (dosedependent) -1 2-4 6-8 <

Long acting
ultralente glargine detemir

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 60

40

Endogenous insulin Soluble insulin

Insulin

20

Intermediate-acting insulin

Breakfast Lunch Supper

Twice a day insulin

60

40

Endogenous insulin Soluble insulin Intermediateacting insulin

Insulin

20

Breakfast Lunch Supper

Three times a day insulin

60

40

Endogenous insulin Soluble insulin

Insulin

20

Intermediateacting insulin

Breakfast Lunch Supper

Basal-bolus regimen
60 40

Endogenous insulin Rapid-acting insulin analogue

Insulin

20

Intermediateacting insulin

Breakfast Lunch Supper

60

Long-acting insulin analogues

Endogenous insulin Rapid-acting insulin analogue Long-acting insulin analogue

40

Insulin

20

Breakfast Lunch Supper

Adjusting insulin what are the targets?

HbA1C Target for most people with diabetes IDF Global guideline for Type 2 diabetes*2 <7% Pre-meal 4-7mmol/L* 90-130mg/dl*1 <6.0mmol/L <110mg/dl 2 hours postmeal 5-10mmol/L* <180mg/dl *1 <8.0mmol/L <145mg/dl

<6.5%

Treatment targets should be individualized, especially for very young and very old Absence of hypoglycaemia
*CDA

2003,

*1ADA

2004,

*2

IDF 2005

Starting insulin in type 2 diabetes

FINFAT: start small dose intermediateacting 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

Diabetic neuropathy

Autonomic neuropathy

Postural hypotension

Arrhythmia Silent ischaemia

Autonomic Neuropathy

Urine retention

Gastroparesis

Erectile dysfunction

Constipation
Diarrhea

Nerve Entrapment
Cranial nerves Seventh nerve - Bells palsy: risk of corneal ulcer Third nerve closed eye Sixth nerve pupil directed nasally

Carpal tunnel

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 neuropathy Peripheral vascular disease

Peripheral neuropathy and peripheral 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

Natural history of diabetic nephropathy

Acute renal hypertrophy-hyperfunction
Normoalbuminuria

10 to 15 years

Microalbuminuria (incipient diabetic nephropathy) Proteinuria (clinical overt diabetic nephropathy) Chronic renal failure

Protein, microalbuminuria and Macroalbuminuria

Protein

Albumin Albumin Excretion Rate

Microalbuminuria:

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

Macroalbuminuria: >300 mg/24 hr or

Factors affecting albumin excretion

Transient increases in albumin excretion

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

Transient microalbuminuria
>2 consecutive measurements >20 g/min therafter 3 measurements normal Example: AER (g/min x 1,73m) 200 200

100
50 20 g/min 15 g/min

Girl Age: 15 years diabetes duration: 5 years

100
50 20

10 5 2
1/90 5/90 7/90 10/90 2/92 6/91 10/91 4/92

10 5 2
9/87 1/88 2/89 7/89
2/87 4/87 2/88 4/88 5/88 8/88 10/89

Permanent microalbuminuria
3 consecutive measurements >20 g/min Example: AER (g/min x 1,73m) 200 Girl 100 Age: 21 years diabetes duration: 50 10 years 20 g/min 15 g/min 10 5 2
6/94 8/87 10/88 11/88 12/88 4/89 1/90 7/90 9/90 10/90 12/90 9/91 11/92 12/93 7/95

278 253

200 100 50

20
10 5 2 1

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 bodys response

Endogenous insulin secretion suppressed Release of glucagon, epinephrine, cortisol, growth hormone Autonomic response

The bodys response

Brain lacks glucose
Temporary cognitive impairment Wide variation in symptoms

Glucagon
Hypoglycaemia 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
Capable of selftreating Tremors, palpitation, sweating, hunger, fatigue Adrenergic

Moderate
May require prompting Headache, mood changes, low attentiveness Neuroglycopenic

Severe
Not capable of selftreatment Conscious or unconscious

Neuroglycopenic

Consequences of hypoglycaemia

Mild-moderate fear anxiety affects selfcare social stigma prejudice

Severe injury seizures transient paralysis cognitive impairment death

People at risk of hypoglycaemia

Only 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 diagnosis Thereafter, 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 and hyperosmolar hyperglycaemic state

What is DKA?
High blood glucose, ketones, acidosis and dehydration

Absolute or relative insulin deficiency Increase in counter-regulatory hormones Breakdown of fat and muscle Biochemical triad hyperglycaemia ketoacids metabolic acidosis

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 Acute illness 5-40% 10-20%

Insulin omission/nonadherence Infection

Heart attack, stroke, pancreatitis

33%
20-38% <10%
Booth 2001, Joslin 2005

Diabetic ketoacidosis
Insulin deficiency Glucose uptake Glycerol Hyperglycaemia Glucosuria Osmotic diuresis Electrolyte depletion Dehydration Acidosis
Adapted from Davidson 2001

Lipolysis Free fatty acids Ketogenesis Ketonemia Ketonuria

Gluconeogenesis

Urinary water losses

DKA investigations
Immediate for diagnosis Capillary blood glucose, urinary glucose and ketones

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

DKA laboratory findings

Blood glucose >14mmol/L (252mg/dL)

Ketones
Osmolality

Urine: moderate to large

Blood: >3mmol/L Increased high blood glucose and urea/creatinine, dehydration Low/normal Na+ and ClLow/normal/high K+ (often misleading) Low HCO3 (normal 23-31)

Electrolytes

Anion gap Blood gases

>10 mild

>12 moderate to severe pH <7.30, HCO3 <15 (mild) pH <7.00, HCO3 <10 (severe)

DKA treatment
Rehydration 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 1020% 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 2hourly 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
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

Incidence
Infection New-onset diabetes Acute illness Medicines, steroids Insulin omission 40-60% 33% 10-15% <10% 5-15%

Booth 2001

Signs and symptoms of HHS

Initially polyuria and polydipsia

Altered mental status Profound dehydration

Precipitating factors

HHS biochemical findings

Blood glucose Ketones Osmolality >33mmol/L (600mg/dl) Urine: negative small

Electrolytes
Anion gap Blood gases

Blood: <0.6 mmol/L >320mOsm/kg - (raised Na, BG, urea) Raised Na, BG, urea creatinine <12
pH >7.30 normal or raised HCO3
Jones 2001

Treatment
Rehydration Caution!

Normal saline 1 l per hour initially

Consider strength normal saline Potassium Insulin Only if hypokalaemic and renal function adequate give before insulin May be needed as slow infusion 0.1 unit/kg/hour to be increased with care if BG is slow to fall BG, BP, neurological function hourly until stable Electrolytes 2-hourly Cardiac or CVP monitoring

Monitoring

HHS complications
Complication Hypoglycaemia Prevention Prevent by adding glucose infusion when glucose <14mmol/L (250 mg/dL) Early potassium replacement and monitoring

Hypokalaemia

Fluid overload

Careful clinical monitoring and central line as needed

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

Vomiting/aspiration NG tube and may be nursed on side Cerebral oedema