Introduction to diabetes

What should I learn to understand diabetes

How the human body works What the relationship is between blood glucose and insulin Factors affecting blood glucose levels Definition of diabetes Diagnosis of diabetes

Glucose
is an essential source of energy used by the human body is stored in the form of glycogen in the liver and the muscles as an energy reserve

Insulin
After a meal carbohydrates are digested and enter the blood system, which transports them to the cells
Some cells (those of muscles and fat tissue) INSULIN is needed for glucose uptake and storage

need assistance to have blood sugar enter into them and to be used for energy production

The liver needs assistance to start the process

of storage of glucose in the form of glycogen

Glucagon
Glucagon is a hormone secreted by the alpha-cells of the pancreas It is secreted in response to low blood glucose concentrations It facilitates glucose release from the glucose store in the liver and induces production of glucose from other sources: gluconeogenesis

Factors affecting blood glucose

Food (carbohydrate) intake increases blood glucose Exercise lowers blood glucose Stress may increase blood glucose Alcohol lowers blood glucose

Definition of Diabetes

Diabetes is a metabolic disorder of multiple aetiology characterised by chronic hyperglycaemia with disturbances of carbohydrate, fat and protein metabolism resulting from defects in insulin secretion, insulin action or both

Types of diabetes
Type 1 diabetes: beta-cells are destroyed and there is no production of insulin Type 2 diabetes: insulin works inefficiently = insulin resistance and more insulin is needed to control blood glucose; betacells produce some amount of insulin, but cannot supply the body with the needed amount of insulin to keep blood glucose in the normal range

Diagnosis of diabetes: symptoms

Frequent and excessive urination Thirst Hunger Weight loss Tiredness/malaise Blurred vision

Some terms in diabetes

Fasting plasma glucose (FPG): Glucose concentration

measured before breakfast after overnight fast Postprandial plasma glucose (FPG) : Glucose concentration

measured 1.52 hours after a meal Random blood glucose: Glucose concentration measured at any time of the day

HbA1c = glycated haemoglobin: blood test reflecting mean

blood glucose concentrations over the past 810 weeks

Diagnosis of diabetes: tests+

mmol/l
Random value Fasting value Diabetes IFG1 2-hour value
(OGTT)

mg/dl
> 200 >126* >100 >200 >140

> 11.0 >7.0* >5.6 >11.0 >7.8

+Values

Diabetes IGT2
Adapted from: A Desktop Guide to Type 2 Diabetes Mellitus, European Diabetes Policy Group 1998-1999

for venous plasma glucose 1Impaired fasting glycaemia 2Impaired glucose tolerance *Repeat and if confirmed = diabetes

The importance of glucose

Blood glucose levels are maintained within a narrow range (47 mmol/L) High enough to satisfy the energy needs of cells
The nervous system is particularly dependent on glucose for energy

Low enough to minimise the toxic effects of glucose

Increases in blood glucose levels

Glucose enters the blood when:
Food is digested and absorbed: this is the main source of glucose
The storage product glycogen is broken down to glucose (glycogenolysis) Glucose is synthesised from sources such as glycerol and amino acids in the liver (gluconeogenesis)

Decreases in blood glucose levels

Glucose is removed from the blood to be:
Broken down within cells to release energy Converted to glycogen for storage (glycogenesis)

Hormonal control in health

Hormonal control of blood glucose: glucagon and adrenaline

Glycogen breakdown Glucose synthesis Liver

Glucagon increases blood glucose levels by:

increasing glycogenolysis in the liver and skeletal muscles increasing gluconeogenesis in the liver

Glycogen breakdown

Skeletal muscle

Glycogen breakdown

Lipid (fat) breakdown

Adipose tissue

Adrenaline increases blood glucose levels by stimulating glycogenolysis and lipid breakdown (lipolysis)

Hormonal control of blood glucose: insulin

Glycogen breakdown Glucose synthesis Liver

Glucose uptake

Skeletal muscle

Glucose uptake

The only hormone to lower blood glucose levels Suppresses endogenous glucose production in the liver inhibits glycogenolysis inhibits gluconeogenesis Stimulates peripheral glucose uptake in skeletal muscle and adipose tissue

Adipose tissue

Other effects of insulin

Increases the storage of lipids that cells could use instead of glucose
e.g. reduced lipolysis in adipose tissue

Increases the storage of protein

e.g. increased amino acid transport

Insulin synthesis and storage

Synthesised by pancreatic beta-cells

Series of biochemical reactions converts the precursor molecule, preproinsulin, into insulin
Insulin is stored as hexamers in secretory granules before release

Insulin secretion
Insulin is released when the secretory granules fuse with the cell membrane (exocytosis) Hexamers dissociate into monomers

Monomers are transported in the blood

Daily insulin secretion

70 60 Insulin (U/mL) 50 40 30 20 10 0 6:00 10:00 Breakfast 14:00 Lunch 18:00 Dinner 22:00 2:00 6:00

Short-lived, rapidly generated meal-related insulin peaks (prandial)

Sustained insulin profile (basal)

Time of day

Polonsky et al. J Clin Invest 1988;81:4428

Biphasic prandial insulin response

Each prandial peak has two phases

Phase 1: rapid insulin release to suppress endogenous glucose production in the liver Phase 2: continued release as glucose from the meal is absorbed

High insulin levels facilitate peripheral glucose uptake (skeletal muscle and adipose tissue) These actions minimise rises in blood glucose associated with meals

Diabetes mellitus: type 1

Type 1 diabetes: review

Primary defect: absent or minimal production of insulin

Cause: destruction of pancreatic beta-cells

Symptoms occur when 90% of beta-cells are destroyed

Characteristics of type 1 diabetes

Usually affects people less than 35 years of age Body weight: normal to low Onset: most often in adolescence (1014 years of age) Present with classical symptoms Insulin treatment is mandatory

Insulin treatment is vital

Insulin treatment should be initiated as soon as diagnosis is confirmed Type 1 diabetes was a fatal disease before the discovery of insulin Today insulin saves the lives of more than 4 million people with type 1 diabetes

Honeymoon
Following the acute onset of type 1 diabetes, there may be a period (honeymoon phase) of normal or nearnormal beta-cell function However, following this honeymoon phase complete beta-cell destruction usually occurs Consequently, insulin should not be discontinued during the honeymoon phase

Diabetes management: objectives

Relief of hyperglycaemic symptoms
Improvement of quality of life Prevention and delay of complications Reduction of mortality Treatment of accompanying conditions (high blood pressure, high fat concentrations, etc.)

Diet Medication

Diabetes under control

Self-testing Education

Exercise

Aetiology of type 1 diabetes

Idiopathic type 1 diabetes Cause unknown Autoimmune destruction of beta cells Thought to be triggered by an environmental agent (e.g. virus) in genetically predisposed individuals Approximately 90% of type 1 diabetes cases Onset tends to be fast and aggressive in children and adolescents Slower onset in adulthood is often named lateonset autoimmune diabetes of adults

Epidemiology of type 1 diabetes

Approximately 10% of all diabetes cases (=25 million)

Incidence peaks in the early teenage years for boys and girls
Geographically: incidence increases considerably from the Equator to the Poles incidence is highest in Finland and lowest in Japan

Incidence has been increasing over the past 20 years

Effects of type 1 diabetes on glucose metabolism

In the absence of insulin:
The liver continues to produce glucose The uptake of glucose by peripheral tissues is diminished Blood glucose levels increase (hyperglycaemia)
Excess glucose is excreted by the kidneys in urine Increased urination (polyuria) and excessive thirst (polydipsia)

Effects of type 1 diabetes on lipid metabolism

In the absence of insulin:
Lipolysis in adipose tissue continues and more fatty acids are released into the blood The breakdown of fatty acids (ketosis) provides energy for cells but also ketones (e.g. acetone) as by-products As ketones build up in the blood, they can be smelt on the breath, they are excreted by the kidneys in the urine and they increase the acidity of the blood (ketoacidosis) Diabetic ketoacidosis is a medical emergency

Effects of type 1 diabetes on protein metabolism

In the absence of insulin:
Protein breakdown is increased and protein synthesis is decreased Muscle wasting and weight loss

Diabetes mellitus: type 2

Type 2 diabetes: pathophysiology

impaired insulin secretion + resistance
Pancreas
Decreased peripheral glucose uptake

Hyperglycaemia

Liver

Increased hepatic glucose production

Muscle

Diabetes Y2003 IDF data

Overall prevalence* 5.1% (2-10%)

Type 1 diabetes 5-10% of all cases with diabetes Type 2 diabetes 90-95% of all cases with diabetes

Diabetes Atlas, IDF 2000

*Prevalence = % of all cases in a given population

The magnitude of the diabetes epidemic 2000 - 2025/2030

400 350 300 250 200 150 100 50 0
References: 1. Global burden of diabetes, 1995-2025: prevalence, numerical estimates, and projections. King H. et al. Diabetes Care. 1998 2. WHO report - 2002

370 300

Affected population in mln

150

176.5

Diab Care 1998 WHO - 2002

2000

2025/2030

Type 2 diabetes: risk factors

First-degree relative with diabetes mellitus (DM) Age > 45 years Obesity (BMI > 27 kg/m2 or > 20% ideal body weight) Sedentary lifestyle Ethnic predisposition

Hypertension Dyslipidaemia History of gestational DM (DM in pregnancy) History of delivering a baby > 9 lbs Polycystic ovarian syndrome History of IFG or IGT

Characteristics of type 2 diabetes

Usually affects people >35 years of age Body weight: 8090% overweight/obese Onset: most often in the sixties Very often asymptomatic May be diagnosed in relation to already existing complication

Type 1 and type 2 diabetes: Similarities

High blood glucose (hyperglycaemia) May have abnormalities in lipids Develop long-term complications

Type 1 and type 2 diabetes: differences

Characteristi cs
Age of onset Peak age Body weight

Type 1
Usually < 35 years 1014 years Usually thin

Type 2
Usually > 35 years 6070 years 80% obese (excluding Asian origin) 50% obese (when of Asian origin)

Symptoms Heredity Treatment

Acute onset of symptoms No Insulin is mandatory

Gradual onset, very often diagnosed without symptoms Yes Diet and tablets Insulin required at a certain stage

Diabetes management: objectives

Relief of hyperglycaemic symptoms
Improvement of quality of life Prevention and delay of complications Reduction of mortality Treatment of accompanying disorders

Type 2 diabetes: management targets

The therapeutic goals for diabetes management can be achieved by:
blood glucose control

blood pressure control

control of lipids reduction of weight stopping smoking active lifestyle

Type 2 diabetes: management options

Medical nutrition therapy and physical activity Oral antidiabetic (OAD) therapy and/or insulin

Achieving glycaemic control

Options for treatment of type 2 diabetes:
Diet and exercise Sulphonylureas (e.g. Glibenclamide, Glucotrol, Amaryl) Biguanides (e.g. Glucophage) Alpha glucosidase inhibitors (e.g. Precose, Glyset) Thiazolidinediones (e.g. Actos, Avandia) Meglitinides (e.g. NovoNorm/Prandin, Starlix) Insulin or insulin analogues

Medical management: side effects

OADs: consider action, duration, contraindications,
side effects, cost

Select medication based on drug/patient characteristics

Insulin: adjust as needed, consider lifestyle changes, hypoglycaemic events

Epidemiology of type 2 diabetes

Approximately 90% of all diabetes cases (=221 million) A disorder related to lifestyle, particularly obesity and physical inactivity Associated with older age but increasing in children due to increasing obesity and decreasing physical activity

Incidence:
increasing worldwide varies among ethnic groups

Natural history: insulin secretion and blood glucose control

Obesity IFG Relative function (%) 250 200 150 100 50 Diabetes Uncontrolled hyperglycaemia Insulin resistance Insulin level Normal

Beta-cell failure

350 300 250 200 150 100 50 10 5 0

Glucose level (mg/dL)

Postprandial glucose Fasting glucose Normal

10

15

20

25

30

Adapted from Bergenstal et al. In: Degroot & Jameson (eds). Endocrinology 2001;82135 IFG, impaired fasting glucose

Years of diabetes

Effects of type 2 diabetes on lipid metabolism

With reduced levels of insulin:
Lipolysis in adipose tissue and thus the release of fatty acids into the blood is slightly increased
Ketosis and the release of ketone byproducts into the blood is also slightly increased but patients do not usually develop ketoacidosis

Effects of type 2 diabetes on protein metabolism

Insulin levels are sufficient to prevent protein breakdown and muscle wasting

Diagnosis
With classical signs and symptoms Random PG 11.1 mmol/L Random PG 5.511.0 mmol/L Diabetes Fasting PG 7.0 mmol/L Fasting PG 5.66.9 mmol/L Without classical signs and symptoms 2-h postchallenge PG 11.1 mmol/L and/or 2-h postchallenge PG 11.1 mmol/L Random PG 11.1 mmol/L
PG, plasma glucose
Data from Watkins et al. Diabetes and its Management. Blackwell Publishing 2003 Pickup & Williams. Slide Atlas of Diabetes. Blackwell Publishing 2004

Fasting PG 7.0 mmol/L

Diagnosis: diabetes and impaired glucose metabolism

Venous plasma glucose mmol/L mg/dL
Random value: diabetes Fasting value: impaired fasting glycaemia diabetes 2-h value (OGTT): impaired glucose tolerance diabetes 11.1 5.6 7.0* 100 126* 200

7.8 11.1

140 200

*Repeated and confirmed for a diagnosis of diabetes; OGTT, oral glucose tolerance test Adapted from A Desktop Guide to Type 2 Diabetes Mellitus, European Diabetes Policy Group 19981999

Metabolic syndrome

Metabolic syndrome
Insulin resistance is associated with other clinical and biochemical features, such as obesity and dyslipidaemia These features are collectively known as the metabolic syndrome People with metabolic syndrome have reduced life expectancy

World Health Organization definition

One or more of:
Diabetes mellitus Impaired glucose tolerance Impaired fasting glucose

Plus two or more of:

Insulin resistance Hypertension Excess lipids in the blood (hyperlipidaemia) Central obesity Increased excretion of albumin in the urine (microalbuminuria)

Diabetic complications

Classification of diabetic complications

Acute diabetic complications:
diabetic ketoacidosis (DKA) hyperosmolar non-ketotic coma (HONK) hypoglycaemia due to treatment

Long-term diabetic complications:

macrovascular complications
coronary heart disease, stroke, peripheral vascular disease

microvascular complications
retinopathy, nephropathy, neuropathy

Diabetic ketoacidosis (DKA)

Caused by severe insulin deficiency Hallmark of type 1 diabetes insulin deficiency ~25% of cases are newly-diagnosed type 1 diabetes patients Hyperglycaemia, ketosis and acidosis
Watkins et al. In: Diabetes and its Management 2003

Diabetic ketoacidosis: symptoms and treatment

Main clinical features of DKA:
Dehydration Hyperventilation Drowsiness Vomiting Hypothermia

Key biochemical markers:

Leucocytosis Elevated serum amylase

Treatment priority: initial rehydration and insulin replacement

Hyperosmolar non-ketotic coma (HONK)

Hyperglycaemic emergency of type 2 diabetes Usually in older people who have consumed a large volume of sugary fluid ketogenesis, hyperglycaemia ensues

Although insulin levels prevent lipolysis and

Patients dehydrated, elderly and frail Treatment: careful rehydration and insulin

Prevalence of diabetic complications

Diabetes increases risk of: Death: 2 times higher Stroke: 2 to 4 times higher Blindness among adults aged 2074 years Kidney failure: 44% of new cases Non-traumatic lower-limb amputations: >60%
Americal Diabetes Association. In: National Diabetes Fact Sheet 2005

Macrovascular complications of diabetes

Stroke Cardiovascular/heart disease

Peripheral vascular disease

International Diabetes Federation. Diabetes Atlas 2006;1112

 Damage to the macrovascular blood vessels by atheroma formation Associated with: coronary heart disease, angina, myocardial infarction and heart failure cardiomyopathy stroke Cholesterol deposits Atherosclerotic plaque peripheral vascular disease
Watkins et al. In: Diabetes and its Management 2003

Macroangiopathy: definition and related conditions

Coronary heart disease (CHD)

stenosis

stenosis

Angina, myocardial infarction (MI), heart failure May be confused with hypoglycaemia because of a lack of pain Immediate and longterm mortality increased in diabetes

Diagram shows stenosis (narrowing) of the coronary arteries

Microvascular complications of diabetes

Retinopathy and blindness

Nephropathy Neuropathy

Diabetic foot disease

International Diabetes Federation. Diabetes Atlas 2006;1112

Microangiopathy: definition and related conditions

Damage to small blood vessels and capillaries
retinopathy nephropathy neuropathy

Severity is related to the duration and degree of hyperglycaemia

DCCT: microvascular complications increase as HbA1c increasesRisk of developing Risk of retinopathy

16 12 8 4 0 0 5 6 7 8 9 10 11 12

Rate per 100 patient years

Rate per 100 patient years

progression

microalbuminuria

16 12 8 4 0 0 5 6 7 8 9 10 11 12

HbA1c (%)
DCCT. N Engl J Med 1993;329:97786

Microangiopathy: definition and classification

Damage to the microvascular circulation Retinopathy (eyes) Nephropathy (kidneys) Neuropathy (autonomic and peripheral nerves)

Diabetic foot

Hypoglycae mia

Hypoglycaemia: overview
Hypoglycaemia:
Blood glucose <4 mmol/L

Imbalance between insulin and food intake

More frequent in patients with type 1 diabetes

Symptoms possible at higher blood glucose concentrations

Hypoglycaemia: causes
Insulin treatment and insulin secretagogues Taking insulin at the wrong time Wrong insulin doses Inaccurate doses Missing meals Dietary changes without dose adjustments Problems with injection technique or

Hypoglycaemic symptoms
Early signs (mild hypoglycaemia)
n n n n n n n n n

Late signs (moderate/major hypoglycaemia)

n n n n n n n n n n n n

Sweating* Light-headedness* Trembling/shaking* Hunger* Anxiety* Fast heart rate Lip tingling Irritability Pallor

Weak legs* Drowsiness* Poor concentration* Blurred vision* Headache* Confusion Poor coordination Slurred speech Glazed eyes Aggressive behaviour Seizures Loss of consciousness

*Indicate most common

Hypoglycaemia: consequences
Hypoglycaemia

Increased vulnerability to further episodes of hypoglycaemia

Impaired physiological responses to hypoglycaemia

Repeated hypoglycaemic episodes impair the autonomic responses to hypoglycaemia

Reduced awareness of hypoglycaemia

Patients become unaware of hypoglycaemia, which increases their risk of severe episodes

Hypoglycaemia: unawareness of symptoms

Hypoglycaemia aware Bood glucose (mmol/L)
4 Adrenaline release Sweating, trem or 3 2

Start of brain dysfunction C onfusion/loss of concentration

C oma/seizure Permanent brain damage

Hypoglycaemia unaware Bood glucose (mmol/L)

4

Adrenaline release Sweating, trem or

Start of brain dysfunction C onfusion/loss of concentration

Autonomic symptoms activate at a lower blood glucose threshold than for cognitive impairment Patients cannot take preventive action Patients may

C oma/seizure Permanent brain damage

Treating mild hypoglycaemia

Treating early signs
First: 1020 g fast-acting carbohydrate, e.g.:
36

glucose tablets mL fizzy drink or squash (not diet)

90180 Two

teaspoons of sugar added to a cup of cold drink

50100

mL energy drink (e.g. Lucozade)

Then:
If If

next meal is due, add extra carbohydrate

next meal is not due, eat longer-acting carbohydrate, such as biscuits or a sandwich

http://www.rcn.org.uk/__data/assets/pdf_file/0009/78606/002254.pdf

Treating moderate-to-major hypoglycaemia

Treating late signs
Patient requires assistance with treatment If conscious:
Carer

should help the patient to consume 1020 g fast-acting carbohydrate gel may be useful

Dextrose

If unconscious:
Dont

put anything in patients mouth

Intramuscular

should be administered

glucagon or intravenous glucose

Emergency

services should be called

http://www.rcn.org.uk/__data/assets/pdf_file/0009/78606/002254.pdf

Changing the dose: some general rules

Combating hypoglycaemia
Reduce insulin dose by at least 20% and review after 1 week
Preventing hypoglycaemia takes priority over correcting hyperglycaemia

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