WHO definition and

diagnostic criteria for

diabetes mellitus

Jan Szewieczek

Jan Szewieczek

Katedra i Klinika

Katedra i Klinika

Chorób Wewnętrznych i Metabolicznych

Chorób Wewnętrznych i Metabolicznych

Śl.A.M. Katowice

Śl.A.M. Katowice

Definition (1)

The term diabetes mellitus describes a

The term diabetes mellitus describes a

metabolic disorder of multiple aetiology

metabolic disorder of multiple aetiology

characterized by chronic

characterized by chronic

hyperglycaemia with disturbances of

hyperglycaemia with disturbances of

carbohydrate, fat and protein

carbohydrate, fat and protein

metabolism resulting from defects in

metabolism resulting from defects in

insulin secretion, insulin action, or

insulin secretion, insulin action, or

both.

both.

Definition (2)

The effects of diabetes mellitus include

The effects of diabetes mellitus include

long-term damage, dysfunction and failure

long-term damage, dysfunction and failure

of various organs. Diabetes mellitus may

of various organs. Diabetes mellitus may

present with characteristic symptoms such

present with characteristic symptoms such

as thirst, polyuria, blurring of vision, and

as thirst, polyuria, blurring of vision, and

weight loss. In its most severe forms,

weight loss. In its most severe forms,

ketoacidosis or a non-ketotic

ketoacidosis or a non-ketotic

hyperosmolar state may develop and lead

hyperosmolar state may develop and lead

to stupor, coma and, in absence of

to stupor, coma and, in absence of

effective treatment, death.

effective treatment, death.

Definition (3)

Often symptoms are not severe, or may be absent,

Often symptoms are not severe, or may be absent,

and consequently hyperglycaemia sufficient to

and consequently hyperglycaemia sufficient to

cause pathological and functional changes may be

cause pathological and functional changes may be

present for a long time before the diagnosis is

present for a long time before the diagnosis is

made. The long-term effects of diabetes mellitus

made. The long-term effects of diabetes mellitus

include progressive development of the specific

include progressive development of the specific

complications of retinopathy with potential

complications of retinopathy with potential

blindness, nephropathy that may lead to renal

blindness, nephropathy that may lead to renal

failure, and/or neuropathy with risk of foot ulcers,

failure, and/or neuropathy with risk of foot ulcers,

amputation, Charcot joints, and features of

amputation, Charcot joints, and features of

autonomic dysfunction, including sexual

autonomic dysfunction, including sexual

dysfunction.

dysfunction.

Definition (4)

People with diabetes are at

People with diabetes are at

increased risk of cardiovascular,

increased risk of cardiovascular,

peripheral vascular and

peripheral vascular and

cerebrovascular disease.

cerebrovascular disease.

Diagnosis (1)

If a diagnosis of diabetes is made,

If a diagnosis of diabetes is made,

the clinician must feel confident

the clinician must feel confident

that the diagnosis is fully

that the diagnosis is fully

established since the

established since the

consequences for the individual

consequences for the individual

are considerable and lifelong.

are considerable and lifelong.

Diagnosis (2)

The requirements for diagnostic confirmation

The requirements for diagnostic confirmation

for a person presenting with severe symptoms

for a person presenting with severe symptoms

and gross hyperglycaemia differ from those

and gross hyperglycaemia differ from those

for the asymptomatic person with blood

for the asymptomatic person with blood

glucose values found to be just above the

glucose values found to be just above the

diagnostic cut-off value. Severe

diagnostic cut-off value. Severe

hyperglycaemia detected under conditions of

hyperglycaemia detected under conditions of

acute infective, traumatic, circulatory or other

acute infective, traumatic, circulatory or other

stress may be transitory and should not in

stress may be transitory and should not in

itself be regarded as diagnostic of diabetes.

itself be regarded as diagnostic of diabetes.

Diagnosis (3)

For the asymptomatic person, at least one

For the asymptomatic person, at least one

additional plasma/blood glucose test result

additional plasma/blood glucose test result

with a value in the diabetic range is

with a value in the diabetic range is

essential, either fasting, from a random

essential, either fasting, from a random

(casual) sample, or from the oral glucose

(casual) sample, or from the oral glucose

tolerance test (OGTT). If such samples fail to

tolerance test (OGTT). If such samples fail to

confirm the diagnosis of diabetes mellitus, it

confirm the diagnosis of diabetes mellitus, it

will usually be advisable to maintain

will usually be advisable to maintain

surveillance with periodic re-testing until the

surveillance with periodic re-testing until the

diagnostic situation becomes clear.

diagnostic situation becomes clear.

Diagnostic algorithm

(1)

1. Symptomatic

1. Symptomatic

or

or

glycosuria

glycosuria

or

or

incidental hyperglycaemia

incidental hyperglycaemia

Check

Check

random venous plasma

random venous plasma

glucose

glucose

If

If

>11.0 mmol/l ( >=200 mg/dl ) =

>11.0 mmol/l ( >=200 mg/dl ) =

"Diabetes"

"Diabetes"

If

If

>5.5 mmol/l ( >=100 mg/dl )

>5.5 mmol/l ( >=100 mg/dl )

then

then

proceed to next step (2.)

proceed to next step (2.)

Diagnostic algorithm

(2)

2. Random

2. Random

or

or

fasting screening glucose

fasting screening glucose

>5.5 mmol/l ( >=100 mg/dl )

>5.5 mmol/l ( >=100 mg/dl )

Check

Check

fasting venous plasma glucose

fasting venous plasma glucose

If

If

>=7.0 mmol/l ( >125 mg/dl ), repeat and

>=7.0 mmol/l ( >125 mg/dl ), repeat and

if confirmed = "Diabetes"

if confirmed = "Diabetes"

If

If

>6.0 mmol/l ( >=110 mg/dl ) do oral

>6.0 mmol/l ( >=110 mg/dl ) do oral

glucose tolerance test ( OGTT )

glucose tolerance test ( OGTT )

If

If

>5.0 mmol/l ( >90 mg/dl ), consider

>5.0 mmol/l ( >90 mg/dl ), consider

yearly reassessment of arterial risk factors

yearly reassessment of arterial risk factors

Diagnostic algorithm

(3)

OGTT ( venous plasma glucose ) :

OGTT ( venous plasma glucose ) :

If

If

2-h >11.0 mmol/l ( >=200 mg/dl ) =

2-h >11.0 mmol/l ( >=200 mg/dl ) =

"Diabetes"

"Diabetes"

If

If

2-h <=11.0 mmol/l ( <200 mg/dl ) and

2-h <=11.0 mmol/l ( <200 mg/dl ) and

>=7.8 mmol/l ( >=140 mg/dl ) = "IGT"

>=7.8 mmol/l ( >=140 mg/dl ) = "IGT"

If

If

fasting >6.0 mmol/l ( >=110 mg/dl )

fasting >6.0 mmol/l ( >=110 mg/dl )

and 2-h <7.8 mmol/l ( <140 mg/dl ) =

and 2-h <7.8 mmol/l ( <140 mg/dl ) =

"IFG"

"IFG"

Diagnosis (4)

4. Diagnostic procedures should not

4. Diagnostic procedures should not

be performed :

be performed :

o

o

      

      

in the presence of

in the presence of

acute

acute

illness or after trauma or

illness or after trauma or

surgery

surgery

during short courses of

during short courses of

blood

blood

glucose raising drugs

glucose raising drugs

Diagnosis (5)

5. Diagnostic tests should be

5. Diagnostic tests should be

interpreted with reservation :

interpreted with reservation :

o

o

      

      

in people on long-term

in people on long-term

blood

blood

glucose raising drugs

glucose raising drugs

o

o

      

      

in people with reversible

in people with reversible

endocrine conditions

endocrine conditions

in

in

pregnant women

pregnant women

Laboratory equivalents

Terminology (1)

It is recommended that the terms

It is recommended that the terms

"insulin-dependent diabetes mellitus"

"insulin-dependent diabetes mellitus"

and "non-insulin-dependent diabetes

and "non-insulin-dependent diabetes

mellitus" and their acronyms "IDDM"

mellitus" and their acronyms "IDDM"

and "NIDDM" no longer be used.

and "NIDDM" no longer be used.

These terms have been confusing and

These terms have been confusing and

frequently resulted in patients being

frequently resulted in patients being

classified based on treatment rather

classified based on treatment rather

than on pathogenesis.

than on pathogenesis.

Terminology (2)

The terms Type 1 and Type 2

The terms Type 1 and Type 2

should be reintroduced. The

should be reintroduced. The

aetiological type named Type 1

aetiological type named Type 1

encompasses the majority of cases

encompasses the majority of cases

which are primarily due to

which are primarily due to

pancreatic

islet

beta-cell

pancreatic

islet

beta-cell

destruction and are prone to

destruction and are prone to

ketoacidosis.

ketoacidosis.

Terminology (3)

Type 1 includes those cases attributable to

Type 1 includes those cases attributable to

an autoimmune process, as well as those

an autoimmune process, as well as those

with beta-cell destruction and who are prone

with beta-cell destruction and who are prone

to ketoacidosis for which neither an aetiology

to ketoacidosis for which neither an aetiology

nor a pathogenesis is known (idiopathic). It

nor a pathogenesis is known (idiopathic). It

does not include those forms of beta-cell

does not include those forms of beta-cell

destruction or failure to which specific

destruction or failure to which specific

causes can be assigned (e.g. cystic fibrosis,

causes can be assigned (e.g. cystic fibrosis,

mitochondrial defects, etc.). Some subjects

mitochondrial defects, etc.). Some subjects

with this type can be identified at earlier

with this type can be identified at earlier

clinical stages than "diabetes mellitus".

clinical stages than "diabetes mellitus".

Terminology (4)

The type named Type 2 includes

The type named Type 2 includes

the common major form of

the common major form of

diabetes which results from

diabetes which results from

defect(s) in insulin secretion,

defect(s) in insulin secretion,

almost always with a major

almost always with a major

contribution from insulin

contribution from insulin

resistance.

resistance.

Aethiological types and stages

IGT and IFG

Impaired glucose regulation (IGT and

Impaired glucose regulation (IGT and

IFG) refers to a metabolic state

IFG) refers to a metabolic state

intermediate between normal glucose

intermediate between normal glucose

homeostasis and diabetes. It should be

homeostasis and diabetes. It should be

stated unequivocally, however, that

stated unequivocally, however, that

IFG and IGT are not interchangeable

IFG and IGT are not interchangeable

and represent different abnormalities

and represent different abnormalities

of glucose regulation, one in the

of glucose regulation, one in the

fasting state and one post-prandial.

fasting state and one post-prandial.

Diabetes type 1 (1)

Type 1 indicates the processes of beta-cell

Type 1 indicates the processes of beta-cell

destruction that may ultimately lead to

destruction that may ultimately lead to

diabetes mellitus in which "insulin is

diabetes mellitus in which "insulin is

required for survival" to prevent the

required for survival" to prevent the

development of ketoacidosis, coma and

development of ketoacidosis, coma and

death. An individual with a Type 1 process

death. An individual with a Type 1 process

may be metabolically normal before the

may be metabolically normal before the

disease is clinically manifest, but the

disease is clinically manifest, but the

process of beta-cell destruction can be

process of beta-cell destruction can be

detected.

detected.

Diabetes type 1 (2)

Type 1 is usually characterized by the

Type 1 is usually characterized by the

presence of anti-GAD, islet cell or

presence of anti-GAD, islet cell or

insulin antibodies which identify the

insulin antibodies which identify the

autoimmune processes that lead to

autoimmune processes that lead to

beta-cell destruction. In some subjects

beta-cell destruction. In some subjects

no evidence of an autoimmune disorder

no evidence of an autoimmune disorder

is demonstrable and these are classified

is demonstrable and these are classified

as "Type 1 idiopathic".

as "Type 1 idiopathic".

Diabetes type 1 (3)

The slowly progressive form

The slowly progressive form

generally occurs in adults and is

generally occurs in adults and is

sometimes referred to as latent

sometimes referred to as latent

autoimmune diabetes in adults

autoimmune diabetes in adults

(LADA).

(LADA).

Diabetes type 1 (4)

Individuals with this form of Type 1

Individuals with this form of Type 1

diabetes often become dependent

diabetes often become dependent

on insulin for survival eventually

on insulin for survival eventually

and are at risk for ketoacidosis. At

and are at risk for ketoacidosis. At

this stage of the disease, there is

this stage of the disease, there is

little or no insulin secretion as

little or no insulin secretion as

manifested by low or undetectable

manifested by low or undetectable

levels of plasma C-peptide

levels of plasma C-peptide

Diabetes type 1 (5)

Markers of immune destruction,

Markers of immune destruction,

including islet cell autoantibodies,

including islet cell autoantibodies,

and/or autoantibodies to insulin, and

and/or autoantibodies to insulin, and

autoantibodies to glutamic acid

autoantibodies to glutamic acid

decarboxylase (GAD) are present in

decarboxylase (GAD) are present in

85-90 % of individuals with Type 1

85-90 % of individuals with Type 1

diabetes mellitus when fasting

diabetes mellitus when fasting

diabetic hyperglycaemia is initially

diabetic hyperglycaemia is initially

detected.

detected.

Diabetes type 1 (6)

There

is

a

genetic

predisposition

to

There

is

a

genetic

predisposition

to

autoimmune destruction of beta cells, and it is

autoimmune destruction of beta cells, and it is

also related to environmental factors that are

also related to environmental factors that are

still poorly defined. Although patients are

still poorly defined. Although patients are

usually not obese when they present with this

usually not obese when they present with this

type of diabetes, the presence of obesity is not

type of diabetes, the presence of obesity is not

incompatible with the diagnosis. These

incompatible with the diagnosis. These

patients may also have other autoimmune

patients may also have other autoimmune

disorders such as Graves' disease, Hashimoto's

disorders such as Graves' disease, Hashimoto's

thyroiditis, and Addison's disease.

thyroiditis, and Addison's disease.

Diabetes type 2 (1)

Type 2 is the most common form of

Type 2 is the most common form of

diabetes and is characterized by

diabetes and is characterized by

disorders of insulin action and insulin

disorders of insulin action and insulin

secretion, either of which may be the

secretion, either of which may be the

predominant feature. Both are usually

predominant feature. Both are usually

present at the time that this form of

present at the time that this form of

diabetes is clinically manifest. By

diabetes is clinically manifest. By

definition, the specific reasons for the

definition, the specific reasons for the

development of these abnormalities

development of these abnormalities

are not yet known.

are not yet known.

Diabetes type 2 (2)

Diabetes mellitus of this type previously

Diabetes mellitus of this type previously

encompassed non-insulin-dependent

encompassed non-insulin-dependent

diabetes, or adult-onset diabetes. It is a

diabetes, or adult-onset diabetes. It is a

term used for individuals who have relative

term used for individuals who have relative

(rather than absolute) insulin deficiency.

(rather than absolute) insulin deficiency.

People with this type of diabetes frequently

People with this type of diabetes frequently

are resistant to the action of insulin. At

are resistant to the action of insulin. At

least initially, and often throughout their

least initially, and often throughout their

lifetime, these individuals do not need

lifetime, these individuals do not need

insulin treatment to survive.

insulin treatment to survive.

Diabetes type 2 (3)

This form of diabetes is frequently

This form of diabetes is frequently

undiagnosed for many years because

undiagnosed for many years because

the hyperglycaemia is often not

the hyperglycaemia is often not

severe enough to provoke noticeable

severe enough to provoke noticeable

symptoms of diabetes. Nevertheless,

symptoms of diabetes. Nevertheless,

such patients are at increased risk of

such patients are at increased risk of

developing macrovascular and

developing macrovascular and

microvascular complications

microvascular complications

Diabetes type 2 (4)

The majority of patients with this form of

The majority of patients with this form of

diabetes are obese, and obesity itself causes

diabetes are obese, and obesity itself causes

or aggravates insulin resistance. Many of

or aggravates insulin resistance. Many of

those who are not obese by traditional weight

those who are not obese by traditional weight

criteria may have an increased percentage of

criteria may have an increased percentage of

body fat distributed predominantly in the

body fat distributed predominantly in the

abdominal region. Ketoacidosis is infrequent

abdominal region. Ketoacidosis is infrequent

in this type of diabetes; when seen it usually

in this type of diabetes; when seen it usually

arises in association with the stress of

arises in association with the stress of

another illness such as infection

another illness such as infection

Diabetes type 2 (5)

The risk of developing Type 2

The risk of developing Type 2

diabetes increases with age,

diabetes increases with age,

obesity, and lack of physical

obesity, and lack of physical

activity. It occurs more frequently

activity. It occurs more frequently

in women with prior GDM and in

in women with prior GDM and in

individuals with hypertension or

individuals with hypertension or

dyslipidaemia.

dyslipidaemia.

Diabetes type 3 (1)

Other Specific Types are currently less

Other Specific Types are currently less

common causes of diabetes mellitus,

common causes of diabetes mellitus,

but are those in which the underlying

but are those in which the underlying

defect or disease process can be

defect or disease process can be

identified in a relatively specific

identified in a relatively specific

manner. They include, for example,

manner. They include, for example,

fibrocalculous pancreatopathy, a form

fibrocalculous pancreatopathy, a form

of diabetes which was formerly

of diabetes which was formerly

classified as one type of malnutrition-

classified as one type of malnutrition-

related diabetes mellitus.

related diabetes mellitus.

Diabetes type 3 A (1)

Several forms of the diabetic state may be

Several forms of the diabetic state may be

associated with monogenic defects in

associated with monogenic defects in





-

-

cell function, frequently characterized by

cell function, frequently characterized by

onset of mild hyperglycaemia at an early

onset of mild hyperglycaemia at an early

age (generally before age 25 years). They

age (generally before age 25 years). They

are usually inherited in an autosomal

are usually inherited in an autosomal

dominant pattern. Patients with these

dominant pattern. Patients with these

forms of diabetes, formerly referred to as

forms of diabetes, formerly referred to as

maturity-onset diabetes of the young

maturity-onset diabetes of the young

(MODY), have impaired insulin secretion

(MODY), have impaired insulin secretion

with minimal or no defect in insulin action.

with minimal or no defect in insulin action.

Diabetes type 3 A (2)

Abnormalities at three genetic loci

Abnormalities at three genetic loci

on different chromosomes have

on different chromosomes have

now been characterized. The most

now been characterized. The most

common form is associated with

common form is associated with

mutations on chromosome 12 in a

mutations on chromosome 12 in a

hepatic nuclear transcription

hepatic nuclear transcription

factor referred to as HNF1alpha.

factor referred to as HNF1alpha.

Diabetes type 3 A (3)

A second form is associated with mutations

A second form is associated with mutations

in the glucokinase gene on chromosome

in the glucokinase gene on chromosome

7p. Glucokinase converts glucose to

7p. Glucokinase converts glucose to

glucose-6-phosphate, the metabolism of

glucose-6-phosphate, the metabolism of

which in turn stimulates insulin secretion

which in turn stimulates insulin secretion

by the beta cell. Thus, glucokinase serves

by the beta cell. Thus, glucokinase serves

as the "glucose sensor" for the beta cell.

as the "glucose sensor" for the beta cell.

Because of defects in the glucokinase gene,

Because of defects in the glucokinase gene,

increased levels of glucose are necessary

increased levels of glucose are necessary

to elicit normal levels of insulin secretion.

to elicit normal levels of insulin secretion.

Diabetes type 3 A (4)

A third form is associated with a mutation in

A third form is associated with a mutation in

the HNF4alpha gene on chromosome 20q.

the HNF4alpha gene on chromosome 20q.

HNF4alpha is a transcription factor which is

HNF4alpha is a transcription factor which is

involved in the regulation of the expression

involved in the regulation of the expression

of HNF1alpha. A fourth variant has recently

of HNF1alpha. A fourth variant has recently

been ascribed to mutations in another

been ascribed to mutations in another

transcription factor gene, IPF-1, which in its

transcription factor gene, IPF-1, which in its

homozygous form leads to total pancreatic

homozygous form leads to total pancreatic

agenesis. Specific genetic defects in other

agenesis. Specific genetic defects in other

individuals who have a similar clinical

individuals who have a similar clinical

presentation are currently being defined.

presentation are currently being defined.

Diabetes type 3 A (5)

Point mutations in mitochondrial DNA have

Point mutations in mitochondrial DNA have

been found to be associated with diabetes

been found to be associated with diabetes

mellitus and deafness. The most common

mellitus and deafness. The most common

mutation occurs at position 3243 in the tRNA

mutation occurs at position 3243 in the tRNA

leucine gene, leading to an A to G

leucine gene, leading to an A to G

substitution. An identical lesion occurs in the

substitution. An identical lesion occurs in the

MELAS syndr

MELAS syndr

.

.

(Mitochondrial myopathy,

(Mitochondrial myopathy,

Encephalopathy, Lactic Acidosis, and Stroke-

Encephalopathy, Lactic Acidosis, and Stroke-

like syndrome); however, diabetes is not part

like syndrome); however, diabetes is not part

of this syndr

of this syndr

.,

.,

suggesting for unknown reasons

suggesting for unknown reasons

different phenotypic expressions of this

different phenotypic expressions of this

genetic lesion.

genetic lesion.

Diabetes type 3 A (6)

Genetic abnormalities that result in the inability

Genetic abnormalities that result in the inability

to convert proinsulin to insulin have been

to convert proinsulin to insulin have been

identified in a few families. Such traits are

identified in a few families. Such traits are

usually inherited in an autosomal dominant

usually inherited in an autosomal dominant

pattern and the resultant carbohydrate

pattern and the resultant carbohydrate

intolerance is mild. Similarly, mutant insulin

intolerance is mild. Similarly, mutant insulin

molecules with impaired receptor binding

molecules with impaired receptor binding

have been identified in a few families. These

have been identified in a few families. These

are also associated with autosomal

are also associated with autosomal

inheritance and either normal or only mildly

inheritance and either normal or only mildly

impaired carbohydrate metabolism.

impaired carbohydrate metabolism.

Diabetes type 3 A (7)

Type 3 A.

Type 3 A.

Genetic defects of beta-cell function

Genetic defects of beta-cell function





       

       

Chromosome 20, HNF4alpha (MODY1)

Chromosome 20, HNF4alpha (MODY1)





       

       

Chromosome 7, glucokinase (MODY2)

Chromosome 7, glucokinase (MODY2)





       

       

Chromosome 12, HNF1alpha (MODY3)

Chromosome 12, HNF1alpha (MODY3)





       

       

Chromosome 13, IPF-1 (MODY4)

Chromosome 13, IPF-1 (MODY4)





       

       

Mitochondrial DNA 3243 mutation

Mitochondrial DNA 3243 mutation

Others

Others

Diabetes type 3 B (1)

There are some unusual causes of diabetes

There are some unusual causes of diabetes

which result from genetically determined

which result from genetically determined

abnormalities of insulin action. The metabolic

abnormalities of insulin action. The metabolic

abnormalities associated with mutations of the

abnormalities associated with mutations of the

insulin receptor may range from

insulin receptor may range from

hyperinsulinaemia and modest

hyperinsulinaemia and modest

hyperglycaemia to symptomatic diabetes.

hyperglycaemia to symptomatic diabetes.

Some individuals with these mutations have

Some individuals with these mutations have

acanthosis nigricans. Women may have

acanthosis nigricans. Women may have

virilization and have enlarged, cystic ovaries.

virilization and have enlarged, cystic ovaries.

In the past, this syndrome was termed Type A

In the past, this syndrome was termed Type A

insulin resistance.

insulin resistance.

Diabetes type 3 B (2)

Leprechaunism and Rabson-Mendenhall

Leprechaunism and Rabson-Mendenhall

syndrome are two paediatric syndromes

syndrome are two paediatric syndromes

that have mutations in the insulin

that have mutations in the insulin

receptor gene with subsequent alterations

receptor gene with subsequent alterations

in insulin receptor function and extreme

in insulin receptor function and extreme

insulin resistance. The former has

insulin resistance. The former has

characteristic facial features while the

characteristic facial features while the

latter is associated with abnormalities of

latter is associated with abnormalities of

teeth and nails and pineal gland

teeth and nails and pineal gland

hyperplasia.

hyperplasia.

Diabetes type 3 B (3)

Type 3 B.

Type 3 B.

Genetic defects in insulin action

Genetic defects in insulin action





       

       

Type A insulin resistance

Type A insulin resistance





       

       

Leprechaunism

Leprechaunism





       

       

Rabson-Mendenhall syndrome

Rabson-Mendenhall syndrome





       

       

Lipoatrophic diabetes

Lipoatrophic diabetes

Others

Others

Diabetes type 3 C (1)

Any process that diffusely injures the pancreas can cause

Any process that diffusely injures the pancreas can cause

diabetes. Acquired processes include pancreatitis, trauma,

diabetes. Acquired processes include pancreatitis, trauma,

infection, pancreatic carcinoma, and pancreatectomy. With

infection, pancreatic carcinoma, and pancreatectomy. With

the exception of cancer, damage to the pancreas must be

the exception of cancer, damage to the pancreas must be

extensive for diabetes to occur. However,

extensive for diabetes to occur. However,

adenocarcinomas

adenocarcinomas

that involve only a small portion of the pancreas have been

that involve only a small portion of the pancreas have been

associated with diabetes. This implies a mechanism other

associated with diabetes. This implies a mechanism other

than simple reduction in

than simple reduction in





-cell mass. If extensive enough,

-cell mass. If extensive enough,

cystic fibrosis and haemochromatosis will also damage beta

cystic fibrosis and haemochromatosis will also damage beta

cells and impair insulin secretion. Fibrocalculous

cells and impair insulin secretion. Fibrocalculous

pancreatopathy may be accompanied by abdominal pain

pancreatopathy may be accompanied by abdominal pain

radiating to the back and pancreatic calcification on X-ray

radiating to the back and pancreatic calcification on X-ray

and ductal dilatation. Pancreatic fibrosis and calcified stones

and ductal dilatation. Pancreatic fibrosis and calcified stones

in the exocrine ducts are found at autopsy.

in the exocrine ducts are found at autopsy.

Diabetes type 3 C (2)

Type 3 C.

Type 3 C.

Diseases of the exocrine pancreas

Diseases of the exocrine pancreas





       

       

Fibrocalculous pancreatopathy

Fibrocalculous pancreatopathy





       

       

Pancreatitis

Pancreatitis





       

       

Trauma / pancreatectomy

Trauma / pancreatectomy





       

       

Neoplasia

Neoplasia





       

       

Cystic fibrosis

Cystic fibrosis





       

       

Haemochromatosis

Haemochromatosis





       

       

Others

Others

Diabetes type 3 D (1)

Several hormones (e.g. growth hormone, cortisol,

Several hormones (e.g. growth hormone, cortisol,

glucagon, epinephrine) antagonize insulin action.

glucagon, epinephrine) antagonize insulin action.

Diseases associated with excess secretion of these

Diseases associated with excess secretion of these

hormones can cause diabetes (e.g. Acromegaly,

hormones can cause diabetes (e.g. Acromegaly,

Cushing's Syndrome, Glucagonoma and Phaeo

Cushing's Syndrome, Glucagonoma and Phaeo

-

-

chromocytoma).

chromocytoma).

Somatostatinoma, and aldostero

Somatostatinoma, and aldostero

-

-

noma-induced hypokalaemia, can cause diabetes,

noma-induced hypokalaemia, can cause diabetes,

at least in part by inhibiting insulin secretion.

at least in part by inhibiting insulin secretion.

Hyperglycaemia generally resolves following

Hyperglycaemia generally resolves following

successful removal of the tumour

successful removal of the tumour

and

and

when the

when the

hormone excess is removed.

hormone excess is removed.

Diabetes type 3 D (2)

Type 3 D.

Type 3 D.

Endocrinopathies

Endocrinopathies





       

       

Cushing's syndrome

Cushing's syndrome





       

       

Acromegaly

Acromegaly





       

       

Phaeochromocytoma

Phaeochromocytoma





       

       

Glucagonoma

Glucagonoma





       

       

Hyperthyroidism

Hyperthyroidism





       

       

Somatostatinoma

Somatostatinoma

Others

Others

Diabetes type 3 E (1)

Many drugs can impair insulin secretion.

Many drugs can impair insulin secretion.

These drugs may not, by themselves,

These drugs may not, by themselves,

cause diabetes but they may precipitate

cause diabetes but they may precipitate

diabetes in persons with insulin

diabetes in persons with insulin

resistance. Certain

resistance. Certain

rare

rare

toxins such as

toxins such as

Vacor (a rat poison) and pentamidine can

Vacor (a rat poison) and pentamidine can

permanently destroy pancreatic beta cells.

permanently destroy pancreatic beta cells.

There are also many drugs and hormones

There are also many drugs and hormones

which can impair insulin action. Examples

which can impair insulin action. Examples

include nicotinic acid and glucocorticoids.

include nicotinic acid and glucocorticoids.

Diabetes type 3 E (2)

Type 3 E.

Type 3 E.

Drug- or chemical-induced

Drug- or chemical-induced





   

   

Nicotinic acid

Nicotinic acid





       

       

Glucocorticoids

Glucocorticoids





       

       

Thyroid hormone

Thyroid hormone





       

       

Alpha-adrenergic agonists

Alpha-adrenergic agonists





       

       

Beta-adrenergic agonists

Beta-adrenergic agonists





       

       

Thiazides

Thiazides





       

       

Dilantin

Dilantin





       

       

Pentamidine

Pentamidine





       

       

Vacor

Vacor





       

       

Interferon-alpha therapy

Interferon-alpha therapy

Others

Others

Diabetes type 3 F (1)

Type 3 F.

Type 3 F.

Infections

Infections





       

       

Congenital rubella

Congenital rubella





       

       

Cytomegalovirus

Cytomegalovirus

Others

Others

Diabetes type 3 G (1)

Diabetes may be associated with several immunological

Diabetes may be associated with several immunological

diseases different from the Type 1 diabetes. Postprandial

diseases different from the Type 1 diabetes. Postprandial

hyperglycaemia of a severity sufficient to fulfil the criteria for

hyperglycaemia of a severity sufficient to fulfil the criteria for

diabetes

diabetes

is present

is present

in rare individuals who spontaneously

in rare individuals who spontaneously

develop insulin autoantibodies

develop insulin autoantibodies

.

.

However, these individuals

However, these individuals

generally present with symptoms of hypoglycaemia rather than

generally present with symptoms of hypoglycaemia rather than

hyperglycaemia. The "stiff man syndrome" is an autoimmune

hyperglycaemia. The "stiff man syndrome" is an autoimmune

disorder of the central nervous system, characterized by

disorder of the central nervous system, characterized by

stiffness of the axial muscles with painful spasms. Affected

stiffness of the axial muscles with painful spasms. Affected

people usually have high titres of the GAD autoantibodies and

people usually have high titres of the GAD autoantibodies and

approximately one-half will develop diabetes. Patients receiving

approximately one-half will develop diabetes. Patients receiving

interferon alpha have been reported to develop diabetes

interferon alpha have been reported to develop diabetes

associated with islet cell autoantibodies and, in certain

associated with islet cell autoantibodies and, in certain

instances, severe insulin deficiency.

instances, severe insulin deficiency.

Diabetes type 3 G (2)

Anti-insulin receptor antibodies can cause diabetes

Anti-insulin receptor antibodies can cause diabetes

by binding to the insulin receptor thereby reducing

by binding to the insulin receptor thereby reducing

the binding of insulin to target tissues. However,

the binding of insulin to target tissues. However,

these antibodies also can act as an insulin agonist

these antibodies also can act as an insulin agonist

after binding to the receptor and can thereby cause

after binding to the receptor and can thereby cause

hypoglycaemia.

hypoglycaemia.

Anti-insulin receptor antibodies are occasionally

Anti-insulin receptor antibodies are occasionally

found in patients with systemic lupus

found in patients with systemic lupus

erythematosus and other autoimmune diseases. As

erythematosus and other autoimmune diseases. As

in other states of extreme insulin resistance,

in other states of extreme insulin resistance,

patients with anti-insulin receptor antibodies often

patients with anti-insulin receptor antibodies often

have acanthosis nigricans. In the past, this

have acanthosis nigricans. In the past, this

syndrome was termed Type B insulin resistance.

syndrome was termed Type B insulin resistance.

Diabetes type 3 G (3)

Type 3 G.

Type 3 G.

Uncommon forms of immune-

Uncommon forms of immune-

mediated diabetes

mediated diabetes





     

     

Insulin autoimmune syndrome

Insulin autoimmune syndrome

(antibodies to insulin)

(antibodies to insulin)





     

     

Anti-insulin receptor antibodies

Anti-insulin receptor antibodies





     

     

"Stiff Man" syndrome

"Stiff Man" syndrome

Others

Others

Diabetes type 3 H (1)

Many genetic syndromes are accompanied by

Many genetic syndromes are accompanied by

an increased incidence of diabetes mellitus.

an increased incidence of diabetes mellitus.

These include the chromosomal abnormalities

These include the chromosomal abnormalities

of Down's syndrome, Klinefelter's syndrome

of Down's syndrome, Klinefelter's syndrome

and Turner's syndrome. Wolfram's syndrome

and Turner's syndrome. Wolfram's syndrome

is an autosomal recessive disorder

is an autosomal recessive disorder

characterized by insulin-deficient diabetes

characterized by insulin-deficient diabetes

and the absence of beta cells at autopsy.

and the absence of beta cells at autopsy.

Additional manifestations include diabetes

Additional manifestations include diabetes

insipidus, hypogonadism, optic atrophy, and

insipidus, hypogonadism, optic atrophy, and

neural deafness.

neural deafness.

Diabetes type 3 H (2)

Type 3 H.

Type 3 H.

Other Genetic Syndromes Sometimes Associated with

Other Genetic Syndromes Sometimes Associated with

Diabetes

Diabetes





       

       

Down's syndrome

Down's syndrome





       

       

Friedreich's ataxia

Friedreich's ataxia





       

       

Huntington's chorea

Huntington's chorea





       

       

Klinefelter's syndrome

Klinefelter's syndrome





       

       

Lawrence-Moon-Biedel syndrome

Lawrence-Moon-Biedel syndrome





       

       

Myotonic dystrophy

Myotonic dystrophy





       

       

Porphyria

Porphyria





       

       

Prader-Willi syndrome

Prader-Willi syndrome





       

       

Turner's syndrome

Turner's syndrome





       

       

Wolfram's syndrome

Wolfram's syndrome

Gestational Diabetes

(1)

Gestational diabetes is carbohydrate

Gestational diabetes is carbohydrate

intolerance resulting in hyperglycaemia of

intolerance resulting in hyperglycaemia of

variable severity with onset or first

variable severity with onset or first

recognition during pregnancy. It does not

recognition during pregnancy. It does not

exclude the possibility that the glucose

exclude the possibility that the glucose

intolerance may antedate pregnancy but

intolerance may antedate pregnancy but

has been previously unrecognized. The

has been previously unrecognized. The

definition applies irrespective of whether

definition applies irrespective of whether

or not insulin is used for treatment or the

or not insulin is used for treatment or the

condition persists after pregnancy.

condition persists after pregnancy.

Gestational Diabetes

(2)

Women who become pregnant and

Women who become pregnant and

who are known to have diabetes

who are known to have diabetes

mellitus which antedates pregnancy

mellitus which antedates pregnancy

do not have gestational diabetes but

do not have gestational diabetes but

have "diabetes mellitus and

have "diabetes mellitus and

pregnancy" and should be treated

pregnancy" and should be treated

accordingly before, during, and

accordingly before, during, and

after the pregnancy.

after the pregnancy.

Gestational Diabetes

(3)

Individuals at high risk for gestational

Individuals at high risk for gestational

diabetes include older women, those with

diabetes include older women, those with

previous history of glucose intolerance,

previous history of glucose intolerance,

those with a history of large for gestational

those with a history of large for gestational

age babies, women from certain high-risk

age babies, women from certain high-risk

ethnic groups, and any pregnant woman

ethnic groups, and any pregnant woman

who has elevated fasting, or casual, blood

who has elevated fasting, or casual, blood

glucose levels. Formal systematic testing

glucose levels. Formal systematic testing

for gestational diabetes is usually done

for gestational diabetes is usually done

between 24 and 28 weeks of gestation.

between 24 and 28 weeks of gestation.

Gestational Diabetes

(4)

To determine if gestational diabetes is present

To determine if gestational diabetes is present

in pregnant women, a standard OGTT

in pregnant women, a standard OGTT

should be performed after overnight fasting

should be performed after overnight fasting

(8-14 hours) by giving 75 g anhydrous

(8-14 hours) by giving 75 g anhydrous

glucose in 250-300 ml water. Plasma

glucose in 250-300 ml water. Plasma

glucose is measured fasting and after 2

glucose is measured fasting and after 2

hours. Pregnant women who meet WHO

hours. Pregnant women who meet WHO

criteria for diabetes mellitus or IGT are

criteria for diabetes mellitus or IGT are

classified as having Gestational Diabetes

classified as having Gestational Diabetes

Mellitus (GDM). After the pregnancy ends,

Mellitus (GDM). After the pregnancy ends,

the woman should be re-classified

the woman should be re-classified