Chapter 3

Classification of Diabetes
3.1. Introduction
Hyperglycemia is the universal feature for all types of diabetes. However distinct subtypes which
differ in aetiology, underlying pathogenic mechanisms, natural history and response to treatment
can be identified.

Classification of diabetes had been evolving from aetiopathological models (e.g., Beta cell-
centric models) to novel cluster classification which is based on a constellation of immunological,
genetic, epidemiological, metabolic, and clinical variables.

These classifications are meant to optimize diabetes care and precision treatment but are based
on additional investigations (C-peptides, beta cell-specific antibodies and genotyping) which are
not standardized or not readily available in most clinical settings.

3.2. Types of diabetes

The World Health Organization (WHO) has published classification systems for diabetes since
1965. The most updated WHO classification was published in 2019. Broad categories of diabetes
subtypes are presented in figure 3.1. The major differences are the inclusion of new categories
(“hybrid types of diabetes” and “unclassified diabetes”) and removal of subtypes of type 1
diabetes and type 2 diabetes.

Figure 3. 1: Broad classification on different type of diabetes

(Based on Classification of diabetes mellitus. Geneva: World Health Organization; 2019)

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3.3. A practical method of assigning diabetes type in clinical settings
This practical clinical protocol guides clinicians to assign a patient with diabetes at the time of
presentation and to decide on treatment options especially insulin therapy when the access to
laboratory investigations are limited.

3.3.1 Steps in clinical subtyping when an individual first diagnosed with diabetes
✔ Confirm diagnosis of diabetes
✔ Exclude secondary causes of diabetes
✔ Consider the following which may assist in differentiating subtypes:
● Age at diagnosis
● Family history
● Physical findings, especially presence of obesity and features of syndromic
diabetes
● Presence of features of insulin resistance and metabolic syndrome
● Presence or absence of ketosis or ketoacidosis
✔ Perform diagnostic tests if available (β-cell autoantibodies, C-peptide, genotyping)

A definitive subtyping may not be possible for an individual at the time of diagnosis. Therefore, a
rational approach to treatment should be adopted with regular monitoring and review to reduce
glucotoxicity and insulin resistance and, to prevent ketosis.

Appropriate assignment to a subtype may be possible over time. For example, the need for longer
term insulin vs disappearance of insulin requirement in a patient presenting with ketosis.

3.4. Type 1 Diabetes (T1DM)

Type 1 diabetes was formerly called juvenile diabetes or IDDM (Insulin Dependent Diabetes
Mellitus). This type is commoner in the northern hemisphere and predominantly affects children
and young adults although no age group is exempted. In Sri Lanka among young adults less than
40 years, type 1 was shown to be 7%.

The cardinal features of patients with T1DM

1. Lower body mass index

2. Use of insulin within 12 months of diagnosis
3. Increased risk of diabetic ketoacidosis
4. Low C peptide
5. Autoantibodies

There is marked variation in the clinical presentation. Characteristic features of T1DM are given in
Table 3.1.

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Table 3. 1: Characteristic features of T1DM

Pathophysiology Characterized by immune (cellular mediated) or non-immune mediated

destruction of the β cells of the pancreas.
Special tests 70-90% of patients have islet autoantibodies at presentation. Rare group of
for diagnosis patients will not have autoimmune markers (non-immune type 1 diabetes)
Islet autoantibodies
● Glutamic acid decarboxylase [GAD-65] antibodies
● Islet cell antibodies
● Zinc transporter 8 (ZnT8)
● Auto-antibodies to insulin
● Auto-antibodies to Tyrosine phosphatase IA-2 and IA-2
Genetics - Strong HLA associations with linkage to DQA and DQB genes in
European patients. However, their specific role in pathogenesis is unclear

Clinical Variable presentations are seen

Characteristics
● Abrupt presentation with DKA (predominantly children and
adolescents and rapid beta cell destruction seen)
● Modest fasting hyperglycemia rapidly changing to severe
hyperglycemia and DKA with infection or other stress.
● Rapid remission after initial presentation with DKA or severe
hyperglycemia (honeymoon phase)
● Decreased insulin requirement for months or years (Predominantly slow
destruction seen in adults leading to variable clinical presentation)

Special remarks ● Worldwide 5% of all diabetes (7% among young diabetes in Sri Lanka)
● Some adults retain sufficient beta cell function to prevent DKA for many
years
● Often prone to other autoimmune disorders such as Hashimoto’s
thyroiditis, Grave’s disease, Celiac disease, etc.

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3.4. Type 2 Diabetes (T2DM)
The worldwide 90-95% of all diabetes is due to T2DM with highest proportions in low- and middle-
income countries. T2DM is most common in adults, but an increasing number of children and
adolescents are also affected.

Characteristic features of T2DM are shown in Table 3.2.

Table 3. 2: Characteristic features of T2DM

Pathophysiology ● β-cell dysfunction with relative insulin deficiency

● Peripheral insulin resistance
● Risk factors for T2DM (Overweight or obesity, increased percentage
of body fat distributed predominantly in the abdominal region
(sometimes with normal BMI), age, lack of physical activity,
gestational diabetes mellitus, hypertension and dyslipidemia,
ethnicity (Asian, African American, Hispanic or Latino), family history

Special tests for None

diagnosis
Clinical ● Substantial proportion are asymptomatic and detected incidentally
Characteristics during screening
● Some may present with Hyperosmotic symptoms, infections or
complications
● DKA very rarely occurs spontaneously; when seen, usually arises in
association with the stress of another illness such as infection or with
the use of certain drugs (e.g., corticosteroids, atypical antipsychotics,
and sodium–glucose cotransporter 2 inhibitors

Special remarks ● 90-95% of all diabetes (90% in young Sri Lankan adults)
● Incidence is increasing among children and adolescents due to
increasing childhood obesity

3.5. Hybrid forms of DM

Some adults will have clinical features of both T1DM & T2DM at the diagnosis, creating a diagnostic
dilemma. Slowly evolving immune-mediated diabetes and ketosis prone T2DM are newly
proposed nomenclature for these types of patients.

3.5.1. Slowly evolving immune-mediated diabetes

A group of patients with slowly evolving forms of diabetes which clinically present like T2DM but
have evidence of pancreatic autoantibodies has been recognized. This form of diabetes was
referred to as “latent autoimmune diabetes in adults” (LADA). A similar subtype has been
described in children and adolescents and was referred to as latent autoimmune diabetes in
youth (LADY).

Characteristic features of slowly evolving immune mediated DM are given in table 3.3.

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Table 3. 3: Characteristic features of slowly evolving immune mediated DM

Pathophysiology  Slowly evolving immune-mediated destruction of

pancreatic β-cells
Special tests for diagnosis ● Glutamic acid decarboxylase (GAD)
● Protein tyrosine phosphatase IA-2
● Anti-insulin antibodies
● ZnT8

Clinical characteristics ● Positivity for GAD autoantibodies

● Age older than 35 years at diagnosis
● Not needing for insulin therapy in the first 6–12 months after
diagnosis

Special remarks Differentiating features from type 1 DM

● Obesity
● Features of the metabolic syndrome
● Retaining greater β-cell function
● Expressing a single autoantibody (particularly GAD65)
● Carrying the transcription factor 7-like 2 (TCF7L2) gene
polymorphism

3.5.2. Ketosis prone T2DM

This unusual and rare form of non-immune ketosis-prone diabetes was first reported in young
African Americans in Flatbush, New York, USA and hence was termed Flatbush diabetes. Similar
phenotypes were described in populations in sub-Saharan African.

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Characteristic features of ketosis prone T2DM are given in table 3.4.

Table 3. 4: Characteristic features of ketosis prone T2DM

Pathophysiology ● Transient secretory defect of β-cells with remarkable

recovery of insulin-secretory capacity during the period(s) of
remission
● Glucose toxicity may contribute to the acute and phasic β-
cell failure
● No genetic or autoimmune etiology recognized

Special tests for diagnosis ● None

Clinical characteristics ● Typically present with ketosis and severe insulin deficiency
but later go into remission not requiring insulin treatment.
● Subsequent clinical course more closely resembled T2DM
● 90% of patients can get recurrent ketosis within 10 years

Special remarks ● First reported in young African Americans in Flatbush, New

York, USA and subsequently in Africans
● Rare in Europeans and South Asians

3.6. Hyperglycemia first detected in pregnancy

The new classification includes two categories of hyperglycemia when first recognized in
pregnancy.

1. Diabetes mellitus; defined by the same criteria as in non-pregnant persons

2. Gestational diabetes: defined by newly recommended glucose cut-off points that are
lower than those for diabetes (Detected during screening between 24 and 28 weeks of
gestation)

3.7. Other specific types of diabetes

Several specific subtypes that do not fall into above categories have been categorized (Table
3.5).

3.7.1. Monogenic diabetes

There have been considerable advances in molecular genetics of diabetes over the last two
decades. These advances have led to identify clinical subgroups and have resulted in the
recognition of new genetic syndromes. Most importantly it has been shown that genetic diagnosis
can result in improved treatment outcomes for some people, even in a small proportion of those
with diabetes. Two broad categories of monogenic diabetes i.e., monogenic defects of β-cell
function and monogenic defects of insulin action have been identified.

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[Link]. Monogenic defects of β-cell function
 Clinical subtypes due to monogenic defects in β-cell function include maturity-onset
diabetes of the young (MODY), permanent neonatal diabetes (PNDM), transient neonatal
diabetes (TNDM), and genetic syndromes where insulin-deficient diabetes is associated
with specific clinical features.

 A subtype of autosomal dominantly inherited early-onset familial diabetes (generally with

onset before the age of 25 years) that does not require insulin initially was recognized
clinically as MODY. The basic pathophysiology was β-cell dysfunction. Mutations in the
glucokinase gene (GCK MODY) and hepato-nuclear factor gene (HNF1A MODY and
HNF4A MODY) are the commonest. In GCK MODY life-long mild fasting hyperglycemia is
seen and patients rarely develop microvascular complications and hence do not require
pharmacological treatment. HNF1A MODY is the commonest form and results in
progressive and marked hyperglycemia with a high risk of microvascular and
macrovascular complications. However, these patients are sensitive to the
hypoglycaemic effects of sulfonylureas.

 Monogenic diabetes that occurs before six months of age is termed monogenic neonatal
diabetes. About 50% have transient form (TNDM) that resolves spontaneously majority
(~70%) having abnormalities in the chromosome 6q24 region. Those who have permanent
neonatal (PNDM) have mutations in KCNJ11 or ABCC8 genes which encode the Kir6.2 and
SUR1 subunits of the ATP-sensitive potassium channel (KATP channel). Hence these
individuals can be treated with oral sulfonylureas without insulin like in HNF MODY.

 Heteroplasmic mitochondrial gene mutation at position 3243 leads to maternally inherited

diabetes and deafness (MIDD) with sensor-neural deafness and diabetes. Some of them
also have myopathy, pigmented retinopathy, cardiomyopathy, and focal
glomerulosclerosis. Several multisystem monogenic syndromes with marked β-cell
dysfunction have been described. Wolfram’s syndrome (WFS1 and WFS2) due to
autosomal recessive inheritance characterized by severe insulin-deficiency is associated
with optic atrophy, diabetes insipidus, and neural deafness (DIDMOAD).

[Link]. Monogenic defects of insulin action

 Less common than monogenic β-cell defects. Characterized by features of insulin

resistance (hyperinsulinemia, acanthosis nigricans, polycystic ovarian disease and
virilization) without having obesity. Mutations in the insulin receptor gene leads to several
hyperglycemic syndromes. Extreme insulin resistance, dysmorphism, severe intra- uterine
retardation and early mortality is seen in two pediatric syndromes, Leprechaunism and
Rabson-Mendenhall syndrome.
 Insulin resistance and lipodystrophy are seen in familial partial lipodystrophy due to
mutations in the LMNA gene coding for nuclear lamin A/C and early onset diabetes due
to PPARG mutations.

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3.7.2. Diseases of the exocrine pancreas
 Processes such as pancreatitis, trauma, infection, pancreatic cancer and
pancreatectomy that diffusely damages the pancreas can cause diabetes. cystic fibrosis
leads to both exocrine pancreatic failure and reduced insulin secretion.

 However, the exact relationship between these two defects is not clear. Abdominal pain
and pancreatic calcification on X-ray or ultrasound and ductal dilatation are
characteristic features in Fibrocalculous pancreatopathy.

3.7.3. Endocrine disorders

 Excess secretion of hormones that have anti insulin actions (e.g., growth hormone, cortisol,
glucagon, epinephrine) leads diabetes (e.g., acromegaly, Cushing’s syndrome,
glucagonoma and phaeochromocytoma).

 Successful treatment of the condition causing hormone excess usually leads to resolution
of diabetes. A rare endocrine tumour somatostatinoma inhibits insulin secretion and
causes hyperglycemia.

3.7.4. Drug or chemical-induced diabetes

Drugs that can affect insulin secretion or insulin action (Table 3.6) can precipitate diabetes in
persons with insulin resistance or moderate β-cell dysfunction.

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Table 3. 5: Specific subtypes of Diabetes Mellitus

Table 3.6.6

Table 3.6

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3.7.5. Infection-related diabetes
Coxsackie B, cytomegalovirus, adenovirus and mumps and several other viruses have been
implicated in inducing T1DM but their role in its aetiology is uncertain. Diabetes has been
recognized in some people with congenital rubella.

Table 3. 6: Drugs or chemicals that can induce diabetes and other genetic syndromes
sometimes associated with diabetes

Drugs or chemicals that can induce diabetes Other genetic syndromes sometimes associated
with diabetes
 Glucocorticoids  Down syndrome
 Thiazides  Friedreich’s ataxia
 Alpha-adrenergic agonists  Huntington’s chorea
 Beta-adrenergic agonists  Klinefelter’s syndrome
 Phenytoin  Lawrence-Moon-Biedel syndrome
 Pentamidine  Myotonic dystrophy
 Nicotinic acid  Porphyria
 Pyrinuron  Prader-Willi syndrome
 Thyroid hormone  Turner’s syndrome Others
 Interferon-alpha Others

3.7.6. Uncommon specific forms of immune-mediated diabetes

 Diabetes has been described in several immunological diseases with a different
pathogenesis to T1DM. Hyperglycemia sufficient to be called diabetes but more
commonly hypoglycaemia has been reported in individuals who develop insulin
autoantibodies.

 Antibodies that bind to insulin receptors can also cause diabetes by reducing the binding
of insulin to target tissues as well as hypoglycaemia due to insulin agonist effect on the
receptor. People with insulin receptor autoantibodies often have acanthosis nigricans and
this syndrome was termed Type B insulin resistance in the past.

 In the “stiff man syndrome” where about 50% develop diabetes is an autoimmune disorder
of the central nervous system, characterized by stiffness of the axial muscles with painful
spasms is associated with very high titers of GAD65 autoantibodies.

3.7.7. Other genetic syndromes sometimes associated with diabetes

Several genetic syndromes associated with an increased incidence of diabetes have been
described (See table 3.6 for details).

3.8. Unclassified Diabetes

With increasing availability of autoantibodies, molecular genetic diagnostics subtyping diabetes
has become increasingly complex. Hence a subtype has been proposed to classify patients who
cannot be assigned to a distinct form until the proper diagnosis is made.

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