Classification of Diabetes

Dr . Samia A Ali Elmiladi

Consultant physician, Diabetes & Endocrinology
Hospital, Associated professor
Diploma in Diabetes2023
 Content
 ADA Classification of Diabetes,,,2023

What tests should be ordered to differentiate T2DM from other conditions?

Aβ classification of ketosis-prone diabetes

Late Autoimmune Diabetes of the Adult

Causes of Severe Insulin Resistance

Insulin Deficiency

Uncommon Types of Diabetes Mellitus

subtypes of maturity-onset diabetes of the young and treatment options

 Classification of Diabetes

1. Type 1 diabetes :

2. Type 2 diabetes

3. Specific types of diabetes due to other causes

4. Gestational diabetes mellitus (diabetes diagnosed in the second or third

trimester of pregnancy that was not clearly overt diabetes prior to gestation)
 Etiologic Classification of Diabetes Mellitus.

Specific types of diabetes due to other causes

A-Genetic defect in ß –cell function

B-Genetic defects in insulin action

C-Disease of the exocrine pancreas

D-Endocrino-pathies

E-Pharmacologically or chemically induced

F-Infections

G-Infrequent forms of autoimmune diabetes

 Etiologic Classification of Diabetes Mellitus
A-Genetic defect in ß –cell function B-Genetic defects in insulin action
1- chromosome 12 ,HNF-1 α (MODY 3). 1-Type A insulin resistance
2-Chromosome 7,glycosidase (MODY2) 2-Leprechhaunism
3-Chromosome 20,HNF-4α (MODY1) 3-Rabson-Mendenhall syndrome
4-Mitochondrial DNA 4-Lipotrophic diabetes
5-Monogenic diabetes
C-Disease of the exocrine pancreas D-Endocrino-pathies

1-Pancreatitis 1-Acromegaly

2-Pancreatectomy/ trauma 2-Cushing syndrome

3-Neoplasis 3-Glucagonoma
4-Cystic fibrosis 4-Pheochromocytoma
5-Hemochromatosis 5-Hyperthyridism
6-Fibrocalcific pancreato-pathy 6-Somatostatinoma
7-Aldosteronoma
E-pharmacologically or chemically induced F-Infections
1-Vacor 1-Congenital rubella
2-Pentamidine 2-Cytomegalovirus
3-Nicotinic acid G-Infrequent forms of autoimmune DM
4-Glucocorticoids 1-Stiff-man syndrome
5-Thyroid hormone 2-Antibodies against insulin receptors
6-Diazoxide
7-β-adrenergic agonists
8-Tiazides
9-Dilantin
10-α-interferon
Other syndrome occasionally associated with diabetes
1- Down syndrome
2-Klinefelter syndrome
3-Tunner syndrome
4-Wolfram syndrome
5-Friedreich ataxia
6-Huntington´s chorea
7-Lanwrence-Moon-Biedel syndrome
8-Myotonic dystrophy
9-Porphyria
10-Prader-Willi syndrome
The features most useful in discrimination of T1DM include younger age at diagnosis (<35
years) with lower BMI (<25 kg/m2), unintentional weight loss, ketoacidosis, and glucose
>360 mg/dL (20 mmol/L) at presentation .

Occasionally, people with T2DM may present with DKA ,particularly members of ethnic
and racial minorities .

classification of diabetes type is not always straightforward at presentation and that

misdiagnosis is common (e.g., adults with T1DM misdiagnosed as havingT2DM ,
individuals with maturity onset diabetes of the young [MODY] misdiagnosed as
havingT1DM )
 What tests should be ordered to
differentiate T2DM from other conditions?
Approximately 10% of people initially diagnosed with T2DM turn out have another form
of diabetes.(3)

In middle age patients ,without the typical type 2 phenotype, we should consider other
diagnoses, including a secondary cause of beta cell failure. The most importantly, if a
person presents with new onset insulin deficiency above over the age of 50- ,present
with the “polys,” weight loss, and steatorrhea- the primary concern should be pancreatic
insufficiency either from pancreatitis or a pancreatic tumor.

3) Harris MI, Robbins DC.. Diabetes Care 1994.

 Aβ classification of ketosis-prone diabetes

the presence or absence of autoimmunity (A) and β-cell function (β) assessed by
autoantibody testing, &the fasting serum C-peptide response to glucagon
stimulation.
 β-Cell testing should be performed a few weeks after resolution of DKA to
minimize any acute effects of glucotoxicity.
Patients are classified as β+ if the fasting serum C-peptide concentration is ≥1
ng/mL or if the peak serum C-peptide response to glucagon is at least 1.5 ng/mL;
otherwise, they are classified as β−. These cutoffs accurately predict β-cell
function and glycemic control after 1 year.

Syndromes of ketosis prone diabetes. Endocr Rev2008

Diabetes Care 2006
• A−β+ patients account for the largest subgroup of KPD. Approximately half of
these patients have new-onset diabetes and develop DKA without a clinically
evident precipitating factor (unprovoked A−β+ KPD), whereas the remainder
have long-standing diabetes before presentation with DKA, which develops in
association with acute illness or treatment noncompliance (provoked A−β+
KPD). Most are obese and have strong family history of T2D

Syndromes of ketosis prone

diabetes. Endocr Rev2008
Attempts to administer noninsulin diabetes therapies should be made on basis of
knowledge of the KPD subgroup and assessment of predictive factors. A−β+ KPD
patients have impaired insulin secretion and action at initial presentation, but
aggressive diabetes management results in significant improvement in β-cell
function and insulin sensitivity, which can allow discontinuation of insulin therapy
within a few months.

A−β+ patients have the highest frequency of metabolic syndrome among KPD
groups, and insulin-sensitizing agents (metformin, thiazolidinedione) should be
used. If BG levels are uncontrolled at 8 weeks, then one could consider adding low
doses of a sulfonylurea, meglitinide, or α-glucosidase inhibitor.

Syndromes of ketosis prone diabetes. Endocr Rev2008

An 80-year-old woman presented to endocrine clinic with complaints of weight loss,
anorexia, and severe bilateral lower extremity pain and numbness. Two years ago she was
diagnosed with T2DM ;her BMI was 17 kg/m2 , (BP) was 100/75 mmHg, and HbA1c was
7.4%. She was treated with metformin 1,000 mg twice daily, but her BG remained in the
200s mg/dL .She had not tried any other medications. She had been told to limit her diet to
control her diabetes and her weight decreased from 50 to 43 kg. The patient has a sister with
thyroid disease and a daughter with multiple sclerosis.

O/E : BP was 110/78 mmHg; HR 68 ,and thyroid, cardiac, and abdominal exams were
normal. she had considerable muscle wasting and neurologic examination revealed
diminished vibratory sensation in the lower extremities. On Lab : Repeat HbA1c was 8.8%.
TSH 15.4 μIU/mL, free T4 0.7 ng/dL, and low vitamin B12 .
This patient has poorly controlled diabetes, which progressed to
requiring insulin in a short period of time. She has a very low BMI, and
a concurrent diagnosis of Hashimoto’s thyroiditis. Her family history of
autoimmune disease and the rapid evolution to insulin dependence
suggested the diagnosis of Late Autoimmune Diabetes of the Adult.
 Late Autoimmune Diabetes of the Adult.

LADA is characterized by anti-islet-cell, anti-GAD, or anti-insulin antibodies, which are

serologic markers of chronic β-cell destruction. LADA patients share clinical features with
T2DM patients, such as older age of onset and a slower progression; however, unlike
mostT2DM , they have low or normal BMI. Most LADA patients initially are treated
forT2DM . The United Kingdom Prospective Diabetes Study detected anti-GAD positivity
in 10% of enrolled patients with presumedT2DM .
Anti-GAD is the most prevalent. It is also the most sensitive marker, as it is present
in the early stages of the disease and has a long duration in the serum. Other islet-
cell antibody titers may decrease over time, Patients with isolated GAD antibodies
develop β-cell failure more slowly as compared with patients having multiple
autoantibodies. Of those LADA patients with two or three autoantibodies, 74%
developed β-cell failure within 5 years.
Proposed diagnostic criteria for LADA include the following:

I. Age of diagnosis >30 years,

II. Presence of autoantibodies,

III. The lack of a requirement for insulin for at least 6 months after diagnosis But the
Patients with LADA will progress to insulin dependence faster than patients
withT2DM.

IV. Patients with T2DM with a low BMI or a personal and family history of
autoimmune disorders, it is important to keep the possible diagnosis of LADA in
mind.
A 60-year-old obese woman with 20-year history of T2DM presented to the clinic for
management of diabetes. She was started on insulin 15 years ago. Her current glycemic
regimen included insulin detemir 60 units twice daily, and insulin aspart according to the
following scale: blood glucose (BG) 300 = 30 units. She was averaging >200 units of
insulin per day with all SMBG readings >200 mg/dL ,and occasionally >400 mg/dL .Her
last HbA1c was 10.5%. She reported following a strict day diet, but She c/o polyuria,
nocturia, numbness, and tingling in the lower extremities and hands.
T2DM is a chronic disease that is characterized by insulin resistance and progressive β-cell
failure. After conventional modalities of treatment (diet, exercise, and noninsulin therapies)
fail to maintain desired levels of glycemic control, insulin therapy is required. Average total
daily insulin requirements for many patients with T2DM are 0.5–0.8 units/kg/day. In the
presence of more pronounced insulin resistance, however, the insulin requirements can
increase to 1–2 units/kg/day or more. Severe insulin resistance is defined as “insulin
requirements in excess of 200 units a day for more than 2 days” and can present in a
number of different conditions
 Causes of Severe Insulin Resistance

Obesity

 Stressful conditions such as severe infection or steroid use

Pregnancy, Polycystic ovary syndrome

HAIR-AN syndrome (Hyperandrogenism, Insulin Resistance, and Acanthosis Nigricans)

Hemochromatosis

Cushing’s syndrome

Werner syndrome

Lipodystrophy (congenital and acquired)

 Genetic defects of the insulin receptor gene

 Classification of Diabetes Mellitus

Insulin Resistance Other or Rare Types

insulin Deficiency Type 2 diabetes Genetic defects in ß-cell function (including 14 distinct
lmmune-mediated (type 1A) Ketosis-prone Maturity Onset Diabetes Of The Young syndromes)
Type 1 diabetes Genetic defects in insulin action
Late Autoimmune Diabetes In Adults
Endocrinopathies Acromegaly, Cushing syndrome,
Rare forms: "stiff man" syndrome, anti-insulin
receptor antibodies glucagonoma, pheochromocytoma, hyperthyroidism
ldiopathic (type 1 B) (seronegative) Somatostatinoma, aldosteronoma
Acquired Drug-related Glucocorticoids, thiazides, B-blockers,
Diseases of the exocrine pancreas: pancreatitis,
diazoxide, tacrolimus, cyclosporine, niacin, HIV protease
trauma/ pancreatectomy, neoplasia, cystic
fibrosis, emochromatosis, fibrocalculous inhibitors, atypical antipsychotics (clozapine, olanzapine)'
pancreatopathy
Genetic syndromes Down syndrome ,Wolfram syndrome
Drug-related: Vacor (pyrinuron) (rat poison),
intravenous pentamidine (Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy, And
infections: congenital rubella, enteroviruses Deafness),Klinefelter, Turner, and Prader-Willi syndromes;
myotonic dystrophy.
 Insulin Deficiency

Immune mediated type (type 1A) : in 5% to 10‘%, of persons newly diagnosed.

The mechanism of the B cell destruction is multifactorial caused by environmental factors

in persons with genetic susceptibilities.

Glutamic Acid Decarboxylase GAD65 and tyrosine phosphatases IA 2 autoantibodies are

recommended as initial testing for type 1A diabetes in newly diagnosed disease.

GAD65 have a high prevalence (70%) at the time of diagnosis and may remain detectable
for years.

Late Autoimmune Diabetes in adults

Idiopathic (type 1B) is characterized by variable insulin deficiency because of B-cell
destruction in the absence of autoantibodies ,may develop episodic DKA. Typically, have a
strong family history of Type 2 diabetes. is more common in Asian and Black people,
particularly those with sub Saharan African ancestry.

Acquired :B Cell destruction may occur from diseases affecting the pancreas or from the
effect of drugs or infections,,,,,,,,, may result in impaired insulin production or secretion with
the subsequent development of type I diabetes.
 Uncommon Types of Diabetes Mellitus
Maturity onset diabetes of the young (MODY) is characterized: Autoantibodies are typically absent

as an autosomal dominant monogenetic defect on different chromosomal loci. has at least 14 known
gene mutations. Although insulin action remains normal ,glucose sensing and insulin secretion are
altered. mutations in three genes (HNF1A, HNF4A, GCK) account for about 95% of all MODY
cases.

present with a clinical course that is frequently atypical of type I or type 2 diabetes. The onset of
symptoms typically occurs before age 25 years, and a strong family history of atypical diabetes is
often present in patients without obesity.

Treatment varies based on the gene mutation, and thus genetic counseling and testing should be
considered.
 subtypes of maturity-onset diabetes of the young and treatment options

MODY type Protein function Age at onset Phenotype Treatment

Gene (gene
location)

MODY1 HNF4A Transcription factor <18 years Progressive decrease in insulin secretion; Diet,
(20q13.12) worsening of glucose control; high risk of sulphonylureas
microvascular complications; low levels of , insulin
apolipoproteins and triglycerides; neonatal
macrosomia; neonatal hypoglycemic events

Diabetes Ther (2020)

MODY type Gene Protein function Age at onset Phenotype Treatment
(gene location)

MODY2 GCK (7p13) Enzyme Preadolescence Mild hyperglycemia Excellent Treatment is

prognosis unnecessary
(usually)

MODY3 HNF1A Transcription 25 years Decreased insulin secretion; Sulphonylureas

(12q24.31) factor high risk of microvascular (additional
complications; low glucose meglitinides, GLP-1
renal threshold RA, SGLT-2
inhibitors), insulin

Diabetes Ther (2020)

MODY type Gene (gene Protein function Age at onset Phenotype Treatment
location)

MODY4 PDX1 (13q12.2 Transcription factor Post-puberty Mild form of diabetes OHAs, insulin

MODY5 HNF1B (17q12) \ Transcription factor 25 years Decreased insulin secretion OHAs (sulfonylurea or
with progressive worsening repaglinide), insulin
of glucose control;
genitourinary
malformations (renal cysts,
azoospermia, uterus
anomaly, etc)

MODY6 NEUROD1 Transcription factor Variable Different degrees of OHAs, insulin

(2q31.3) hyperglycemia

Diabetes Ther (2020)

MODY type Gene Protein function Age at onset Phenotype Treatment
(gene location)
MODY7 KLF11 Transcription factor Variable Decreased Insulin
(2p25.1) sensitivity to insulin;
mild hyperglycemia
MODY8 CEL Lipolytic enzyme >25 years [Impaired endocrine OHAs, insulin
(9q34.13) and exocrine
pancreatic function

MODY9 PAX4 Transcription factor Postpuberty Progressive Diet, OHAs, insulin

(7q32.1) hyperglycemia;
occurrences of
ketoacidosis
MODY10 INS Hormone >10 years Hyperglycemia; [Diet, insulin
(11p15.5) diabetes

MODY11 BLK Enzyme Variable Hyperglycemia; Diet, OHAs, insulin

(8p23.1) diabetes
MODY type Gene Protein function Age at onset Phenotype Treatment
(gene location)

MODY12 ABCC8 Subunit of ATP Variable Diabetes Sulphonylureas

(11p15.1) sensitive channels

MODY13 KCNJ11 Subunit of After second decade Diabetes Sulphonylureas

(11p15.1) ATPsensitive of life
channels

MODY14 APPL1 Adaptor protein 10–50 years Hyperglycemia; Diet, OHAs, insulin
(3p14.3) diabetes

Diabetes Ther (2020)

 diabetes due to single gene defect

Inherited Sporadic
Autosomal recessive Spontaneous
Autosomal dominant (de novo) mutation
X-linked recessive

constitute 2-3% of children & adults T1DM

Diagnosed with diabetes-but majority MGD
are not recognized T2DM 92.6
750.000 Diabetic pts in USA

 On insulin inappropriately

They don't need it (MODY2)

Better treated with SU (MODY1 ,3 & NDM due to K-channel mutation)

76% of patients are incorrectly treated, 51% with insulin

 Summary of MODY2
MODY2 is not rare(1 in 1000)
Fasting hyperglycemia since birth
They are asymptomatic
Usually discovered accidently
Mainly fasting hyperglycemia (100-150mg/dl)
Usually misdiagnosed as T1 or T2
HgbA1C almost never>7.5%
Normal OGTT
No complications
Does not need treatment
When you expect it ,,,, Test parents & siblings (FBG)
MODY Probability Calculator

http://www.diabetesgenes.org/content/mody-probability-calculator
 What are the features that exclude MODY2?

Symptomatic

HgbA1C>7.5

GTT increment >5mmol/L(90mg/dl)

Develop hypoglycemia with SU

Parent FBG is normal

Sever familial diabetes with an affected parent ,,, (MODY1 & MODY3)
 Important points to diagnose MD

Age of diabetes onset

Clinical features & pattern of hyperglycemia
Severity and Progression
Associated extra-pancreatic features
Family history (Draw family pedigree)
 Hepatic nuclear factor 1-α (HNF1A)diabetes
Commonest MODY subtype

Diabetes in more > one generation

Negative pancreatic autoantibodies

Mild fasting hyperglycemia & very high glucose response to OGTT

Usually present after puberty

Age of presentation depends on the mutation site

Low renal glucose threshold

Early microvascular complications

Low level of high sensitivity CRP

 Neonatal diabetes mellitus(NDM)

Congenital diabetes
Monogenic diabetes of infancy
Diabetes diagnosed in the 1st six months
Incidence of NDM range from 1:90,000 to
1:160,000 live births

DM in the 1st six months of life is not T1DM

It is NDM and need molecular genetic testing
26 mutations
Almost all have
Extra pancreatic features
 Variable TNDM PNDM
Onset Early -1st week Late 5wks
1-80days

Birth weight Average 2kg Average 2.5kg

DKA Rare Common
Insulin requirements Less More
Umbilical hernia and Yes (25%) Non
macroglosia

Remission Yes No
Average 12wks

incidence 60% 40%

 MODY-Biomarkers

UCPCR(urine C-peptide creatinine ratio(cut-off 0.22 nmol/ mmol )

CRP(LOW)
Characteristic for MODY3
HDL(High)

Apolipoprotein M

Transthyretin

Complement C8

Have been proposed to distinguish MODY from T1DM&T2DM.

Richter, S.,et al . " Diabetes, 2003, Cervin C. et al. J Intern Med, 2010,
 This is probably MODY not type 1 Diabetes
One of parents have diabetes(below 30years).
Absence of auto-antibodies.
Detectable C-peptide (>200nmol/l) after 3 years of diagnosis.
No DKA.
Insulin holidays.
Low insulin requirements(<0.5 U/kg/day) after Honey Moon Period

 T1DM is unlikely if:

 No islet autoantibodies or
 Stimulated C-peptide >200 pmol/L 5 yr after diagnosis
 This is probably MODY not type 2 Diabetes

Young age at onset

A normal or low BMI T2DM is unlikely if;

No marked obesity or
Strong family history (2-3 generations) No acanthosis nigricans.

Absence of clinical features of insulin resistance

High HDL

Very low CRP

Sulphonylurea sensitive
Thank you