1. A historical perspective on the
diagnosis of diabetes mellitus
Aaron Neinstein, MD

2. • 1674: Physician
Thomas Willis of
Oxford notes sweet
flavor of urine in
patients with diabetes
• Initial diagnosis
centered around
presence of sugar in
the urine

3. Early 1900s: Glucose tolerance tests
• 1917: Oral glucose tolerance test introduced by
Jacobsen
Jacobsen, Aa. Th.B. (1917). The Blood Sugar in Normal
Persons and Diabetic Patients (in Danish).
Gyldenal, Copenhagen.
• 1923: Failed attempt made to establish IV glucose
tolerance test as standard by Jorgensen
Jorgensen, S.(1930). The Intravenous Glucose Tolerance
Test (in Danish). Levin and Munksgaard, Copenhagen. And
Pim, T (1923). Acts med scand., 58, 161.

4. 2-hour OGTT value was generally
diagnostic test of choice before 1979
• Studies in Pima Indian population
• Demonstrated a bimodal distribution of
glucose levels following OGTT
• The problem with this: Most populations have
a unimodal distribution of glucose levels
1. Nathan D. International Expert Committee report on the role of the A1C assay in the diagnosis of
diabetes. Diabetes Care 2009.
Bimodal distribution

5. The diagnosis of diabetes mellitus
before 1979

6. 1979: National Diabetes Data Group
• Pre-1979: At least six different criteria used
• 1979: First-ever generally accepted classification
system in the US published by NDDG
• Numerous etiologically and clinically distinct disorders
sharing hyperglycemia in common
– Insulin-dependent diabetes mellitus
– Non-insulin dependent diabetes mellitus
– Gestational diabetes mellitus
– Malnutrition-related diabetes mellitus
– “Other” diabetes mellitus
• 1980: NDDG recommendations endorsed by WHO
1. Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Report of the expert committee on the
diagnosis and classification of diabetes mellitus. Diabetes Care 2003;26 Suppl 1:S5–20.

7. 1979: National Diabetes Data Group
• Diabetes:
– FPG ≥140 mg/dl or
– OGTT 2-hr glucose ≥200 mg/dl or
– Classic symptoms present
• Impaired glucose tolerance:
– FPG ≤ 140 mg/dl and
– 2-hour OGTT glucose 140-200 mg/dl
1. Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care
2003;26Suppl 1:S5–20.
2. Nathan DM, on behalf of the International Expert Committee. International Expert Committee Report on the Role of the A1C Assay in the Diagnosis of Diabetes: Response to
Kilpatrick, Bloomgarden, and Zimmet. Diabetes Care 2009 Nov.;32(12):e160–e160.

8. NDDG’s Methods For Creating
Criteria
• NDDG acknowledged that: “there is no clear
division between diabetics and non-diabetics in
the FPG concentration or their response to an
oral glucose load,” and consequently, “an
arbitrary decision has been made as to what level
justifies the diagnosis of diabetes.”
• Criteria chosen based on glucose concentrations
that allegedly predicted development of
retinopathy
• Based on 3 prospective trials with total of 1,213
patients, 77 of whom developed retinopathy
1. Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Report of the expert committee on the diagnosis and classification of diabetes
mellitus. Diabetes Care 2003;26 Suppl 1:S5–20.
2. Nathan DM, on behalf of the International Expert Committee. International Expert Committee Report on the Role of the A1C Assay in the Diagnosis of Diabetes:

9. 1997: ADA expert committee convened
• Goal 1: To make FPG concentration and 2-hour OGTT glucose
equivalent (and negate 2HPG as gold-standard test)
• Goal 2: To focus on making relationship between glucose levels
and presence of long-term complications the basis for diagnosis
• Only 25-50% of patients with 2-hour OGTT ≥200 mg/dl had FPG
≥140 mg/dl so the FPG criteria was lowered to ≥126 mg/dl
• Terms IDDM and NIDDM eliminated (now Type 1 and Type 2)
• Impaired fasting glucose created as category
• Assigning a name to someone’s type of diabetes not as
important as understanding and treating their particular
pathogenesis
1. Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care
2003;26Suppl 1:S5–20.
2. Nathan DM, on behalf of the International Expert Committee. International Expert Committee Report on the Role of the A1C Assay in the Diagnosis of Diabetes: Response to
Kilpatrick, Bloomgarden, and Zimmet. Diabetes Care 2009 Nov.;32(12):e160–e160.

10. Prevalence of retinopathy by deciles of
distribution of FPG, 2HPG, and A1c in
Pima Indians
1. Nathan D. International Expert Committee report on the role of the A1C assay in the diagnosis of diabetes. Diabetes
Care 2009
FPG 140

11. Prevalence of retinopathy by deciles of
distribution of FPG, 2HPG, and A1c in
40-74 year-old participants in NHANES
III
1. Nathan D. International Expert Committee report on the role of the A1C assay in the diagnosis of diabetes. Diabetes
Care 2009;
FPG 140

12. 1. Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Report of the expert committee on the
diagnosis and classification of diabetes mellitus. Diabetes Care 2003;26 Suppl 1:S5–20.

13. 1997 Report + 2003 revision: Criteria
for diagnosis of diabetes mellitus
1) Symptoms of diabetes plus casual plasma glucose
concentration ≥200 mg/dl (11.1 mmol/l). Casual is defined as any
time of day without regard to last meal. Classic symptoms of
diabetes include polyuria, polydipsia, and unexplained weight
loss.
or
2) FPG ≥126 mg/dl (7.0 mmol/l). Fasting is defined as no caloric
intake for at least 8 hours.
or
3) 2-hr PG ≥200 mg/dl (11.1) mmol/l during an OGTT. The test
should be performed as described by WHO, using a glucose load
containing the equivalent of 75 gm anhydrous glucose dissolved in
water.
1. Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Report of the expert committee on the
diagnosis and classification of diabetes mellitus. Diabetes Care 2003;26 Suppl 1:S5–20.

14. 1997: Fasting plasma glucose
• FPG now preferred test over 2HPG
– More convenient
– Less costly and time consuming
– Better repeat-test reproducibility
• Problem: Only 70.4% of people with FPG ≥
126 mg/dl on first test in NHANES III had FPG
≥ 126 mg/dl when test repeated 2 weeks later

15. Impaired fasting glucose
• Established as category in 1997
• 1997: cut-off of ≥ 110 mg/dl
• 2003: cut-off lowered to ≥ 100 mg/dl

16. 2009: Expert committee recommends
HbA1c as new diagnostic criteria
• Correlation had already been shown between A1c and long-
term complications
• A1c had been considered in 1997 but not used because of lack
of standardization of assay
• Advantages of A1c over FPG or OGTT
– Better index of overall glycemic exposure
– Less biologic variability
– Stable samples
– No need for fasting or timed samples
– Relatively unaffected by acute stressors
– Used to guide management and adjust therapy
1. Nathan D. International Expert Committee report on the role of the A1C assay in the diagnosis of
diabetes. Diabetes Care 2009;

17. Prevalence of retinopathy by 0.5% A1c
intervals
1. Nathan D. International Expert Committee report on the role of the A1C assay in the diagnosis of
diabetes. Diabetes Care 2009;

18. 2009: Diagnose diabetes at A1c > 6.5%
• Confirm diagnosis with repeat A1c testing
• Risk for diabetes is on a continuum
• Pre-diabetes, impaired fasting glucose, and
impaired glucose tolerance will start to be
phased out of use
• People with A1c between 6.0-6.5% should
“receive demonstrably effective preventive
interventions.”
1. Nathan D. International Expert Committee report on the role of the A1C assay in the diagnosis of
diabetes. Diabetes Care 2009;

19. Prevalence of retinopathy by 0.5% A1c
intervals
1. Nathan D. International Expert Committee report on the role of the A1C assay in the diagnosis of
diabetes. Diabetes Care 2009;

20. The evolution of testing for diabetes
• Early criteria were attempt to categorize
people who were at risk of overt clinical
symptoms or future progression to symptoms
• Later criteria are attempt to classify people
who are at risk of long-term complications and
would benefit from treatment

21. The evolution of testing for diabetes
Urine
testing
Oral
Glucose
Tolerance
Test
Fasting
glucose
HbA1c