Diabetes Mellitus
Symptoms of DM
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Decrease of body weight
Excessive thirst (polydipsia)
Polyuria
Weakness
Purulent skin lesions and inflammatory changes of urogenital tract
In the absence of hyperglycemia
 Screening should be performed:
o Every 3 yrs in persons >45 yrs of age
 Yearly in high risk groups :
o Obesity
o Family history of DM
o With low physical activity
o With diagnosed fasting hyperglycemia (>100 mg/dL) or glucose
intolerance
o In women with past GDM; in women which delivered a baby >4
kgs
o With HT >140/90 mmHg
o With dyslipidemia (HDL<40 mg/dL; TG> 250 mg/dL) and CVD
o In women with PCOS
Hyperglycemic states
 Normal fasting glycaemia
 Impaired fasting glycaemia (IFG 100-125 mg/dL)
 Impaired glucose tolerance (IGT; in 2h OGTT glucose 140-199 mg/dL;
according to WHO)
 Prediabetes state – IFG and/or IGT
 Diabetes mellitus:
o 1.symptoms of hyperglycemia and incidental glucose ≥ 200
mg/dL
o 2. Twice measured IFG ≥ 126 mg/dL
o 3. Glycaemia in 2h OGTT ≥ 200 mg/dL (according to WHO)
Classification of DM
 T2DM – prevalence 90%; identified in patients >30 yrs, overweight/
obese with positive family history but lack of auto-Ab characteristic of
T1DM.
 Most cases with T2DM have insulin resistance (high TG, low HDL-C)
and concurrent relative insulin deficiency and glucagon excess.
 T2DM remains undiagnosed for years in many affected persons, as a
result up to 25% of patients with t2DM have already developed 1 or
more microvascular complications by the time of diagnosis.
 T1DM – accounts for < 10% of all DM cases, occurs more commonly in
in younger persons, usually characterized by absolute insulin
deficiency; may be confirmed by the presence of anti GAD-Ab
(glutamic acid decarboxylase), anti IA-2 (anti-pancreatic islet β-cells
tyrosine phosphatase) and/or anti-insulin (IAA).
 Some T1DM are idiopathic.
 In children concentrations of Ins or C-peptide may be helpful to
establish correct diagnosis (T1DM or T2DM ?).
 The severe insulinopenia predisposes patients with T1DM to diabetic
ketoacidosis.
 Diabetic ketoacidosis may occur also in patients with T2DM.
 GDM – in women without previously diagnosed DM
 Monogenic DM – MODY (maturity –onset diabetes of the young)- 12% of all types of DM; in children with atypical presentation, course or
response to therapy. Defect or insulin secretion (mutations in HNF1A
and glucokinase genes). Family history important.
 Neonatal DM- diagnosed in children before 6 month of life.
Making the diabetes diagnosis – a new diagnostic standard NACB 2011
 The most significant change is to use HbA1c as a means of diagnosing
diabetes in addition to glucose-based methods – FPG (fasting plasma
glucose) and OGTT (oral glucose tolerance test).
 Enough of data to use HbA1c for diagnosis; the assay is based on
chemical standard.
Two steps in standardization of HbA1c assay
(1) Int Fed Clin Chem developed a reference method using mass
spectrometry for HbA1c with a chemically defined standard
(2007/2009):
Hemoglobin A β-chain glycated at N-terminal valine
(2) Proficiency testing program – in some CV ±7% (instead of 15%).
HbA1c assay manufacturers have to show traceability to the IFCC
reference method.
A new unit for reporting IFCC- standardized values has been introduced:
mmol of HbA1c/ mol of unglycated Hb mmol/ mol
Interpretation of results
We have to be aware of limitations of laboratory measurements.
Change in HbA1c of 0.5% means a change in the average glucose of 14
mg/dL.
HbA1c change of 1% means a change in AG of ~28 mg/dL.
NACB recommendation 2011 – Glucose
 Glucose measurement used to establish the diagnosis of diabetes
should be performed in venous plasma. (high)
 Glucose measurement used for screening of high-risk individuals
should be performed in venous plasma. (moderate)
 Plasma glucose should be measured in an accredited laboratory
when used for diagnosis or screening for DM. (good practice point)
Prediabetes
 There is a continuum of risk for poor patient outcomes in the
progression from normal glucose tolerance to overt T2DM.
 Prediabetes can be identified by the presence of impaired glucose
tolerance (in OGTT glucose 140-199 mg/dL at 2h) or impaired fasting
glucose of 100-125 mg/dL.
 HbA1c – as a screening tool
 FPG and OGTT – should be used for definitive diagnosis
Recommendations - Glucose
 Routine measurement of FPG is not recommended as the primary
means of monitoring or evaluating therapy in individuals with
diabetes. (low)
 Blood for FPG analysis should be drawn in the morning after at least
8h fasting. (low)
 To minimize glycolysis the sample tubes should be placed
immediately in ice-water slurry, plasma should be separated within
30 min.
 Alternatively, tube should contain rapidly effective glycolysis inhibitor
(citrate); tubes with only enolase inhibitors (NaF) should not be used
(do not prevent glycolysis). (M)
Recommendation – Glucose Meters
 Portable meters or finger-stick blood samples are not sufficient for
the diagnosis of diabetes or population screening; cause - imprecision
of results.
 SMBG = self-monitoring blood glucose is recommended for all insulintreated patients.
 In patients with t2DM treated with diet and oral agents SMBG may
help achieve better control. (H)
 Patients should be instructed in the correct use of glucose meters,
including quality control!!!
 Comparison between SMBG and laboratory glucose analysis should
be performed at regular intervals to evaluate performance of the
meters in patient’s hands.
 Total error of meters should be ≤15% at glucose concentrations of
≥5.6 mmol/L (100 mg/dL); that means <0.8 mmol/L (15 mg/dL) (L)
 Meters should measure and report plasma glucose concentrations to
facilitate comparison with laboratory assays.
Recommendation – Gestational DM
 All pregnant women, not previously known to have diabetes, should
undergo testing for gestational diabetes (GDM) at 24-28 weeks of
gestation. (H)
 GDM should be diagnosed by a 75-g oral GTT (M).
Recommendations – Urinary Glucose and Ketone Testing
 Semiquantitative urinary glucose testing is not recommended.
 Ketones measured in urine or blood (at home or in the hospital
setting) should be considered only an adjunct to the diagnosis of
DKA.
 Urine ketone measurement should not be used to diagnose or
monitor the course of DKA.
 Blood ketones that rely on the nitroprusside reaction should be used
only as an adjunct to diagnose DKA but not to monitor DKA
treatment!!
 Measurement of β-OH-butyric acid in the blood can be used for
diagnosis and monitoring DKA.
Recommendations HbA1c
 HbA1c should be measured routinely in all patients with DM to
document their degree of glycemic control. (M)
 HbA1c methods used should be certified by Natl Glycohemoglobin
Standardization Programs NGSP as traceable to DCCT
(DiabControlComplicationTrial). The manufacturers of HbA1c assays
should also show traceability to the IFCC reference method.
 Laboratories measuring HbA1c should participate in a proficiency
testing programs.
 Higher intervals are recommended for children, adolescents and
patients with limited life expectancy, extensive comorbid illnesses,
history of severe hypoglycemia etc. (H)
 HbA1c testing should be performed at least biannually in all patients
and quarterly for patients whose therapy has changed or are not
meeting treatment goals.
 HbA1c may be used for diagnosis of DM with values ≥6.5% being
diagnostic. Factors that interfere with or adversely affect the HbA1c
assay will preclude its use in diagnosis!!! POCT are not useful for the
diagnosis.
Recommendations - Genetic Markers
 There are more than 60 distinct genetic disorders associated with
glucose intolerance or frank diabetes, but there are substantial
complex genetic factors that contribute to risk of type 2 Diabetes.
 Routine measure of genetic markers is not of value for diagnosis and
management of patients with T1DM.
 For neonatal diabetes (f ex) – definition of diabetes-associated
mutations may be valuable.
 No role for routine genetic testing in T2DM.
Recommendation - Autoimmune Markers
 ICA- islet cell autoAb – recommended for screening non-diabetic
family members – donors of their pancreas for transplantation into
relatives with end-stage T1DM.
 ICA – not recommended for routine diagnosis of diabetes but can be
used for classification of DM in adults and in prospective studies of
children at genetic risk of T1DM after HLA typing at birth.
 Screening for ICA in relatives if patients with T1DM – not
recommended.
Recommendations – Albuminuria
 Annual testing for albuminuria in patients without clinical proteinuria
should begin in pubertal or postpubertal individuals 5 yrs after
diagnosis of T1DM and at the time of T2DM diagnosis, regardless of
treatment.
 Urine albumin at concentrations ≥30 mg/g creatinine should be
considered as a continuous risk marker for cardiovascular events (M).
 Spot urine collections- in the early morning; if repeated should be at
the same time of the day to minimize variation.
 No food ingestion 2h preceding the collection but good hydration is
important.
 Low urine albumin concentration (<30 mg/g creat.) are not associated
with high CV risk if eGFR is >60 mL/min-1/1.73 m2-1 and the patient
is normotensive eGFR<60 mL and UA ≥30 mg/g creat on a spot urine
sample repeat testing within a year in hypertensive patients.
Treatment goals for person with DM
Outpatient glucose targets for non-pregnant adults:
 Glucose targets should be individualized taking into account residual
life expectancy, presence of microvascular/ macrovascular
complications, CVD risk etc.
 HbA1c ≤ 6.5% or ≤ 48 mmol/mol
 FPG < 110 mg/dL
 2h OGTT < 140 mg/dL
 In some patients (history of severe hypoglycemia, limited lifeexpectancy, advanced micro/ macrovascular complications, longstanding DM) less stringent goals may be considered
 HbA1c 7.0 – 8.0 % or 53-64 mmol/mol
Inpatient glucose targets for non-pregnant adults:
 For most hospitalized persons with hyperglycemia recommended
 FPG 140-180 mg/dL
Outpatient glucose targets for pregnant woman:
 For women with GDM
 FPG ≤ 95 mg/dL
 1h OGTT ≤ 140 mg/dL
 2h OGTT ≤ 120 mg/dL
 For pregnant women with preexisting T1DM or T2DM
 FPG 60-99 mg/dL
 HbA1c ≤ 6.0% or ≤ 42 mmol/mol
Treatment period of GDM is short:
Serum fructosamine is a better retrospective marker for monitoring
Glycaemia (glycaemia within last 3 weeks).
Treatment goals for person with DM
 A DM comprehensive care plan should include:
o Modification of CVD risk factors,
o Reduction of blood pressure
o Life-style changes
o Anti-hyperglycemic pharmacotherapy
How should glucose monitoring be used
 HbA1c should be measured at least twice yearly in patients with DM
 At least 4 times yearly in those not at target
 SMBG – by all patients using insulin min twice daily; ideally before
insulin injection
 More frequent SMBG – in patients with frequent hypoglycemia, not at
HbA1c target
 Patients not requiring insulin may benefit from SMBG
 CGM (continuous glucose monitoring) can be useful to improve HbA1c
levels and reduce hypoglycemia
How should micro vascular and neuropathic disease be prevented and
diagnosed?
Diabetic nephropathy:
 Beginning 5 years after diagnosis of T1DM and at diagnosis of T2DM;
annual assessment of serum creatinine to estimate GFR and urinary
albumin excretion should be performed to identify, stage and monitor
progression of diabetic nephropathy.
 When therapies with ACE inhibitors or angiotensin II receptor blockers
are used – renal function and serum K+ concentration must be closely
monitored.
Diabetic Retinopathy
 At the time of T2DM diagnosis – patients should refer to
ophthalmologist
 Optimal glucose, blood pressure and lipid control should be
implemented to slow progression of retinopathy.
Diabetic neuropathy
 Reduction of oxidative stress, improved glycemic control, improved
dyslipidemia and hypertension might have a beneficial effect.
 Elevated TG concentrations are independent predictor of myelinated
fiber density loss in patients with mild to moderate diabetic
neuropathy.
 Hyperglycemia and aberrant glucose metabolism are not the only
factors contributing to nerve damage.(Diabetes 2009, 58, 1634-40)
American Diabetes Association screening and diagnostic criteria for T2DM in
children 2008.
 FPG as the test of choice – (in adults) more reproducible than 2h
OGTT; the day-to-day intra-individual CV for FPG was 6.4-11% while
that for OGTT was 14.3-16.7%.
 The reproducibility of FPG has not been studied in children. If FPG –
the only test, some individuals may be missed.
 HbA1c seems not to be a good screening test for diagnosis of diabetes
in children/ adolescents.
Screening for DM in children/ adolescents
 To date universal screening in children/adolescents is not justified.
 It may be important for those at risk:
o Obese/overweight, with a strong family history of diabetes.