GLYCEMIC VARIABILITY

Speaker Name
GLYCEMIC VARIABILITY

Glycemic Variability (GV) means swings in
blood glucose level
GLYCEMIC VARIABILITY
Diminished glycemic auto-regulation or insulin shortage are
hypothesized etiological factors for these glycemic bumps.
High Glycemic Variability Low Glycemic Variability
DCCT & UKPDS
DCCT - tight glycemic control is of paramount importance in
preventing late-stage complications of T1DM, especially
cardiovascular complications.

UKPDS - confirmed the positive effect of tight glycemic
control in the prevention of micro-vascular complications in
T2DM.

Both studies demonstrated good correlation between
HbA1C and patient-relevant endpoints

DCCT- Diabetes Control and Complications Trial ; T1DM- Type 1 Diabetes Mellitus
UKPDS- United Kingdom Prospective Diabetes Study; T2DM- Type 2 Diabetes Mellitus
Patients with similar HbA1C levels can have different
Glucose variability parameters
Kohnert KD, et al; Horm Metab Res 2009; 41: 137 141
GLYCEMIC VARIABILITY

There is a growing body of evidence that not only the average
HbA1c values, but also short-term glycemic peaks and nadirs
(lasting minutes or hours), represent an independent risk factor
for complications of diabetes.

These short term glycemic peaks and nadirs represent glycemic
variability

GV & ITS RISK FACTORS
Can be of 2 Types:
within day variability- with differences between fasting and
postprandial blood glucose values throughout 24 hours
between day variability- reflecting differences in blood glucose
control from day to day

Risk Factors:
Erroneous dosage and timing of anti-diabetic drugs
Inadequate medication
Improper adherence to the treatment
Improper diet
Lack of exercise
GV & POST-PRANDIAL GLUCOSE
GV takes into account the intraday glycemic excursions including
episodes of hyperglycemia & hypoglycemia.

Major contribution to GV by PPG as most time spent in the post-
prandial state.

Also PPG correlates better with HbA1C as compared to FPG.

Variations in HbA
1C
is indicative of long term glucose variability.

Variation in intraday FPG and PPG is indicative of short term
variability.

PPG- Post-prandial Plasma Glucose; FPG- Fasting Plasma Glucose
PPG VS FPG
PPG correlates better with HbA1C as compared to FPG.
HbA
1C
HbA
1C
Avignon A et al. Diab Care 1997;20:1822-1826
Hyperglycemic spikes following every meal induce oxidative stress,
endothelial dysfunction and inflammatory reactions
Node K et al, Cardiovascular diabetology; 2009; 8:23
Weber C et al, Diabetes Technol Ther. 2009 Oct;11(10):623-33
MEASURES OF GLYCEMIC VARIABILITY
MEASURES OF GLYCEMIC VARIABILITY
Several methods to quantify glucose variability

No universally accepted gold standard

SD & CV
Easiest way is to calculate SD (standard deviation) or CV (co-
efficient of variation) from the glucose measurements

Possible to calculate SD and CV with seven-point glucose curve

But, in 7 point glucose curve some peaks and nadirs will be missed
SD & CV less accurate
MEASURES OF GLYCEMIC VARIABILITY
M-value
Measure glucose excursions via six SMBG values per 24 hrs.
The M-value is 0 in ideal controls which rises with increasing glycemic
variability or poorer glycemic control
Limitations - Number of readings are less and makes it difficult to
distinguish whether patient has high mean glucose or high glucose
variability

MAGE (Mean amplitude of glycemic excursions)
Most widely used method
Hourly blood glucose sampling for 48 hrs, CGM data can also be used
Generates a value for variation around a mean glucose level
It ignores excursions less than 1 SD
May incorrectly disregard smaller excursions
SMBG- Self Monitored Blood Glucose; CGM- Continuous Glucose Monitoring
CONTINUOUS GLUCOSE MONITORING SYSTEMS (CGMS)
Glucose measurements every
10 sec/Average level every 5
min

Sensor containing glucose
oxidase

Electric current generated by
oxidation of glucose

Electric current correlated with
glucose level

Glucose is not displayed
instantly

Continuous measurements for
72 hours
MEASURES OF GLYCEMIC VARIABILITY
CONGA (Continuous overlapping net glycemic action)
Developed specifically for CGM data
It is calculated as the SD of the summated differences between a
current observation and an observation n hours previously.
Because CONGA does not require arbitrary glucose cutoffs or
arbitrarily defined rises and falls, it seems to be a more objective
manner to define glucose variability than M-value or MAGE
Limitation cannot be calculated on SMBG data & CGM data in
daily practice is not feasible
MEASURES OF GLYCEMIC VARIABILITY
Serum measurement of 1,5-anhydroglucitol (1,5-AG)
Its re-absorption in the kidney is inhibited by excessive excretion of
urinary glucose
The higher the plasma glucose concentration, the lower the plasma
1,5-AG concentration
Urinary glucose seen at 160-190 mg/dl.
Hence, of little use in patients below this level

SD is the easiest way to quantify glycemic variability.

As easy to measure, it is the only measure which has demonstrated
correlation between GV and patient-related outcomes i.e.
mortality in ICU patients
METABOLIC EFFECTS OF GV
GV was significantly higher in the insulin treated group as
compared to the diet only and oral drug treatment group.
GV had a positive correlation with age, diabetes duration,
HbA
1C
.
GV had a negative correlation with HDL, weight, BMI and
WC.
GV showed no correlation with the lipid parameters
GV significantly correlated with 10 year risk of CHD and
fatal CHD.
373 T2DM
patients
GV was measured via
MAGE, SD, MG, nMAGE
For patients controlled on
Diet, oral or insulin therapy
Correlated with age, diabetes
duration, weight, BMI, WC,
Cholesterol, LDL, HDL, TG &
HbA
1C


Gribovschi et al. Appl Med Inform 2013; 32(1): 53-60.
BMI- body mass index, WC- Waist Circumference,
LDL- Low Density Lipoproteins, HDL- High density
lipoproteins, CHD- coronary heart disease; MG- Mean
interstetial glucose measurements
GV & OXIDATIVE STRESS
Hyperglycemia drives production of reactive oxygen species
(ROS) via 4 mechanisms:

the polyol pathway
the hexosamine pathway
protein kinase C activation
formation of advanced glycation end-products

ROS defective angiogenesis in response to ischemia, activate a
number of proinflammatory pathways, and cause long-lasting
epigenetic changes that drive persistent expression of pro-inf
ammatory genes even after glycemia is normalized
GV & OXIDATIVE STRESS
Different complications (eye, kidney, nerve, blood vessels) arise from a
number of triggers perturbing a number of metabolic pathway(s)
The urinary excretion rate of 8-iso-PGF2, a reliable marker of oxidative stress, was
found to be strongly, positively correlated (r = 0.86, p < .001) with glycemic variability
assessed from the mean amplitude of glycemic excursions (MAGE) as estimated by
continuous glucose monitoring systems (CGMS).
Monnier et al, Diabetes Care 31 (Suppl. 2):S150S154, 2008
Normo-insulinemic, hyperglycemic glucose clamp study

Different concentrations of glucose given as single spike or
oscillating between basal and high levels over a 24 hr period

T2DM paitients and healthy controls were studied

Suggested that oscillating glucose levels enhances oxidative stress &
has more deleterious effects on endothelial function as compared to
constant high glucose levels
Ceriello et al, Diabetes 2008;57:1349-54
GV AND MICROANGIOPATHY
Hyperglycemia has been known to cause endothelial apoptosis and
arterial denudation.

This increased ROS d/t GV will augment the endothelial damage
and dysfunction.

This endothelial dysfunction can lead to a number of micro- and
macro-vascular complications.

In vitro, animal & some human studies consistently report a
deleterious effect of intermittently high glucose as compared to
constant high glucose levels

However, human studies performed are less consistent in their
findings

GV & DIABETIC COMPLICATIONS
Microvascular and macrovascular complications are dependent
on dysglycemia, which has two components:
chronic sustained hyperglycemia
acute glycemic fluctuations from peaks to nadirs.

Hence, global antidiabetic strategy should be aimed at
attacking different components of dysglycemia (i.e., HbA1C,
FPG, PPG, as well as glucose variability).


GV & MICROVASCULAR COMPLICATIONS
Bragd et al, GV was found as a independent predictor of peripheral
neuropathy
However, no relation was found with other microvascular
complications like retinopathy or neuropathy

Oyibo et al, relation between painful neuropathy and M-value
calculation

Gimeno-Orma et al, correlation was found between diabetic
retinopathy and GV of FBG
Diabetic retinopathy increased with a increased FBG variation

Zoppini G et al, GV of FBG significantly
associated with diabetic retinopathy
Diabetes Metab 2008;34:612-6
Diabet Med 2002;19:870-3
J Diabetes Complications 2003;17:78-81
Nutr Metab Cardiovasc Dis 2009;19:334-9.
GV & MACROVASCULAR COMPLICATIONS
Studies produced controversial results for relation of GV &
cardiovascular complications

Gordin et al, arterial stiffness was not correlating to GV but
was positively associated with changes in SBP & DBP

Verona diabetes study in elderly T2DM, GV-FPG was found as
an independent predictor of all-cause mortality

DIGAMI 2 Trial, assessed relation between GV &
cardiovascular complications in patients with AMI & T2DM
The 1-year risk for death, reinfarction, or stroke did not relate
to glycaemic variability in T2DM patients with AMI
Diabetes Res Clin Pract 2008;80:e4-7
Circulation 1997;96:1750-4
Eur Heart J. 2013 Feb;34(5):374-9
SBP- Systolic Blood Pressure; DBP- Diastolic Blood Pressure;
AMI- Acute Myocardial Infarction; DIGAMI- Diabetes Mellitus
Insulin Glucose Infusion in Acute Myocardial Infarction
GV & CRITICALLY ILL PATIENTS
Convincing relation between short term GV and death in critically ill
patients

Dossett et al, Egi M et al, Krinsley J, all concluded that that GV
measured as SD was significant predictor of mortality in critically ill
patients, irrespective of severity of illness

However, in the subgroup of diabetic patients, no correlation
between GV and death was seen

Wintergerst et al, Hirschberg et al, showed similar correlation
between GV & mortality in pediatric ICU patients.

Interventional studies are still lacking
Am Surg 74: 67985
Anesthesiology,105:24452
Crit Care Med,36:300813
Pediatr Crit Care Med, 9:3616
Pediatrics 118: 1739 ICU- Intensive Care Unit
Hospital mortality related to mean glucose and glycemic variability.
Q1-Lowest quartile of glycemic variability; Q4-highest quartile of
glycemic variability
J.S. Krinsley: Crit Care Med 2008;36:300813
GV AND AUTONOMIC NEURAL IMBALANCE
Chronic hyperglycemia is involved in the development of
autonomic neural imbalance.

However, it has been suggested that acute fluctuations (GV) in
glucose levels lead to an increased level of circulating cytokines
and ROS.

Sustained hyperglycemia; cytokines & ROS (d/t acute
fluctuations) can lead to destruction of the myelin sheath and
nerve fiber damage leading to Diabetic Autonomic Neuropathy
(DAN).

GV AND AUTONOMIC NEURAL IMBALANCE
Fleischer J et al, J Diabetes Sci Technol 2012; 6(5): 1207-15.
GV AND AUTONOMIC NEURAL IMBALANCE
Jamali et al, hypoglycemia affects more the somatic motor nerves
whereas hyperglycemia affects only somatic sensory nerves.

Ohlsson et al, demonstrated that parasympathetic dysfunction was
associated with increased glucose fluctuations in 20 diabetic patients.

Literature mentions DAN, can be an early risk marker for diabetic
complications.

Fleischer J et al, cross sectional study, in 653 diabetic patients
autonomic imbalance was associated proliferative retinopathy, micro-
and macro-albuminuria and obesity.
Fleischer J et al, J Diabetes Sci Technol 2012; 6(5): 1207-15.
GV AND MOOD DISORDERS
GV is also said to be associated with mood disorders and decreased
quality of life.

Cox DJ et al, demonstrated that negative mood (depression, anxiety)
and cognitive symptoms (difficulty concentrating, slowed thinking)
were associated with within-day glucose variability in 60 T2DM
patients.

Penckofer S et al, those with diabetes and co-morbid depression had
higher anxiety, more anger, and reduced quality of life.

Also, higher anxiety traits were associated with steeper glucose
excursions
Cox DJ et al, Diabetes Care 2007; 30(8): 2001-2
Penckofer S et al, Diabetes Technol Ther 2012;14:303-10
GV & QUALITY OF LIFE
Frequent fluctuations in blood glucose with hypoglycemia and
glycemic excursions are associated with a poor quality of life
Penckofer et al, demonstrated large GV was associated with
low quality of life as compared to HbA1c and average BG.
Glucose Triad vs Glycemic Pentad

FPG PPG
HbA
1C
FPG PPG
HbA
1C
GV QoL
Penckofer S et al, Diabetes Technol Ther 2012;14:303-10
BG- Blood Glucose; QOL- Quality of Life
MEASURES TO MINIMIZE GV
Life style measures
Diet & exercise induced weight loss can significantly improve
insulin sensitivity & beta-cell function
Reducing glucose excursions along with the average glucose
levels
ALPHA-GLUCOSIDASE INHIBITORS
HbA
lc
and plasma glucose in the patients who had received voglibose
were comparable to those of patients in the control group

M-value was lower in the patients treated with voglibose than in the
control subjects

1,5-AG was higher in the patients treated with voglibose than in the
control subjects

A statistically significant decrease in AUC
insulin
occurred after treatment
with voglibose

Insulin sensitivity was improved to a statistically significant level in the
patients treated with voglibose
Diabetes Care 1998; 21(2): 256-60.
1,5-AG- 1,5-anhydroglucitol
ALPHA-GLUCOSIDASE INHIBITORS
Study using CGMS measures of glucose intraday variability, MAGE, SD,
mean glucose levels, CONGA and interday variability, MODD. All were found
to be significantly reduced when treated with acarbose + metformin in a
16 week intention-to- treat study in comparison to glibenclamide + metformin

Drugs like alpha-glucosidase inhibitors which target post-prandial
Hyperglycemia, not only reduce the glycemic excursions but also
reduces oxidative stress and improve endothelial function
Diabetes Technology & Therapeutics 2009,11(6): 339-44
INSULINS
In T1DM & T2DM, treatment with long-acting analogs has
been shown to diminish hypoglycemia and glucose variability.

Prandial insulins, and even more short-acting analogs, diminish
postprandial hyperglycemia and consequently glucose variability
specifically in type 2 diabetes patients.

Use of continuous sc insulin infusion is in type 1 diabetes
associated with a decrease in glucose variability

Whether diminishing glycemic variability in these patient
groups translates into improved outcome is unknown
Sc- Subcutaneous
CONCLUSION
GV seems related to oxidative stress and endothelial dysfunction

Apart from the standard glycemic parameters, GV can also be a
target for optimal glycemic control

Applicable in T1DM, T2DM, gestational diabetes and critically ill
patients

Studies have shown, although not conclusively, improved outcome in
micro- & macro-vascular complications

Inspite of all the formulas, a simple and standard formula is yet to
evolve.

Various treatments like alpha-glucosidase inhibitors, GLP-1 agonists,
basal and prandial insulins have shown to significantly improve GV