The document discusses the "glucose triad" which refers to the relationship between HbA1c, fasting plasma glucose, and postprandial plasma glucose in glycemic control. It notes that while HbA1c has traditionally been the target, more recent studies show intensive control to reach very low HbA1c levels may be detrimental. The document explores how the relationship between the components of the glucose triad changes over time as diabetes progresses, with postprandial glucose being more influential at lower HbA1c levels and fasting glucose becoming more important at higher levels. Treatment should target both fasting and postprandial hyperglycemia simultaneously for optimal control.

1. The glucose triad and its role in
comprehensive
glycemic control: current status,
future management
REVIEW ARTICLE
A. Ceriello

3. What is “Glucose Triad”?

4. INTRODUCTION to “GLUCOSE TRIAD”
Type 2 diabetes mellitus (T2DM) has reached
pandemic levels in India.
It is characterized by worsening metabolic
control as the disease progresses incessantly
in spite of all known treatments, causing
micro- and macrovascular
complications, leading to severe morbidity
and mortality.

5. Since the publication of the seminal UK
Prospective Diabetes Study (UKPDS) in the late
1990s, controlling blood glucose as measured by
glycosylated hemoglobin (HbA1c) has been the
cornerstone for the management of T2DM.
HbA1c in turn is a function of the values of fasting
plasma glucose (FPG) and postprandial plasma
glucose (PPPG), an integrator of fasting and
prandial glycemic disorders.

6. GLUCOSE TRIAD
• This relationship
between HbA1c, FPG
and
PPPG, therefore, play a
central role in the
metabolic changes
central to T2DM and
this troika is known as
the glucose triad

7. The glucose triad and its role in
comprehensive glycemic control:
current status, future management
A. Ceriello
Review article
2010 Blackwell Publishing Ltd Int J Clin
Pract, November 2010, 64, 12, 1705–1711

8. Introduction
• Based on the outcomes of several landmark
studies, guidelines for good glycemic control
have been agreed upon and a patient is
generally considered to have achieved
successful disease control when their HbA1C is
< 7%

9. • it was previously accepted that HbA1C should be
as low as is realistically achievable.
• The strategy of ‘the lower, the better’ was
reinforced by data from the UK Prospective
Diabetes Study (UKPDS) in nineties that showed
that any reduction in HbA1C in patients with type
2 diabetes is likely to reduce the risk of
complications, with the lowest risk being in those
with HbA1C values < 6%

10. Changing the paradigm
However, more recent studies have raised
concerns that intensive treatment and stringent
HbA1C targets may be detrimental in some
patients.
The Action to Control Cardiovascular Risk in
Diabetes (ACCORD) trial was stopped early when
it was found that there was an increased risk of
death in patients who received intensive blood
glucose-lowering therapy with an HbA1C target
of < 6%

11. Changing the paradigm
• Both ACCORD (target HbA1C < 6%) and
ADVANCE (the Action in Diabetes and Vascular
Disease: Preterax and Diamicron Modified
Release Controlled Evaluation) (target HbA1C
< 6.5%) trials failed to show that achievement
of good glycemic control was associated with
reduction of cardiovascular risk.

12. Changing the paradigm
• These findings appear to be supported by
results from a retrospective cohort study that
was conducted in the UK which showed that
both Low and high HbA1C levels were
associated with increased mortality and
cardiac events, with the lowest risk seen at an
intermediate HbA1C of 7.5%.

13. Question
So if driving HbA1C down to lower target
levels is not the answer, what other factors
involved in glucose homeostasis can or
should be targeted?

14. • Following phenomenon have been described
as the possible explanations :
daily plasma glucose variability
postprandial glucose excursions

15. Comprehensive glycemic control –
the role of postprandial glucose and
glucose variability

16. • In individuals with normal glucose tolerance, the
plasma glucose concentrations generally rise no
higher than 7.8 mmol ⁄ l after a meal and return
to normal levels within 2–3 h. In contrast, in
individuals with type 2 diabetes, postprandial
plasma glucose levels > 7.8 mmol ⁄ l are common,
even in those who are considered to have good
overall glycemic control according to
measurement of HbA1C.

17. Blood glucose profile over 24 h in an individual
with type 2 diabetes

18. • In fact, achievement of target HbA1C and
fasting plasma glucose levels does not
necessarily indicate that good glycemic control
is continuous throughout the day.

19. Individual 24-h recordings from a continuous glucose monitoring
system in four patients with type 2 diabetes on
insulin therapy and a mean HbA1C of 6.7%
DESPITE THE SAME HbA1c LEVELS AT 3 MONTHS , PATIENTS TEND TO HAVE
MARKED GLYCEMIC VARIABILITY THROUGHOUT THE DAY
WHICH IS DIRECTLY RELATED TO INCREASED MICRO AND
MACROVASCULAR MORBIDITY

20. • Patients who have impaired glucose tolerance, but
have not yet developed type 2 diabetes tend to have
near normal fasting plasma glucose, but show
variable glucose excursions after the three meals of the
day.
• The key pathological effect at this prediabetes stage is
loss of first phase insulin secretion. This is the early
surge of insulin that occurs within 5 min of eating and
is critical for suppression of hepatic glucose production
and priming the liver and peripheral
tissues, particularly muscle and fat, for glucose uptake.

21. • The onset of frank type 2 diabetes is characterised by
a progressive decline in insulin sensitivity together with
progressive deterioration in beta-cell function leading
to reduced insulin secretion.
• Increased fasting plasma glucose levels in patients
with type 2 diabetes are largely attributable to reduced
hepatic sensitivity to insulin leading to overproduction
of glucose by the liver during the overnight fast.
• As diabetes progresses, these effects persist into the
morning and result in particularly marked
hyperglycaemia following breakfast

22. • Type 2 diabetes is a progressive disease. The typical course
is ....
a gradual loss of glycemic control after meals, followed by
the development of fasting hyperglycaemia in the morning
and finally
sustained hyperglycaemia during the night

23. Postprandial Hyperglycemia….
• Postprandial glucose levels are influenced by
the blood glucose level before the meal and
the glucose load from the meal, as well as
physiological factors such as insulin secretion
and insulin sensitivity in the peripheral
tissues.

24. • The incretin hormones, glucagon-like peptide
(GLP)-1 and gastric inhibitory polypeptide
(GIP) are released by the intestine in response
to ingestion of carbohydrate.These hormones-
 enhance insulin secretion,
 Suppress hepatic glucose production and
 decrease gastric emptying
 and have a greater effect on postprandial glucose levels than
fasting glucose levels.
• Patients with type 2 diabetes have reduced
levels of the incretin hormones

26. “the glucose triad…..
 It is important to understand the relationships
between HbA1C, and fasting and postprandial
blood glucose, and how these change during
progression of the disease, if type 2 diabetes is to
be managed optimally.
 Fasting and postprandial plasma glucose both
contribute to HbA1C. However, the relative
contribution of these two factors depends on the
HbA1C level, with postprandial glucose
contributing relatively more at lower HbA1C
levels

27. • Early in the course of the disease, when fasting
plasma glucose levels are near normal, postprandial
glucose is more important in determining HbA1C.
• Measurement of 24-h plasma glucose profiles in
patients with HbA1C of < 6.5%, > 6.5% to < 7%
and >7% to 8% showed that fasting plasma
glucose levels were very similar in these three
groups, with the principal difference being in
postprandial glucose.
• These data suggest that reduction of HbA1C in
patients who are close to target (< 8%) is best
achieved by specifically targeting postprandial
glucose levels.

28. • As glucose control deteriorates and HbA1C
rises, the contribution of fasting plasma
glucose becomes more significant.
• In groups of patients with HbA1C of > 8% to <
9% and > 9%, fasting plasma glucose
progressively increased, indicating that
control of both fasting and postprandial
glucose is important at these higher HbA1C
levels .

29. The 24-h recordings from a continuous glucose monitoring
system in five groups of patients with type 2
Blue: < 6.5%
red: 6.5% to < 7%;
diabetes.
green: 7% to < 8%;
orange: 8% to < 9%;
purple: 9%.
THUS AT HbA1c < 8% = POSTPRANDIAL
HYPERGLYCEMIA IS THE MAIN CULPRIT
HbA1c > 8% = FASTING HYPERGLYCEMIA IS
THE MAIN CULPRIT

30. Impact of HbA1c, fasting plasma
glucose and postprandial glucose
on
management approaches
and
treatment choice

31. • Foods with a lower glycemic index contain
carbohydrates that are more slowly digested
and absorbed. There is some evidence that
diets with a low glycemic load are beneficial in
reducing postprandial glucose excursions.

32. • Treatment of both fasting and postprandial
hyperglycaemia should be initiated
simultaneously at all levels of HbA1C above
agreed levels.
• Traditional treatments such as metformin and
thiazolidinediones primarily lower fasting
plasma glucose.

33. • An ideal approach to the treatment of a patient with
newly diagnosed type 2 diabetes might be to start with
the combination of metformin and a DPP-4 inhibitor.
• This combination effectively targets the two key
pathophysiological features of type 2 diabetes: loss of
first phase insulin secretion and insulin resistance.
• Combination of a DPP-4 inhibitor with metformin is
likely to be better tolerated than combination with a
sulphonylurea, with a lower incidence of weight gain
and a very low risk of hypoglycaemia.

34. Conclusions

35. • The optimal glycemic control equation equates
to
HbA1C (target)
+
fasting plasma glucose (target)
+
postprandial glucose (target)
without hypoglycaemia and weight gain.

36. • Although target HbA1C levels can be reached
by lifestyle modification together with
combination drug therapy…….
• optimal glycemic control may be best
achieved by selection of agents that target
both fasting and postprandial
Hyperglycaemia.

37. THANK YOU

39. • The postprandial state, with respect to glucose, is defined as a 4-h
period that immediately follows ingestion of a meal. During this
period, dietary carbohydrates are progressively hydrolyzed through
several sequential enzymatic actions. Even though the insulin
response rapidly reduces the postprandial glucose excursion with a
return to baseline levels within2 h, the overall period of absorption
has approximately a 4-h duration that corresponds to the
postprandial state.
• The postabsorptive state consists of a 6-h period that follows the
postprandial period. During this time interval, glucose
concentrations remain within a normal range in nondiabetic
individuals through the breakdown of the glycogen (glycogenolysis)
stored during the postprandial period.

40. • The “real” fasting state commences only at
the end of the postabsorptive period(10–12 h
after the beginning of the
• last meal intake). During the fasting state,
• plasma glucose is maintained at a nearnormal
• level by the gluconeogenesis: glucose
• derived from lactate, alanine, and
• glycerol.

41. • Therefore, it appears that in a nondiabetic patient who
takes three meals per day at relatively fixed hours, the 24-h
period of the day can be divided into three periods
corresponding to fasting, postprandial, and postabsorptive
states. The postprandial period (4 h each) is equal to 12 h
and covers a full half-day period of time. The real fasting
period is only limited to a 3- to 4-h period of time at the
end of the night. Furthermore, taking into account the
overlap
• between the postprandial and postabsorptive
• periods, it can be asserted that all
• the remaining parts of daytime correspond
• to postabsorptive states