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GETTING IT RIGHT FROM DAY ONE
Metabolic Memory and Tracking
Dr Joe Delaney PhD CSci FIBMS PhySoc
Session Outline
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Individualising treatment: A Holistic Approach
Metabolic Memory and The Legacy Effect
The Evidence
Tracking – what, how and how often?
When is Day 1?
Let’s start at the very beginning...
Beyond genetics
Future directions
Type 1
TYPE 2
Type 2 diabetes across generations: from
pathophysiology to prevention and management
Christopher J Nolan, Peter Damm, Marc Prentki.
Lancet 2011; 378: 169–81
TIME FOR A SHIFT IN THINKING?
Shift happens...
According to the Oxford English Dictionary, a shift is
defined as: a change in position, direction or
tendency
A paradigm shift is described as:
a radical change in underlying beliefs or a complete
change in thinking or belief systems that allows the
creation of a new condition previously thought
impossible or unacceptable.
Ridiculous?
As a new paradigm or truth emerges it passes
through three distinct stages:
• Firstly, it is ridiculed
• Secondly, it is violently opposed
• Thirdly, it is accepted as being self-evident.
So here goes then…
An Integrative Approach
IQ
SQ
MENTAL
SPIRITUAL
PQ
EQ
PHYSICAL
EMOTIONAL
Case Study
The shape of things to come?
Lifestyle choices
Case study (Male)
THEN
• Height: 1.83m
• Weight: 105kg
• BMI: 31.3
• Waist: 107cms
• RBP: 148/98
• RHR: 76bpm
• FBG: 6.3
• Mood: Very low
• Vitality: None
NOW
• Height 1.83m
• Weight: 91kg
• BMI: 27.2
• Waist 100cms
• RBP: 106/74
• RHR: 48bpm
• FBG: 4.7
• Mood: Much higher
• Vitality: LOADS
Exposed
A Whole-Hearted Approach
Hyperglycaemia
• Most of the microvascular complications of
diabetes are related to the degree and the length
of exposure to hyperglycaemia.
• New data from the follow-up studies of the
Diabetes Control and Complications Trial- the
Epidemiology of Diabetes Intervention and
Complications Study (DCCT- EDIC), and the
United Kingdom Prospective Diabetes Study
(UKPDS) emphasize the role of glycaemic control
early in the course of the disorder and its value in
prevention of later complications.
Legacy Effect
• The phenomenon of ongoing beneficial effects on
diabetic complications after a period of improved
glycaemic control, even if followed by a return to
usual (often poorer) metabolic control, has been
described as representing “metabolic memory” by
the DCCT/EDIC investigators and as a “legacy effect”
by the UKPDS investigators.
Legacy
• According to the Oxford English Dictionary a legacy
is:
‘Anything left to or handed down from an ancestor
or predecessor...’
DCCT and EDIC
• The Diabetes Control and Complications Trial (DCCT)
was designed to test the glucose hypothesis and
determine whether the complications of type 1
diabetes (T1DM) could be prevented or delayed.
• The Epidemiology of Diabetes Interventions and
Complications (EDIC) observational follow-up
determined the durability of the DCCT effects on the
more-advanced stages of diabetes complications
including cardiovascular disease (CVD).
Conventional v Intensive Treatment
• The DCCT (1982–1993) was a controlled clinical trial
in 1,441 subjects with T1DM comparing intensive
therapy (INT), aimed at achieving levels of glycaemia
as close to the non-diabetic range as safely possible,
with conventional therapy (CON), which aimed to
maintain safe asymptomatic glucose control.
• INT utilized three or more daily insulin injections or
insulin pump therapy guided by self-monitored
glucose.
• EDIC (1994–present) is an observational study of the
DCCT cohort.
Metabolic Memory
• The DCCT followed >99% of the cohort for a mean of 6.5
years and demonstrated a 35–76% reduction in the early
stages of microvascular disease with INT, with a median
HbA1c of 7%, compared with CONV, with a median
HbA1c of 9%.
• The major adverse effect of INT was a threefold increased
risk of hypoglycaemia, which was not associated with a
decline in cognitive function or quality of life.
• EDIC showed a durable effect of initial assigned therapies
despite a loss of the glycaemic separation (metabolic
memory) and demonstrated that the reduction in earlystage complications during the DCCT translated into
substantial reductions in severe complications and CVD.
Healthy Prospects...
• DCCT/EDIC has demonstrated the effectiveness of INT
in reducing the long-term complications of T1DM and
improving the prospects for a healthy life span.
UKPDS
Although the UKPDS set out to determine whether
any class of anti-diabetic agent had advantages or
disadvantages, the use of multiple therapies made
such assessment difficult.
• What was clear from UKPDS was:
– early intervention is necessary
– ongoing adjustment of therapy is required to prevent
progressive deterioration of blood glucose control
– multiple agents are often needed to achieve optimal
blood glucose control
– choice of drug therapy should be individualised
UKPDS 2
• Given the natural history of type 2 diabetes it is
conceivable that its onset could be prevented if the
early rise in insulin secretion was avoided
• In general, clinical symptoms and patient
presentation for medical intervention occur late in
the disease when fasting hyperglycaemia is already
present
• Implications for pre-diabetes and patient
responsibility for active engagement and ‘taking it
seriously’
Causes of hyperglycaemia
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Not enough or bad insulin or oral diabetes medication
Eating or drinking more carbohydrate than usual
Less activity or exercise than usual
Illness or infection (cold, urinary tract infection, heart
attack)
Injury or surgery
Pain
Stress
Any change in normal daily routine
Certain medications
Poor absorption of insulin at injection sites
Insulin pump, insulin pen or meter (device issues)
BALANCE
From this/that to and/both...
Behaviour...
Autonomic Integration
Higher Centres
Cognitive
Hypothalamus
Affective
Medullary
Psychomotor
SNS
Centres
PNS
+
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Receptor
Afferents
Complex or Complicated?
A matter of perspective...
EMOTIONAL TURMOIL
As quickly as possible call out the COLOUR of
the words....
GREEN
BLACK
BLUE
DIABETES
RED
SEX
RELEEF
MONEY
PINK
MORON
ORANGE
INSULIN
PURPLE
YELLOW
LEGACY
BLACK
GREEN
CYAN
ORANGE
From Chaos to Coherence
It’s all about...
ENERGY BALANCE
On the wrong track?
Memory and habit
• If you keep doing what you always did you’ll
keep getting what you always got!
• We are what we repeatedly do...
• Gene expression is based upon emotional
interpretation of environmental cues
STRESS!!!
More than our genes...
• Type 2 diabetes is now pandemic and shows no
signs of abatement
• Substantial evidence is now emerging indicating
that a major part of diabetes susceptibility is
acquired early in life, probably owing to foetal or
neonatal programming via epigenetic phenomena.
• Maternal and early childhood health and
behaviour might, therefore, be crucial to the
development of effective prevention strategies
Ancestry.com
• There is now considerable evidence that the
foetal and early postnatal environment also
strongly influence the risk of developing such
diseases in later life.
• Furthermore, there is increasing evidence of a
strong interconnectivity between genetic predispositions, epigenetic processes, stress-related
hormonal systems and immune parameters in all
forms of (mal)-adjustment to adverse living
conditions.
Heredity and Cardiometabolic Disease
• Recent studies have
identified certain
‘susceptibility genes’.
• ‘Heredity loads the gun
BUT behaviour pulls the
trigger’!
Hereditary influences…
The Evidence
Functional teratogenesis
Perinatal programming
Quality of Life
Health: Well-informed
Quality of Life
Disease: Ill-informed?
Progress?
Survival advantage?
THE END
Say what you see! Quickly
•Research has shown that young
children cannot identify the intimate
couple because they do not have
prior memory associated with such a
scenario.
•Children see nine dolphins.
•This is a test to determine if you
already have a corrupted mind.
•If it is hard for you to find the
dolphins within six seconds, your
mind is indeed corrupted.