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VOLUME 9 NUMBER 1 • MARCH 2012
REPORT
SA JOURNAL OF DIABETES & VASCULAR DISEASE
be too toxic for humans, leading to the pro-
duction of dimethyl biquanide (metformin)
and other biquanides, such as phenformin.
Early use in the United States focused on
phenformin, a pro-drug that was later with-
drawn as it was the main culprit for the
lactic acidosis observed in the 1950s.
The UKPDS study of type 2 diabetes and
the global use of metformin are intrinsically
related, although earlier clinical studies
3
had
shown that metformin works in poorly con-
trolled diabetics, primarily, it was thought,
by re-sensitising tissues to insulin. ‘In a nut-
shell, today we regard the principle actions
of metformin as increasing sensitivity of the
liver to circulating glucose load, and reduc-
ing gluconeogenesis and improving insulin
sensitivity peripherally. The loss of adipose
tissue and its anorectic action in today’s
world is an additional valued benefit’, Prof
Joshi noted.
With relevance to current knowledge,
metformin also acutely increases the plasma
levels of GLP-1, not by DPP-4 inhibition but
by stimulating GLP-1 production. ‘Met-
formin has a synergistic action with the
incretins, giving an increased effect when
used together, compared to when either
agent is used alone’, Prof Joshi noted.
An important principal to note is that
the reduction of cardiovascular events
with oral anti-diabetic agents takes a long
time to show results. ‘In metformin’s case,
vascular protection was measurable only
after chronic exposure of at least six years.
Patience should be exercised with regard to
this aspect; and the newer oral agents prob-
ably require studies in excess of five years
to evaluate their cardio-protective benefits’,
Prof Joshi cautioned. ‘The side effects of
diarrhoea and nausea occur initially in 20%
of patients, but over time and with the use
of slow-release tablets, this can be greatly
reduced’, he added.
The known side effect of low vitamin
B
12
levels and vitamin B
12
deficiency occur
in 10 to 30% of patients after long-term
metformin use (vitamin B
12
levels: deficiency
< 150 pmol/l, low levels 150–220 pmol/l).
‘Well-defined studies are needed in our
populations and this is a clinical priority for
local research’, Prof Joshi pointed out. ‘In
principle, after a patient has been on met-
formin for 10 to 12 years, vitamin B
12
levels
should be tested once a year, and if found
to be low, a single dose of 1 000 mg vita-
min B
12
should be given. This could be com-
bined with calcium as it facilitates vitamin
B
12
absorption, as shown in initial study find-
ings’, Prof Joshi said.
4
The use of metformin in type 1 diabetes
patients with high insulin usage is growing.
Studies have shown that we could reduce
doses of insulin by about 10% in patients
with type 1 diabetes. A reduction in insulin
doses of about 20 to 30% are observed in
type 2 diabetics on higher doses of insulin.
Does exercise improve or impede
glycaemic control in type 1
diabetes?
Andrew Heilbrunn began his fascinating pres-
entation on the impact of exercise on glycae-
mic control in the type 1 diabetes patient,
by referring to the findings of Ralph Paffen-
barger’s 36-year follow-up study in the 1993
article in
New England Journal of Medicine
,
‘The Harvard Study.
5
Findings indicated that
there was a dose response to exercise with
a percentage reduction in risk of death from
certain chronic illnesses, including cardiovas-
cular disease and diabetes.
Up to a point, increased energy expendi-
ture correlated with a reduction in risk of
mortality. It was found that those with the
highest levels of fitness had the lowest risk
of cardiovascular death, in particular. The
unfit non-diabetic person has twice the car-
diovascular risk of the physically active indi-
vidual. The unfit type 2 diabetes patient is a
‘time-bomb’.
Ming Wei concluded his 15-year study
(
n
= 1 200 type 2 diabetes patients) in
2000, by suggesting that the type 2 diabe-
tes patient would benefit more from regular
exercise than any other chronically ill patient.
Data from a seven-year follow-up type 1 dia-
betes patient cohort study indicated that the
mortality rate was 50% lower in the type 1
diabetes patient who burned 2 000 calories
per week, opposed to those burning less
than 1 000 calories per week.
The evident benefit of exercise on risk
of mortality raises the question of how
much exercise is appropriate to bring about
physiological changes to decrease mortality.
Answers to this question have ranged from
75 minutes per day, to 60 to 85% aerobic
capacity for 30 to 60 minutes, to 60 min-
utes of moderate-intensity exercise (a brisk
walk).
For the type 2 diabetes patient, the latest
ADA and Society for Endocrinology, Metabo-
lism and Diabetes of South Africa (SEMDSA)
guidelines recommend a minimum of 150
minutes’ exercise per week, combining mod-
erate-intensity aerobic exercise and strength/
resistance training. One would think that
these guidelines would be suitable for the
type 1 diabetes population. However, a large
percentage of type 1 diabetes patients prefer
to participate inmarathons, high-intensity ball
sports, body building, and some may chal-
lenge themselves with recreational climbing
and diving. A fair number of these patients
do not realise that there is a complex rela-
tionship between exercise and type 1 diabe-
tes, and exercise may lead to hypoglycaemia
or hyperglycaemia. This raises the question
‘Does regular exercise improve or impede
blood glucose control in type 1 diabetes?’
There are numerous theories as to why
exercise may improve insulin sensitivity,
increase muscle blood flow, increase insulin
binding by muscle receptors, and increase
insulin-regulatingglucose transporters. How-
ever, the primary theory and benefit occurs
during the 12 to 24 hours post exercise; the
time for glycogen replenishment. During
the course of exercise, liver and muscle gly-
cogen stores are used as an energy source.
Post exercise, the liver and muscle draw glu-
cose from the blood to replenish the stores
used during exercise. This process requires
little insulin and is enzyme initiated.
Regular chronic exercise/training has a
different effect to a single session of exer-
cise and the literature suggests that patients
with type 1 diabetes should exercise daily
or on alternate days to improve their insulin
sensitivity. However, with cessation of regu-
lar activity, insulin sensitivity is rapidly lost.
In the non-diabetic, insulin levels decrease
with the onset of exercise. This allows for an
increase in counter-regulatory hormones, in
particular glucagon. This response leads to
hepatic glucose production, and the subse-
quent increase in blood glucose is met by
glucose uptake in the muscle. Due to this
precise neuro-endocrine function, blood
glucose levels remain stable under most
exercise conditions.
In type 1 diabetes, the pancreas does not
regulate insulin levels in response to exercise
and there may be impaired glucose counter-
regulation, making normal fuel regulation
nearly impossible. Therefore the type 1 dia-
betes patient is at risk of becoming hypogly-
caemic or hyperglycaemic, dependent to
a great extent on the levels of circulating
insulin and the duration and intensity of the
exercise.
Fear of hypoglycaemia is the primary
factor affecting the attitude of patients
towards exercise. According to Remi-Rabasa
Lohret, 2008, those individuals who best
understood how insulin works in their body
were shown to be less fearful of physical
activity and hypoglycaemia. Furthermore,