Hyperglycaemia Clinical Trial
Official title:
Effects of Carbohydrase-inhibiting Polyphenols on Glycaemic Response in Vivo
Consumption of carbohydrate containing foods or sugary drinks brings about changes to the
blood glucose levels. After a meal or drink, blood glucose levels rise until it reaches a
peak concentration usually after 30 minutes. When the body senses the increase in blood
glucose, a hormonal process involving insulin takes place to ensure that the glucose is
taken up from the blood for storage and where it is needed for energy in the body. This
process then brings about a decrease in the concentration of glucose until it reaches
approximately the starting concentration. The original concentration of glucose is attained
approximately 2 hours after eating or drinking a carbohydrate food or sugary drink
respectively.
Different carbohydrates and sugary drinks have different effects on blood glucose response
depending on the amount as well as the type of carbohydrate. Those that give rise to a high
glucose response compared to a reference carbohydrate (usually glucose) are said to be high
glycaemic index (GI) foods and those with a lower glucose response compared to a reference
carbohydrate (usually glucose) are said to be low glycaemic index (GI) foods.(1)
Research has shown that diets that give rise to a high glucose response are associated with
a number of abnormalities like increased metabolic syndrome (2). Metabolic syndrome mostly
comprises of insulin resistance and glucose intolerance which gives an increased risk of
type 2 diabetes. (3) It also gives rise to other conditions like high blood pressure
(arterial hypertension), elevated blood insulin levels (hyper-insulinemia), elevated amounts
of fat in the liver (fatty hepatosis) and elevated amounts of lipids in the blood
(dyslipidemia). After type 2 diabetes become clinically apparent, the risk of cardiovascular
disease also rises. (4) Research has also shown that foods/drinks which raise blood glucose
levels gradually (low GI) rather than rapidly (high GI) have health benefits which include
reducing the risk of metabolic syndrome (5). In vitro studies have shown that polyphenols
found in fruits, vegetables and plant based foods have a positive effect on carbohydrate
metabolism and can lower the blood glucose levels. (6)
This research will determine whether the presence of polyphenols in the diet has any
lowering effect on the blood glucose levels and hence the glycaemic index of foods. This
will be determined by asking volunteers to consume polyphenol rich drink/food together with
white bread and determine the glycaemic response. The GI of bread will be determined
initially as a reference.
Analysis will be done by measuring blood glucose response to white bread alone as reference
and then to white bread with test sample containing polyphenols and then determine GI and
see how the GI of bread will be affected. Other analyses to be done are plasma insulin,
glucagon, gastric inhibitory polypeptide (GIP) and glucagon like peptides-1 (GLP-1) as they
all relate to glycaemic response.
Study hypothesis is that glucose metabolism will be affected.
NOTE:
1. Only healthy participants undertook the study (Hence metabolic syndrome participants
not part of the study)
2. Only glucose and insulin were analysed in the plasma (hence GIP, GLP-1 and glucagon not
part of end points)
The world health organisation has reported that over 220 million people suffer from diabetes
worldwide and that by the year 2030, this number will be doubled. The WHO also reports that
in 2004, about 3.4 million people died from high blood sugar (WHO fact sheet number 312,
January 2011). About 90% of all diabetes cases is due to type II diabetes. Type 2 diabetes
is largely due to overweight and lack of physical activity characterised by high glucose
levels (hyperglycaemia).
In the human diet, the source of blood glucose are carbohydrates. Dietary carbohydrate is
important to maintain glycaemic homeostasis and provides the most of the energy in the diets
of most people. The control of blood glucose is a hormonal process and it is very important
to human physiology. Hormonal processes involve the release of insulin from the β- cells of
the pancreatic cells which stimulates the uptake of glucose after a meal, to other tissues
either for utilisation (glycolysis) or to be stored in the liver as glycogen (glycogenesis).
When blood glucose falls below normal, glucagon is secreted from the pancreatic α-cells and
it promotes liver glucose production by inducing the generation of glucose from non
carbohydrate substrates such as amino and fatty acids (gluconeogenesis) and the generation
of glucose from glycogen (glycogenolysis). In addition to insulin and glucagon, there are
gut hormones which also play a role in controlling plasma glucose concentrations in the
body. The two important peptide hormones are called Glucagon like peptides-1 (GLP-1) and
Gastric Inhibitory Polypeptide (GIP). They are said to have incretin activity (promotion of
glucose dependent insulin secretion). GIP is secreted from the upper small intestines by the
K cells and its primary function is to stimulate glucose-dependent insulin secretion by
acting on pancreatic islets. It also stimulates glucagon and it is said to respond to the
presence of nutrients (Seino et al., 2010). GLP-1 is secreted from the lower intestine and
colon by the L cells following exposure to ingested nutrients. It also stimulates insulin
secretion and biosynthesis but inhibits glucagon. GLP-1 is said to have other health and
disease related functions (Marathe et al., 2013).
When the glucose homeostasis hormonal control fails, it entails high blood glucose levels
(postprandial hyperglycaemia) which can lead to metabolic syndrome which includes obesity,
impaired glucose tolerance (IGT), hypertension and dyslipidemia. Disturbance of glucose
homeostasis can also lead to other symptoms such as inflammation and oxidative stress at the
whole body level as well as disturbances of the functionality in several organs as well as
diabetes (Hanhineva et al). Therefore, as much as carbohydrates are required in the human
body as a major source of energy, too much in the diet can have adverse health effects
especially the one with high glycaemic effect.
The proposed mechanism adapted from (Aston, 2006) of how carbohydrates may affect human
health is that when there is a continual presence of high glycaemic index foods in the diet,
this gives rise to postprandial glucose rise as well as high insulin demand to act on the
high blood glucose levels in the blood. This is by the action of the hormones GIP and GLP-1
which stimulates insulin release when they sense the presence of nutrients. Postprandial
glucose rise and high insulin demand may lead to insulin resistance which is the major
component of metabolic syndrome. High insulin demand may also lead to β-cell failure which
may also result in hyperglycaemia which is also a cause of insulin resistance. Insulin
resitance and hyperglycaemia are risk factors for metabolic syndrome and diabetes type 2.
Scientific evidence suggest that postprandial hyperglycaemia in humans has a major role to
play in health priorities like type 2 diabetes and blood glucose control. It has been
reported that about 90% of all diabetes cases consist of type 2 diabetes. Apart from type I
and type 2 diabetes, there are other related conditions which include pre-diabetes (impaired
glucose tolerance (IGT) and impaired fasting glucose (IFG) as well as metabolic syndrome
(obesity, hypertension and insulin resistance). It has been reported that pre-diabetes and
metabolic syndrome increases the risk of developing cardiovascular disease and diabetes
mellitus (Coutinho et al., 1999). The glycaemic index was originally proposed with the aim
of managing diabetes. However, recent studies have shown that the GI has potential in the
prevention of type 2 diabetes as well as in the treatment of metabolic syndrome. Research
has shown that high GI diets are associated with increased risk of developing type 2
diabetes (Hodge et al., 2004) and (Steven et al., 2002). More research by (Mckeown et al.,
2004) and (Scaglioni et al., 2004) have shown that high GI diet is associated with a number
of abnormalities like increased metabolic syndrome and insulin resistance. In the same way,
a low GI diet is said to improve insulin sensitivity but more research is needed to support
this. A few studies like that of (Frost et al., 1996) have shown this to be the case.
However it was observed that it was difficult to know whether this was as a result of
improved insulin sensitivity, or improved insulin secretion or due to reduced rate of
glucose absorption.
Having anything in the diet that can either slow down the digestion and absorption of
carbohydrates can help reduce the risk (Barclay et al., 2008). Among others, two potential
solutions are that of consumption of low glycaemic index foods or having ingredients in the
diet that can reduce the glycaemic index of foods as well as postprandial blood glucose
levels. The presence of inhibiting components in the diet that can reduce postprandial
glucose can also be a solution to reducing the risk. Drugs like carbose are currently used
in some countries for the management of type 2 diabetes which act by inhibiting carbohydrate
digestive enzymes. However, the use of acarbose has side effects such as nausea, flatulence
and diarrhoea. It has been reported that polyphenols also have the potential to inhibit the
rise in blood glucose by hindering the rapid absorption of glucose (Hanhineva et al.,
Williamson, 2013).
A review by (Hanhineva et al.) reported that research using animal models as well as a
limited number of human studies, have shown that polyphenols and polyphenol rich foods or
beverages have the potential to affect postprandial glycaemic responses and fasting
glycaemia as well as an improvement of acute insulin secretion and sensitivity. Other
possible mechanisms as reported in the review by (Hanhineva et al.), include pancreatic β-
cells stimulation to secrete insulin as well as activation of insulin receptors, modulation
of the release of glucose from the liver as well as of intracellular signalling pathways and
gene expression.
A recent review by (Williamson, 2013) concluded that it is very possible that the effects of
polyphenols in the diet will affect glycaemic index of foods as well as postprandial glucose
responses in humans. The two mechanisms highlighted by which this can be achieved being the
inhibition of sugar metabolising enzymes as well as transporters. This potential action of
polyphenols can thus be compared to that of acarbose which acts by the same mechanism and
research in chronic intervention studies has shown that it reduces diabetes risk (Chiasson
J. et al., 2002). The review by Williamson, 2013 also mentioned the possibility of different
mechanisms being inhibited at the same time would give the most promising effects.
Therefore, the most effect would be observed when more than one of the suggested pathways
was inhibited.
This research has utilised available information from literature on in vitro studies carried
out and we came up with a food polyphenol rich mixture (PRM) containing polyphenols that
showed the highest inhibition towards carbohydrates digestion and absorption at different
stages. The polyphenol rich breakfast food to be used as the test food will comprise of
Green tea and a combination of four fruit extracts. For the test, the PRM is consumed
together with bread containing 50g available carbohydrates and the control meal is composed
of bread, sugars (fructose, sucrose and glucose) present in the fruit extracts with water.
The polyphenol rich mixture constituents have been analysed in our laboratory for total
polyphenol contents, specific polyphenols and for inhibitory potential to make sure that the
test sample has the capacity to inhibit in vitro before they can be used in humans. The
results obtained are good and justifies their use in the human study.
The study was approved by the University of Leeds Mathermatical and Physical Sciences (MAPs)
ethical commitee with application number MEEC12-037. A total of 16 volunteers will need to
complete the study and should be healthy and their fasting blood glucose levels fall within
the healthy range of 4.3-5.9mmol/L.
The volunteers are scheduled to attend 4 visits, once per week for 4 weeks. During each of
the four visits, the volunteer comes fasted in the morning and the fasting blood glucose is
collected by a trained nurse. The volunteer is then given a test meal and blood samples are
collected at 15, 30, 45, 60, 90, 120,150 and 180 minutes after the first bite of the test
meal. On the first and last visit, they are saved with the reference meal which is composed
of bread, water and sugars to compensate those found in the fruit extracts. On the third and
fourth days, they consume test meals of either the low dose or high dose of green tea and
fruit extracts in addition to bread. The blood samples are processed accordingly to obtain
plasma and stored in the -80°C. Plasma samples will be analysed for concentrations of
glucose, insulin, glucagon, GIP and GLP-1. The results will be used to plot the area under
the curve and results obtained after consuming test meals will be compared to those obtained
after consumption of control meals.
NOTE:
1. Only healthy participants undertook the study (Hence metabolic syndrome participants
not part of the study)
2. Only glucose and insulin were analysed in the plasma (hence GIP, GLP-1 and glucagon not
part of end points)
;
Allocation: Randomized, Intervention Model: Crossover Assignment, Masking: Single Blind (Outcomes Assessor), Primary Purpose: Basic Science
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