Effects of Carbohydrase-inhibiting Polyphenols on Glycaemic Response in Vivo
Condition: Hyperglycaemia
MeSH terms: Hyperglycemia
Study type: Interventional

Summary: 
      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)
    

Detailed description: 
      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)
    

Intervention name(s): Reference food; Test food dose 1; Test food dose 2
Intervention type(s): Other; Other; Other
Intervention description(s): Reference food will be used to which test food samples will be compared to.; Will contain low dose of a mixture of polyphenols in addition to the reference food; Will contain high dose (twice of the low dose) of a mixture of polyphenols in addition to the reference food
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Single (Outcomes Assessor)
Primary purpose: Basic Science