Blood glucose regulation
The resting body uses about 10 grams of glucose per hour (2 teaspoons) for energy and all body functions. Blood glucose is regulated by 2 opposing hormones - insulin (an anabolic hormone and glucagon - a catabolic hormone (Roach & Benyon 2003). After a meal insulin secretion is activated and glucagon secretion is minimized. When there is a fall in blood glucose (under about 4 mmol/l) it leads to a pronounced decrease in insulin secretion and increase in glucagon secretion. Glucagon increases blood glucose levels by releasing glucose stored as glycogen in the liver.
Other hormones involved in blood glucose regulation are adrenaline, noradrenaline, growth hormone, cortisol and gastric hormones GIP and GLP-1 (see later). Adrenaline nor-adernaline and cortisol increase blood glucose via glycogenolysis and gluconeogenesis. Adrenal hormones are therefore critical in maintaining normal blood sugar levels, especially during stress (Wilson 2004).
Insulin is secreted by β cells of the pancreas in response to increased circulating levels of glucose and amino acids after a meal (Pessin & Saltiel 2000). High glycaemic index (GI) foods such as sugars and refined carbohydrates which are rapidly converted to glucose provoke exaggerated insulin response. Insulin facilitates glucose transport into the cells via specific glucose transporters. Insulin binding on cell membrane receptors increases the number of glucose transporters (Lord & Bralley 2008:556). There are four glucose transporters - GLUT-1, GLUT-2, GLUT-3 & GLUT- 4. Each of them has different tissue distribution (Roach & Benyon 2003:7).
Insulin primarily increases the rate of glucose uptake into striated muscle and adipose tissue by shuttling GLUT-4 proteins to the membrane (Cloe 2010). Skeletal muscles account for approximately 75% of insulin-stimulated glucose uptake (Shulman et al 1990). The ability of insulin to stimulate glucose uptake by muscles and adipose tissue is key to blood glucose homeostasis (Leney & Tavare 2009) as the skeletal muscle is the main determinant of insulin sensitivity (Vessby 2000).
Post-prandial phase
If body cells require energy, glucose is immediately metabolized for energy production. However, excess glucose, not utilised for energy is either used for amino acid synthesis by cells throughout the body or stored as glycogen in the liver and muscle cells. Glycogen stored in the liver maintains blood glucose concentrations between the meals or during a fast. Its stores last about 12 – 24 hours (Roach & Benyon 2003:30). Although muscle is much larger than liver and we store twice as much glycogen in the muscle, glycogen stored in the muscles provides fuel for muscle contraction only, and does not help to maintain blood glucose levels. Muscle lacks the enzyme glucose-6-phosphatase, which in the liver converts glucose-6-phosphate to glucose (Roach & Benyon 2003:30).
When glycogen stores are full, insulin, an anabolic hormone, increases lipid synthesis from extra glucose in liver and fat cells. These are exported as lipoproteins (eg LDL cholesterol) to other tissues, including adipose tissue, which uses fatty acids to synthesize triglycerides (Tortora & Derrickson 2006:953).
Insulin inhibits fatty acid release from triglycerides stored in adipose and muscle tissue as it inhibits the activity of hormone sensitive lipase (Lafontan & Langin 2009), which is the key enzyme in the mobilization of FAs from adipose tissue (lipolysis). Insulin also inhibits gluconeogenesis and glycogenolysis.
Insulin resistance (IR)
Metabolic insulin resistance is a highly complex condition, defined as higher than normal concentrations of insulin required to maintain normal blood glucose level - euglycaemia. On a cellular level IR is a defect in signal transduction via the insulin receptors (Adochio et al 2009). As suggested by Pessin & Saltiel (2000), this complex phenomenon may be a combination of genetic defects combined with environmental stressors, such as obesity or infections, or there may be reduced key molecular functions within the cell, resulting in insufficient signal transduction to generate the full response of glucose uptake.
According to Hyman (2008:359), common signs and symptoms of IR are central obesity, PCOS or infertility, fatigue, post-prandial fatigue after carbohydrate meals, sugar craving, hypoglycaemia night sweats, irritability, palpitation, dizziness and fatigue relieved by eating), hypertension, chronic fungal infection and family history of diabetes, hypoglycaemia or alcoholism. IR, if not managed can further progress to type 2 diabetes mellitus (T2DM) (Corcoran et al 2007).
Macronutrients and insulin resistance (IR)
Studying macronutrients in isolation does not give a complete picture, as we normally eat a mixture of macro- & micro-nutrients (Frayn 2001). It is well known that addition of fat to a carbohydrate meal slows gastric emptying and reduces the glycaemic response (Jenkins et al 1981). Normand et al (2001) demonstrated that addition of moderate amount of fat (17g) to a meal delayed absorption of carbohydrates and reduced glucose concentration up to 3 hours after meal ingestion. However, a large amount of fat (42g) leads to two-phase increased glucose concentration; first immediately after a meal and a second peak approx. 3 hours after the meal ingestion, concurrently with elevated plasma insulin and non-esterified fatty acids (NEFAs) concentrations, which as reported by Frayn et al (1996) may be associated with IR. Adochio et al (2009) also noted that high-fat (HF) overfeeding resulted in significant insulin resistance in skeletal muscles.
IR and FA composition in phospholipid cell membrane
Research regarding the FA composition in phospholipid membrane and IR is under intensive investigation; however, the results are inconclusive as no method of measuring dietary fat intake is entirely reliable. Most studies suggest that some FA promote IR while others protect against it. For example, high dietary MUFA abundant in olive oil are largely associated with improved insulin sensitivity, while saturated fatty acids (SFAs) promote it (Soriguer et al 2004 Marshall et al 1997). Vessby et al (2001), Perez-Jimenez et al (2001) noted that replacement of saturated fats with either mono or polyunsaturated fats (PUFAs) improve insulin sensitivity. FAs incorporated into phospholipid membrane influence membrane rigidity and ‘fluidity’, which is vital for signalling and recruitment of GLUT proteins to the cell membrane. Since insulin signalling and transport of GLUT-4 to the cell membrane are greatly membrane related events, membrane fluidity is essential to insulin sensitivity (Frayn et al 2010). As observed by Vessby (2000), obese patients and those with T2DM have a higher concentration of saturated FAs and a lower concentration on n6 FAs in the cell membrane, both associated with IR.
Giaco et al (2007) observed that in healthy individuals, moderate fish oil supplementation (3.6 g of n3 containing 2.1 g of EPA & 1.5g DHA) did not affect cell function, insulin secretion or insulin sensitivity. They also noted that a higher n6 / n3 phospholipids ratio, had a significant reduction in insulin sensitivity. However, fish oil supplementation worsened their glucose tolerance. They concluded that those individuals should not be supplemented with n3, instead their n6 intake should be reduced. However, they agreed that there is an inverse relationship between n3 and T2D, which they suggested may be due to the anti-inflammatory properties of fish oils or other properties.
Adochio et al (2009) also observed macronutrient composition influence on insulin signalling. They found that high-calorie high carbohydrate diet (HC) increased insulin signalling in skeletal muscles. They attributed it to modest hyperinsulinemia which is characteristic of high carbohydrate overfeeding.
Similar to intake of saturated fats, dietary intake of trans fatty acids (TFA) is equally associated with detrimental effects on insulin sensitivity (Corcoran 2007). Stender and Dyerberg (2004) suggest that TFA may affect cell membrane function via their effect on ion channels and transport proteins such as GLUT-4. Studies on rats by Saravanan et al (2005) showed that TFAs and SFAs altered the expression of different genes associated with insulin sensitivity in rat adipose tissue. This was confirmed by Mozaffarian (2006) who proposed that TFA incorporated into the cell membranes directly affect transcription factors and signalling pathway for genes involved in inflammation. Shoelson et al (2007) in their review attributed IR to proinflammatory cytokines such as TNF-α, which as reported by Mozaffarian (2009) are produced by TFAs, as well as IL-6 and other markers of inflammation.
IR and intramyocellular lipid metabolism
Coen et al (2010) Pan et al (1997) and Lee et al (2006) observed that some IR phenotypes are associated with accumulation of fatty acids in skeletal muscle. Ceremide and diacyglycerol (DAG) levels are increased following high saturated fat intake. Both ceramide and diacyglycerol (DAG) are signalling molecules which have been shown to interfere with insulin sensitivity (Chavez et al 2003 Montell et al 2001). Ceramides may also be also responsible for reduced GLUT-4 translocation to the plasma membrane and diminished glycogen synthase activity (Corcoran et al 2007), consequently increasing lipogenesis.
The benefits of n6 PUFA on IR are inconsistent. Marotta et al (2004) observed substantial increase of triaglycerol (TGA) concentrations in muscle cells of rats fed high calorie diet rich in sunflower oil. However, when these lipids were substituted for SFAs or MUFAs there was no change in the lipid composition. Studies in rats by Taouis et al (2002) showed that n6 PUFA reduced GLUT-4 content in muscle cells, while diets rich in n3 and n6 PUFAs maintained insulin sensitivity. Contrary Lee et al (2006) noted that rats fed diet high in n6 FAs increased TAG formation rather than other metabolites and actually improved insulin sensitivity.
GIP & GLP-1 functions and secretion
Two gastric hormones involved in enhanced postprandial insulin secretion are glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Their actions are called the ‘incretin effect’. As observed by Yoder et al (2009), in rats, secretion of both hormones is induced by the release of carbohydrates, fats, protein or mixed meals. Although the mechanisms are not clear, they suggest that GIP secretion depends on nutrient absorption, while GLP-1 is secreted in the presence of nutrients in the lumen. This was previously expressed in a review by Drucker (2006) who noted that in humans GIP is secreted by entero-endocrine K cells in duodenum and proximal jejunum and GLP-1 is secreted by intestinal L cells mainly in the distal ileum and colon, in response to a range of nutrients, and within minutes of food ingestion. Ahren (2004) reports that GLP-1 receptors have been found in various organs in the body including stomach, duodenum, heart, lungs, hypothalamus and other tissues.
Some scientists believe that secretion of GLP-1 and GIP depends on the caloric value of the meal. Yoder et al (2009) noted increased GLP-1 and GIP output in rats fed high fat diet, (high calorie density), and that secretion is dose-dependent. Baggio & Drucker (2007) in their review also observed that GLP-1 secretion is dependent on the caloric value of the ingested meal.
Meier et al (2003) observed therapeutic value of GLP-1 - exogenous administration of the hormone normalised blood glucose levels in type 2 diabetics by slowing gastric emptying and transit of nutrients from the stomach to small intestine. This confirms the role of GLIP-1 in the ileal brake reflex, which slows small bowel transit in presence of fat.
GIP & GLP-1 and insulin secretion
Wang et al (1996) noted that GIP increases the postprandial insulin secretion by upregulating cells insulin gene transcription and synthesis. This was confirmed by Baggio and Drucker (2007) who observed that GIP stimulates cells proliferation and reduces their apoptosis. They also noted that GIP increases fatty acids synthesis and their inclusion into triglycerides, while down regulating lypolysis (same functions as insulin).
GLP-1 functions are similar to GIP; it stimulates insulin secretion by stimulating cells proliferation and reducing their apoptosis (Yoder et al 2009). However, Nauck et al (1997 & 2002) and Maljaars et al (2008) noted that GLP-1 improves glycaemic control by inhibiting gastric emptying, decreasing GI motility and reducing delivery of absorbed nutrients. Nauck et al (2002) also noted that GLP-1 effect on cells is dose-dependent; the higher the blood glucose level, the greater its effect on insulin secretion.
Heller et al (1997) and Drucker (2006) noted that in α cells of the pancreas GLP-1 inhibits glucagon secretion when blood glucose is high (same as insulin). However, as GLP-1 secretion is glucose dependent, it is unlikely that it will impair glucagon secretion in response to hypoglycaemia (Nauck et al 2002). Also, as observed by Drucker & Nauck (2006) GLP-1 is rapidly degraded - circulating half life of 2 minutes.
Beysen et al (2002) reported increased plasma GLP-1 concentration following MUFA and PUFA ingestion and a delayed increase with saturated fatty acids ingestion, which slow down intestinal absorption.
Reactive Postprandial Hypoglycaemia (RPH) and incretin secretion (GLP-1 & GIP)
The cause of RPH is still being debated. Symptoms occur within 4 hours of eating (NIDDK 2008). Shortage of other hormones involved in blood glucose regulation – eg glucagon, cortisol, growth hormone and adrenaline ca also contribute to RPH. However, the main cause appears to be exaggerated insulin response (Brun et al 2000).
Tamburrano et al (1989) suggested that PRH is due to idiopathic reactive hypoglycaemia (IRH) due to increased insulin sensitivity and inadequate glucagon secretion. Miholic et al (1991) and Owada et al (1995) suggested that PRH may be due to exaggerated response to GLP-1 (as observed after gastric surgery). Leonetti et al (1989) observed increased insulin sensitivity and a reduced glucagon response, which led to an increase of glycogen synthase activity and increased glycogen synthesis in the muscle, while at the same time inhibiting glycogenolysis in the liver, causing RPH. Saha (2006) who observed RHP in healthy individuals during routine screening attributed it to exaggerated insulin and GLP-1 response and defects in counterregulation raising plasma glucose levels. Saha (2006) suggested that a mixed meal containing complex carbohydrates, fats and protein would provoke a more natural stimulus and ensure slower entry of glucose into intestine and therefore slower absorption. This was echoed by Ells et al (2005) who observed in a small double-blind randomized crossover design including ten healthy female volunteers that rapidly digested starches increased both glucose and insulin concentration more rapidly and to higher peaks than slowly digestible starch. This could be due to increased GLP-1 secretion, which as noted by Nauck et al (2002) is dose-dependent - the higher the blood glucose level, the greater GLP-1 & insulin secretion.
Blood glucose and brain function
Mental functions and the feeling of well-being are dependent on a steady supply of fuel to the brain as the brain is normally entirely dependent on glucose for energy. The brain cannot synthesize glucose or store substantial amounts as glycogen in astrocytes (Cryer 2007). When blood glucose level is high, the glucose transport into the brain exceeds the rate of brain glucose metabolism (Blomqvist 1991). However, when the blood glucose falls, the brain glucose metabolism is reduced and the brain is starved of its primary fuel resulting in hypoglycemia and symptoms such as anxiety, irritability, aggression, panic attacks, depression, poor concentration, etc. (Thomas & Bishop 2007:554).
Nocturnal hypoglycemia
If blood glucose drops too low at night, it can lead to nocturnal hypoglycaemia, which causes the release of glucose regulatory ‘stress hormones’, such as adrenaline, noradrenaline and cortisol, which breakdown glucose stored as glycogen (Wilson 2004).
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Written by Breda Gajsek, Principal BCNH
