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ANTC41H3 Chapter Notes -Thrifty Gene Hypothesis, Insulin Resistance, Dietary Fiber

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Professor Sawchuck

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ANTC41 Notes
CVD, Diabetes and Cancer, Diet, Insulin Resistance and Diabetes: The Right (pro)Portions Spence, McKinley and
-diet and lifestyle mod are the cornerstone of prevention of type 2 diabetes
-aims to reduce body weight, improve insulin resistance, and modify CV risk factors
-idea that overconsumption leads to weight gain has been around since 460 BC
-hyperglycaemia and abnormal glucose metabolism is the defining feature of diabetes and there is still a widely held
belief that a high intake of sugar is a particular risk factor
-it is now est that excess fat intake and disturbances in fat metabolism are associated with insulin resistance and
Insulin Resistance
-concept of insulin resistance emerged following discovery of insulin
-insulin sensitive = type 1, insulin resistant = type 2
-early experiments investigated the effect of altering relative amounts of carbs and fat on insulin action showing that
blood glucose lowering effect of insulin is enhanced as carbs increase
-but this highlights that the reciprocal changes in macronutrients make interpretation of causality difficult
-the modern def of insulin resistance is a condition in which “a normal con of insulin produces a less than normal
biological response”
-insulin acts on skeletal muscle, to stimulate glucose uptake and formation of glycogen; the liver, whre insulin
suppresses hepatic gluconeogenesis; adipose tissue, causing suppression of lipolysis
-following secretion from the pancreatic B cells, insulin travels in the bloodstream to its target tissue and binding to
receptors activates tyrosine kinase which initiates a cascade that influences the expression of GLUT4 protein allowing for
glucose uptake
-insulin resistant states show downstream effects that are attenuated
-type 2 diabetes involves impairment of insulin action or insulin resistance combined with defects in insulin secretion
-insulin resistance precedes the onset of glucose intolerance
-hyperinsulinaemia occurs initially as a response to insulin resistance in order to maintain glucose homeostasis
-as insulin resistance progresses this compensatory mechanism is overwhelmed resulting in impaired
glucose tolerance
-a vicious cycle evolves in which hyperglycemia glucose toxicity exacerbates insulin resistance
-the relationship b/w insuln secretion and insulin resistance becomes disconnected and B cell function declines,
the so called “starling curve” and Type 2 diabetes reflects the “tip of the iceberg
-diabetes is also defined based on the level of blood glucose
-a substantial proportion of the excess cv risk attributed to diabetes is already present
-treat aimed at glucose lowering have little or no effect on macrovascular events
-insulin resistance is also associated with a cluster of abnormalities that collectively constitute the insulin
resistance or metabolic syndrome
-insulin resistance not only is a mechanism contributing to the deve of diabetes, but also an inde risk factor of
-global prevalence of diabetes is often linked to changing patterns of diet and exercise but there is marked variation b/w
diff ethnic groups
-“thrifty gene hypothesis” proposes that certain thrifty genes promote storage of energy and deve of insulin
resistance which conferred a survival advantage historically during times of food scarcity, but when exposed to the
excess of a modern westernized lifestyle results in obesity, insulin resistance and diabetes

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Role of Dietary Fat
-high fat, and therefore energy dense diets, contribute to hyperenergetic intake and weight gain, which increases the
risk of obesity and diabetes
-the amount of saturated fat has been shown to influence the risk of diabetes
-may be related to the fatty acid composition of cell membranes or to lipid storage muscles
Role of Carbs and Sugars
-carbs consist of starch, sugars and fibre
-simple sugars = monosaccharides and disaccharides; complex sugars = monosaccharide polymers; fibre = indigestible
carb polymers
-common dietary advice advocates complex carbs and restriction of simple carbs based on the assumption that simple
sugars are rapidly digested and absorbed
-however, it has been shown that the chemical structure of carbs poorly predicts the glycaemic response
-glycemic index was proposed to provide a physiological clarification of carbs
-defined as the incremental area under the blood glucose response curve for a 2h period of a standard 50 g
portion of the given food
-expressed as a % of the response to a reference standard
-provides a physiological measure of the postprandial glycaemic response and depends on the rate of digestion
and speed of absorption of carb
-factors that may influence the glycaemic response include: fat content, cooking method and duration, meal
-it is only feasible to use simple techniques to assess insulin resistance, such as the frequently employed homeostasis
model assessment of the oral glucose tolerance test
-prob is that they lack reproducibility
-smaller intervention have the advantage of being carefully controlled, with detailed assessments but they are short
term and address surrogate rather than clinical end pnts
-the euglycaemic hyperinsulinaemic clamp technique is the gold standard
-involves the constant infusion of insulin to achieve steady state hyperinsulinaemia
-time consuming and labour intensive
-can be combined with other techniques
Animal Studies
-consistently shown that high intake of sucrose and fructose in rodents cause insulin resistance BUT their diets
contained 69% total energy from sucrose which is in excess of levels consumed by humans
-studies on rodents have shown detrimental effect on insulin action of high fructose intakes
Epidemiological Studies
-modern westernizes diets contain an increased amount of carbs and sugars and is widely perceived that this may
contribute to the increase in insulin resistance and risk of type 2 diabetes
-a prospective study found a high risk of deve of diabetes in those participants with the highest scores, particularly in
obese participants
-westernized diet included high intake of carbs and sugar; however, the def also included red meat, processed meat,
fries and high fat dairy products
-therefore difficult to determine the effect of sugar
-studies have shown an inverse relationship b/w intake of dietary sugars and insulin resistance, others have revealed the
opposite effect
-inconsistencies may relate to methodological diff

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Intervention Studies
-studies have generally shown no association or an increase in insulin sensitivity with increased fructose intake across a
range of subject groups
-one study demonstrated that an increase in insulin sensitivity in subjects with type 2 diabetes in response to
high fructose intake
-studies have also suggested a detrimental effect of high sucrose intake on insulin resistance
-but picking subjects based on their insulin resistance at baseline and used indirect measures of insulin
sensitivity which may limit the generalizability of these studies
-it is possible that chronic over secretion of insulin may lead to receptor down regulation
-results have shown that a high sucrose intake has no detrimental effect on hepatic or peripheral insulin sensitivity or on
glycaemic profiles
-it is concluded that a high sucrose intake as part of a euenergetic weight maintaining diet has no detrimental
effect on insulin sensitivity in healthy overweight subjects who are not diabetic
Role of Fruit and Veggies
-consumption of 3 major daily servings of veggies is not associated with a substantial reduction in the risk for type 2
-evidence an inverse association b/w fruit and veggie intake and diabetes risk
-a high consumption of fruit and veggies was shown to be associated with a 20% risk reduction of type 2
-the association with vit c was shown to be even stronger, equating to a 62% reduction
-association was stronger for fruits
-in a study from china, veggie intake was inversely related to the risk of type 2 diabetes
-association stronger for veggies
-an association b/w intake or status of carotenoids and glucose metabolism
-randomised controlled trials provide the most convincing evidence
-beneficial association b/w fruit and veggies and insulin resistance may be explained by the notion that the high
fibre content of fruit and veggies, as dietary fibre may be able to favourably modulate glucose homeostasis
-the antioxidant properties of fruits and veggies may also be imp as it is postulated that oxidative stress may
impair insulin action
-best kind of study are large scale epidemiological clinical intervention studies
Weight loss Diets and Insulin Resistance
-the risk of deve diabetes is strongly related to measures of adiposity rising exponentially as BMI increases in the
overweight and obese range
-traditionally, a hypernergetic low fat diet has been the most widely recommended which supply balanced fat:
carb: protein in reduced quantities to produce an energy deficit
-little evidence that low fat diets cause weight loss inde of energy restriction
-atkins diet
-idea that restriction of carbs leads to metabolism of fat resulting in ketogenesis, which promotes an
unintentional reduction in energy intake
-restriction of carbs may however be associated with an increase in fat intake
-high protein weight reduction diets are also claimed to reduce hunger and satiety
-diets should contain a broad range of foods to ensure nutritional adequacy and promote compliance
-low carb diets may be deficient in micronutrients
-the composition of weight loss is also imp
-in the short term, low carb diets are associated with a greater reduction in body water than fat
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