Non-communicable Diseases Flashcards
Describe the twin cycle hypothesis
The twin cycle hypothesis describes the relationship between T2D and fatty liver disease.
- Calorie surplus = lipogenesis in the liver (fat production and accumulation in liver)
- fat accumulation in liver = insulin resistance
- insulin resistance causes hyperinsulinaemia (high level of insulin in blood)
- hyperinsulinaemia causes hyperglycaemia (high level of glucose in bood)
- hyperinsulinaemia stimulates de novo lipogenesis (new fat production)
= more fatty liver
Fatty liver = increased production of vLDL
vLDL is deposited at the pancreas
pancreatic function deteriorates as vLDL damages insulin producing beta cells.
this contributes to the development of T2D.
T2D is characterised by inhibited response to glucose which increases plasma glucose which then feeds back into the liver cycle producing more fatty liver as insulin production continues.
Describe how obesity can induce insulin resistance and subsequent T2D.
Twin cycle hypothesis.
Obesity involves the expansion of adipose tissue (Adipose tissue is an active endocrine organ).
Adipose tissue produces and secretes adipokines.
Macrophages build up in the adipose tissue and secrete pro-inflammatory cytokines (TNF-a)
= state of chronic inflammation
= pro-inflammatory cytokines disrupt normal insulin signalling pathways
= cells become less responsive to insulin
Cells unresponsive to insulin
= beta cells work harder and produce more insulin to achieve glucose homeostasis
= beta cells deteriorate over time (lose mass & function)
= insulin production decreases and blood glucose increases
= T2D
Describe the role of insulin resistance in the development of atherosclerosis
Increased risk and accelerated development of atherosclerosis have been shown in diabetic patients.
Mechanisms of action include:
- dyslipidaemia
- chronic inflammation
- oxidative stress
- hyperglycaemia
Dyslipidaemia:
- Diabetic dyslipidaemia is characterised by high LDL, low HDL and high TG’s.
- Insulin resistance + enhanced body fat mass = release of FFA’s from adipose tissue
additionally, lipoprotein lipase activity is reduced (due to lack of insulin) = decreased clearance of lipoproteins. - In liver cells, hyperinsulinaemia + elevated FFA’s = increased TG synthesis and vLDL secretion
- Additionally, insulin is responsible for regulating serum LDL and vLDL concentrations - hyperinsulinaemia overstimulates vLDL production.
Chronic inflammation:
- T2D = increased inflammasome and pro-inflammatory cytokine (interleukin) activity
Oxidative stress:
T2D is associated with increased ROS (reactive oxygen species) activity
Hyperglycaemia:
Elevated blood glucose level = AGE accumulation
AGE accumulation = endothelial disruption
= WBC accumulation and adhesion in plaque formation stage
AGE also encourage pro-inflammatory cytokine release = chronic inflammation.
Describe how hypertension can lead to atherosclerosis
- Atherosclerosis tends to occur in those parts of the vascular system subjected to high pressure demonstrating that HTN causes stress to the arterial wall which intensifies atherosclerosis.
- Hypertensive arteries are thickened with smooth muscle cells - contributes to the development of the mature plaque.
- Changes in endothelial function as a result of HTN can promote atherosclerosis.
- Oxidative stress generates an inflammatory response that, in the presence of hyperlipidemia, leads to the formation of atherosclerotic plaque.
blood vessels become narrow or volume of circulating blood becomes too high:
= Increases workload of the heart
= Damages the blood vessel endothelial lining
= Increases infiltration of blood components (e.g., lipids) into arterial wall which promotes atherosclerosis and CVD
Describe the stages of atherosclerosis
Inflammation is a key player in the development of atherosclerosis.
- LDL cholesterol builds up within the intima (endothelial inner layer of arterial wall) and become oxidated and modified by the endothelial cells.
- WBC’s accumulate within intima as LDL signals to endothelial cells to cling on
- WBC’s engulf LDL cholesterol forming ‘foam cells’ and a fatty streak develops.
- plaque continues to grow and develop - smooth muscle cells from the media contribute to the maturation of the plaque - fibrous cap develops.
- Plaque ruptures causing blood clot = blockage/occlusion of blood vessel = stroke/MI
Describe obesity and explain the role of obesity in the development of:
- HTN
- T2D
- Atherosclerosis and CVD
- cancer
Obesity is considered an inflammatory disease characterised by the expansion of adipose tissue which is fundamentally the result of chronic positive energy balance.
Defined as BMI >30 and further categorised as clinically obese (BMI 35-40) and morbidly obese (BMI 40+)
Central obesity describes accumulation of fat around abdomen, which is associated with increased risk of CVD and other metabolic complications such as T2D, HTN, cancer.
Adipose tissue produces and secretes a type of cytokine known as adipokines:
- resistin
- leptin
- TNF-a
- interleukin 6 (IL-6)
- adiponektin
These adipokines are pro-inflammatory and act at an endocrine level.
Visceral fat is more inflammatory than subcutaneous fat.
Obesity and T2D:
- Twin cycle hypothesis
- Increased body fat mass = increased NEFA (non-esterified fatty acids) - especially in ppl with central, visceral obesity.
lipolysis in visceral fat adipocytes releases NEFA directly into portal vein
= accumulation and secretion of vLDL
excess accumulation of fat has ‘lipotoxic effect’ on surrounding organs/tissue which can impair normal insulin signalling (mechanisms include inflammation and oxidative stress).
Obesity and HTN:
- obesity accounts for 65–78% of primary HTN
- structural and functional renal changes e.g., SNS overactivation and stimulation of renin angiotensin aldosterone system (RAAS)
- alteration in adipose-derived cytokines (leptin)
- insulin resistance
- increased FFA in circulation = endothelial dysfunction relation to absence of insulin induced vasodilation and reduced NO release.
Obesity and CVD:
dyslipidaemia + hypertension = atherosclerosis = CVD
Obesity and Cancer:
Adipose tissue expansion = increased oestrogen = cancer (breast + ovarian)
- 10% of all cancer deaths from non-smokers are related to obesity
- One study suggests however that only 2-3% of cancer mortality is explained by obesity (Danaei et al., 2005)
Describe the role of inflammation in the development of HTN
inflammation = immune cell activation
immune cells (WBC) migrate to BV lining
accumulation of WBC in arterial wall = release of pro-inflammatory cytokines
= oxidative stress
= vascular remodelling (altered NO, collagen deposition, endothelial dysfunction)
= HTN
Describe insulin resistance and T2D
- what are the risk factors?
T2D is a type of diabetes that is caused by lifestyle factors - primarily being obese.
insulin resistance is when cells become resistant to insulin and do not take glucose up into cells so glucose accumulates in blood stream (also called impaired glucose tolerance)
T2D is when pancreatic beta cells do not produce enough insulin.
Risk factors for T2D:
- Age > 45
- BMI > 25
- Ethnicity
- Sedentary lifestyle
- Poor diet (high in sat fat)
- Low HDL + high LDL & TG
- PCOS
- Gestational diabetes (60% women will develop T2D)
- Family history of T2D and heart disease (genetics)
Describe the metabolic syndrome
the metabolic syndrome describes the clustering of several interrelated metabolic conditions including obesity (central obesity) hypertension, dyslipidaemia and insulin resistance.
significantly increases risk of CVD.
Caused primarily by diet and sedentary lifestyles.
Describe the relationship between insulin resistance and hypertension
IR and hypertension are common co-morbidities
Mechanisms involved include:
- Hyperinsulinaemia stimulates muscle sympathetic nerve activity = increased arterial vasoconstriction.
- IR is associated with increased plasma FA concentration = endothelial dysfunction such as altered NO activity = impaired vasodilation/arterial stiffness
- Hyperglycaemia causes widespread damage to tissues and organs including renal function. E.g., Na resorption in kidneys = fluid retention = increased blood volume + arterial stiffness = HTN
Describe the role of nutrition in the development and management/prevention of atherosclerosis
dietary factors that promote atherosclerosis/CVD include:
- saturated fats (myristic acid & palmitic acid)
- trans fatty acids
- high sodium intake
- excess alcohol consumption
- high cholesterol
- being overweight/obese
dietary factors that prevent/manage atherosclerosis include:
- wholegrains and fibre
Reduce total and LDL cholesterol and contain some antioxidants notably vitamin E - fruit and veg
Antioxidants such as Vit C&E can reduce LDL oxidation in vitro
French paradox - French have low rate of CHD despite high intake of dietary cholesterol and saturated fat. Reduced susceptibility of LDL to oxidation due to high intake of antioxidants (red wine drinking?) may offset the detrimental effects of this potentially atherogenic lipoprotein) - fish oils and PUFA’s
Reduced platelet aggregation, positive effect on cardiac electro-physiology, arterial compliance, endothelial function, blood pressure, vascular reactivity and inflammation - omega 6
can reduce LDL and platelet aggregation
Describe the role of diet and lifestyle in the development and the prevention/management of hypertension
overweight/obesity:
- BP increases as adiposity increases
- weight loss results in decrease in BP
Physical activity:
- regular BP has direct effect on BP
- increasing PA reduces BP and BP increases when PA level is reduced
- exercise needs to be aerobic to have antihypertensive effect however does not have to be high intensity e.g., walking
- yoga shown to increase odds of maintaining normal BP
Alcohol:
- regular EtOH consumption associated with high BP
- reducing EtOH redices BP in a dose response relationship - biggest reduction in alcohol = biggest reduction in BP
Sodium and potassium:
- there is an independent, positive relationship between dietary sodium
- high sodium is an independent risk factor for mortality from CVD
- potassium has a negative effect on BP
- dietary patterns with the greatest ratio of Na to K have the biggest effect on blood pressure compared to Na intakes alone
- sodium replacements are effective in reducing BP
- DASH diet developed to reduce hypertension
Dash diet:
Vegetables, fruits and wholegrains
Fat free/low-fat dairy products
Lean protein (fish, poultry, legumes, pulses, nuts)
Limit foods high in sat fat e.g., tropical oils
Limit sugar sweetened bevs and sweets
How is HTN defined?
British hypertension society guidelines:
Optimal BP (120/80)
Normal (<130/85)
High BP (130/85 - 139/89)
Grade 1 HTN (140/90 - 159/99)
Grade 2 HTN (160/100 - 179/109)
Grade 3 HTN (>180/110)
Describe three challenges associated with establishing a link between sodium intake and HTN
Hard to accurately estimate Na intake from doetary records e.g., accounting for salt added during cooking or at the table.
There is a wide variation in Na content within similar foods
there is heterogeneity in the response to salt - some individuals are more sensitive to its effects on blood pressure than others
Describe the role of diet in the management of T2D
(NICE guidelines)
- Individualised care
- Diabetes education
- Dietary advice:
High fibre (early satiation) and attenuated postprandial glycaemic response
Low GI carbs (shown to improve HbA1c levels) should be around 40-60% total energy (be mindful that GI of foods can change depending on which other foods they are consumed with)
Reduce consumption of simple sugars (less than 10% total energy) however sucralose may not affect glycaemic control negatively.
Reduce intake of saturated fats:
Dietary fat impacts FA composition of cell membrane – affects insulin binding to its receptor
Replace sat fat with unsat fat particularly MUFA (Omega 6 improves insulin sensitivity)
fatty acid profile of diet determines fatty acid profile of phospholipid bilayer of cells = increased insulin sensitivity
(35% of total energy should come from healthy fat)
Weight loss target of 5-10% BW (in patients who are overweight)
- weight loss can be achieved by DiRECT trial or bariatric surgery.
