Human Nutrition Notes (Adjusted)-13-33 PDF

Chapter 11: Water-soluble vitamins: Vitamin C and B-complex vitamins (B1, B2, B3, B5, B6, B7, B9 and B12) 1) Water soluble vitamins act as coenzymes in the intermediary metabolism (reactions related to energy production and storage) and these vitamins can be obtained via the diet and many of them a...

Chapter 11: Water-soluble vitamins: Vitamin C and B-complex vitamins (B1, B2, B3, B5, B6, B7, B9 and B12) 1) Water soluble vitamins act as coenzymes in the intermediary metabolism (reactions related to energy production and storage) and these vitamins can be obtained via the diet and many of them are produced by our intestinal microbiota. What is the general function of thiamine in metabolic pathways and nervous system? Metabolic Pathways: Thiamine, in its active form (Thiamine Diphosphate, TDP), acts as a coenzyme for pyruvate dehydrogenase, 2-oxoglutarate dehydrogenase, and oxo-acid dehydrogenase, critical for glucose metabolism, amino acid metabolism, and energy production in the citric acid cycle. Nervous System: Thiamine supports electrical conduction in nerve cells by activating chloride channels via thiamine triphosphate (TTP) and regulates cholinergic neurotransmission. 2) Thiamine deficiencies can develop amongst others upon excessive alcohol use, diuresis, diabetes, inflammatory bowel disease. Why can thiamine deficiencies develop rather quickly (when intake/uptake is low in certain conditions) and why does this lead to increased plasma lactate (see also metabolic map) concentrations? Rapid Turnover: The body has limited thiamine stores (~30 mg) with a fast turnover rate (short half life). Deficiency develops quickly when intake or absorption is impaired. Increased Lactate: Thiamine is essential for pyruvate dehydrogenase activity. Without it, pyruvate cannot enter the citric acid cycle and is converted to lactate instead, leading to lactic acidosis. 3) Which foods are rich in riboflavin? Milk, dairy products, meat, egg, fish, fortified cereals. 4) Does (non-clinical) riboflavin deficiency occur? Clinical signs of riboflavin deficiency are not specific and the condition is usually accompanied by other micronutrient deficiency. This overlap makes it harder to isolate riboflavin as the primary cause of symptoms such as fatigue, skin issues, or mouth sores (e.g., angular stomatitis) and therefore making non-clinical deficiency hard to identify however they still can happen. 5) What role does riboflavin play in the oxidation of fatty acids and entrance of pyruvate into the citric acid cycle (also check metabolic map)? And what is its role in the antioxidant defense system (ed 14)? Fatty Acid Oxidation: Riboflavin is a precursor for FAD, required by acyl-CoA dehydrogenase in beta-oxidation. Pyruvate Conversion: FAD, derived from riboflavin, is essential for pyruvate dehydrogenase activity, converting pyruvate into acetyl-CoA for the citric acid cycle. Antioxidant System: FAD is crucial for glutathione reductase, which maintains reduced glutathione levels for cellular antioxidant defense. 6) Riboflavin is also involved in the regeneration of free-folate into its form as methyl donor. What is the function of riboflavin in this? Riboflavin-derived FMN is a cofactor for MTHFR, which regenerates 5-methyltetrahydrofolate, the active folate form that donates a methyl group in homocysteine metabolism to form methionine. This function links riboflavin to folate metabolism and methylation pathways, which are essential for DNA synthesis and repair. 13 7) How does riboflavin deficiency affect iron (bio)availability? Riboflavin deficiency is associated with hypochromic anemia as a result of secondary iron deficiency. There is an increased rate of iron loss from GI tract and some animal studies showed that the absorption of iron is impaired in riboflavin deficiency. Additionally, riboflavin deficiency may impair mobilisation of iron from intracellular stores. Overall, riboflavin decreases iron bioavailability. 8) Pellagra can occur upon combined tryptophan and/or riboflavin (and niacin) deficiency. FAD is essential in tryptophan metabolism. Which metabolic coenzyme can be formed out of tryptophan (see also metabolic map)? Tryptophan is a precursor for the synthesis of niacin. In this pathway, riboflavin (as FAD, flavin adenine dinucleotide) is an essential coenzyme for an enzyme which helps convert tryptophan into kynurenine and downstream metabolites that eventually form NAD⁺. Additionally, other vitamins like vitamin B6 are also required in the pathway and without riboflavin will be deficient. 9) How can certain drugs lead to functional riboflavin deficiency? Iatrogenic riboflavin deficiency: A variety of drugs, including phenothiazines, tricyclic antidepressants, antimalarials, and adriamycin are structural analogs of riboflavin and inhibit flavokinase (converts riboflavin into FAD/FMN), leading to functional deficiency because of impaired formation of the flavin coenzymes. 10) Which micronutrient deficiencies are associated with riboflavin deficiency? Deficiencies in vitamin B6, niacin, folate, iron, and vitamin A are associated with riboflavin deficiency. Niacin (Vitamin B3): Riboflavin is involved in the conversion of tryptophan to niacin. Vitamin B6 (Pyridoxine): Riboflavin is required for the conversion of vitamin B6 into its active form Folate (Vitamin B9): Riboflavin plays a role in the regeneration of (the active form of folate), essential for DNA synthesis. Iron: Riboflavin is involved in the metabolism of iron and can influence iron absorption. Vitamin A: Riboflavin is important for the conversion of beta-carotene to retinol (the active form of vitamin A). 11) NAD can be formed in the kynurenine pathway. Which factors can affect NAD synthesis (only in ed 14)? In the liver, NAD is synthesised from tryptophan by the kynurenine pathway, and then hydrolysed to release nicotinamide, which is exported to other tissues. It is controlled predominantly by the activities of the enzymes which in turn ar independent on the adequate supply of riboflavin, vitamin B6, and iron and are affected by some hormones (glucagon, glucocorticoids, and oestrogen) as well as various drugs (isoniazid). Diets rich in leucine could also depress the conversion of tryptophan into niacin. 12) Can niacin be fully taken up from cereals and become bioavailable? Most of the niacin in cereals is in the form of nicotinic acid and it is biologically unavailable, since it is bound covalently to complex carbohydrates forming indigestible compounds called niacytin. However, alkaline processing of grain foods results in hydrolysis of most of the niacytin with release of highly bioavailable free niacin. 13) Check out the role of coenzymes NAD(P)/NAD(P)H in the pentose phosphate pathway, glycolysis and citric acid cycle, fatty acid synthesis and beta oxidation in the (see metabolic map)? Citric acid cycle: NAD⁺ → NADH and FAD → FADH₂. NADH is oxidized in the ETC, driving ATP synthesis. 14 Pentose Phosphate Pathway: NADP⁺ → NADPH. The PPP generates NADPH, which is critical for reductive biosynthetic reactions and antioxidant defense. This reduces glutathione, helping neutralize reactive oxygen species and provides reducing power for fatty acid and cholesterol synthesis. Glycolysis: NAD⁺ ↔ NADH. NADH generated in glycolysis is transported to the mitochondria and used in the electron transport chain to produce ATP. Regeneration of NAD⁺ is essential to sustain glycolysis, especially in anaerobic conditions (e.g., lactate formation via lactate dehydrogenase). Fatty acid synthesis: Required reducing power of NADPH (from the PPP). Beta-oxidation: NAD⁺ → NADH and FAD → FADH₂. Both enter the ETC, contributing to ATP generation. NAD⁺/NADH: Catabolic reactions (glycolysis, TCA, beta-oxidation) generate NADH, which is oxidized in the ETC for ATP production. NADP⁺/NADPH: Anabolic reactions (PPP, fatty acid synthesis) use NADPH as a reducing agent. 14) Which vitamins are required to synthesize NAD (deficiencies of these can lead to secondary pellagra if intake of tryptophan and niacin is low) (note: niacin deficiency (and pellagra) is rare)? Riboflavin, vitamin B6, and iron deficiencies can impair NAD synthesis, potentially leading to secondary pellagra. 15) Which metabolic pathways require active vitamin B6 derivatives as a cofactor/ coenzyme? The metabolically active vitamin B6, derivatives are PLP and PMP, which act as coenzymes in more than 100 reactions in amino acids metabolism, one carbon metabolism, glycogenolysis and glycogenesis, haem synthesis, niacin formation, and recycling of steroid hormone receptors from tight nuclear binding. 16) Vitamin B6 can be neurotoxic, at which dose will this happen when taken for a prolonged time? Large doses of pyridoxine 500-2000 mg/day taken for several months or longer were associated with progressive sensory ataxia presented by unstable gait, numbness of the feet and hands 17) Which are sources of vitamin B6? Rich quantities in meat, fish, fortified breakfast cereals, potatoes, and bananas, but also milk, nuts, beans, and vegetables provide significant amounts. 18) Folate (biological form in bread cereals, (green leavy) vegetables, beans, legumes, potatoes; folic acid is synthetic form as supplemented) is required for the one-carbon metabolism (methyl group donation for biosynthesis) and thus essential for biological pathways such as DNA synthesis and repair, homocysteine metabolism and methylation reactions. Reduced form of Tetrahydrofolate (free THF) and the positions where the one-carbon- groups can be added, making THF active as methyl-donor. 15 19) Good to note is that cysteine can be used in the glutathione pathway and SAM, S-adenosylmethionine is a methyl donor in methyltransferases that facilitate methylation of a wide range of substrates including DNA, proteins, and neurotransmitters which further regulates cellular and physiological processes. Which B vitamins are involved as cofactors/coenzymes in the folate metabolism and what is their function? Vitamin B6 (Pyridoxine): Cofactor for SHMT, aiding in forming 5,10-Methylene-THF. Vitamin B2 (Riboflavin): Cofactor for methylenetetrahydrofolate reductase (MTHFR), converting 5,10-Methylene-THF to 5-Methyl-THF. Vitamin B12 (Cobalamin): Cofactor for methionine synthase, converting homocysteine to methionine. These vitamins work in tandem to maintain the functionality of one-carbon metabolism. 20) Suboptimal folate status is generally common in developed countries. Which dose of folic acid is recommended to prevent neural tube defects (spina bifida) in newborns and when should supplementation be started to become effective? To prevent neural tube defects (NTDs) in newborns, a 400 µg/day dose of folic acid is recommended, starting preconception and continuing through the first trimester of pregnancy. 21) Epigenetic changes related to neuro/brain development and function (cognition) in the first 10 years of life, have been linked to maternal folate status during pregnancy. DNA methylation is required for these processes. Do these only rely on folate as cofactor (see question 20)? DNA methylation in neurodevelopment and cognitive function depends not only on folate but also on: ​ Vitamin B12 (cofactor for methionine synthase) ​ Methionine and SAM (methyl donors) ​ Riboflavin (supporting MTHFR enzyme). 22) When affluent levels of folate are available this can mask vitamin B12 deficiency since megaloblastic anemia -as an indicator for vitamin B12 deficiency- will then not develop. What can be the consequence of an unnoticed vitamin B12 deficiency? -​ High folate intake prevents the development of megaloblastic anemia, a key indicator of B12 deficiency. -​ This causes irreversible nerve damage, leading to cognitive decline, neuropathy, or dementia and homocysteine accumulation which leads to Increased cardiovascular and cerebrovascular risk. 23) Increased homocysteine blood levels are associated with increased risk of CVD and cognitive decline in older age. Can plasma homocysteine concentrations be interpreted as a functional indicator of folate status? -​ Folate is required to demethylate homocysteine into methionine. Low folate or B12 leads to elevated homocysteine, associated with: Increased risk of CVD. -​ However, elevated homocysteine might also indicate vitamin B12 or B6 deficiency, so it’s not folate-specific. 24) Which groups of people are at risk for vitamin B12 deficiency? 16 Older adults (due to atrophic gastritis). Vegans (dietary deficiency. Individuals with gastrointestinal disorders or infections. Those taking medications that impair absorption. 25) What are sources of vitamin B12? Foods of animal origin: Meat, poultry, fish, shellfish, eggs, and dairy products. 26) Why is the stomach important in making vitamin B12 bioavailable (which thus explains that atrophic gastritis in elderly plays a role in vitamin B12 deficiency), and where is vitamin B12 taken up? -​ Stomach acid releases B12 from food. -​ Intrinsic factor (produced by parietal cells) binds B12, facilitating its absorption in the terminal ileum. 27) Why can vitamin B12 deficiency cause 5-methylTHF to be trapped (it cannot exert its function; folate trap) and why can this cause megaloblastic anemia? In B12 deficiency, folate recycling becomes impaired because of a decrease in the activity of the B12-dependent enzyme methionine synthase, therefore 5-methyl THF cannot be converted to THF. Thus folate cofactors become “trapped” in a form that cannot be used for DNA synthesis and, as a result, DNA synthesis becomes impaired and causing megaloblastic anemia. 28) Why can vitamin B12 deficiency cause neurological damage? Causes demyelination of peripheral and central neurons which leads to neurological complications. Impaired methylation of myelin basic protein, affecting nerve function. This damage is progressive and often irreversible without treatment. 29) Which cells can store vitamin C? Vitamin C is primarily found in the plasma and erythrocytes (red blood cells), with smaller amounts in white blood cells (mononuclear leukocytes, platelets, and granulocytes). The adrenal and pituitary glands show significant concentrations of vitamin C, but there is no specific storage organ for the vitamin. 30) Which vitamin collaborates with vitamin C to regain its radical scavenger (anti-oxidant) properties? Vitamin C is a potent reducing agent, meaning that it readily donates electrons to recipient molecules. Related to this oxidation-reduction (redox) role, two major functions of vitamin C are as a potent antioxidant and as an essential cofactor for numerous enzymatic reactions. Vitamin C can protect critical molecules in the body such as DNA and DNA from damage by free radicals. Vitamin C also participates in redox recycling of other important antioxidants; for example vitamin C can regenerate vitamin E from its oxidised form. 31) Vitamin C acts as a cofactor to certain hydroxylases, in which processes do these enzymes play a critical role? By maintaining enzyme-bound metals in their reduced forms, vitamin C is required by mixed-function oxidases in the biosynthesis or hydroxylation of several critical biomolecules, including noradrenaline, collagen, and carnitine. 32) With intake of more than 100 mg vitamin C/day plasma levels may reach the renal threshold (plasma concentrations above about 85 uM). What is the fate of ascorbic acid when this threshold is reached? Kidneys excrete excess vitamin C into the urine, preventing plasma concentrations from rising significantly beyond the range of 70-80 µmol/L. 17 33) Is it helpful to take vitamin C to enhance iron absorption? Yes, vitamin C enhances iron absorption. It reduces ferric iron (Fe³⁺) to the more absorbable ferrous form (Fe²⁺) and chelates iron, facilitating its uptake in the intestine. A 25 mg dose of vitamin C increases iron absorption by about 65%, and a 1 g dose provides a nine-fold increase. 34) There is rather a large number of vitamins being produced by the microbiome, one of those is pantothenic acid. It is crucial in many metabolic pathways since it is a functional moiety in Coenzyme A for example in the form of acetyl-CoA. Check out the metabolic map for the role of acetyl-CoA in providing substrate for the citric acid cycle as generated by a) beta-oxidation of fatty acid and b) oxidative degradation of amino acid. Beta-oxidation of fatty acids: Fatty acids are broken down into two-carbon units, forming acetyl-CoA, which enters the citric acid cycle to produce energy. Oxidative degradation of amino acids: Amino acids are degraded to produce acetyl-CoA, which then enters the citric acid cycle. Examples include: ​ Alanine is converted to pyruvate, which forms acetyl-CoA. ​ Leucine is directly converted to acetyl-CoA. ​ Isoleucine and valine are processed into propionyl-CoA → succinyl-CoA → acetyl-CoA. ​ Tryptophan and phenylalanine generate intermediates that form acetyl-CoA. 35) Biotin (vitamin H) is also involved in carbohydrate, fat and/or protein metabolism. Check out the metabolic scheme, what is the role of biotin in fatty acid synthesis? Biotin acts as a coenzyme for acetyl-CoA carboxylase (ACC), catalyzing the conversion of acetyl-CoA to malonyl-CoA, the rate-limiting step in fatty acid synthesis. Malonyl-CoA provides the two-carbon units required for the elongation of fatty acid chains, ensuring efficient synthesis when energy is available. Chapter 12: Fat soluble vitamins: Vitamin A, E, D and K. 1) Which are the fat soluble vitamins? Vitamin A, E, D and K. 2) How does severe (leading to xerophthalmia) or marginal vitamin A deficiency affect children in low income countries? Vitamin A deficiency can lead to xerophthalmia, a condition that causes dry eyes, which can result in blindness if untreated. Even marginal deficiencies increase susceptibility to infections, including respiratory infections, diarrhea. 3) Which dietary sources contain retinol and which contain beta-carotene (which can be oxidized to retinol)? Retinol: Found in liver, full-fat dairy products, fortified margarine, eggs, and oily fish. Beta-carotene: Found in dark-green leafy vegetables and yellow/orange fruits and vegetables like carrots, sweet potatoes, pumpkins, and mangoes. Beta-carotene can be converted to retinol. 4) Which form of vitamin A is ligand for nuclear receptors and involved in gene expression and how can this be formed? Retinoic acid (active form) is the main metabolite of retinol and is a ligand for nuclear receptors involved in modulation of gene expression, rather than a catabolic product. It is formed in the liver and other tissues and 18 transported bound to serum albumin. Once formed, retinoic acid enters the nucleus of cells, where it binds to RARs or RXRs, initiating gene transcription. Vitamin A is stored in the liver. 5) Which form of vitamin A is required for formation of rhodopsin and what is the function of rhodopsin? 1-cis-retinaldehyde is required for the formation of rhodopsin, which is a light-sensitive pigment found in the rod cells of the retina essential for vision in low-light conditions. Rhodopsin undergoes a change upon light absorption, triggering nerve impulses related to vision. 6) Which nuclear retinoid receptors are known, and -beyond forming homodimers- with which receptors can these form heterodimers to regulate gene expression and metabolism and/or insulin signaling? There are two families of nuclear retinoid receptors: the retinoic acid receptor (RAR), which binds to all-trans retinoic acid, and the retinoid X receptors (RXP). RXP forms active homodimers, and also forms heterodimers with the vitamin D receptors, the thyroid hormone receptor, and the peroxisome proliferator activated receptor (PPAR), involved in the expression of genes regulating lipid and carbohydrate metabolism, including enhancement of insulin signaling. 7) Vitamin A deficiency can cause night blindness, blindness (xerophthalmia and xerosis can develop in irreversible blindness), enhance epithelial permeability and loss of mucus protection (in lung and intestine). It can cause skin problems, and affect immune function, increasing the susceptibility to infection. Vitamin A deficiency can also cause (functional) iron deficiency anemia, since it interferes with hemoglobin formation. How can vitamin A deficiency contribute to the development of anemia? Vitamin A deficiency impairs hemoglobin formation and reduces the mobilization of iron for hemoglobin synthesis (which is crucial for oxygen transport in red blood cells), leading to functional iron deficiency anemia. 8) Vitamin A is stored in the liver in the form of retinol. Which dose is given to children in developing countries to fight deficiencies and for how long is this protective? Single doses of 60mg of retinol are given to children in developing countries as a prophylactic against vitamin A deficiency – an amount to meet the child's needs for 4-6 months. 9) At which dose of chronic use will retinol become toxic in adults and what is the recommended dose in adults? And what about carotenoids can these cause hypervitaminosis A? Retinol toxicity: Chronic intake of over 7500-9000 µg/day of retinol can cause toxicity in adults. The recommended daily intake is 650-750 µg RE/day. Carotenoid toxicity: Carotenoids do not cause hypervitaminosis A because they are not readily converted to retinol in excess. However, excessive carotenoids may cause yellow-orange skin discoloration (carotenemia). 10) Check out figure 12.5 (12.4 in ed 13), which form of vitamin can be obtained from the diet, is present in supplements and can be synthesized in the skin upon exposure to the sun (UVB radiation; benefitting from brief regular periods to large skin surface )? Vitamin D3 (cholecalciferol) can be obtained from food, supplements, and synthesized in the skin upon UVB exposure from sunlight. 11) Vitamin D is a precursor hormone and 25(OH)D plasma levels represent the reservoir available for activation and regulation of physiological functions. Which is the active form of vitamin D, which physiologic functions are regulated by it and how does it regulate gene expression? 19 The active form is 1,25-dihydroxyvitamin D (calcitriol). It regulates calcium homeostasis, enhancing calcium absorption, reabsorption, and bone resorption. It also regulates gene expression related to immune function and cell growth. 12) How and where is the biologically active form of vitamin D formed from the endogenous and dietary D3 precursor? Vitamin D3 is converted in the liver to 25-hydroxyvitamin D (25(OH)D). It is further hydroxylated in the kidneys by 1α-hydroxylase to form the active 1,25-dihydroxyvitamin D (calcitriol). 13) Low vitamin D levels during pregnancy increases the risk of nutritional rickets in early life since the newborns depend on maternal transfer of vitamin D via the mother during pregnancy and lactation. Supplementation can prevent this. Also elderly are at risk of vitamin D deficiency, Since 7-dehydrocholesterol synthesis in the skin is decreasing and due to low sun exposure, this can cause osteomalacia. Is only vitD supplementation sufficient to overcome these problems? Vitamin D supplementation is essential to prevent rickets in infants and osteomalacia in the elderly. However, vitamin D alone may not fully address these issues, as calcium intake is also important. 14) How does skin pigmentation interfere with formation of cholecalciferol? Darker skin contains more melanin, which reduces the absorption of UVB radiation, requiring longer sun exposure to synthesize adequate vitamin D. 15) Which foods contain cholecalciferol? Food sources of vitamin D3 (cholecalciferol): fatty fish, cod liver oil, egg yolks, milk, cereal, margarine and some plant based alternatives 16) Nowadays the recommended daily intake of vitamin D for amongst other young children and elderly in the Netherlands is 10 ug/day (20 ug/day> 70 years) (source: Voedingscentrum). What is the maximal tolerated daily dose of intake in adults? And what is the risk of chronic intake of too high doses of vitamin D? -​ According to EFSA (European Food Safety Authority), the tolerable upper intake level (UL) of vitamin D for adults (including the elderly) is 100 µg/day. -​ Chronic high doses can lead to toxicity, causing symptoms like weakness, headache, abdominal pain, hypercalcemia, and kidney damage. 17) Alpha-tocopherol is the form of vitamin E most known for its biologic functions. It is mainly known as anti-oxidant and since it is fat soluble it can be located within the cell membrane. What is its main known antioxidant function and why are other antioxidants such as water soluble ascorbic acid and/or glutathione needed as well for proper function of vitamin E? Vitamin E acts as an antioxidant by scavenging lipid peroxyl radicals before they attack PUFAs. Other antioxidants, such as vitamin C and glutathione, are needed to regenerate vitamin E and maintain its antioxidant function. 18) Is vitamin E deficiency common in the general population? Vitamin E deficiency is rare in the general population but can occur in individuals with fat malabsorption conditions or certain genetic disorders. 19) Can vitamin E supplementation prevent cardiovascular disease? 20 There is no evidence that vitamin E supplementation can prevent cardiovascular disease, and high doses may even pose risks, such as interfering with blood clotting. 20) Vitamin K1 and K2 are naturally occurring, what is their source? Phylloquinone Vitamin K1: Found in green leafy vegetables, vegetable oils, and some fruits. Menaquinone Vitamin K2: Found in animal products, fermented foods, and bacteria-fermented foods. 21) Vitamin K is a cofactor coupling glutamate to vitamin K dependent proteins (yielding gamma-carboxyglutamate for these proteins). What is the best known function of vitamin K related to this phenomenon? Vitamin K is essential for the activation of clotting factors (prothrombin, factors VII, IX, and X) by gamma-carboxylation, which enables calcium binding necessary for blood coagulation to prevent bleeding. Vitamin K is a cofactor of Gamma-glutamyl carboxylase which carboxylates glutamate residues in vitamin K-dependent clotting factors, enabling calcium binding and proper function in the coagulation cascade to form blood clots. 22) Which drug interferes with vitamin K reduction/recycling/activity and what is the effect of this drug? Warfarin (an anticoagulant) interferes and inhibits vitamin K epoxide reductase, preventing vitamin K recycling back to active form and impairing clotting factor activation, which reduces blood clotting but increases the risk of bleeding. Inactive form: Vitamin K epoxide (KO) Active form: Vitamin K hydroquinone (KH2) 23) Why are newborns given Vitamin K1? Newborns are given vitamin K1 prophylactically to prevent vitamin K deficiency bleeding (VKDB), which can cause serious bleeding in the first days or weeks of life. -​ Low levels of vitamin K store at birth -​ Limited vitamin K available in breastmilk -​ Delayed development of liver glutamate carboxylase. 21 Chapter 19: Nutrition and cardiovascular disease 1) In atherosclerotic lesions macrophages are present which form foam cells due to lipid accumulation. Which components accumulate in these inflammatory cells? Atherosclerosis is a chronic inflammation of the large and medium sized arteries (coronary, carotid, and femoral arteries). Atherosclerotic lesions develop at the select sites of the vascular system, largely determined by dynamics of the blood flow at those sites, with plaques developing at sites of disrupted blood flow. These lesions are characterised by the accumulation of monocyte/macrophage and smooth muscle cell-derived foam cells in the arterial wall intima. The lipid droplets of these cells are composed mainly of cholesterol esters thought to be derived from native and modified LDL that enters the subendothelial space from plasma (LDL cholesterol infiltrates the arterial wall and becomes oxidised, triggering an inflammatory response) they are ultimately taken up by these macrophages forming foam cells, which accumulate to create fatty streaks. Beyond the cholesterol esters of the lipid droplets, free cholesterol or cholesterol oxidation (+triglycerides) products may accumulate in lesional foam cells. 2) How can cholesterol contribute to plaque disruption/rupture and what is the role for macrophages in this process resulting in thrombosis responsible for clinical events such as stroke and myocardial infarction? Cholesterol esters, free cholesterol, and oxidised cholesterol products accumulate in lesional foam cells and as a result will cause them to undergo apoptosis. If the phagocytic activity of neighbouring macrophages is intact, the apoptotic cells will be effectively removed, if not, the apoptotic cells will undergo secondary necrosis, which if substantial, forms a necrotic core that promotes plaque instability. Macrophages will release lytic enzymes (metalloproteinases) that will disrupt fibrous cap leading to plaque rupture and thrombus formation, increasing susceptibility to myocardial infarction (coronary arteries) or stroke (carotid arteries). Smooth muscle cells migrate to the intima where they release proteins that give rise to the fibrous cap and protects the necrotic core from being damaged. 3) Which lipoprotein carries cholesterol into the artery wall and which nutrients enhance or reduce the levels of this cholesterol packed lipoprotein? The major lipoprotein carrying cholesterol into the artery wall is low-density lipoprotein (LDL). The cells of the plaque, particularly macrophages and smooth muscle cells, take up native and modified LDL by macropinocytosis or receptor mediated endocytosis respectively. This makes diet important for circulating LDL levels. Cholesterol packaged in the LDL may be derived from the diet (exogenously) or from endogenous synthesis. Saturated/trans fats and dietary cholesterol increase LDL levels, while fiber and unsaturated fats lower LDL. 4) How is dietary cholesterol taken up in the intestine (trafficking and released by enterocytes), carried to the liver and what will then happen with the cholesterol? Dietary cholesterol is absorbed by enterocytes via NPC1L1 (small intestine to ER) and esterified into cholesterol esters by ACAT2 enzyme. It is packaged and transported as chylomicrons, which enters the lymphatic system. Then dietary cholesterol is stored either as cholesterol esters or distributed by HDL or LDL for storage, metabolism, or excretion. 22  -​ Be stored as cholesterol esters in very low-density lipoproteins (VLDLs). -​ Be secreted into bile (either as free cholesterol or bile acids, which are cholesterol derivatives). -​ Be redistributed to the liver via high-density lipoproteins (HDL). HDL delivers cholesterol to liver cells (hepatocytes) through specific receptors. The liver regulates plasma LDL by removing it from the bloodstream using LDL receptors. If LDL levels are too high, excess LDL can accumulate in artery walls, leading to atherosclerosis (hardening of arteries) and increasing the risk of cardiovascular disease. Cholesterol Recycling (Enterohepatic Circulation): Cholesterol doesn’t just come from diet; it’s also recycled through the enterohepatic circulation: -​ Chylomicron remnants (rich in cholesterol) are taken up by the liver. -​ The liver also clears cholesterol from plasma LDL and synthesizes cholesterol. -​ Cholesterol is then secreted into bile either as free cholesterol or bile acids. Bile helps digest food and is stored in the gallbladder until needed. This recycling process maintains cholesterol balance, but excess cholesterol intake or disrupted metabolism can elevate plasma LDL and exacerbate atherosclerosis. 6) Both statin and ezetimibe are drugs used to treat hypercholesterolemia. Why can they act complementary (using only statin is the first choice, example of combination preparate Ezetimibe/simvastatin)? Statins inhibit HMG-CoA reductase (rate limiting step in liver) to reduce cholesterol synthesis as well as upregulates the synthesis of the LDL receptor, while ezetimibe blocks absorption in the small intestine via inhibiting NPC1L1. Together, they maximize LDL reduction. Lower cholesterol in the intestine, means less cholesterol travels to the liver, less liver cholesterol upregulates LDL receptors, increasing LDL uptake from the bloodstream and reducing plasma LDL levels. 7) Which different types of dietary fats, which percent of food energy is from dietary fats in a standard Western standard diet, and what is the source of the different fats? Saturated fats: Animal products (dairy/meat), tropical oil (coconut oil) Monounsaturated fats: Mediterranean oils (olive oil) Polyunsaturated fats (n-3 and n-6): plant oil (corn/safflower oil) and fish oil Dietary fat provides about ~35% of food energy in the average Western diet. 8) When considering the amount (low/high) and type of fat, what is an atherogenic diet contributing to hypercholesterolemia (high levels of cholesterol in blood) and cardiovascular disease, and what is preventive? Atherogenic diet: Preventive diet for cardiovascular health High saturated fats Low in saturated/trans fat Excessive total fat High in monounsaturated and polyunsaturated fats High in refined sugar and carbohydrates Omega-3 fatty acids Increased fibre intake + Antioxidant rich foods The lower the level of fat and the higher its unsaturated fat content, the lower is the extent of hypercholesterolemia and cardiovascular disease. 9) Can carbohydrates contribute to risk of myocardial infarction? 23 High glycemic index carbs increase risk of myocardial infarction, especially when combined with high saturated fat. 10) How does the Mediterranean diet vs vegetarian diet affect the risk for mortality due to CVD as evidenced by schematic reviews of meta-analyses of observational studies? And what about high grain, chocolate, and low sodium? Feeding the Mediterranean diet had a risk ratio (RR) of 0.55 for cardiovascular mortality, and 0.64 for stroke. The RR in SRMA was 0.87 for vegetarian diet; legume 0.89; fish 0.82; high grain intake 0.68; and high chocolate 0.55. In randomised controlled trials (RCT), the RR for low sodium was 0.67. The Mediterranean diet shows the most protective effect against CVD, followed by vegetarian diets. High grain and chocolate consumption lower risks; low sodium is beneficial. 11) Which B vitamin affects cholesterol levels? Vitamin B3 or nicotinic acid (niacin) has been shown to decrease LDL cholesterol, triglyceride levels and lipoprotein. It also increases HDL cholesterol levels thus has been used as a treatment to control hyperlipidemia. 12) Which B vitamins convert homocysteine? Elevated serum levels of homocysteine are associated with increased vascular damage and risk of cardiovascular diseases. Both folic acid (vitamin B9) and vitamin B12 participate in the remethylation of homocysteine to methionine and vitamin B6 participates in the degradation of homocysteine which is an important pathway in regulating homocysteine levels, reducing risk of stroke. 13) Do fat soluble vitamins provide protection against CVD? Vitamin D deficiency to be associated with an increased risk of cardiovascular disease and hypertension however, lacks strong evidence. Vitamin A, E and K have modest to no measurable effects. 14) How can your microbiome protect against CVD? Complex carbohydrates are metabolised to yield the short chain fatty acids acetate, propionate, and butyrate. These fatty acids can be oxidised to provide energy and can signal through G protein coupled receptors to infounce blood pressure homeostasis. They may also have an impact on myocardial repair. Primary bile acids may also regulate energy metabolism, brown adipose tissue activation and insulin sensitivity. 15) How can your microbiome contribute to CVD development? -​ Bacterial cell wall lipopolysaccharide and peptidoglycan promote vascular inflammation, insulin resistance and enhance atherosclerosis by decreasing reverse cholesterol transport -​ Dietary phosphatidylcholine that are generated by intestinal enzymes and gut microbes namely choline, trimethylamine (TMA) and betaine – all associated with increased CVD risk. -​ TMA can be oxidised to TMAO in the liver, plasma TMAO is a better predictor of CVD risk over LDL cholesterol. -​ Diets with these increases accelerate the development of atherosclerosis. -​ Large amounts of lecithin in the bile provides a source of choline for transformation into TMA. -​ Phenylacetylglutamine (PGA) is generated from a gut microbial metabolite of phenylamine and activates adrenergic receptors causing thrombosis and atherosclerosis. 16) What is the DASH diet and how can it impact hypertension? 24 Pathogenesis of hypertension is affected by environmental factors as well as gut microbiome which is regulated by diet and is a major risk factor for coronary artery disease and stroke. High consumption of sodium/alcohol ^ blood pressure. The DASH (Dietary Approaches to Stop Hypertension) diet, is low in sodium and high in potassium has been recommended as an environmental approach to limit elevations of blood pressure through fruits and vegetables, whole grains, fish, poultry, low fat dairy products, and nuts. Chapter 21: Diabetes mellitus 1) What is the difference between diabetes type 1 and 2? Diabetes mellitus is a metabolic disorder of multiple aetiology characterised by chronic hyperglycemia associated with impaired carbohydrate, fat, and protein metabolism. These abnormalities are the consequence of either inadequate insulin secretion or impaired insulin action, or both. Type 1 diabetes is characterised by cell mediated autoimmune destruction of pancreatic beta-cells that result in a partial or total inability to secrete insulin, and life-long need for insulin administration. Type 2 diabetes is characterised by a progressive loss of insulin secretion on the background of insulin resistance. Most patients are obese or have increased body fat, predominantly in the abdominal region. 2) The normal fasting glucose (FG) level is 100 mg/dL (5.6 mM), what are the levels in prediabetes with impaired fasting glucose and what are these levels when diabetes is diagnosed? ‘Prediabetes’ is the term used for individuals with impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT) and indicates an increased risk for future development of diabetes. (associated with type 2 diabetes) IFG is defined by fasting plasma glucose >110 mg/dl and 126 mg/dl. 3) What is meant with an oral glucose tolerance (GT) test (and what are the values in pre-diabetes and diabetes) and HbA1c? Oral Glucose Tolerance Test (OGTT): Measures plasma glucose 2 hours after ingesting 75g of glucose. -​ Prediabetes: 2-hour glucose >140 mg/dL and 200 mg/dL (11.1 mM). HbA1c: Reflects average plasma glucose over the past 8–10 weeks. -​ Diabetes: HbA1c >6.5% (48 mmol/mol). 4) Which percentage of individuals with impaired glucose tolerance (IGT) are prone to develop diabetes type 2 (DM2) and are these individuals at risk for CVD? If untreated, approximately ⅓ (33.3%) of people with IGT will develop T2D within 5-10 years and the risk of mortality due to cardiovascular disease or cerebrovascular diseases double compared to normal glucose tolerance. 5) What are the main clinical parameters that define the diagnostic criteria for metabolic syndrome? -​ Raised arterial blood pressure -​ Raised plasma triglycerides -​ Low HDL (high density lipoproteins) -​ Central obesity 25 6) What are the long term complications of untreated DM2? Microvascular complications: Retinopathy, nephropathy, and neuropathy. Macrovascular complications: Myocardial infarction, heart failure, and stroke. Reduced life expectancy by 5–10 years. 7) What are the main risk factors for developing DM2? Obesity and sedentary lifestyle, high intake of saturated fats, diets with high glycemic index. 8) How does insulin deficiency in DM1 present and does it develop instantly or gradually? Insulin deficiency develops gradually as 80–90% of beta cells are lost 9) What is the source of blood glucose causing hyperglycemia in untreated DM1? Hyperglycemia results from both increases glucose production by the liver and reduced glucose utilisation by peripheral tissue (mainly skeletal muscle) due to (A) lack of insulin stimulatory effect on glucose transport into muscle tissues and (b) increased availability of free fatty acids, which are known to inhibit glucose transport across the muscle membrane through operation of glucose–fatty acid. 10) How does DM1 lead to ketogenesis (follow also these steps (see p 436), in the metabolic routes map, see PDF on blackboard, will also be available during MC test)? In uncontrolled T1D, fatty acid mobilisation from adipose tissue is markedly increased. Normally in the liver fatty acids undergo beta-oxidation to acetyl CoA, which is totally oxidised in the Krebs cycle to water and carbon dioxide. When there is an excessive breakdown of fatty acids, as occurs in an insulin deficient state, the capacity of the liver to oxidise all acetyl CoA is exceeded and two carbon fragments combine to form acetoacetate (ketone body). Hepative ketone body synthesis is further enhanced by the low insulin to glucagon ratio that critically regulates the activity of the key enzymes of ketogenesis. 11) Which dietary fats and carbohydrates increase risk of DM2 development? High intake of saturated fats and high glycemic index carbohydrates. 12) Which two metabolic defects can be recognized in untreated DM2 patients? 1.​ Impaired insulin secretion 2.​ Resistance to insulin action on target tissues, namely the liver, skeletal muscle and adipose tissue. 13) In untreated DM2 insulin responses towards glucose can be low or absent, how come? (please only focus on the effect on the pancreas and main elements on page 437) To compensate for reduced peripheral insulin sensitivity, b-cell usually increases its insulin secretion so as to prevent persistent hyperglycemia. In this way, a near normal blood glucose is maintained at the expense of increased insulin level, However, when pancreatic b-cells are no longer able to compensate with an appropriate increase in insulin secretion diabetes will further develop. Beta-cell unresponsiveness due to the toxic effects of chronic hyperglycemia 14) GLP-1 is a satiety hormone, and GLP-1 analogues (Semaglutides, such as Ozempic or Wegovy) meant to treat diabetes are now also being used to assist weight loss in non DM individuals. Why are incretins analogues, like those for GLP-1, interesting for DM2 management? 26 Normally after meal ingestion, GI produces various peptides including glucagon-like peptide-1 (GLP-1) and the glucose dependent insulinotropic peptide (GIP) – collectively known as incretins – they act on b-cells to enhance the insulin release induced by hyperglycemia. In T2D, the incretin effect is markedly reduced since the GLP-1 response to nutrients is diminished. Infusion of GLP-1 analogues in T2D patients is able to increase insulin release and to reduce glucose levels (and glucagon which raises glucose levels). They also delay stomach emptying and act on hypothalamus to decrease appetite. + Protect b-cells making incretin based therapy a new strategy for management of T2D. 15) What is the main effect of insulin resistance on the peripheral tissues (e.g. glucose uptake in muscle) and liver? In T2D, the effect of insulin on the liver and peripheral tissues is impaired, producing the major metabolic abnormalities observed in diabetic patients. Liver: abnormally increased glucose production in the postabsorptive state which contributes to fasting hyperglycemia. Ability to take up and dispose of dietary glucose also is reduced. = Increased hepatic glucose production Skeletal muscles: Ability for insulin to stimulate glucose uptake by skeletal muscles is reduced by 40-50%. Due to the defect in the glucose transport step involving the translocation and/or activity of the GLUT-4. = Reduced glucose uptake in skeletal muscle Adipose tissue: In T2D patients, the ability of insulin to suppress lipolysis is impaired. Glucose transport is impaired and because this occurs less glycerophosphate is formed and consequently there is an increased flux of free fatty acids (FFA) from adipose tissue. These FFA concentrations fail to be suppressed and chronic elevation of FFA causes detrimental effects on both b-cells by dysregulating them, and insulin action in peripheral tissues (lipotoxicity). 16) Via which insulin dependent transporter is glucose normally taken up by skeletal muscle. Why is this process insulin dependent? (please check molecular mechanism on internet, this is not clearly explained in the book) Skeletal muscle takes up glucose via the insulin-dependent transporter GLUT4, which is stored in intracellular vesicles in its inactive state. Insulin binding to its receptor triggers the PI3K-Akt signalling pathway, causing GLUT4 vesicles to translocate to the cell membrane. Once embedded, GLUT4 facilitates glucose entry into the cell via diffusion. This process is insulin-dependent, ensuring efficient glucose uptake, particularly after meals, to maintain normal blood glucose levels. 17) Which two metabolic processes in adipose tissue are disturbed in case of insulin resistance (see also figure 8.12 page 180 for overview of pathways)? Insulin resistance: Occurs when a given concentration of insulin produces a less than normal biological response. As known insulin exerts its biological effects by binding to its specific cell surface receptors. After, a number of signals are generated that interact with a variety of effector units (enzymatic systems) leading to multiple metabolic effects. Insulin promotes the storage of nutrients by stimulating glycogen synthesis , protein synthesis and lipogenesis and by inhibiting lipolysis, glycogen and protein breakdown. In insulin resistance, there is impaired glucose transport and increased lipolysis and free fatty acid reflux. 18) How can chronic high plasma glucose and free fatty acid levels worsen/ contribute to DM2? Glucose toxicity hypothesis: a chronic increment in plasma glucose concentration leads to progressive impairment of insulin secretion and insulin sensitivity by damaging beta cells. 27 Lipotoxicity: Once adipose tissue reaches its maximum capacity to expand, fat begins to accumulate in other tissues (liver, heart, muscle) causing apoptosis and inflammation which is responsible for the progression of the disease and the deterioration of the glucose control over time. 19) What is meant by glucose toxicity in DM2 and how can glycemic control help in DM2? Chronic high glucose impairs insulin secretion and sensitivity. Tight glycemic control improves insulin action by delaying and reducing the likelihood of DM2. 20) Can enhanced plasma insulin levels precede DM2 development? Yes, increased insulin compensates for insulin resistance until beta cells fail 21) In the long run diabetes can cause blindness due to microvascular complications. In how many (%) of DM1 and DM2 patients blindness will occur and at which age and what is the main causative factor? DM1: 95% have retinopathy after 20 years; 60% risk of proliferative retinopathy after 40 years. DM2: 20% risk of proliferative retinopathy after 20 years and 60% for any type of retinopathy. Causative factor: Chronic hyperglycemia and microvascular damage. 22) Obesity or being overweight is prevalent in 60-70% of DM2 patients. Would body weight reduction improve DM2? Most patients (60-70%) with T2D are overweight or obese, and the frequency of overweight and obesity has increased over the last year also in T1D patients. Large evidence shows that body weight reduction, even if modest (5-10% of basal body weight), is able to improve blood glucose control, reduce insulin resistance, and favourably affect the other cardiovascular risks such as blood pressure, and lipid abnormalities. 23) DM2 lifestyle prevention programs are proven effective. What are the elements in these programs? Lifestyle prevention programmes: -​ Moderate weight reduction (about 5%) -​ Increased physical activity (at least ½ hour of brisk walking everyday) -​ Changes in composition of diet (reduction in saturated fats, increased consumption of dietary fibre) -​ Reduction of daily calorie for calorie deficit of 300-500 kcal/day 24) What is the recommended amount of fiber to prevent DM2, which products can be used and what are the health benefits? High consumption of vegetable fibre (25-29g/day) as well as whole grains is associated with significant reduction in the risk of T2D, cardiovascular diseases and mortality. Dietary fibre is only one of the factors able to modulate the glycemic response to carbohydrate-rich foods. 25) Fibers modulate the glycemic response to carbohydrate rich food, thus fiber rich foods often have a low glycemic index. How can this response be measured? Glycaemic index (GI) is based on the increase in blood glucose concentrations (the incremental area under the curve of glucose concentration) after the ingestion of portion of a test food containing 50g of carbohydrates, divided by the incremental blood glucose are achieved with the same amount (50g) of carbohydrates present in an equivalent portion of a reference food (glucose or white bread). 26) Do low carbohydrate diets (