Nutrition 10 Lecture Notes PDF

**[Obesity:]** **[Obesity statistics:]** - Increasing in the US and the world; 15% (1976-80) to 33% in US adults now (becoming common in youth) - Highly related to [cardiovascular disease, diabetes mellitus, liver disease, and other serious disorders], leading cause of death in wo...

**[Obesity:]** **[Obesity statistics:]** - Increasing in the US and the world; 15% (1976-80) to 33% in US adults now (becoming common in youth) - Highly related to [cardiovascular disease, diabetes mellitus, liver disease, and other serious disorders], leading cause of death in world and correlated w/ obesity **[Obesity:]** - ***Disorder of body fat (excess body fatness relative to lean tissue)*** - Identified in practice usually by body weight or BMI (Body Mass Index = kg/m^2^) - BMI \> *30 (obese*); BMI \> *27 (overweight)* - BMI is not a perfect metric -- obesity is defined by body fat stores, not muscle or other types of weight -- but it is convenient and usually works - Criteria for obesity vary by age/sex/ethnic group **[Demographics:]** - Prevalence is now higher in lower socio-economic groups in western, developed world -- poorer people have a higher incidence, not lower - Opposite to historical pattern and iconic imagery for centuries - Prevalence is higher in minority groups in the US - Some demographic groups have \> 70% prevalence - Tremendous increase in prevalence in young people - Accelerating increase in less developed countries (Asia, S. America, urban Africa, central Europe, etc. (obesity used to be rare, now common) - Implications: will be part of political, economic and health discussions no matter what field of work - Because so common, people argue it could be a normal variation; but it has serious consequences **[Diseases related to obesity:]** - - Diabetes mellitus (type 2) - High BP - Dyslipidemia - Cardiovascular disease, Stroke - Liver disease (NAFLD) - Cancers (colon, prostate, breast) - Gall bladder disease - Reproductive dysfunction (PCOS) - Depression - Sleep/breathing disturbances - Cognitive dysfunction (Alzheimer's) **[History of Nutrients against diseases:]** - **Pellagra**: Fortification of *Niacin* in bread ended the epidemic (1906-1920) - **Rickets**: *Vitamin D* supplementation of milk, margarine, and cereals reduced from 80-90% to rare - *Iodination* of salt prevented endemic thyroid hormone deficiency (cretinism) - **Beriberi** (extreme weakness): impairment of nerves/heart; common after polished (white) rice; caused by thiamine deficiency; supplementation cured - **Scurvy*:*** *Vitamin C* supplementation prevented this - **Anemia:** *Iron and Folate* administration reduced high prevalence among healthy young women - **Pernicious anemia:** A horrible condition that led to death cured w/ monthly shot of *Vitamin B12* **[\ ]** **[General Overview and a Fantastic Voyage through the Gastro-Intestinal Tract, aka GUT]** **[Critical Organs]** - GI tract is the gateway where food becomes a nutrient - *Lumen* (outside) of the gastrointestinal tract (from mouth to rectum) faces the outside of the body - **Accessory organs:** - Salivary glands, liver, pancreas, gallbladder - ***Salivary glands*** -- aid in lubricating and initiating starch breakdown - ***Parotid glands*** -- produce serous, watery secretion - ***Submaxillary (mandibular) glands*** produce mixed serous & mucous secretion - Protects against infection and toxins - Alters peripheral metabolic responses and feeding behavior (Vagus nerve for example) - *Sensory receptors* are similar to *taste receptors* and activate the same neural pathways - **Digestive Organs:** - Esophagus, Stomach, S intestine (lots of surface area), Colon (L intest -- can't live w/o b/c most hormones here) - Most organs linked by the **vagus nerve** (stomach, small intestine, liver, gallbladder, bile ducts, pancreas, adrenal medulla, kidney, colon - Others controlled by the **pelvic nerve:** Rectum, Bladder **[Other functions aside from digestion of food and nutrient absorption]** 1. Gate keeper of nutrients into the body 2. Barrier and immune defense 3. Fluid and electrolyte absorption 4. Synthesis and secretion of several proteins (such as apolipoproteins) 5. Production of bioactive peptides as hormones and neurotransmitters 6. Nutrient sensing **[Hepatic portal circulation:]** - Carries blood (stomach/intestines liver); hepatic portal vein transports nutrients absorbed by blood **[Enterohepatic Circulation (not the same as hepatic portal circulation)]** - Recycling process; bile (liver gallbladder small intestine); aids digestion - Bile reabsorbed (small intestine liver for reuse) **[Phases:]** 1. **Cephalic Phase** -- B4 food enters, thought/smell/sight/taste of food brain signals stimulate gastric secretions (prepping) 2. **Gastric Phase** - Food enters stomach increases rate of gastric secretion and motility a. **Stomach** holds food and controls its passage into the small intestine b. Acid, enzymes, and signal molecules help in digestion i. **HCl** -- prepares protein for digestion; activates enzyme ii. **Pepsin** -- begins protein digestion iii. **Gastric lipase** -- some fat digestion iv. **Gastrin (hormone)** -- stimulates gastric secretion and movement v. **Intrinsic factor --** needed for B12 absorption c. Stomach acid destroys many bacteria and other pathogens. Stomach protects itself w/ thick mucus 3. **Intestinal Phase** -- food leaving the stomach and entering small intestine distends intestine -\> hormone decreases stomach motility and slows gastric secretion d. **Small intestine** -- Duodenum, jejunum, ileum e. **Bicarbonate** -- neutralizes stomach acid (regulated by secretin f. **Goblet cells** -- secret mucus for protection/lubrications g. **Bile --** emulsifies fat (digestion) h. Pancreatic and intestinal enzymes vi. CHO, Fat, Protein A graph of a normal diet Description automatically generated with medium confidence **[Food:]** - Must have macronutrients: carbohydrates, protein, fat, minerals, vitamins, ater **[Food energy:]** - Gross Energy: Carbohydrates (4.12 kcal), Fat (9.4 kcal), Protein (5.6 kcal) - Digestible Energy: Feces, Carbohydrates (4.0 kcal), Fat (9.0 kcal), Protein (5.2 kcal) - Metabolizable Energy: Urine, CHO (4), Fat (9), Protein (4) **[Example of some gut hormones:]** - Secretin, Somatostatin (released by acid). Cholecystokinin,GLP-1 (incretin), GIP (incretin), Peptide YY, Neuro peptide Y, Ghrelin (hunger when not eaten), Substance P **[When do we begin the process of digestion?]** - Alcohol absorbs very easily in the stomach **[Taste sensations:]** Sweet -- often indicates energy rich food Salty -- allows for regulating diet electrolyte balance Sour -- taste of acids Bitter - natural toxins Umami -- taste of meat and cheese (amino acid glutamate) **[Pepsinogen production:]** - Pepsinogen itself can't digest; Once mixed with HCl, it can be a digestive enzyme (turns into pepsin)  **[Gastrointestinal Motility requires integration of signals from nerve cells and smooth muscle cells]** - **Propulsion** -- food propelled along length of digestive (peristalsis) to be processed (disassembly/absorption) - **Mixing** -- rings of contraction chop/mix ingesta; **[Enzymes:]** - Pancreatic digestive enzymes stored in granules of pancreas (inactive form) *Trypsinogen (inactive tnt) + enteropeptidase trypsin (activated tnt)* **[\ ]** **[Macronutrients:]** Fat (9 kcal/g) \| Carbohydrate (4 kcal/g) \| Protein (4kcal/g) \| Ethyl Alcohol (7 kcal/g) **[Dietary Carbohydrates:]** - Basis of most modern diets (Provide *half* of kcals) - Provide a readily available source of energy (only source of energy for nervous system -- Brain uses glucose) - Provide a wide variety of nutrients needed for health when consumed in "whole food form" A chart of food and nutrition Description automatically generated with medium confidence **[Whole grains vs Refined Grains:]** - Whole grains -- unrefined or whole - Refining grains separates many essential nutrients in whole unrefined foods **(magnesium, vitamin E, B vitamins, etc)** - Refined grains may be enriched with **thiamin**, **riboflavin**, **niacin** and **iron** and fortified with **folate** **[High Fructose Corn Syrup and Obesity]** - Fructose does not store fat; But as HFCS increases, so does obesity A graph showing the amount of obesity in years Description automatically generated **[Types of Carbs:]** - *Simple carbs:* - **Monosaccharides** -- made up of a single sugar unit; basic unit of carb - 3 most common monosaccharides: **glucose, fructose, and galactose** - ***Glucose*** -- circulates in blood; most important carb fuel - ***Fructose*** (fruits, vegetables, honey, and hfcs) - ***Galactose*** (milk sugar) - **Disaccharide** -- made up of two sugar units - ***Sucrose*** -- glucose + fructose; table sugar (only sweetener labeled as **sugar**) - ***Lactose*** -- glucose + galactose; milk sugar and found in milk products - ***Maltose*** -- two glucose; formed in digestive tract when starch digested - *Complex carbs:* - **Polysaccharide** -- made up of many sugar units; long chains of monosaccharides - Include *glycogen* found in animals & *starch* and *fiber* found in plants - **Oligosaccharides** -- short chains containing 3-10 monosaccharides **[Glucose:]** - Main circulating sugar (constant source of fuel) - Must be under [tight regulatory control] to maintain blood glucose at a constant level - Prod from liver and disposal in muscle - Primary fuel for the CNS - Low blood sugar can lead to hypoglycemia - Sources of glucose - Dietary carb - Gluconeogenesis -- occurs in the liver - Precursor -- amino acids from protein - Dietary protein or breakdown of body protein (muscle) - If you stop eating carbs, and fast, then glucose will be mobilized from muscle (amino acids make sugar) **[Making and Breaking Sugar chains:]** - **Hydrolysis reaction -** Breaks sugar molecules apart - **Dehydration reaction -** Links two sugar molecules together **[Glycogen, Starches, and Fiber:]** - *Glycogen* -- increases after a meal and is depleted by an overnight fast - *Starches* -- unique size, shape, and organization; account for properties during cooking - *Fiber* -- Cannot be broken down by digestive enzymes; adds bulk (increases stool volume) When you go on a run and deplete glycogen, after you eat, you fill back those stores in the muscles and then liver **[Dietary Fiber:]** - Cannot be digested/absorbed by humans, but is an important part of the digestive process and health of the GI tract - Two types of fiber**: Soluble and Insoluble** - Fibers can be added to processed foods to thicken and reduce fat and calories; slows down digestion/absorption - ***Good sources of soluble fibers:*** legumes, prunes, apricots, raisins, oranges, bananas, oats, apples, eggplant, flaxseed - ***Good sources of insoluble fiber:*** wheat bran, whole-wheat bread, broccoli, corn, eggplant, apple skins, nuts and seeds **[Carb Digestion]** - **Salivary Amylase (**enzyme in mouth) breaks starch into shorter polysaccharides Inactivated in stomach by acids - **Pancreatic Amylase** in S intest breaks starch into disaccharides/oligosaccharides (villi digest into monosaccharides) - In L intest, *fiber* partially broken down by bacteria short-chain fatty acids/gas remaining fiber excreted **[Lactose Intolerance:]** - Not enough lactase enzyme in S intest to digest the milk sugar lactose - Undigested lactose cannot be absorbed and passes into the large intestine - Lactose rapidly metabolized by intestinal bacteria acids and gas - Symptoms: abdominal distention, flatulence, cramping, and diarrhea  **[Delivering glucose to body cells:]** - **Glycemic response:** how quickly/high glucose rises after carbs consumed - **Glycemic index:** ranking of how a food affects glycemic response - GI of 70 = CHO food causes 70% of blood glucose response w/ same amt of CHO from pure glucose or white bread. - **Glycemic load:** multiply food's glycemic index by amount of food you eat **[GI of common foods:]** - ***Foods with very low GI: (\< 40)*** - Apple, lentils, soy beans, kidney beans, cow's milk, carrots (boiled), barley - ***Foods with low GI (41 -- 55)*** - Noodles/pasta, apple juice, raw oranges/orange juice, raw banana, specialty grain bread, strawberry jam, sweet corn, chocolate - ***Foods with an intermediate GI (56 -- 70)*** - Brown rice, rolled oats, soft drinks, soft drinks, pineapple, sucrose, honey - ***Foods with a high GI (\> 70)*** - Bread (white/wholemeal), boiled potato, cornflakes, French fries, mashed potatoes, white rice (low amylose or sticky rice), rice crackers A diagram of food consumption Description automatically generated **[Metabolic Fate of Carbs:]** - Glycogen storage - **Oxidation**: conversion to energy - Metabolic pathway: 6 molecules of O2 convert 1 molecule of glucose 6 molecules of C02, H2O and approx. 38 molecules of ATP - Very little glucose (starches such as rice, bread, pasta) is converted to fat - No storage capacity of fructose -- lipogenesis (fat synthesis) **[Diabetes Mellitus:]** - ***Type 1 diabetes:*** insulin no longer made in body - ***Type 2 diabetes:*** insulin is present, but cells do not respond (insulin resistance) - ***Gestational diabetes:*** occurs during pregnancy **[Insulin Resistance:]** - Occurs in two tissues: - ***Skeletal muscle*** - Primary site of glucose disposal (transport requires insulin) - Insulin resistance: greater secretion of insulin needed for glucose transport into muscle - **Result**: decreased glucose disposal and elevated blood glucose (BG) - ***Liver:*** - Site of glucose storage (releases glucose to maintain blood glucose levels constant) - Hepatic Glucose Production is under hormonal control - After a meal, blood glucose levels rise in secretion of insulin - **Insulin shuts down Hepatic glucose production** - *However as liver becomes insulin resistant, insulin has a diminishing effect on hepatic glucose production* - **Result**: overprod of glucose and elevated BG **[Glycosylation:]** - Glucose is "sticky" -- binds to proteins high BG glycosylated hemoglobin + other proteins - Hemoglobin A1C = poor glucose control - Cataract formation in eye (Consequences of glycosylation (eye lense proteins)) **[Diabetes symptoms and complications:]** - Immediate symptoms: Excessive thirst/frequent urination (unfiltered glucose), blurred vision, weight loss - Long-term complications: Heart/blood vessel/kidney/eye/nervous damage; more common infections  **[Components of Daily Energy Expenditure:]** - BMR (Basal Metabolic rate) -- Depends on what food you eat - **Body composition** (muscle mass most important determinant) - **Energy balance:** hypocaloric diet reduces metabolic rate - Physical Activity: - Voluntary: Exercise/Daily activities - Involuntary (fidgeting): Non-exercise Activity Thermogenesis (NEAT) - People who do this: more energy expenditure & tend to be leaner/less fat **[Myth: All calories contribute equally to energy balance]** - Calorie is a calorie - Thermogenic effect of macronutrients - Protein \> Carbs \> Fat A graph of energy consumption Description automatically generated **[Induced Obesity:]** - 5 times as many kcal to produce the same weight gain w/ mixed compared to a high fat diet **[Lipogenesis from a large amount of sugar]** - Consumption of 500 g (2,000 kcal) of glucose (maximum glucose storage) - Only 5 g (45 kcal) of lipid made - Metabolic fate: Oxidation or Glycogen storage - Unlimited capacity to store fat; Rest of glucose is burnt as calories via oxidation; Excess protein and carbs burnt **[Myth:]** - Carbohydrates cause an increase in fat - Carbohydrates increase the risk of diabetes - Carbohydrates should be eliminated from the diet **[High carbohydrate, low fat diet Ad Libitum:]** - A shift in macronutrient intake away from fat will produce weight loss - Groups: - Control (40K fat, 40% CHO, 20% pro), no exercise - HICHO (20% fat, 60% CHO, 20% Pro), no exercise - HICHO, exercise: 3 days/wk, 75% max, 45 min/day **[High Carbohydrate ad libitum diet found to have resulted in loss of weight]** - 1 lb/wk of weight loss - No reduction in basal metabolic rate; No attempt at kcal restriction - Improvement in insulin sensitivity: Decreased risk of type 2 diabetes  **[Low-fat dietary pattern and weight change over 7 years]** - 48K postmenopausal women:30K decrease fat, increase fruit/grain intake w/ no kcal restriction goal; 20K control - **Outcome**: Women in intervention group lost an average of 2.2 kg maintained lower weight compared to control for 7.5 years - Weight loss was greatest among women in either group who decreased their % energy from fat A graph with numbers and lines Description automatically generated **[Carbohydrates and Heart Disease:]** - Diets high in whole grains have been found to reduce the risk of heart disease - Water-soluble fiber binds dietary cholesterol and reduces absorption**[\ ]** **[Proteins and Amino Acids:]** - Protein deficiency is rare in the US; About 2/3 of dietary protein from meat, poultry, seafood, eggs, and dairy - Most of the world relies on plant proteins from grains and vegetables - As a country's economy improves, proportion of animal foods increases tends (total fat/sat fat consumption increases)  **[Protein Source:]** - Animal products have *B vitamins, iron, zinc,* and *calcium*; Animal products low in *fiber* but high in *fat* - Plant sources of protein are good sources of B *vitamins*, *iron,* *zinc*, *fiber*, *phytochemicals*, and *calcium* **[Amino Acids:]** - Building blocks of proteins - Central carbon atom bound to a hydrogen atom, an amino group, an acid group, and a side chain - **Essential amino acids** cannot be synthesized by the human body in sufficient amounts to meet needs - Must be included in the diet - **Essential Amino acids:** - Histidine, Isoleucine, Leucine, Lysine, Methionine, Phenylalanine, Threonine, Tryptophan, Valine - **Nonessential Amino Acids:** - Alanine, Arginine\*, Asparagine, Aspartic acid, Cysteine\*, Glutamic acid, Glutamine\*, Glycine\*, Proline\*, Serine, Tyrosine\* ---- \*Considered conditionally essential **[Amino Acids: Transamination:]** - When a nonessential amino acid is not available from the diet, it can be made in the body by the process of *[transamination]* **[Protein Structure:]** - Amino acids are linked by peptide bonds (b/t acid group of one AA and nitrogen group of other AA) - Dipeptide bonds are two amino acids - Polypeptides formed by many Protein made of one or more polypeptide chains folded into a 3D shape - Shape Determines function - Connective tissue proteins and collagen are elongated - Hemoglobin is spherical - If shape of a protein is altered, function disrupted **[In sickle cell anemia:]** - Hemoglobin polypeptide shape slightly altered long chains of molecules of hemoglobin leads to a sickle-shape **[Protein digestion:]** - Stomach -- HCl and Pepsin begin chemical digestion of protein - S intest -- Trypsin and others secreted by pancreas break down polypeptides into AA, dipeptides, and tripeptides - Transport proteins move digested proteins into mucosal cell; Dipeptides/Tripeptides broken down into AA Blood Liver **[Protein Turnover:]** - Body continuously synthesizes and breaks down protein (recycling) **[Protein Functions:]** 1. Provide structure 2. Enzymes speed up metabolic reactions 3. Transport proteins move substances in and out of cells 4. Antibodies help the immune system in fighting foreign bodies 5. Contractile proteins help muscles move 6. Hormones are chemical messengers, such as insulin and glucagon 7. Proteins help to regulate fluid and acid base balance **[Protein Deficiency]** - **Protein energy malnutrition** -- range of protein def conditions that may include only prot def, prot def plus energy def - **Kwashiorkor** -- pure protein deficiency - **Marasmus** -- energy and protein deficiency **[Dietary Protein requirement:]** - Determined by nitrogen balance - Intake -- Output (urine + fecal + sweat + misc) - **Requirement**: 0.6 g/kg**; Recommended Dietary Allowance:** 0.8 g/kg per day - ***Acceptable Macronutrient Distribution Range (AMDR)*** is 10 to 35% of energy for adults - Needs increase during periods of growth, pregnancy, and lactation - Regular aerobic exercise increases the oxidation of EAA as a fuel; Increase food and protein requirement for athletes - RDA for protein may not be adequate for older people to maintain skeletal muscle **[Protein Synthesis:]** - 115 g (4 oz) beef (10 g) = 50% increase in PS - 15 g whey protein (7 g) = 30% increase (most effective intact protein) - 15 g essential amino acids = 80% increase - Protein synthesis maximal at 15 g EAA and 20 g whey, excess is oxidized. - Weightlifting makes it more efficient for protein to be synthesized  - DIAAS (Digestible Indispensable Amino Acid Score) -- 100 or more is considered to be high quality **[Protein w/ Vegan diet;]** - - Rice and Beans / Rice and Lentils / Rice and Tofu - Bread and Peanut Butter - Cashew and Tofu stirfry - Corn torilla and beans - Sesame seeds and chick peas / sesame seeds and peanut sauce - Corn bread and Black-eyed peas - Rice and Tofu **[Energy balance and Obesity:]** - Often stated that obesity is state of energy imbalance (intake \> expenditure) - This is wrong - Consider energy intake vs weight gain over a year (efficiency of matching) - 1,000,000 kcal ingested/year - Weight typically stable within \ - Treatment of obesity: why diets almost always fail! - Easy to lose weight; hard part is maintenance (frustrating to eat same w/ diet that works but then stop losing weight) - Alternative to gaining weight for achieving energy balance - Healthy and unhealthy - Healthy: exercise/weightlifting/muscle building - Unhealthy: drugs, medical conditions - Characteristics of individuals with long-term maintenance of weight loss. **[Why do most diets fail (to keep weight lost off)]** - Body wants to defend bodyweight reduce cal burned (energy expend) w/ weight loss/reduced intake + increased appetite - Bodies actively work against us when trying to lose weight (high weight can't be defended for many years) - (our fat stores are "harsh masters with a long memory") **[How do successful weight losers maintain weight loss?]** - 2 main factors observed for people w/ successful long-term weight loss, defined as \ 30\# for \> 5 years 1. Voluntary exercise \~ 3 kcal/week 2. Tendency to low energy density/low-fat diets **[Fitness vs Fat:]** - What is fitness? -- Capacity to do aerobic work - Can you be "fat" and "fit?" -- Sumo wrestlers - How many people "fat/fit"? Thin but unfit? -- Overweight/obese and fit is possible and not a contradiction but is unusual - Why care about fitness? -- Relation to health outcomes **[Cardiorespiratory Fitness:]** - **Operationally**: Exercise capacity on a treadmill - **Conceptually**: Capacity of body to do aerobic work - Physiologic basis (complex) - Capacity to deliver oxygen to tissues - Output/delivery working tissues, Oxygen carriage (RBCs/hemoglobin), Blood oxygenation (lung function) - Capacity of tissues to consume oxygen - Working tissue mitochondrial mass/function, Energy storage/mobilization capacity, Tissue Capillarization - Lean people who are unfit have higher CVD mortality than obese fit men (called "skinny fat"  RR = Relative Risk; CRF = Cardiorespiratory fitness A table of numbers and symbols Description automatically generated  **[Why might fitness matter?]** - **Secondary effects:** fitness may alter risk factors for disease (blood lipids, blood pressure, insulin sensitivity and glycemia) - Fitness may alter risk factors for disease directly (better mitochondrial function, perfusion of organs, etc.) - Consider the health of sumo wrestlers while active then after retiring (applies to other athletes as well) **[Lean Tissue (Muscle) burns energy:]** - Main determinant of ***Resting Energy Expenditure (REE)*** is lean body mass - About half of lean body mass is muscle - So exercise not only burns calories during the activity being performed - But it changes the composition of your body (more muscle, less fat), so you burn more calories even while you are resting **[Diseases:]** **[Some diseases associated with overweight/obesity]** - - Diabetes mellitus - High BP (hypertension) - Dyslipidemia - Cardiovascular disease - Stroke - Liver disease (NAFLD) - Cancers (colon, prostate, breast) - Osteoarthritis - Gall bladder disease - GERD - Reproductive dysfunction (PCOS) - Early Puberty - Depression - Sleep apnea/breathing disturbances - Cognitive dysfunction (Alzheimer's) **[Risk Factors associated w/ obesity]** - - High BP High cholesterol (LDL) - Dyslipidemia (high \[TG\], low \[HDLc\], dense LDL, high \[apoB\]) - Diabetes (glucose intolerance, impaired fasting glucose) - (Obesity) - Clotting alterations (dysfibrinolysis) - Cigarette smoking **[Synergistic effects of multiple risk factors for cardiovascular disease]** - Most people who get C-V D do not have marked elevations in ONE risk factor (several risk factor increases) - Combination of multiple risk factors has therefore been considered as a separate condition ("syndrome") - Multiple Risk Factor syndrome names: - Metabolic syndrome (Syndrome Metabolique), Syndrome X, Insulin Resistance Syndrome, Deadly Quartet, Familial Dyslipidemia Hypertension **[Metabolic Syndrome:]** - At least 3 of the following: 1. Fasting Glucose ≥ 100 mg/dL 2. Waist Circumference \> 102 cm in men; 88 cm in women 3. Serum triglycerides ≥ 150 mg/dL 4. HDL cholesterol \< 40 mg/dL in men; 50 mg/dL in women 5. BP ≥ 130/85 **[Associations with Obesity:]** - - Sleep apnea/breathing disturbances - Cognitive dysfunction (Alzheimer's) - Liver Disease - Cancer - - Polycystic Ovarian Syndrome (PCOS) 6. Insulin stimulate ovarian hormone prod disturb normal periods/fat cells convert estrogens to male hormone menstrual disorders and skin problems **[Body Fat:]** Why might type of fat matter? 1. Tendency to release fatty acids into bloodstream: big fat cells/visceral fat cells **release more fatty acids** 2. Adequacy of adipose fat storage capacity: paradoxical effects of lipoatrophy (absence of subcutaneous body fat) and drug therapies that increase subcutaneous fat (glitazones) 3. Consequences of fat in non-adipose tissues (liver, muscle, pancreas): "metastatic fat syndrome" - The fat in adipose stores under the skin may not be the real problem -- but when it spills into rest of body it is 1. Fat location: *central vs gluteo-femoral adipose*, or *subcutaneous vs internal* ("apple" vs "pear" shaped obesity) - Central obesity (internal fat) is associated with much worse health outcomes 2. Cell size and number ("hypertrophic" vs "hyperplastic" obesity): big fat cells worse than many small fat cells - Do adults make new fat cells (adipogenesis)? - Can this be modulated **[Metastatic Fat:]** 1. Paradoxical effects of lipoatrophy (absence of s-c fat) and lipodystrophy (e.g. related to anti-HIV medicines) - Lipoatrophy: Rare genetic disease with inability to store s-c fat. Might expect this to protect against disorders related to obesity (insulin resistance, dyslipidemia, metabolic syndrome) - But these individuals all have features of metabolic syndrome! - Loss of s-c fat with HIV-antiretroviral medications has the same adverse metabolic consequences - The real problem may be **fat in non-adipose tissues** (liver, muscle, pancreas): "metastatic fat syndrome" 2. Drugs that increase subcutaneous fat (glitazones) - Glitzones (pioglitazone/rosiglitazone) treat T2D and insulin resistance (act in adipose tissue) - Glitazone stimulate adipose precursor cells to divide/differentiate into mature adipose (increases s.c. fat but reduces size of fat cells (more) - Insulin resistance reduced and liver fat often reduced; Fat in adipose stores under skin not real problem - When fat spills into the rest of the body, trouble occurs **[Insulin Resistance:]** - Defined as a state of cell/tissue/body in which greater-than-normal amounts of insulin are required to elicit a quantitatively normal response - Discovered high blood insulin levels in early type 2 diabetes w/ high blood glucose  **[Incretin /GLP-1 Revolution in Obesity Treatment:]** A screenshot of a data Description automatically generated **[The "Incretin" Effect: "INCREased secreTion of INsulin"]** 1. Discovery came from two measurements: blood glucose and insulin levels after meals. 2. **1906** (before insulin was discovered) -- studies suggested a gut-derived substance that improved glucose metabolism 3. Proposed that small intestine secretes a hormone, similar to secretin (first known hormone -- regulates water balance) also from small intestine -- affecting disposal of glucose: as "a chemical excitant for the internal secretion of the pancreas" 4. **1920s** -- injection of intestinal secretions lowered blood glucose, depended on pancreas, and worked less well in T2D 5. All this pointed to an insulin-stimulating factor from the intestine: "INCREased secreTion of INsulin" -- incretin **[Incretin Theory could not be tested until Insulin was measurable:]** - Clinical diabetes researchers Berson and Yalow invented Radioimmunoassay to measure insulin (Nobel Prize) - More insulin in blood measured in people after oral glucose compared to IV glucose (75 g oral disposed fast as 25 g IV) - Hormones (intestine blood stim pancreas more insulin when glucose present: GLP-1 and GIP **[The Therapeutic Problem asSolved in Ususual Way: Gila Monster Venom:]** - **The problem:** GLP-1 cleared from blood in minutes; too fast for Rx - Dr. Eng - Interested in proteins in venom (Gila Monster) whose bite enlarges pancreas: a stimulatory effect? - Found new protein, extendin-4, w/ effects like GLP-1 in animals (raise blood insulin, lowering blood glucose); lasting hours - Extendin-4 is resistant to enzyme that breaks down GLP-1 - Gila monster has a GLP-1 in its own intestine that has a short lifespan but, makes a different GLP-1 in its saliva as a poison! - This became the first GLP-1 drug and was approved for diabetes A diagram of a pancreas Description automatically generated **[Remarkable clinical surprise about GLP1/Incretin Effects:]** - "Intestinal Brake" idea (intestinal nutrient storage and satiety program) - Food gets into the distal small intestine (ileum) and causes release of signals: - Not only increase nutrient storage via insulin (Incretin effect) but also signal satiety and reduce food intake: large weight loss observed from GLP-1 treatment **[Weight loss effects in GLP-1/Incretin Trials]** A graph of weight loss across a drug use Description automatically generated **GLP-1 Improves Clinical Outcomes (including heart failure CV deaths, all deaths (by 15-20%)**  **GLP-1 Reduces CV Risk Score** A close-up of several different colored bars Description automatically generated with medium confidence **GLP-1 Reduces Kidney Events in T2D**  Shown are cumulative incidence plots of the primary outcome, major kidney disease events (a composite of the onset of kidney failure \[dialysis, transplantation, or an estimated glomerular filtration rate {eGFR} of \50% of dietary CHO - Even change from 60/40% to 40/60% complex/simple sugar will alter TGs - Fiber or whole food intake -- results in reduced effect - Fructose is particularly causal (makes it worse at any level of CHO) - Are there sensitive people? - Yes! Sensitive when also these factors: - Obesity, Insulin resistance/glucose intolerance, Baseline increased fasting TG, Post-menopausal state - So what is recommended to public? - High saturated fat diets increase LDL cholesterol = strong risk factor for HD - Certain types of high carb diets increase BLDL TG, which lowers HDL cholesterol - Strong risk factor for heart disease - What should people eat, to avoid "dyslipidemia" and risk for heart disease - CHO have little to no effect on TG or HDL if they are mostly complex and not simple sugars (esp fructose) - If weight is lost or exercise present, fat is replaced in part by protein if fiber is included **[Diets are shown by data to be associated w/ less heart disease?]** - Mediterranean diet -- probably has the best epidemiologic data (whole grains/complex carbs, low simple sugars, olive oil/monounsaturated fats, fish protein/omega-3 fatty acids over red meat, moderate alcohol intake, vegetables) - Intervention data w/ low fat/high carbohydrate and fiber - Pritikin diet