Pathology of Nutrition: Malnutrition, Hypernutrition & Diabetes PDF

Pathology of Nutrition: Malnutrition, Hypernutrition, & Diabetes Andrea C. Gore, PhD Professor, Division of Pharmacology and Toxicology [email protected] 1 Learning Objectives In these units you will learn about: Pathophysiology of malnutrition, undernutrition, and nutritional deficienci...

Pathology of Nutrition: Malnutrition, Hypernutrition, & Diabetes Andrea C. Gore, PhD Professor, Division of Pharmacology and Toxicology [email protected] 1 Learning Objectives In these units you will learn about: Pathophysiology of malnutrition, undernutrition, and nutritional deficiencies. Obesity Diabetes – Insulin and its secretion – Features and types of diabetes mellitus 2 Pathophysiology of malnutrition An appropriate diet should provide: 1. Sufficient energy in the form of carbohydrates, fats, and proteins for body’s daily metabolic needs 2. Essential (and nonessential) amino acids and fatty acids for synthesizing structural and functional proteins and lipids 3. Vitamins and minerals for acting as coenzymes or hormones in vital metabolic pathways Behaviors/circumstances that lead to malnutrition include: poverty, ignorance, common alcoholism, acute and chronic illnesses, self-imposed dietary restriction (e.g. anorexia nervosa, bulimia). Diseases including GI diseases, chronic wasting, or acute critical illness, can result in nutrient malabsorption, impaired nutrient utilization or storage, excess nutrient losses, or increased need for nutrients 3 Common deficiencies that can be remediated by education 1. Iron – often develops in infants fed exclusively artificial milk diets 2. Thiamine – when rice is a dietary mainstay 3. Iodine – supplementation is often provided in salt but certain “natural” salt products may lack iodine. 4 Pathophysiology of Undernutrition Protein energy malnutrition (PEM): Major contributor to death rate for children under 5 in poorer countries – Marasmus: severe malnutrition, usually in children, when weight falls 30 kg/m2 – CDC reports 39.8% of the US population was obese in 2015-2016 (93.3 million) – Accurate index of obesity for most, but may be a skewed measure for individuals with very high muscle mass (e.g. weightlifters) Importance to healthcare: – Increases risk of heart disease, stroke, type 2 diabetes, and certain types of cancer. Importance to Pharmacists: – Affects “dosing weight” – Affects Volume of distribution (Vd) – Affects drug deposition in body – Affects half-life (t ½ ) 10 Multifactorial causes of obesity Both genetic and environmental factors contribute to obesity: – Hereditary tendencies: obesity is rarely attributable to a single gene (monogenetic), but there are rare instances of leptin or leptin receptor mutations, POMC pathway mutations (POMC or MC4-R gene), can increase eating. – An abundance of convenient, highly palatable, energy-dense, relatively inexpensive foods – Differences in extracting energy from food – Composition of colonic bacterial communities (microbiome) – Lack of exercise, sedentary lifestyle – Psychological factors – stress, emotional disturbances – Circadian disruption – Prior history of obesity 11 Scope of Obesity & Diabetes 12 Diabetes ¡ Diabetes = greek “passing through” ¡ Mellitus = latin “honey sweet” ¡ Diabetes mellitus consists of a group of syndromes with different etiologies, all of which result ultimately in a failure of glucose homeostasis ¡ Clinically defined as a failure to maintain blood glucose levels within a normal range (70 – 120 mg / dL) ¡ Functional deficiency of insulin action. Diabetes occurs when your body either doesn’t make enough insulin or cannot use the insulin it makes – this causes blood sugar to rise to pathological levels. 13 Prevalence 14 Insulin - review 1. 2. 3. 4. 5. 6. Insulin is released from glucose sensing beta cells in the pancreas Formed as a precursor, proinsulin (from preproinsulin), with an alpha and beta chain (connected by two disulfide bonds), and a “C”onnecting peptide. The release of insulin from β-cells is triggered by glucose entry and a subsequent cascade of intracellular events resulting in exocytosis of secretory vesicles. At target cells, insulin binds to its receptor (tyr. kinase family), translocates GLUTs, and allows glucose entry. This lowers blood glucose, promotes storage as glycogen. Also lowers amino acid and fatty acids and promotes storage. C peptide Pro-insulin 15 Clinical Features of Diabetes Clinical diagnosis: – Any of the following: Random glucose > 200 mg/dL with symptoms Fasting glucose > 126 mg/dL OGTT – oral glucose tolerance test (75 gram oral glucose load) > 200 mg/dL over 35 hr monitoring period Glycated hemoglobin (HbA1c) > 6.5% – Reflects average blood glucose levels during the previous 2-3 months Symptoms: – Glucose > 150 mg / dL = may be asymptomatic opportunistic infections – Glucose > 200 mg / dL Fatigue Polyuria (200 mg/dL the “magic number” for kidneys) Polydipsia Weight loss and muscle wasting (usually Type I only) Ketonemia (usually Type I only) Opportunistic infections 16 Categories of Diabetes Mellitus (DM) Type 1 DM – Complete β-cell destruction and absolute insulin deficiency (5-10% of cases) Type 2 DM – includes insulin resistance with insulin deficiency, due to insulin secretory defect with insulin resistance (90-95% of cases) Other forms of diabetes MODY: Maturity-onset diabetes of the young – monogenic disease usually due to mutation in glucokinase, characterized by mild diabetes in lean individuals before age 25 yrs. Gestational DM: second half of pregnancy, precipitated by increasing hormones that have counter-regulatory anti-insulin effects. 9% of general population, 30% of Native Americans. Up to half develop 17 Type II DM for life. Age at diabetes diagnosis Type 2 Type 1 MODY 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 Age of diagnosis Type I DM (T1DM) Type I. Diabetes associated with the autoimmune destruction of the beta cell pool (autoantibody-positive). Also known as juvenile diabetes or insulindependent diabetes: – Young age of onset + autoantibodies – Rapid requirement for insulin to survive. – Most difficult form for controlling blood glucose levels – Polygenic Symptoms: – Increased thirst and urination (bed wetting in children) – Extreme hunger – Weight loss – Fatigue, weakness – Blurred vision 19 Type 1 DM, cont’d Etiology: – Unknown – Rates of T1DM have risen 3-5% globally over the past several years (implicating environmental contributors) – Twin studies show that identical twins have 27% disease concordance. Treatment: – Lifestyle changes – Insulin 20 Type 2 DM (T2DM) Type 2. Diabetes not associated with significant autoimmunity, characterized by insulin resistance – Patients typically have metabolic syndrome – cluster of features including obesity, large waist circumference, high triglycerides, low HDL, high glucose, and high blood pressure. – Average onset > 40 yrs + no autoantibodies – 1/3rd progress to eventual insulin dependence – Polygenic – Variable phenotype, but all type 2 DM has deficiency of insulin action. Symptoms: – Increased thirst and urination – Hunger – Fatigue – Blurred vision – Slow healing sores, frequent infection 21 T2D is largely an “environmental” disease Type II DM has increased substantially in the US over the past decades People who don’t live in western societies tend to not get type 2 diabetes. Hunter gatherer tribes still in existence have no identified cases of type 2 diabetes Domesticated cats often become diabetic, unlike their wild counterparts. Mexican born Latinos have far less diabetes than do American born Latinos. 85% of patients with T2DM that undergo bariatric surgery are cured of T2DM even before significant weight loss. 22 Pathogenesis of Type 2 DM: Impaired β-cell function: Cells lose sensitivity to glucose or other stimuli Insulin resistance: Normal insulin fails to elicit proper clearance of glucose from the blood Hepatic glucose metabolism dysregulation: Liver becomes resistant to insulin and undergoes excessive gluconeogenesis and glycogenolysis 23 Acute Complications of Diabetes Mellitus Hyperglycemia – Polyuria, polydipsia, polyphagia Diabetic ketoacidosis (DKA) – In the absence of insulin, lipolysis is stimulated, providing fatty acids that are converted to ketone bodies in the liver (due to unopposed glucagon). – Severe hyperglycemia with polyuria, together with nausea and vomiting, leads to uncompensated fluid loss. – Can result in coma if extreme. – Treated with replacing water and electrolytes, and giving insulin Care must be taken not to cause hypoglycemia if insulin is given. 24 Chronic Complications Microvascular disease – Nephropathy – Neuropathy – Retinopathy Macrovascular disease – Coronary artery disease – Cerebrovascular disease – Peripheral vascular disease, hypertension Associated complications – Foot ulcers – Infections – Skeletal fractures 25 Pathology: high blood sugar destroys neurons and vessels Vascular endothelial cells, pancreatic beta cells, and peripheral neurons are the most easily damaged cells in response to high glucose. – – – – – – Leading cause of blindness Leading cause of leg amputations Leading cause of kidney failure Leading cause of peripheral neuropathy Major risk factor for stroke Major risk factor for heart attack à risk of MI in diabetes = that for person that already has had one MI 26 Summary: Presentation of Major Subtypes of Diabetes Type I Type 2 Age < 30 > 30 Onset Abrupt Gradual (~10 yrs at diagnosis) Body type Lean Overweight / obese Insulin resistance No Yes Autoantibodies Yes No Symptomatic Yes Not always Insulinopenia Yes No (often hyperinsulinemic) Requires insulin Rx Yes Sometimes 27 Note: These are the most common presentation, but there is individual variability. Importance of lifestyle in treatment of T2DM Lifestyle changes: – – – – – Diet – avoid foods with high glycemic index Choose diets low in animal products, high in fruits, vegetable, whole grain Exercise – recommend 30 min of activity most days Checkups Manage stress – – Quit smoking Restrict alcohol intake Lifestyle changes may be all that is required to completely reverse the symptoms of T2DM In contrast, Type I diabetes REQUIRES INSULIN 28 Comprehensive diabetes care 29 Learning Objectives In these units you will learn about: Review of the fundamentals of energy balance and metabolism Pathophysiology of malnutrition, undernutrition, and nutritional deficiencies. Obesity Diabetes 30