AI Notes on Physiology Review PDF

Physiology review Insulin is a hormone produced by beta cells in the Islets of Langerhans, which are groups of cells located in the pancreas. It primarily regulates carbohydrate and lipid metabolism, but has a minor impact on protein metabolism. As a peptide hormone, its half-life is short, meaning...

Physiology review Insulin is a hormone produced by beta cells in the Islets of Langerhans, which are groups of cells located in the pancreas. It primarily regulates carbohydrate and lipid metabolism, but has a minor impact on protein metabolism. As a peptide hormone, its half-life is short, meaning it breaks down quickly. Any insulin secreted into the blood is cleared from the body within 15 minutes. Synthesis Preproinsulin: This is the initial form of insulin, a larger protein. Proinsulin: Preproinsulin is processed into proinsulin, which consists of three peptide chains (A, B, and C). Think of this as a building block for insulin. Insulin: Proinsulin is further processed, removing the C peptide and leaving only the A and B peptides bonded together - the active form of insulin. C-peptide: The removed C peptide is still important. It's used to measure how much insulin is being produced. It may also help slow down complications in people with diabetes. Secretion Stimulated by: Insulin secretion is primarily driven by increased levels of glucose in the blood, along with amino acids and free fatty acids. Inhibited by: Conversely, low levels of glucose in the blood and high levels of insulin itself will suppress further insulin release. This is a feedback mechanism to prevent overproduction. Other Stimuli: In addition to blood sugar, other factors like gastrointestinal hormones (e.g., gastrin, cholecystokinin (CCK), and secretin) and stimulation of the parasympathetic nervous system can also influence insulin release Action Cell Receptors: Insulin receptors are found on the membranes of most cells, allowing them to "receive" the insulin signal. Structure: These receptors have two alpha subunits that bind to insulin and two beta subunits that have tyrosine kinase activity. Tyrosine kinases are enzymes that add phosphate groups to other proteins, eLectively "turning them on." Activation Cascade: When insulin binds to its receptor, it activates the tyrosine kinase. This activates other intracellular enzymes, such as protein kinase B (PKB) and MAP kinase, leading to a series of physiological eLects. Glucose Uptake: One of the key eLects of insulin is to stimulate glucose uptake into cells. Insulin binding activates a pathway that brings glucose transporter proteins (GLUT4) to the cell surface. These proteins facilitate glucose diLusion into the cell. General Physiological e0ect Control of postprandial plasma glucose levels: Insulin helps regulate blood sugar levels after eating by promoting glucose uptake into cells and reducing its concentration in the blood. Promotes glucose storage as glycogen: It facilitates storage of excess glucose in the liver and muscles as glycogen, a form of stored carbohydrate. Fatty acid synthesis and triglyceride formation: Insulin promotes the synthesis of fatty acids and their storage as triglycerides, particularly in adipose tissue (fat). Transport of amino acids into cells and stimulates protein synthesis: Insulin helps transport essential amino acids into cells and stimulates the process of protein synthesis, building and repairing tissues. Stimulates cell growth and diEerentiation: Insulin plays a role in cell growth and development, supporting the diLerentiation of cells into specialized types.  Facilitates K+ transport into cells: Insulin facilitates the transport of potassium ions (K+) into cells, contributing to normal potassium levels. Glucagon Glucagon is another hormone produced by the pancreas, but by alpha cells, acting as an antagonist to insulin. Insulin antagonist: It opposes the eLects of insulin, primarily by acting on the liver to increase blood glucose levels. Secretion: Glucagon release is triggered by low blood glucose levels, serving as a counter-regulatory mechanism to insulin. Physiological eEects: Glucagon stimulates the liver to break down glycogen into glucose (glycogenolysis) and produce glucose from other sources (gluconeogenesis). It also promotes the breakdown of fat (lipolysis) and ketone body production (ketogenesis). Limited circulation: Glucagon mainly aLects the liver, with minimal circulation to other tissues. Diabetes Mellitus Diabetes mellitus is a group of disorders characterized by problems with insulin activity, leading to high blood sugar levels (hyperglycemia) and diLiculty regulating glucose metabolism. This aLects how the body uses carbohydrates, fats, and proteins for energy. Here's a breakdown of the diagnostic criteria: HbA1c > 6.5%: This test measures average blood sugar levels over the past 2-3 months. A value above 6.5% signifies diabetes. FPG > 126 mg/dl (7.0 mmol/L): This is a fasting plasma glucose test, measuring blood sugar after at least 8 hours of fasting. A value above 126 mg/dl indicates diabetes.  2-hr plasma glucose > 200 mg/dl (11.1 mmol/L) during an OGTT: This is a glucose tolerance test, measuring blood sugar two hours after drinking a sugary beverage. A value above 200 mg/dl indicates diabetes. Random plasma glucose > 200 mg/dl (11.1 mmol/l): A blood sugar test taken at any time, even without fasting, exceeding 200 mg/dl suggests diabetes, especially if the person has classic diabetes symptoms. Type 1 diabetes is an autoimmune disease where the body's immune system mistakenly attacks and destroys the insulin-producing beta cells in the pancreas. It's often diagnosed in childhood, hence the former name "juvenile onset diabetes". Type 1 Diabetes Mellitus Type 1A DM Autoimmune-mediated Type 1A DM: The most common type, it's caused by the immune system. Beta-cell destruction: This leads to a complete (absolute) lack of insulin production. Autoantibodies and cytotoxic T cells: The immune system forms antibodies and specialized T cells that target beta cells and destroy them. Causes: o Genetics: A person's genetic background can increase the risk of developing Type 1 diabetes. o Environmental factors: Environmental factors like viral infections (e.g., mumps, Coxsackie virus) and certain dietary aspects (low vitamin D, nitrates) can trigger the autoimmune response in genetically predisposed individuals. This includes early introduction of gluten in infants. Type 1B DM Type 1B diabetes is a rarer form compared to Type 1A, where the cause of beta-cell destruction is not the immune system. Nonimmune-mediated: It's not due to an autoimmune response. Beta-cell destruction: Like Type 1A, this type results in a lack of insulin production. No evidence of autoimmune disease: There are no antibodies found in the blood targeting the beta cells, as seen in Type 1A. Causes: The beta-cell destruction is caused by other underlying illnesses, such as: o Chronic pancreatitis: This involves inflammation of the pancreas, damaging the beta cells. o Cystic fibrosis: This genetic disorder aLects various organs, including the pancreas, potentially causing beta-cell damage. Pathophysiology type 1DM Destruction of pancreatic beta cells leads to insulin deficiency: The loss of insulin-producing beta cells results in a lack of insulin, which is crucial for regulating blood sugar levels. Alpha cells are uninjured leading to relative glucagon excess: Alpha cells, which produce the counter-regulatory hormone glucagon, remain intact. This means that even though insulin is absent, glucagon continues to be secreted, leading to a relative increase in glucagon levels. Decreased glucose uptake into cells: Without insulin, glucose cannot enter cells eLiciently, leading to high blood glucose levels. Hyperglycemia (need destruction of 80-90% of beta cells to see hyperglycemia): Interestingly, the destruction of a large portion of beta cells (80- 90%) is necessary for hyperglycemia to become noticeable. This is because the  body's metabolic systems can compensate for some degree of insulin deficiency initially. Cell starvation: When cells cannot access glucose for energy, they become starved, leading to various complications. Osmotic diuresis: High blood glucose overwhelms the kidneys' ability to reabsorb all the glucose filtered from the blood. This causes excess glucose to remain in the urine, drawing water along with it (osmosis), resulting in increased urination (diuresis). Decreased potassium uptake into cells leads to hyperkalemia: Insulin helps transport potassium into cells. When insulin is deficient, potassium levels can increase in the blood (hyperkalemia). Fat breakdown in adipose tissue: Without insulin to help store energy, the body turns to fat as an alternative fuel source, breaking down stored fat in adipose tissue. Liberation of fatty acids for fuel: The breakdown of fat releases fatty acids into the bloodstream to be used for energy. Release of ketones: When the body relies heavily on fat for energy, ketones (acids produced from fat breakdown) are released. Lowers pH of blood, potentially leading to ketoacidosis: Ketones are acidic. Their accumulation in the bloodstream lowers blood pH, potentially leading to a dangerous condition called ketoacidosis.  Type 2 Diabetes Mellitus Type 2 diabetes is a chronic condition where the body either doesn't produce enough insulin or doesn't use insulin properly, referred to as insulin resistance. Previously known as "non-insulin-dependent diabetes" or "adult-onset diabetes", it's now understood that it can develop at any age. Here's a breakdown of the risk factors: Genetics: Genetic variations can increase the likelihood of developing Type 2 diabetes. These can aLect insulin production, insulin receptor function, or how cells respond to insulin. Obesity: Being overweight or obese significantly increases the risk of type 2 diabetes, as it often contributes to insulin resistance. Age: The risk of developing Type 2 diabetes increases with age, particularly after 40 years. Ethnicity: Certain ethnicities have a higher incidence of Type 2 diabetes. This includes Native Americans. Hispanic/Latino, Pacific Islander, and African American populations. Polycystic ovarian syndrome (PCOS): This hormonal disorder can increase the risk of developing type 2 diabetes by 7 times. Metabolic syndrome: This cluster of conditions associated with central obesity, high cholesterol, high blood pressure, and elevated fasting blood sugar are all linked to an increased risk of developing Type 2 diabetes.  Pathophysiology type 2 Diabetes Mellitus Insulin resistance: Type 2 diabetes is primarily a condition of insulin resistance, where cells don't respond properly to insulin, even though it's being produced. This decreased cellular responsiveness can be caused by: o Genetics: Genetic factors can predispose individuals to insulin resistance. o High-caloric/carbohydrate diet: A diet high in calories and carbohydrates can lead to hyperinsulinemia (elevated insulin levels) as the body tries to manage high blood sugar levels. However, persistent hyperinsulinemia can eventually result in down-regulation of insulin receptors (fewer receptors, less responsiveness). o Adipokines: Obese individuals often have elevated levels of adipokines (hormones released by fat cells) that can contribute to insulin resistance. Consequences of insulin resistance: Insulin resistance makes it harder for glucose to enter cells. This leads to: o Hyperglycemia: Elevated blood sugar levels due to reduced glucose uptake. o Complications of hyperglycemia: High blood sugar can lead to: § Osmotic diuresis: Increased urination due to excess glucose in the urine. § Hyperosmolarity: High blood sugar can draw water out of cells, aLecting their function. § Dyslipidemia: Insulin resistance also aLects lipid metabolism, leading to elevated levels of harmful cholesterol (LDL) and triglycerides and decreased levels of beneficial cholesterol (HDL).  Insulin resistance in adipose cells leads to lipolysis: The lack of insulin responsiveness in fat cells can lead to a breakdown of fat (lipolysis), releasing fatty acids into the bloodstream. Hyperlipidemia: Long-term release of fatty acids due to ongoing insulin resistance contributes to hyperlipidemia, high levels of fat in the blood. Beta-cell destruction: Over time, the persistent hyperglycemia and high levels of fatty acids can contribute to the death or malfunction of beta cells, further exacerbating insulin deficiency. Essentially, Type 2 diabetes is a complex condition with a vicious cycle. Insulin resistance leads to hyperglycemia, which, in turn, contributes to further insulin resistance and can eventually lead to beta cell destruction, accelerating the disease process. Chronic Complication of Diabetes Mellitus Pathophysiology: The underlying mechanisms of these complications revolve around hyperglycemia and its eLects on protein structure. Nonenzymatic glycosylation: This refers to the binding of glucose to proteins, lipids, and nucleic acids (components of cells) without the involvement of enzymes. This process is essentially a chemical modification of these molecules, altering their structure and function. High blood sugar: Persistent high blood sugar leads to the formation of advanced glycation end products (AGEs), which are harmful molecules that can: o Cause capillary basement membrane thickening: This thickening can hinder the exchange of oxygen and nutrients between the blood and tissues, leading to reduced oxygen delivery. o Increase capillary permeability: This can lead to fluid leakage from the capillaries into surrounding tissues (edema), further impairing tissue function.  o Promote arterial smooth muscle proliferation: This thickening of arterial walls can lead to hypertension, the buildup of plaque, and eventually, clogging of arteries. o Generate oxygen free radicals: AGEs can cause damage to blood vessel linings (endothelial cells) by generating reactive oxygen species (free radicals), leading to inflammation and further damage. o Inactivate nitric oxide: Nitric oxide is a molecule that helps relax blood vessels. AGEs can inactivate this molecule resulting in vasoconstriction (narrowing of blood vessels), increasing blood pressure and causing poor blood flow (ischemia). o Promote coagulation: AGEs can also contribute to the formation of blood clots in the capillaries and veins, leading to restricted blood flow (ischemia) and deep vein thrombosis (DVT), a condition where clots form in the deep veins, typically of the legs. Shouting of Glucose to the polyol pathway Shunting of Glucose to the Polyol Pathway: Normally, these tissues use other mechanisms to take in glucose, but when blood sugar is very high (hyperglycemia), more glucose gets diverted to the polyol pathway. Conversion to Sorbitol: The polyol pathway converts glucose into sorbitol, a sugar alcohol. Increased Osmotic Pressure: Sorbitol accumulates within cells, increasing osmotic pressure (the tendency of water to move into areas with higher solute concentration). This draws water into cells. Cell Swelling and Injury: The excess water causes these cells to swell and potentially become damaged.  Consequences for Specific Tissues: o Cataracts: The lens of the eye is particularly susceptible to polyol pathway activation, which can contribute to the formation of cataracts. o Disruption of Nerve Conduction: Nerve cells (neurons) can also be aLected, disrupting nerve signals. o RBCs: Red blood cells become swollen and less flexible (stiLer) due to sorbitol accumulation, impairing their ability to eLectively carry oxygen throughout the body. Essentially, the polyol pathway is an alternative glucose utilization route that can become problematic when blood sugar is consistently high. It leads to cell swelling and potential damage, contributing to complications in specific tissues. Inapropiate Protein Kinase C (PKC) Activation Inappropriate PKC activation: High blood sugar levels can lead to prolonged activation of protein kinase C, which is normally involved in cell signaling and cellular processes. This persistent activation is not beneficial. Promotes insulin resistance: PKC activation disrupts normal insulin signaling, making cells less responsive to insulin, contributing to insulin resistance. Increases capillary permeability: PKC activation weakens the barriers between blood vessels and surrounding tissues, increasing leakage (permeability) of fluids and proteins into the tissues. Increases basement membrane thickening: This thickening of the membrane surrounding capillaries can hinder the exchange of oxygen and nutrients between the blood and tissues, impairing tissue function. Promotes vasoconstriction: PKC activation can also contribute to the contraction (vasoconstriction) of blood vessels, reducing blood flow.  Microvascular Disease Severity: The severity of microvascular complications is influenced by various factors: o Age: Older individuals are more susceptible. o Duration of diabetes: The longer a person has diabetes, the greater the risk. o Blood glucose control: Poorly controlled blood sugar significantly increases the risk. Pathophysiology o Advanced glycation end products (AGEs): These molecules, formed by long-term high blood sugar, damage blood vessels. o Polyol pathway activation: High blood sugar can trigger this metabolic pathway, leading to cell swelling and damage, particularly in the eye's lens and nerve cells. o Inappropriate protein kinase C activation: As discussed earlier, this enzyme can disrupt cell signaling and contribute to blood vessel damage. Specific complications Retinopathy: Damage to the blood vessels in the retina (the back of the eye). o Causes: Retinal ischemia (reduced blood flow) due to vessel thickening and clotting. o Symptoms: Infarcts (tissue death) in the nerve layer of the retina, potentially leading to retinal detachment and hemorrhages (bleeding).  Nephropathy: Kidney disease. o Causes: The mechanisms leading to damage in the kidney's filtering units (glomeruli) and tubules are not fully understood but likely involve the factors listed above. o Signs: Intraglomerular hypertension (high blood pressure within the glomeruli), thickening of the basement membrane surrounding the glomeruli, and glomerulosclerosis (scarring of the glomeruli). o Clinical progression: The first sign is often proteinuria/albuminuria (protein in the urine), which can progress to chronic renal failure and eventually end- stage renal disease (ESRD), where the kidneys fail completely. Macrovascular Disease atherosclerosis Macrovascular Disease - Atherosclerosis: Atherosclerosis is a condition where fatty deposits (plaque) build up in arteries, narrowing them and restricting blood flow. This can occur prematurely in people with diabetes. Premature onset: Diabetes can accelerate the development of atherosclerosis compared to people without diabetes. Contributing factors: o Hyperglycemia: High blood sugar contributes to the development of atherosclerosis through several mechanisms. o Dyslipidemia: Imbalances in blood lipid levels (high LDL, low HDL) are also associated with atherosclerosis. o AGEs (advanced glycation end products): These harmful molecules, as discussed earlier, contribute to vascular damage and promote plaque formation. Clinical Consequences: o Coronary artery disease: Atherosclerosis in the coronary arteries, which supply blood to the heart, can lead to chest pain, shortness of breath, and heart attack. o Myocardial ischemia: This refers to a reduced blood flow to the heart muscle, often leading to heart failure. o Myocardial infarction: A heart attack occurs when a blood clot completely blocks a coronary artery, cutting oL blood supply to part of the heart muscle. o Cerebral infarct (stroke): Atherosclerosis in the arteries supplying the brain can lead to a stroke, a blockage that restricts blood flow to a portion of the brain. o Renal arterial stenosis: Narrowing of the arteries supplying the kidneys, reducing blood flow and potentially leading to kidney problems. o Intestinal vascular insuEiciency: Reduced blood flow to the intestines, potentially leading to digestive problems. o Peripheral arterial disease: Atherosclerosis in the arteries of the legs and feet can impair blood flow, leading to: § Skin ulceration: Open sores due to lack of blood supply. § Gangrene: Tissue death due to severe lack of blood flow. § Amputation: In severe cases, amputation may be necessary. Neuropathies  Peripheral neuron dysfunction: It refers to problems with the nerves that extend outside of the brain and spinal cord (peripheral nerves), aLecting sensation, movement, and organ function. Pathophysiology: o Polyol pathway activation: As discussed before, this pathway can lead to cell swelling and damage, including in nerve cells. o AGEs (advanced glycation end products): These harmful molecules can damage nerve cells and contribute to inflammation. o PKC activation: Prolonged protein kinase C activation can disrupt normal nerve cell function. Results of neuropathy o Ischemia of peripheral neurons: Reduced blood flow to peripheral nerves, causing them to become starved of oxygen. o Axonal degeneration: Damage to the main fibers (axons) of the nerve cells, which transmit signals. o Demyelination of neurons: Damage or loss of the myelin sheath (the insulating coating around nerve fibers). This slows down or disrupts nerve signal transmission (conduction velocity). Clinical Consequences Sensory Deficits: These involve a loss of sensation or altered sensations, including: o Tingling: A prickling or buzzing sensation. o Burning: A sensation of warmth or heat. o Numbness: A loss of feeling.  Motor Deficits: These aLect muscle control and movement, leading to: o Alterations in gait: Changes in walking pattern or balance. o Strength: Weakness or diLiculty with movement. Autonomic Dysfunction: This aLects the autonomic nervous system, which controls involuntary functions such as: o Diarrhea: Loose stool or frequent bowel movements often triggered by the parasympathetic nervous system. o Orthostatic hypotension: Low blood pressure upon standing up, caused by the sympathetic nervous system's failure to regulate blood pressure properly. Increase Risk of Infection Decreased perfusion: Diabetes, particularly its microvascular and macrovascular complications, can reduce blood flow (perfusion) to tissues. Skin breakdown: Poor blood flow can lead to weakened skin and tissues, making them more prone to damage and breakdown. Impaired vision and sensation: Diabetic neuropathy (nerve damage) can aLect a person's ability to notice injuries or infections. Glucose as a fuel source: Excess glucose in the blood provides a rich fuel source for bacteria and other pathogens, allowing them to multiply quickly. Decreased WBC supply: Reduced blood flow also means fewer white blood cells (WBCs) can reach infected areas to fight the infection.  Impaired WBC function: Hyperglycemia can also negatively aLect the function of white blood cells, making them less eLective at combating infection.