BIOQUI - 16/06/2023

Understanding Diabetes and Its Treatment

Overview of Diabetes Pathology

• The discussion begins with the relationship between diabetes and gluconeogenesis, emphasizing that Type 1 diabetes is characterized by a complete absence of insulin, leading to hyperglycemia.

• Treatment for Type 1 diabetes involves insulin injections due to the lack of endogenous insulin production, while Type 2 may utilize various drug combinations that stimulate secretion or act as receptor agonists.

Pharmacological Approaches

• The importance of pharmacological treatment is highlighted alongside lifestyle changes such as diet management (low carbohydrates and fats), exercise (at least 30 minutes five days a week), and weight control.

• Consultation with a diabetologist is recommended for better management, especially in cases like metabolic acidosis or diabetic ketoacidosis.

Monitoring and Management

• Continuous monitoring using a glucose meter is crucial for diabetics to manage symptoms like headaches or excessive thirst effectively.

• Patients should measure their glucose levels regularly; elevated levels can lead to glucosuria (glucose in urine) and ketone bodies during complications.

Classification of Oral Hypoglycemics

• Oral hypoglycemic agents are classified into three groups based on their mechanisms: insulin secretagogues, insulin sensitizers, and those inhibiting carbohydrate absorption.

• Insulin secretagogues block ATP-dependent potassium channels, leading to depolarization and subsequent insulin secretion from pancreatic cells.

Detailed Mechanisms of Action

• Insulin sensitizers enhance receptor activity through genetic expression stimulation. Examples include thiazolidinediones and biguanides.

• The action of sulfonylureas involves blocking potassium channels in pancreatic cells, increasing positive charges inside the cell which triggers insulin exocytosis.

Generations of Sulfonylureas

• Sulfonylureas are primarily used for Type 2 diabetes treatment due to their ability to stimulate insulin secretion. They have four generations with varying effectiveness.

• First-generation examples include tolbutamide; second-generation includes glibenclamide; current use favors glimepiride known commercially as "yellow."

Effects and Side Effects

• Besides stimulating insulin secretion, sulfonylureas also inhibit lipolysis and gluconeogenesis, contributing further to lowering blood sugar levels.

Understanding Gluconeogenesis and Insulin Sensitizers

Mechanisms of Gluconeogenesis

• Gluconeogenesis is the process of producing glucose, which can be inhibited if lipolysis does not occur, as it relies on glycerol for activation.

• Metformin is a commonly used insulin sensitizer that primarily decreases glucose production and enhances glucose uptake in muscle tissues.

• These drugs inhibit gluconeogenesis (the synthesis of glucose) and promote glycolysis (the breakdown of glucose), effectively lowering blood sugar levels.

Side Effects of Metformin

• A significant side effect of metformin is metabolic acidosis due to increased glycolysis leading to pyruvate production.

• Gastrointestinal effects include nausea, vomiting, diarrhea, and a metallic taste; it may also cause gastric mucosa damage resulting in gastritis.

Thiazolidinediones and Their Action

• Thiazolidinediones stimulate the expression of PPAR (peroxisome proliferator-activated receptor), enhancing gene transcription related to insulin receptors at the genetic level.

• They increase the production of insulin receptors in tissues by promoting gene transcription and translation processes.

Anti-inflammatory Effects

• These drugs also reduce inflammation by decreasing free fatty acid release, which mitigates oxidative stress linked to beta oxidation.

• By inhibiting inflammatory processes, thiazolidinediones enhance insulin sensitivity in muscle and adipose tissues through GLUT4 expression stimulation.

Challenges with Technology During Presentation

• Technical difficulties were encountered during the presentation, affecting screen sharing capabilities. The speaker expressed frustration over connectivity issues impacting their ability to share content effectively.

Inhibitors of Intestinal Enzymes

Role of Alpha-glucosidase Inhibitors

• Another group discussed includes drugs that act at the intestinal level by inhibiting enzymes like alpha-glucosidases (e.g., amylase).

Understanding the Role of Enzymes and Drugs in Carbohydrate Absorption

Mechanisms of Carbohydrate Absorption Inhibition

• Enzymes at the intestinal level release monosaccharides, which prevents carbohydrate absorption. This inhibition affects not only pancreatic amylase but also other glucosidases, particularly alpha-1,4 and alpha-1,6 enzymes that degrade dextrins and maltodextrins.

• Disaccharidases such as maltase and sucrase are inhibited, leading to a decrease in monosaccharide generation and consequently reducing intestinal absorption. The structure of arcobrasas resembles an oligosaccharide, acting as a substrate that binds to enzymes to inhibit their action.

Effects of Drug Interventions on Intestinal Health

• Medications like militol and corbasa drugs prevent monosaccharide absorption by inhibiting intestinal alpha-glucosidases. However, these drugs can cause adverse effects such as diarrhea and flatulence due to undigested biomolecules.

• Hepatotoxicity is another concern with these drugs; while they may provide benefits for certain conditions, they also have potential harmful effects on liver function.

Implications for Diabetic Patients

• In diabetic patients (especially type 2), increased glucose levels lead to greater synthesis of fatty acids and triglycerides. Managing glucose levels is crucial to prevent metabolic alterations.

• Orlistat (also known as cenital) blocks pancreatic lipase at the intestinal level, preventing fat synthesis from dietary sources. This is important since high glucose levels can increase fatty acid synthesis.

Cholesterol Management Strategies

• Statins inhibit HMG-CoA reductase, regulating cholesterol synthesis. Common statins include pravastatin, atorvastatin, simvastatin, lovastatin, and fluvastatin; they help reduce cholesterol absorption in the intestine.

• Ezetimibe inhibits cholesterol absorption by targeting esterified cholesterol within chylomicrons. It works alongside fibrates that activate lipoprotein lipase to lower triglyceride levels in the body.

Addressing Complications from Diabetes

• Treatment should not only focus on glucose concentration but also address complications arising from diabetes such as nephropathy (kidney damage), neuropathy (nerve damage), and retinopathy (eye damage).

Diabetes Complications and Their Mechanisms

Overview of Diabetic Ulcerations and Associated Conditions

• Diabetes can lead to ulcerations, particularly in the feet, due to poor circulation and inflammatory processes. This condition is often linked with cardiovascular diseases such as atherosclerosis.

• The disease affects multiple organs, including the liver, leading to hepatic insufficiency. Skin manifestations are also common, increasing susceptibility to infections.

Multi-organ Impact of Diabetes

• Atherosclerosis results from plaque deposits in vascular endothelium, causing blood flow obstructions and oxygen deprivation essential for cellular respiration.

• Diabetic ketoacidosis (DKA) is a critical acute complication primarily associated with Type 1 diabetes due to lack of insulin which inhibits ketone body synthesis.

Acute Complications: Ketoacidosis and Hyperglycemic States

• DKA presents with clinical signs like polyuria (excessive urination), polydipsia (excessive thirst), nausea, vomiting, anorexia, and glucosuria (glucose in urine).

• Symptoms include abdominal pain, hypotension due to dehydration from polyuria, peripheral vasodilation from ketone formation leading to fruity-smelling breath.

Pathophysiology of Diabetic Ketoacidosis

• Patients may experience tachypnea (rapid breathing), lethargy, disorientation, or even coma due to metabolic acidosis caused by elevated ketone bodies.

• Cetonuria refers to the presence of ketones in urine; diabetic patients are often advised to use urine test strips for monitoring glucose and ketone levels.

Insulin's Role in Metabolism

• In Type 1 diabetes, insulin deficiency leads to increased lipolysis (fat breakdown), resulting in weight loss and further complications through metabolic pathways.

• Lack of insulin decreases glucose transport into muscle and adipose tissues while promoting lipolysis; this contributes significantly to the production of ketone bodies.

Consequences of Insulin Deficiency

• Insulin deficiency can be absolute or relative; it causes hyperglycemia which leads to osmotic diuresis—frequent urination that depletes intravascular volume.

• Electrolyte imbalances occur due to dehydration; key electrolytes affected include sodium, potassium, and chloride. Lipolysis produces glycerol which enters gluconeogenesis contributing further to hyperglycemia.

Catabolic Processes Activated by Insulin Deficiency

• Increased triglyceride degradation results in fatty acids being converted into acetyl-CoA leading towards more ketone body production—resulting in hyperketonemia.

Beta-Oxidation and Ketone Bodies

Understanding Beta-Oxidation

• The process of beta-oxidation degrades fatty acids, producing acetyl-CoA, which is crucial for synthesizing ketone bodies.

• Ketone bodies arise from the degradation of fatty acids; however, they are not utilized as bioenergetic molecules but rather eliminated through respiration.

Formation and Role of Ketone Bodies

• The three primary ketone bodies include acetoacetate, beta-hydroxybutyrate, and acetone. Their formation increases significantly in type 1 diabetes.

• Elevated levels of ketones can lead to metabolic acidosis and dehydration due to electrolyte loss (e.g., sodium, potassium).

Complications Associated with Diabetes

• Diabetic patients face increased risks of renal insufficiency, vomiting, infections, and poor wound healing due to compromised skin integrity.

• Immediate treatment involves administering liquid insulin and replenishing electrolytes like potassium.

Glucose Regulation in Diabetes

Insulin's Role in Glucose Metabolism

• In type 1 diabetes, glucose levels rise because insulin does not facilitate glucose transport into muscle and adipose tissues.

• Type 2 diabetes may lead to hyperosmolar non-ketotic coma due to insufficient insulin action or receptor resistance.

Hyperglycemia Consequences

• Extreme hyperglycemia can reach up to 1000 mg/dL without significant production of ketones in type 2 diabetes.

• To compensate for hyperosmolarity caused by high glucose levels, the body induces osmotic diuresis leading to dehydration.

Clinical Manifestations and Treatment Strategies

Symptoms of Severe Diabetes Complications

• Patients may experience polyuria leading to weight loss; severe dehydration can cause mental disturbances such as confusion or lethargy.

• Cardiac complications include tachycardia or myocardial infarction; diabetic patients are at higher risk for surgical complications.

Hormonal Responses and Metabolic Effects

• Relative insulin deficiency triggers counter-regulatory hormones (glucagon, cortisol), increasing protein breakdown and gluconeogenesis.

• These processes elevate blood glucose levels further exacerbating dehydration and electrolyte imbalances.

Management Approaches

Complications of Diabetes and Their Effects

Acute Complications

• Cetoacidosis can lead to various complications, including gastrointestinal issues such as diarrhea and sexual dysfunction. Dermatological problems may include glaucoma, periodontal diseases, cataracts, and urinary tract infections.

Chronic Complications

Microvascular Complications

• Chronic complications are categorized into microvascular and macrovascular types. Microvascular damage primarily affects small blood vessels, leading to ocular complications like retinopathy and macular edema.

• Neurological effects include both motor and sensory neuropathies, as well as autonomic polyneuropathies.

Macrovascular Complications

• Macrovascular complications mainly involve coronary artery disease, peripheral vascular diseases, and cerebrovascular diseases. Hyperglycemia contributes to these conditions through glycosylation processes that affect protein interactions in the vascular matrix.

Pathophysiology of Retinopathy

• Hyperglycemia causes cross-linking of proteins in retinal capillaries, leading to increased permeability and dilation. This results in serious exudates such as microaneurysms which contribute to retinal ischemia.

Renal Impairments

Nephropathy Development

• In nephropathy, hyperglycemia leads to glomerular damage characterized by thickening of the basement membrane due to glycosylation. This can result in proteinuria (30-200 mg/dL for microalbuminuria; >200 mg/dL for macroalbuminuria).

Consequences of Renal Damage

• Increased creatinine levels indicate nephron damage; hypertension may develop due to structural changes in glomeruli caused by glycosylation.

Neurological Effects

• Hyperglycemia activates aldose reductase leading to sorbitol accumulation which disrupts nerve conduction through edema at axonal levels. This can cause both sensory and motor nerve compression.

Gestational Diabetes Impact on Newborns

Macrosomia and Hypoglycemia

• Infants born from mothers with uncontrolled gestational diabetes often present with macrosomia (large size), hypoglycemia at birth due to maternal hyperglycemia stimulating excessive insulin production in the infant.

Management Strategies

• Immediate correction of hypoglycemia is crucial for newborn management post-delivery; this condition arises from the infant's compensatory hyperinsulinemia against maternal high glucose levels.

Understanding Hypoglycemia and Its Complications

Key Concepts of Hypoglycemia

• The decrease in glucagon levels leads to a reduction in catecholamines (adrenaline and noradrenaline), resulting in symptoms such as lethargy, hypotonia, difficulty breathing, tremors, and convulsions due to hypoglycemia.

• Associated conditions include hypoparathyroidism and hypomagnesemia. The presence of hyaline membrane disease is noted, which is linked to insulinism interfering with surfactant synthesis necessary for alveolar function.

• Increased erythropoiesis results in polycythemia (elevated red blood cell count), with hematocrit levels exceeding 65%. Hyperbilirubinemia occurs due to the breakdown of excess erythrocytes.

• Myocardial hypertrophy can develop from hyperinsulinemia, leading to thickening of the interventricular septum and potential cardiac malformations affecting various organ systems including skeletal, renal, pulmonary, and gastrointestinal.

Treatment Approaches for Hypoglycemia

• Immediate treatment involves administering glucose boluses (2-4 mL/kg/min intravenously). Prednisone may also be given as it stimulates gluconeogenesis.

• Glucagon serves as a hyperglycemic agent; recommended dosage is 30-200 micrograms/kg via intramuscular or intravenous routes.

• Diazoxide has an opposite effect by activating potassium channels which reduces calcium influx into cells, inhibiting insulin exocytosis.

Conclusion on Metabolism Discussion