Diabetes Mellitus Biochemistry and Molecular Biology PDF

Biochemistry and Molecular Biology MBS00501 Fall 2024 Diabetes Mellitus Likhitha Dandu (Ph.D. Candidate) [email protected] November 5th, 2024 ...

Biochemistry and Molecular Biology MBS00501 Fall 2024 Diabetes Mellitus Likhitha Dandu (Ph.D. Candidate) [email protected] November 5th, 2024 Learning Objectives Type 1 and Type 2 diabetes mellitus - prevalence, symptoms, insulin deficiency/insulin resistance Pathophysiology of T1D & T2D - Progression and metabolic changes in T1D - Role of obesity, VWAT, adipose tissue remodeling & insulin resistance in T2D Pancreatic B cells (Islet of Langerhans), GSIS, insulin release & GLUT4 translocation & Hepatic gluconeogenesis (T1D & T2D) Insulin receptor vs Glucagon receptor signaling in the liver Hyperglycemia & advanced glycation end-products (AGE and RAGE) Diabetes diagnosis & tests Treatment goals for T1D vs T2D  Type I = Autoimmune Diabetes Mellitus A chronic, metabolic disease characterized by elevated levels of blood glucose (or blood sugar), which leads Cant Produce Insulin over time to serious damage to the heart, blood vessels, eyes, kidneys and nerves (WHO) body. ur body produces insufficient needs use disali it 3 main types of diabetes: Type 1, Type 2, and gestational diabetes (diabetes while pregnant) produces https://www.cdc.gov/diabetes https://newsroom.heart.org/file/diabetes-2024-statistics-infographic?action=  Symptoms of Diabetes ↑ blood glucen Levels-Kidmys Pitter and excess into urie pulling sugar , watea Polyuria (increased urination) due to lostPluids Polydipsia (increased thirst) Polyphagia (increased hunger) Fatigue Blurred Vision Develop rapidly Develop slowly/subtle (weeks) (several years) in type 1 diabetes in type 2 diabetes Pathophysiology(T1D) heads too pancreas loses Ability to , produce desalin - so can't properly regulate A blood glucose levels Cause: Autoimmune attack on pancreatic islet β cells = dufiliation formed in WBC's) Insulitis: Infiltration of islets of Langerhans by activated T & lymphocytes β-cell Loss: Gradual destruction over years & symptoms appear immediately after 80-90% β-cell loss! Trigger Factors: Environmental stimuli (e.g., viral infections) and genetic predisposition Genetic determinants leading to misidentification of β cells Katsarou, A. et al. (2017) Type 1 diabetes mellitus Nat. Rev. Dis. Primers doi:10.1038/nrdp.2017.16 Variations in HDL Genes as “nonself” - contribute to immune system misidentification (as body's own B-cells) as Poriege markers Katsarou, A. et al. (2017) Type 1 diabetes mellitus Nat. Rev. Dis. Primers doi:10.1038/nrdp.2017.16  (dusulin Hyperglycemia deficiency) Metabolic Changes in T1D DKA HighGlucose Ketosis Acidosis ① Hyperglycemia: , ↑ hepatic glucose production via gluconeogenesis/glycogenolysis + reduced peripheral utilization ② Ketonemia: Mobilization of fatty acids → ketone body production ③Diabetic Ketoacidosis (DKA): Occurs in 25-40% of newly diagnosed cases Symptoms of metabolic acidosis from ketone imbalance ⑪ Hypertriacylglycerolemia: ↑ FATVLDL Excess fatty acids converted to TAG and ↑ VLDL levels due to low lipoprotein lipase activity Impact on Tissues: Katsarou, A. et al. (2017) Type 1 diabetes mellitus Nat. Rev. Dis. Primers doi:10.1038/nrdp.2017.16 Affects liver, skeletal muscle, and white adipose tissue metabolism  Intertissue relationships in T1D Figure 25.3 Lippincott® Illustrated Reviews: Biochemistry, 8e, 2022  Pathophysiology(T2D) (insulin Resistance) Insulin resistance combined with impaired β-cell function leads to T2D! Insulin Resistance: Decreased ability of target tissues to respond to insulin. ↑ hepatic glucose production. ↓ glucose uptake in muscle/adipose tissue. /breakdown of Pats) ↑ adipose lipolysis leading to elevated free fatty acids (FFA). - β-cell Dysfunction: (Pancreas compensates 4 Insulin Resistance) Initially compensatory with ↑ insulin levels Over time, β-cell dysfunction leads to inadequate insulin secretion and worsening hyperglycemia Metabolic Differences: Milder metabolic alterations compared to Type 1 Diabetes Lippincott® Illustrated Reviews: Biochemistry, 8e, 2022  Dysfunctional β cells In T2D Deterioration of β-cell function may be accelerated by: Sustained hyperglycemia Elevated free fatty acids (FFA) Proinflammatory environment Lippincott® Illustrated Reviews: Biochemistry, 8e, 2022 Typical progression of type 2 diabetes Insulin Resistance and Obesity (T2D) Obesity is the most common cause of insulin resistance, significantly increasing the risk of T2D Insulin Compensation: Many obese individuals with insulin resistance do not develop diabetes if they maintain β- cell function. Insulin secretion in obese individuals can be 2-3 times higher than in lean individuals Blood Glucose Control: Elevated insulin levels can compensate for insulin resistance, keeping blood glucose levels similar to those of lean individuals The relationship between obesity and T2D is complex  Lippincott® Illustrated Reviews: Biochemistry, 8e, 2022 Daily blood insulin (A), and blood glucose (B), level changes in normal-weight and obese subjects The relationship between obesity and T2D is complex: emphasizing the role of insulin secretion in regulating glucose levels despite insulin resistance. Causes/Impact of Insulin Resistance Weight and Insulin Resistance: ↑ with weight gain, ↓ with weight loss ↑ the secretion of proinflammatory Cytokines Adipose Tissue Function: Secretes pro-inflammatory cytokines (e.g., IL-6, TNF-α). Changes in leptin and adiponectin levels contribute to chronic inflammation Impact of Free Fatty Acids (FFA) Increased lipolysis and elevated FFA levels lead to decreased glucose utilization. Contributes to hepatic steatosis and potentially nonalcoholic fatty liver disease (NAFLD). Influencing Factors: Sustained hyperglycemia, elevated FFA, and inflammation accelerate dysfunction Lippincott® Illustrated Reviews: Biochemistry, 8e, 2022 Visceral White Adipose Tissue (WAT) & Insulin Resistance Role of Adipose Tissue = Vampert Visceral WAT is the fat stored within the abdominal cavity, surrounding vital organs Function: Release various inflammatory cytokines and hormones that influence metabolism Role of WAT: Excess VAT is associated with ↑ release of free fatty acids and pro-inflammatory cytokines, → impair insulin signaling →insulin resistance Obesity often correlated to increased WAT → worsens insulin resistance → increases the risk of T2D Adipose Tissue Remodeling Changes in the structure /function of adipose tissue in response to various factors ( obesity, excess WAT etc.) Adipokines Signaling molecules secreted by adipose tissue ↑ WAT alters adipokine secretion, leading to elevated levels of pro-inflammatory cytokines and decreased levels of anti-inflammatory adiponectin→ insulin resistance.  ⑳ Slide adapted from Dr. Lakshman Segar’s “ Diabetus Mellitus Fall 2022” Slide adapted from Dr. Lakshman Segar’s “ Diabetus Mellitus Fall 2022”  circled Things Contribute to Insulin Resistance Slide adapted from Dr. Lakshman Segar’s “ Diabetus Mellitus Fall 2022”  Slide adapted from Dr. Lakshman Segar’s “ Diabetus Mellitus Fall 2022” to Leads #A floaty Cu2 n * Inhibit Inhibit Are = ① & Leads to formation es  Intertissue relationships in T2D Lippincott® Illustrated Reviews: Biochemistry, 8e, 2022 Comparison of type 1 and type 2 diabetes mellitus. (Figure 25.1) Lippincott® Illustrated Reviews: Biochemistry, 8e, 2022 Slide adapted from Dr. Lakshman Segar’s “ Diabetus Mellitus Fall 2022” Slide adapted from Dr. Lakshman Segar’s “ Diabetus Mellitus Fall 2022”  released by once b-cells--enter copillaries ↳ dreinig into portal circ. f Slide adapted from Dr. Lakshman Segar’s “ Diabetus Mellitus Fall 2022”  glucose glut2 : glucose into enters systemic circ. goes when Parmed bloodstream > - then portal circ. ↓ enters counts insulin Released Pancreatic Cells thru This Glutz demostrates & norm S promotes diffusion op didiviel Ansaln ↳ In drabetes promotes - Inhibits - no Inhibition / b of K-P channel > - causes depolarization of memb Slide adapted from Dr. Lakshman Segar’s “ Diabetus Mellitus Fall 2022”  Isr20 30AA Slide adapted from Dr. Lakshman Segar’s “ Diabetus Mellitus Fall 2022”  Insulin Receptor Signaling Binding: Insulin binds to the insulin receptor on target cells (muscle and adipose tissue). Activation: Receptor autophosphorylation of tyrosine residues! -Activated) PI3K/Akt Pathway: Triggers GLUT4 translocation to the cell membrane & promotes glucose uptake and storage. GLUT4 Translocation: Insulin signaling stimulates the movement of GLUT4-containing vesicles to the plasma membrane. Result: Increased glucose entry into cells, reducing blood glucose levels. Type 1 Diabetes: Lack of insulin severely disrupts insulin receptor signaling, leading to significant metabolic consequences Type 2 Diabetes: Insulin resistance impairs GLUT4 translocation → decreased glucose uptake and hyperglycemia.  Slide adapted from Dr. Lakshman Segar’s “ Diabetus Mellitus Fall 2022” where bind, dusalm, - Ards conformational Chain In cytoplasmic domain furthe S Activate Tyrosine Reside Activity Slide adapted from Dr. Lakshman Segar’s “ Diabetus Mellitus Fall 2022” Slide adapted from Dr. Lakshman Segar’s “ Diabetus Mellitus Fall 2022” Hepatic Gluconeogenesis in Type 1 Diabetes normall Insul Lack of insulin → unregulated gluconeogenesis (normally suppressed by insulin) Surpress Glucosegesis , of Increased Gluconeogenesis: Liver continues to produce glucose without insulin, causing elevated - blood glucose levels (hyperglycemia) Unopposed glucagon stimulates gluconeogenesis further Role of Glucagon Without insulin to counteract it, glucagon levels remain elevated! Ketoacidosis Risk: High glucose production, coupled with inability to utilize glucose for energy →ketogenesis (fat breakdown) Diabetic ketoacidosis (DKA): high ketone levels, acidosis, and severe metabolic disturbances Hepatic Gluconeogenesis in Type 2 Diabetes Impairs effective response to insulin → dysregulated gluconeogenesis continues despite of Insula pressence Dysregulated Gluconeogenesis: Elevated gluconeogenesis occurs even with insulin present ↑ in glucagon activity contributes to excessive hepatic glucose production. Persistent hyperglycemia, particularly in the fasting state Role of Glucagon Glucagon secretion is ↑ and unopposed by insulin, leading to ↑ hepatic glucose production Role of Lipotoxicity and Inflammation: Lipid accumulation in the liver worsens insulin resistance Chronic low-grade inflammation → stimulates gluconeogenesis Insulin Receptor Signaling in the Liver Insulin Receptor (IR): A tyrosine kinase receptor that autophosphorylates upon insulin binding Effects on Gluconeogenesis: Inhibition: Insulin suppresses gluconeogenesis by: Reduces the expression of PEPCK and FBPase-1 promotes their dephosphorylation & inactivation. Effects on Glycogenolysis: Inhibition: Insulin inhibits glycogenolysis by: Activates glycogen synthase (↑ glycogen storage) Inhibits glycogen phosphorylase (↓ glycogen breakdown) T1D: Absolute insulin deficiency leads to unchecked gluconeogenesis and glycogenolysis → hyperglycemia and ketoacidosis. T2D: Insulin resistance reduces insulin’s effectiveness → increased gluconeogenesis & glycogenolysis → persistent hyperglycemia  ore phos ↳ Slide adapted from Dr. Lakshman Segar’s “ Diabetus Mellitus Fall 2022”  Protein CG-coupled) Glucagon Receptor Signaling in the Liver Glucagon Receptor (GCGR): A GPCR that activates Gs proteins upon glucagon binding Effects on Gluconeogenesis: Stimulation: Glucagon enhances gluconeogenesis by: Increasing the expression/activity of PEPCK and FBPase-1. Promoting the conversion of pyruvate to glucose→ elevating blood glucose levels. Effects on Glycogenolysis: Stimulation: Glucagon stimulates glycogenolysis by: Activating glycogen phosphorylase and inhibiting glycogen synthase → increased glucose release T1D: Glucagon signaling is unopposed due to the absence of insulin, leading to excessive gluconeogenesis and glycogenolysis. T2D: ↑ glucagon levels + insulin resistance, exacerbate hyperglycemia due to unregulated gluconeogenesis & - glycogenolysis.  - * Slide adapted from Dr. Lakshman Segar’s “ Diabetus Mellitus Fall 2022” IR vs GCGR Signaling Summary in the Liver Insulin Signaling Glucagon Signaling Receptor Type Tyrosine kinase receptor G protein-coupled receptor Primary Pathway PI3K/Akt pathway cAMP/PKA pathway * Effect on Gluconeogenesis Inhibits gluconeogenesis Stimulates gluconeogenesis Effect on Glycogenolysis Inhibits glycogenolysis Stimulates glycogenolysis Overall Impact on Blood ↓ blood glucose levels ↑blood glucose levels Glucose T1D: Leads to hyperglycemia and T1D: Unopposed glucagon action; Role in Diabetes ketoacidosis; T2D: Resistance leads to T2D: Excessive glucagon exacerbates hyperglycemia hyperglycemia  Hyperglycemia and Advanced Glycation End Products (AGEs and RAGE) in Diabetes Receptor of AGE! Advanced Glycation End Products (AGEs) Formed when glucose binds to proteins/lipids. due to chronic hyperglycemia Govenzymea Accumulate in tissues, linked to inflammation and oxidative espects stress Inflammation: AGEs can promote inflammatory pathways, exacerbating tissue damage. Oxidative Stress: They can lead to increased production of reactive oxygen species, contributing to cellular damage. Vascular Damage: AGEs can alter the structure and function of blood vessels, leading to atherosclerosis and other cardiovascular issues. https://www.researchgate.net/figure/The-formation-of-advanced-glycation-end- products-AGEs-A-schematic-representation-of_fig1_365490825 Splague build-up Hyperglycemia and Advanced Glycation End Products (AGEs and RAGE) in Diabetes Receptor for Advanced Glycation End Products (RAGE) RAGE is a receptor on endothelial cells, neurons, and immune cells Aactivates signaling pathways upon binding with AGEs, triggering inflammation and oxidative stress ↑ Complications Associated with AGEs and RAGE: Diabetic retinopathy, nephropathy, neuropathy, and cardiovascular disease. Chronic inflammation exacerbates tissue damage. https://www.researchgate.net/figure/AGE-RAGE- interaction-in-immune-related-cells-transduces-signals- for-gene-expressions-of_fig1_347220066 Diabetes Diagnosis & Tests 1. Hyperglycemia - Elevated blood glucose levels. Diagnosis: Typically diagnosed using random blood glucose tests, fasting plasma glucose tests, or during an oral glucose tolerance test (OGTT). A random blood glucose level of 200 mg/dL or higher may indicate diabetes. 2. HbA1c (Glycated Hemoglobin) - A measure of average blood glucose levels over the past 2-3 months. Diagnosis: An HbA1c level of 6.5% or higher is diagnostic for diabetes. It’s commonly used for monitoring long-term glucose control in individuals with diabetes. 3. Glucose Tolerance Test (GTT) - A test to assess how well the body processes glucose. Procedure: After fasting, a person drinks a glucose solution, and blood glucose levels are tested at intervals (usually 2 hours). Diagnosis: A 2-hour blood glucose level of 200 mg/dL or higher indicates diabetes; levels between 140-199 mg/dL suggest prediabetes.  Diabetes Diagnosis & Tests If you rember middle can help mob Know Normal Test Prediabetes Diabetes Range Fasting 100-125 < 100 mg/dL ≥ 126 mg/dL Blood Sugar mg/dL HbA1c < 5.7% 5.7% - 6.4% ≥ 6.5% Glucose 140-199 < 140 mg/dL ≥ 200 mg/dL Tolerance mg/dL (2 (2 hours post) (2 hours post) Test hours post) https://www.cdc.gov/diabetes  Diabetes Diagnosis & Tests 4. Glycosuria - The presence of glucose in the urine. Testing: Usually detected through urinalysis. Significance: Indicates blood glucose levels exceeding renal threshold ↳ 5. Ketones - Detect the presence of ketones (β-Hydroxybutyrate (BHB)) in the body, indicating fat metabolism & potential DKA Testing: Ketones (BHB levels) can be measured in urine or blood. Significance: High levels indicate diabetic ketoacidosis (DKA) particularly T1D 6. C-peptide - A byproduct of insulin production; levels indicate how much insulin the pancreas is producing Testing: Blood test Significance: Helps differentiate between type 1 and type 2 diabetes. Low levels suggest type 1 diabetes (little to no insulin production), while normal to high levels indicate type 2 diabetes  T1D Treatment Therapeutic Injection Regimens: Standard Treatment: Modee 2-3 daily injections magnot are a Mean blood glucose: 225-275 mg/dl Complete HbA1c: 8%-9% Intensive Treatment: Missions ≥4 injections/day or pump therapy Mean blood glucose: ~150 mg/dl HbA1c: ~7% Goal: Lippincott® Illustrated Reviews: Biochemistry, 8e, 2022 Tight control to minimize long-term complications Complications of Insulin Therapy Hypoglycemia: & Most common complication (occurs in >90% of patients) Higher risk with intensive treatment Hormonal Response: Deficiency of glucagon and impaired epinephrine secretion Leads to "hypoglycemia unawareness" Impact of Exercise: ↑ risk of hypoglycemia; check blood glucose before/after exercise Lippincott® Illustrated Reviews: Biochemistry, 8e, 2022 Contraindications for Intensive Therapy Who Should Avoid Tight Control: e S e Children under 8: Risk of affecting brain development Elderly: Increased risk of strokes and heart attacks Tight Control Goals: Best for healthy individuals with a life expectancy of ≥10 years Individual Treatment Strategies: bit Based on duration of diabetes, age, and comorbid conditions Estat T2D Treatment Goal of Treatment: Maintain normal blood glucose levels Prevent long-term complications Initial Management: Weight reduction Regular exercise Medical nutrition therapy → dietary modifications (low-carbohydrate diet) Lippincott® Illustrated Reviews: Biochemistry, 8e, 2022 Pharmacological Options (T2D) Oral Antihyperglycemic Agents: Biguanides (e.g., Metformin): Decrease hepatic gluconeogenesis. Improves insulin sensitivity in peripheral tissues Sulfonylureas & Meglitinides: Increase insulin secretion from β -cells, by inhibiting ATP-sensitive potassium channels in pancreatic β-cells Thiazolidinediones: Increase peripheral insulin sensitivity α-Glucosidase Inhibitors: Decrease carbohydrate absorption Incretins: Increase insulin secretion and satiety SGLT Inhibitors: Decrease renal glucose reabsorption Insulin Therapy: May be required for satisfactory glucose levels Lippincott® Illustrated Reviews: Biochemistry, 8e, 2022 Chronic Effects and Prevention Strategies (T2D) Chronic Complications of T2D: Macrovascular: Cardiovascular disease (CVD), stroke Microvascular: Retinopathy, nephropathy, neuropathy Importance of Blood Glucose Control: Intensive treatment can delay and slow progression of complications HbA1c reduction linked to decreased incidence of retinopathy Prevention of T2D: Lifestyle modifications (nutrition, weight loss, exercise) Aggressive management of hypertension and dyslipidemias Lippincott® Illustrated Reviews: Biochemistry, 8e, 2022