Medicine Marrow Pg No 915-924 (Endocrinology)

Pathophysiology of Diabetes

• Glucose and Lipid Toxicity: A key factor in the development of diabetes.
  • Increases glucose output.
  • Causes toxic effects on beta cells.
  • Leads to defective insulin secretion from beta cells.
• Ominous Octet of Defronzo: A set of eight factors that contribute to insulin resistance.
  • A: Adipose Tissue: Responsible for initiating the process of fat storage. This includes:
    • Centripetal obesity: Increased fat storage in the abdomen.
    • Adipose tissue converts free fatty acids (FFAs) to glycerol.
    • Increased sensitivity of beta-2 receptors leads to increased lipolysis by hormone sensitive lipase, resulting in increased FFAs.
  • G: Gastrointestinal Tract:
    • Increased incretin effect.
    • Increased glucagon production.
  • P: Pancreas:
  • R: Renal:
    • Increased activation of SGLT-2.
    • Increased sodium and water absorption, leading to edema.
• FFA (Free Fatty Acids): The main substrate for gluconeogenesis.
  • Increased FFAs lead to increased gluconeogenesis (production of glucose from non-carbohydrate sources).
• Insulin Resistance: Leads to the accumulation of fatty acyl Co-A in the liver.
  • CPT-1: A key enzyme for the breakdown of fatty acids (beta-oxidation) is absent in the liver.
• Beta-Oxidation: The normal pathway for breaking down fatty acids.
  • Impaired beta-oxidation leads to FFA accumulation.
• GLUT-4: An insulin-dependent glucose transporter found in skeletal muscle, heart, and adipose tissue.
  • Insulin resistance impairs the normal glucose uptake process in the body.

Genetic Syndromes Associated with Diabetes

• Type A Resistance: Primarily seen in females, characterized by:
  • Acanthosis nigricans (darkening of skin in certain areas).
  • Hyperandrogenism (excess male hormones).
  • Often linked to Polycystic Ovary Syndrome (PCOS).
  • Pathogenesis: Insulin receptor resistance.
• Type C Resistance:
  • HAIR AN Syndrome: A syndrome associated with hyperinsulinism, acanthosis nigricans, and rapid growth.
  • Presents with childhood diabetes, acanthosis nigricans, rapid hair growth, and abnormal dentition.
  • Pathogenesis: Post-binding defect in insulin action, involving mutations of the insulin receptor.

Other Types of Diabetes

• Type 4 DM (Middle Age Related DM (MARD)):
  • Characterized by an increased number of T regulatory cells, which have a role in preventing autoimmune diseases like Type 1 Diabetes.
  • Leads to a milder form of diabetes.
• MODY (Maturity-Onset Diabetes of the Young):
  • A group of monogenic forms of diabetes.
  • It is not insulin-dependent, manifests before 25 years old, and is characterized by an increased activity of the SGLT2 transporter, resulting in glycosuria (glucose in urine).
  • Patients do not typically experience major complications associated with diabetes.

Treatment for Pre-Diabetes

• ADA Recommendations:
  • Start metformin for individuals:
    • Age 60 years or older.
    • HbA1c ≥ 6.5%.
    • Fasting blood sugar (FBS) ≥ 110 mg/dL.
    • Overweight.
    • With gestational diabetes.
  • Add pioglitazone to manage diabetes.
    • Pioglitazone acts on the PPAR-gamma receptor, which helps fight insulin resistance.
    • Slows the progression of cardiovascular disease risk.
    • Decreases the risk of stroke.

Screening for Diabetes

• Indications for Screening:

  • Every 6 months:
    • Individuals with a history of gestational diabetes (due to the high risk of developing diabetes later).
    • Pre-diabetic population (previously diagnosed with pre-diabetes).
    • Individuals at high risk:
      • Stroke.
      • Cardiovascular disease.
      • HIV.
      • PCOS.
      • Signs of insulin resistance.
      • People over 35 years old.

• Screening Tests:

  • HbA1c:
    • Offers the best sensitivity and specificity for detecting pre-diabetes.
    • Provides a 6-8 week window of blood glucose control.
    • Shows an average blood glucose value over time.
    • Limitation: Provides average values over a long period, not real-time data.

Factors Interfering with HbA1c Levels

• False Lower Values:
  • Hemoglobinopathies (abnormal hemoglobin in red blood cells).
  • Hemolytic anemia (red blood cell breakdown).
  • Malnutrition.
  • Blood loss.
  • Chronic liver disease.
• False Elevated Values:
  • Renal failure.
  • Iron deficiency.
  • Anemia.
  • Elevated bilirubin levels.
  • Elevated triglycerides.

Type 2 & Type 1 DM

• Natural History of the Disease:

  • Common complications:
    • Non-alcoholic fatty liver disease (NAFL).
    • Hypogonadism (impaired hormone production).
    • Periodontal disease.
    • Fractures.
    • Atherosclerosis (hardening of arteries).

• Metabolic Syndrome Criteria:

  • Meeting three or more of the following criteria indicates metabolic syndrome:
    • Waist Circumference (WC):
      • Male (m) > 102 cm
      • Female (F) > 88 cm
    • Triglycerides (TG): > 150 mg/dL (Least important factor in the criteria).
    • HDL Cholesterol:
      • Male (m) < 40 mg/dL
      • Female (F) < 50 mg/dL
    • Blood Pressure (BP): > 130/85 mmHg
    • Impaired Fasting Glucose (IFG): > 100 mg/dL

• BMI (Body Mass Index):

  • WHO Criteria (World Health Organization):
    • Normal: 18.5 - 24.9
    • Overweight: 25 - 29.9
    • Obese: ≥ 30
  • Indian Criteria:
    • Normal: 18 - 22.9
    • Overweight: 23 - 24.9
    • Obese: ≥ 25

• Diabesity/Adiposopathy (Common in Indian populations):

  • Waist Circumference (WC) :
    • Male (m) > 90cm
    • Female (F) > 80cm
  • Hyperglycemia
  • Hypertension
  • Hyperlipidemia
  • Increased CRP (C-reactive protein) - a marker of inflammation.
  • Decreased adiponectin (a hormone with anti-inflammatory properties).
  • Prothrombotic state (increased likelihood of blood clotting).

Type 1 vs Type 2 Diabetes Mellitus

• Type 1 DM: Caused by the autoimmune destruction of beta cells.
  • Characterized by insulitis (inflammation of pancreatic islets).
  • Markers: Auto-antibodies such as GAD (glutamic acid decarboxylase) and ZNT-8 (zinc transporter 8, found in >95% of patients).
  • HLA association: Strong association with HLA DRB1-04.
• Type 1 vs Type 2 DM Chart*

Newer Discoveries in Diabetes

• Dirty Dozen:
  • The eight factors from the "Ominous Octet" plus four more.
  • D: Decreased dopamine levels.
  • Vit-D: Decreased Vitamin D levels.
  • G: Hypogonadism (decreased testosterone levels).
  • R: Renin-aldosterone system activation.
• Treacherous 13:
  • Dirty dozen plus one more.
  • Serotonin: Increased serotonin levels lead to increased hormone sensitive lipase (HSL).
• Faithless 14:
  • Treacherous 13 plus one more.
  • Iron in beta-cell: Toxicity and resistance.

Diagnostic Criteria for Diabetes and Pre-diabetes

• Diabetes*

• Pre-Diabetes/Impaired Glucose Tolerance*

Introduction to Diabetes Mellitus and Classification

• Classification:

  • Type-1 Diabetes mellitus: Immune-mediated destruction of pancreatic beta cells leading to insulin deficiency.
  • Type-2 Diabetes mellitus (most common): Insulin resistance (cells do not respond to insulin properly).
  • Hybrid Diabetes mellitus (Type-1.5):
    • Ketosis-prone diabetes (KPD).
    • Latent Autoimmune diabetes in adults (LADA).
  • Type-3 Diabetes mellitus:
    • Alzheimer's disease: The accumulation of APO-B2 protein is linked to Alzheimer's disease.
    • Type 3 C: Pancreatic Diabetes.
    • Type 3 D: Drug-induced Diabetes.
  • Type 4 Diabetes mellitus: Mild, age-related diabetes (MARD).
  • GDM (Gestational Diabetes mellitus): Diabetes developing during pregnancy.

• Artificial pancreas:

  • A device that automatically monitors glucose levels and delivers insulin.

Thyroid Gland Issues

• Mechanisms of Hormone Release:

  • Stored hormone release.
  • Increased free T3, increased free T4, decreased TSH (thyroid-stimulating hormone), and a T3/T4 ratio.
  • Symptoms: Neck pain, sore throat, ear pain, and elevated ESR (erythrocyte sedimentation rate).

• Recovery Management:

  • Aspirin 600mg every 6 hours (DOC - drug of choice).
  • NSAIDs (nonsteroidal anti-inflammatory drugs).
  • Steroids.

Thyroid Levels

• TSH levels:
  • Elevated TSH: Hypothyroidism (low thyroid hormone).
  • Normal TSH: Central hypothyroidism (problem with the pituitary gland that regulates the thyroid).
  • Decreased TSH and Elevated FT3/FT4: Graves' disease (overactive thyroid), Toxic multinodular goiter (MNG), adenoma (thyroid tumor), or thyrotoxicosis (high levels of thyroid hormone).

Types of Thyroiditis

• Postpartum thyroiditis: Also known as painless/silent thyroiditis.
  • Often occurs in patients with underlying autoimmune conditions, like systemic lupus erythematosus (SLE) or Sjogren's syndrome.
• Subacute Thyroiditis v. Postpartum Thyroiditis*

Effects Of Amiodarone On Thyroid

• Amiodarone: A medication that can disrupt thyroid function.

Thyrotoxicosis

• Type-1:
  • Amiodarone is started in a patient with pre-existing thyroid disease (e.g., Graves or MNG).
  • Jod-basedow phenomenon occurs (increase in thyroid hormone production due to iodine exposure).
  • Treatment: Stop amiodarone treatment and start thionamide (DOC).
  • Color Doppler: Reduced thyroid vascularity (blood flow).
• Type-II:
  • Occurs in patients without pre-existing thyroid disease.
  • Amiodarone-induced destruction of the thyroid gland (lysosomal mediated).
  • No antibodies (no Graves' disease).
  • Color Doppler: Reduced thyroid vascularity.
  • Treatment: Stop amiodarone; Treat with steroids.

Hypothyroidism

• Transient hypothyroidism (temporary).
• Caused by the Wolff-Chaikoff phenomenon (iodine excess temporarily inhibits thyroid hormone production).

Subacute Thyroiditis vs Graves' vs Toxic MNG

Type 1.5 Diabetes

• Features of Type-1 and Type-2 Diabetes:

• Diagnostic Algorithm - Autoantibodies in LADA/TIDM*

This quiz focuses on the pathophysiology of insulin resistance, its connection to diabetes, and the features of different types of MODY. Test your knowledge on the mechanisms behind glucose uptake and metabolism in the context of diabetes. Perfect for students studying endocrinology or diabetes management.