Endo 2

Overview of Diabetes Mellitus

• Definition: Diabetes Mellitus is a disorder of glucose metabolism related to either an absent or insufficient insulin supply, or the poor utilization of insulin that is available within the body.

• Etiological Theories: Current theories link the cause of diabetes to a single factor or a combination of the following:

  • Autoimmune factors: The body's immune system attacking insulin-producing cells.

  • Genetic predisposition: Inherited susceptibility to the disorder.

  • Viral triggers: Exposure to certain viruses (e.g., Rubella, Coxsackie, Mumps).

  • Environmental factors: Including obesity, a sedentary lifestyle, and high levels of stress.

Specific Etiologies and Primary Types

Type 1 Diabetes Mellitus

• Pancreas: Characterized by the autoimmune destruction of $\beta$ cells.

• Autoantibodies: These are often present for months or even years before clinical symptoms manifest.

• Insulin Production: Results in insufficient production of insulin, eventually leading to an absolute insulin deficit.

Type 2 Diabetes Mellitus

• Pancreas: Involves defective $\beta$ cell secretion of insulin. Initially, insulin resistance stimulates an increase in insulin secretion, which eventually leads to $\beta$ cell exhaustion in many individuals.

• Liver: Features excess glucose production and inappropriate regulation of glucose output.

• Adipose Tissue: Characterized by decreased levels of adiponectin and increased levels of leptin, resulting in altered glucose and fat metabolism.

• Muscle: Defective insulin receptors and insulin resistance lead to decreased uptake of glucose by cells, resulting in hyperglycemia.

• Glucagon: There is an increase in glucagon secretion.

Risk Factors and Metabolic Syndrome

• Metabolic Syndrome: A cluster of at least three of the following medical conditions that increases the risk of developing cardiovascular (CV) diseases and Type 2 DM:

  • Abdominal obesity.

  • Hypertension (high blood pressure).

  • High Glucose levels.

  • High Triglycerides.

  • Low HDL (High-Density Lipoprotein) cholesterol.

Prediabetes and The Glucose Continuum

• Definition: An intermediate stage between normal glucose homeostasis and diabetes.

• Impaired Fasting Glucose (IFG): Fasting glucose levels are between $6.1–6.9\,mmol/L$.

• Impaired Glucose Tolerance (IGT): 2-hour plasma glucose levels are between $7.8$ and $11\,mmol/L$.

• HbA1C: Levels ranging from $6\%$ to $6.4\%$.

• Clinical Significance:

  • Increased risk for developing Type 2 diabetes.

  • Often asymptomatic, but long-term damage to the heart and blood vessels may already be occurring.

• Management Strategies:

  • Regular screening of glucose and A1C.

  • Managing risk factors.

  • Monitoring for symptoms of diabetes.

  • Maintaining a healthy weight, exercising, and making healthy food choices.

• Screening Recommendation: Screening should be done at least every 3 years for patients aged 40 and up.

Detailed Characteristics of Type 1 Diabetes

• Former Labels: Previously known as "juvenile-onset" or "insulin-dependent" diabetes.

• Demographics: Most often occurs in people younger than 30 years of age; occurs more frequently in younger children.

• Pathogenesis and Genetic Susceptibility:

  • Genetic Susceptibility: $IDDM1$ ($HLA$) mutations (specifically $HLA-DR3$ and $HLA-DR4$) and $IDDM2$ (Insulin gene) mutations.

  • Environmental Triggers: Viruses (Rubella, Coxsackie, Mumps), Diet (cow's milk, nitrosamines), Drugs/Toxins (vacor, alloxa, streptozocin, pentamidine), and Stresses (repeated sickness, surgery, puberty).

• Immune System Failure:

  • Failure of maturing T-cells in the thymus to develop recognition of the insulin gene leads to an abnormal attack on insulin-producing $\beta$ cells.

  • Molecular Mimicry: Foreign antigens mimic $\beta$ cell antigens, causing the immune system to attack both.

  • Insulitis: Direct T-cell attack of $\beta$ cells involving both innate and acquired immune systems.

  • Auto-antibodies: Detectable in serum, specifically Anti-Insulin and anti-$GAD65$.

• Clinical Manifestations:

  • Long preclinical period where $\beta$ cell mass reduces to less than half of the original mass.

  • Symptoms develop rapidly once $\beta$ cells are $< 10\%$ functional.

  • Often presents at the Emergency Department (ED) with ketoacidosis.

  • Requires exogenous insulin to sustain life.

Detailed Characteristics of Type 2 Diabetes

• Prevalence: More than $90\%$ of patients with diabetes; 80 to $90\%$ of patients are overweight.

• Age of Onset: Usually occurs in people over 35 years of age.

• Core Concepts:

  • Pancreas produces some endogenous insulin, but it is insufficient or poorly utilized.

  • Strong genetic basis: 90% concordance rate for monozygotic twins. Risk is 5–10x above baseline if a first-degree relative is affected.

• Pathogenesis of Type 2 DM:

  • Accumulation of "visceral fat" in the intraperitoneal cavity acting as an endocrine organ.

  • Secretes Adipokines (inflammatory mediators like $TNF\text{-alpha}$) and Free Fatty Acids (FFAs).

  • Lipotoxicity: FFAs inhibit the function of $GLUT2$ on $\beta$ cells, decreasing glucose import.

  • Glucotoxicity: Persistent hyperglycemia is directly toxic to $\beta$ cells.

  • Insulin Resistance: Decreased expression of $GLUT4$ channels and decreased affinity of $IRS-1$ for $PI3K$.

  • Islet Amyloid Polypeptide (Pro-amylin): Accumulation in the pancreas contributes to $\beta$ cell dysfunction.

Variations: Gestational and Secondary Diabetes

Gestational Diabetes

• Incidence: Occurs in about $3\%$ of pregnancies in non-Indigenous populations; rates are 2 to 3 times higher in Indigenous populations.

• Detection: Screened at $24–28$ weeks of gestation.

• Risks: Increased risk for birth trauma, neonatal hypoglycemia, hyperbilirubinemia, and respiratory distress syndrome.

• Therapy: First nutritional management, second insulin.

• Prognosis: Usually glucose levels normalize at 6 weeks postpartum, but there is an increased risk ($5–10\%$) of developing Type 2 DM within 5–10 years.

Secondary Diabetes

• Causes: Result of medical conditions or treatments causing abnormal blood glucose.

• Associated Conditions: Cushing’s syndrome, Hyperthyroidism, Cystic fibrosis, Schizophrenia.

• Medical Treatments: Parenteral nutrition, Immunosuppressive therapy.

• Associated Medications: Corticosteroids (e.g., Prednisone), Phenytoin (Dilantin).

Clinical Manifestations and Acute Complications

Hypoglycemia (Low Blood Glucose)

• Causes: Too little food, too much insulin/medication, or extra physical activity.

• Onset: Sudden; may progress to insulin shock.

• Physical Signs (Cold and Clammy): Shaking, sweating, anxious, dizziness, fast heartbeat, hunger, impaired vision, weakness, fatigue, headache, irritability.

• Treatment: Drink $1/2$ glass of juice/soda or 1 glass of milk, or eat soft candies. Test blood glucose within 20 minutes. Follow with a light snack (e.g., $1/2$ peanut butter sandwich).

Hyperglycemia (High Blood Glucose)

• Causes: Too much food, too little insulin, illness, or stress.

• Onset: Starts slowly; can lead to a medical emergency.

• Physical Signs (The 3 Ps):

  • Polyphagia (extreme hunger).

  • Polydipsia (extreme thirst).

  • Polyuria (need to urinate often).

  • Other signs: Dry skin, blurry vision, drowsiness, slow-healing wounds.

• Treatment: Check blood glucose and call a healthcare provider if levels remain high for 3 days without a known cause.

Diagnostics and Laboratory Findings

• Physical Exams: Blood pressure, weight, podiatric (foot), fundoscopic (dilated eye), neurological, and dental exams.

• Blood Tests: Fasting Blood Glucose (FBG), postprandial glucose, glycated hemoglobin (A1c), fasting lipid profile, serum creatinine, electrolytes, calculation of creatinine clearance, TSH.

• Imaging/Other: Doppler scan (ankle-brachial index), ECG.

• Urine Tests: Random urine for microalbuminuria (MAU), complete urinalysis, and acetone/ketones.

Explanation of Lab Results

• Glycated Hemoglobin (HbA1C): Glucose in the bloodstream glycates (coats) hemoglobin in red blood cells. High blood glucose leads to higher A1c.

• Glucosuria: Occurs when filtered glucose exceeds the reabsorption capacity of renal tubules in the kidney.

• Ketonuria: Filtered ketone bodies exceed reabsorption capacity.

• Albuminuria: Build-up of glycation end products damages glomerular tissue, causing proteins like albumin to leak into urine.

Management and Treatment Goals

Glycemic Goals

• HbA1c: Less than $7\%$.

• Fasting Blood Glucose: $4$ to $7\,mmol/L$.

• 2-hour Postprandial: $5$ to $10\,mmol/L$.

Drug Therapy

• Diabetes Specific: Oral antihyperglycemic agents, noninsulin injectable agents, and insulin.

• Secondary Drugs:

  • ACE inhibitors or ARBs (for high cardiovascular risk).

  • Enteric-coated acetylsalicylic acid (ASA/Aspirin) ($80\,mg$ or $325\,mg$).

  • Lipid-lowering therapy.

Specific Treatment per Type

• Type 1: Insulin therapy.

• Type 2: Lifestyle changes, oral drug therapy, and insulin if oral drugs are ineffective.

Chronic Complications

Diabetic Retinopathy

• Pathogenesis: Chronic high blood sugar leads to an inflammatory response and increased Vascular Endothelial Growth Factor (VEGF).

• Non-proliferative: Characterized by micro-aneurysms, dot/blot hemorrhages, hard exudates (yellow opaque solids), and cotton-wool spots (nerve fiber layer infarcts).

• Proliferative: Presence of neovascularization (fragile new vessels) extending into the vitreous humor; can lead to traction retinal detachment.

Diabetic Polyneuropathy

• Metabolic Pathway: High intracellular glucose activates the Polyol pathway (sorbitol/fructose accumulation) and Protein Kinase C (PKC) pathway, resulting in inflammation and oxidative stress.

• Advanced Glycation End Products (AGEs): Carbohydrates added to proteins inducing vascular permeability and monocyte influx.

• Manifestations:

  • Sensory: Pain, paresthesias, loss of light touch/temperature.

  • Motor: Atrophy of intrinsic foot muscles, claw toe deformity.

  • Autonomic: Gastroparesis, erectile dysfunction, resting tachycardia, orthostatic hypotension.

Diabetic Nephropathy

• Mechanism: High glucose load to the kidney increases the activation of the renin-angiotensin system (RAS) and intrarenal Angiotensin II.

• Kimmelstiel-Wilson Lesions: Pink hyaline nodules due to the accumulation of damaged proteins.

• Progression: Initial glomerular hyperfiltration followed by a decrease in Glomerular Filtration Rate (GFR) and overt nephropathy (usually takes 15–25 years).

Diabetic Foot

• Causes: Combination of peripheral vascular disease and neuropathy.

• Outcomes: Ulcer formation, infection, and collapse of the arch (Charcot Arthropathy).

• Osteomyelitis: Infection of the bone due to contiguous spread from superficial tissues.

Critical Comparisons: DKA vs. HHS

Questions & Discussion

• The presentation concludes with a prompt for audience questions regarding the pathophysiology, management, or complications of Diabetes Mellitus.