DPI Wk 1-8

Historical Context and Definition of Diabetes Mellitus

The understanding of diabetes has evolved significantly over centuries. In 1790, Crawly first identified the disease as being specifically related to the pancreas. It was not until 1921 that Banting and Best identified diabetes as an endocrine-related disease linked specifically to insulin within the pancreas. The term "Diabetes" originates from the Greek for "running through," referring to increased urinary volume, while "Mellitus" comes from the Greek word for "sweet," a terminology established over 2,000 years ago. Pathophysiologically, Diabetes Mellitus (DM) is caused by either a deficiency of insulin or a hyporesponsiveness of tissues to insulin. Globally, it affects over 95 million people, with 7 million new cases diagnosed annually. On average, the disease shortens the human life span by approximately 15 years.

Anatomy and Physiology of the Pancreas

The pancreas is a complex organ containing approximately 1 million "islets of Langerhans" or pancreatic islets. These islets contain various cell types with distinct secretory functions:

Alpha cells secrete glucagon.
Beta cells secrete insulin.
Delta cells secrete somatostatin.
Pancreatic polypeptide cells secrete enzymes and control feedback loops.

Anatomically, the pancreas consists of a head, body, and tail. It contains pancreatic ducts and the duodenal papilla, which interface with the duodenum of the small intestine. The organ is located near the inferior vena cava, abdominal aorta, and spleen. The exocrine portion of the gland consists of acini, while the endocrine portion consists of the islets.

Insulin Dynamics: Function and Secretion

Insulin is a vital metabolic hormone whose primary targets include cardiac and skeletal muscle, adipose tissue, and the liver. Its actions are categorized into metabolic effects (carbohydrate, lipid, and protein synthesis) and growth-promoting effects (DNA synthesis, cell division, and differentiation). The biochemical pathway of insulin involves:

Insulin binding to its specific insulin receptor.
Activation of multiple protein cascades.
Translocation of the Glucose-4 (GLUT-4) transporter to the plasma membrane, which requires phosphorylation by glucokinase. Because the plasma membrane is impermeable to glucose without a transporter, this translocation is essential for glucose influx.
Intracellular processes: Glycogen synthesis, glycolysis (breakdown of glucose to pyruvate, leading to amino acid and protein synthesis), and fatty acid (FA) synthesis leading to triacylglycerols.

Insulin secretion is stimulated by meal-induced blood sugar increases, ingestion of protein-containing meals, parasympathetic activation, and Glucose-dependent insulinotropic peptide. Conversely, sympathetic activation and high stress levels decrease insulin release.

Comparative Actions of Insulin and Glucagon

Insulin and Glucagon act as antagonistic hormones to maintain homeostasis.

Insulin Actions:

Carbohydrates: Increases glycogen synthesis and decreases gluconeogenesis.
Fats: Increases fatty acid and triacylglycerol (TG) synthesis and maintains fat storage by inhibiting lipolysis.
Protein: Increases protein synthesis and decreases protein breakdown.

Glucagon Actions:

Carbohydrates: Increases glycogen breakdown and increases gluconeogenesis.
Fats: Decreases fatty acid and TG synthesis and promotes lipolysis.
Protein: Decreases protein synthesis.

Diagnosis and Classification of Diabetes

Diagnosis is based on blood glucose thresholds.

Normal: Fasting glucose < $5.6\,mmol/l$ ; 2-hour post-75g load < $7.8\,mmol/l$ .
Impaired Glucose Tolerance (IGT): Fasting $5.6-7.0\,mmol/l$ ; 2-hour load $7.8-11.0\,mmol/l$ .
Diabetes: Fasting > $7.0\,mmol/l$ ; 2-hour load > $11.1\,mmol/l$ .

Classification of DM:

Type I (Insulin-dependent, IDDM): Characterized by a total or near-total absence of insulin in the islets and plasma. It usually affects those < 25 years old and involves autoimmune destruction of Beta cells (Autoimmune Insulitis via lymphocytes). Causes include genetics and viral infections.
Type II (Non-insulin dependent, NIDDM): Characterized by insulin resistance and relative insulin deficiency. It usually affects those > 25 years old and is strongly linked to obesity and lifestyle. Plasma insulin may be normal or elevated. Over time, chronic hyperglycemia leads to Beta cell exhaustion and hyalinization, where Beta cells are replaced by Amyloid protein deposits.

Chronic Complications of Diabetes Mellitus

Diabetes complications are divided into short-term metabolic issues and long-term angiopathy.

Short-term: Hypoglycemia, Diabetic Ketoacidosis, Hyperosmolar diabetic coma, and Lactic acidosis.
Long-term: Retinopathy, Nephropathy, Neuropathy, Dermatopathy, and Atherosclerosis.

Microangiopathy and Nephropathy: High blood glucose promotes pericyte death, reducing capillary integrity. Glycosylation cycles lead to protein deposition, thickening vessel walls and narrowing the lumen, causing ischemic organ damage. In the kidneys, hyperfiltration and hypertension in the glomerulus lead to glomerular lesions (membrane thickening), renal vascular lesions (arteriolosclerosis), and pyelonephritis (inflammation of tubules and glomeruli), resulting in albuminuria. GFR (Glomerular Filtration Rate) decreases significantly over time as serum creatinine and urea nitrogen levels rise.

Neuropathy and Retinopathy: Neuropathy affects both motor and sensory functions. Microvascular injury leads to nerve damage. Peripheral neuropathy causes paresthesia, pain, and muscle atrophy, potentially resulting in Charcot's foot (painless, swollen, deformed foot due to neuropathy-induced osteoporosis) or neuropathic ulcers. Visceral neuropathy affects the GIT (constipation/diarrhea) and CVS (hypotension). Diabetic Retinopathy includes nonproliferative injury (dots, blots, hard/soft exudates, macular edema) and proliferative injury (large hemorrhage, retinal detachment, blindness).

Thyroid Anatomy and Physiology

Macroscopically, the thyroid consists of two lobes joined by an isthmus, with parathyroid glands embedded in the poles. Microscopically, it is formed of follicles containing colloid, which stores hormones and thyroglobulin (the precursor). Production is controlled by a negative feedback loop: the Hypothalamus releases Thyroid Releasing Hormone (TRH), stimulating the Pituitary to release Thyroid Stimulating Hormone (TSH). Iodine is essential for this process.

Thyroid hormones function to increase metabolism, cardiac output, and pulse rate. They also promote the breakdown of protein and fat, excite the CNS, and are critical for the growth and development of the skeleton, teeth, epidermis, and CNS.

Thyroid Disorders: Goitre, Hypo- and Hyperthyroidism

Goitre: An enlarged thyroid. Simple goitres (soft/symmetrical) involve no hormone excess and are caused by iodine deficiency, goitrogens, or pregnancy. Diffuse or multinodular goitres involve hyperplasia and palpable nodules.

Hypothyroidism: Failure to produce enough hormone (hypometabolism). Causes include Hashimoto’s Thyroiditis (an autoimmune reaction to thyroglobulin), surgical removal, radioactive ablation, or iodine deficiency. Symptoms include weight gain, apathy, constipation, yellow skin, dry hair, and a dull face.

Hyperthyroidism: Excessive hormone production (hypermetabolism/thyrotoxicosis). Causes include Graves' Disease (autoantibodies stimulate TSH receptors), toxic multinodular goitre, or toxic adenoma. Symptoms include weight loss, diarrhea, hair loss, osteoporosis, exophthalmos (protruding eyes), tremors, and anxiety.

Gastrointestinal Anatomy and Gastric Secretion

The digestive tract consists of four layers: Mucosa (enzymes/mucus), Submucosa (neutralization), Muscularis externa (movement), and Serosa (lubrication). The stomach features specialized cells:

G cells: Secrete gastrin (stimulated by ethanol, amino acids, calcium). Increases acid, pepsinogen, and blood flow.
Parietal cells: Secrete Hydrochloric acid (HCl) and intrinsic factor.
Chief cells: Secrete pepsinogen (converted to pepsin by HCl) and lipase.
ECL cells: Synthesize and secrete histamine.

Acid secretion depends on the activation of Gastrin, Histamine ( $H_2$ ), and Muscarinic ( $M_3$ ) receptors on parietal cells. The proton pump ( $H^+/K^+\text{ ATPase}$ ) is the final step. Prostaglandins act as a protective factor by inhibiting proton secretion and stimulating mucus production. Bicarbonate ( $HCO_3^-$ ) produced during acid formation moves into the blood, causing an "alkaline tide" after meals.

Peptic Ulcer Disease (PUD) and Gastritis

Dyspepsia is characterized by upper abdominal discomfort or gnawing pain. Gastritis involves inflammatory changes in the mucosa and can be acute (transient, caused by NSAIDs, alcohol) or chronic (often caused by $Helicobacter\,pylori$ , leading to atrophy).

PUD represents discrete mucosal defects in areas exposed to acid-pepsin secretion (gastric or duodenal). It results from an imbalance between aggressive factors (acid, pepsin) and defensive factors (mucus, bicarbonate, blood flow). Major risks include $H.\,pylori$ infection and NSAID use. Gastric ulcers typically cause sharp pain soon after eating; duodenal ulcers cause pain when the stomach is empty, often relieved by food or milk. Complications include hemorrhage (hematemesis/melena), perforation (peritonitis), and penetration into adjacent organs (liver, pancreas).

GastroEsophageal Reflux Disease (GERD)

GERD is the backward movement of gastric contents into the esophagus, primarily due to a weak lower esophageal sphincter. Factors include impaired esophageal clearance, delayed gastric emptying, and compromised mucosal defense (dilated intercellular spaces). Heartburn is the hallmark symptom, worsened by lying down or bending. Chronic reflux can cause Barrett esophagus, where squamous mucosa is replaced by columnar epithelium, increasing the risk of esophageal cancer.

Bowel Function Disorders: Constipation and Diarrhea

Constipation: Defined as < 3 motions per week, straining, or hard stools. Causes include low fiber/fluid, aging, drugs (opiates, calcium channel blockers), pregnancy, and diseases (hypothyroidism, Parkinson's). Non-pharmacologic therapy involves increasing dietary fiber (soluble like beans; insoluble like whole grains) and fluid.

Diarrhea: An abnormal increase in stool frequency or liquidity. Acute diarrhea can be food-induced, viral (noroviruses), protozoal ( $Giardia$ ), bacterial ( $Salmonella$ , $E.\,coli$ ), or drug-induced (antibiotics). Chronic diarrhea (> 4 weeks) is associated with IBD, IBS, or malabsorption. Irritable Bowel Syndrome (IBS) is a functional disorder (> 12 weeks) involving abdominal pain relieved by defecation, linked to gut sensitivity and stress.

Inflammatory Bowel Disease (IBD): Includes Crohn's Disease and Ulcerative Colitis.

Crohn's: Affects any GI area; involves all layers (submucosal most); granulomatous "skip" lesions; nutritional deficiencies common.
Ulcerative Colitis: Affects rectum and colon; involves only the mucosal layer; continuous inflammation; high risk of colon cancer; stools often contain blood and mucus.

Hemorrhoids

Hemorrhoids are swollen veins of the hemorrhoidal plexus caused by increased venous pressure (pregnancy, constipation, heavy lifting).

Internal: Above the dentate line; painless; may prolapse.
External: Below the dentate line; painful (sensory fibers); may thrombose (turn blue/purple). Management involves high-fiber diets, improved toilet habits (avoiding sitting > 5 mins), anal hygiene, and Sitz baths (warm water at $40-46^\circ\text{C}$ ).

The Immune System: Properties and Barriers

The immune system protects the host through three levels: Barriers (1st line), Innate (2nd line), and Adaptive (3rd line).

Properties:

Non-reactivity to self-antigens: Prevents host tissue damage.
Diversity: Ability to recognize many different foreign antigens.
Specificity: Optimized responses to distinct antigens.
Memory: Enhanced response to recurrent infections.

First Line (Barriers):

Physical: Skin (dry), Mucus (traps microbes), Saliva, Nose hairs, Defecation, and Vomiting.
Chemical: Sebum (lipids), Perspiration (acidic pH), Lysozyme (enzyme in tears/urine that destroys bacterial cell walls), Gastric juice ( $HCl$ ).
Normal Flora: Non-pathogenic microbes ( $E.\,coli$ , $S.\,epidermidis$ , $Lactobacilli$ ) that colonize space, utilize nutrients, and produce bacteriocins to inhibit pathogens.

Pathogenesis and Pathogens

Pathogens include Bacteria (Salmonella), Viruses (Influenza), Fungi (Candida), and Parasites (Plasmodium). Pathogenesis follows specific steps:

Maintain a reservoir (human, animal, or environmental like soil).
Leave reservoir via portal of exit (respiratory droplets, feces).
Adhere to host using adhesins (proteins) or invasins.
Invade via portal of entry.
Evade defenses: Using capsules to avoid phagocytosis, antigenic variation (changing surface proteins), or IgA proteases.
Multiply within the host, often using Exotoxins (secreted proteins) or Endotoxins (LPS component of gram-negative cell walls).
Leave host to find a new one.

Innate Immunity: Cellular Components and PAMPs

Innate immunity is non-specific and rapid. Its main components are White Blood Cells (Leukocytes):

Neutrophils (PMNs): Multilobed; phagocytose bacteria/fungi.
Eosinophils: Bilobed; orange-pink granules; kill parasites by releasing toxic granule contents.
Basophils: S-shaped nucleus; deep purple granules; release histamine for inflammation.
Mast Cells: Found in tissues; contain histamine; involved in allergic reactions and parasite expulsion.
Monocytes: Largest WBC; horseshoe nucleus; differentiate into tissue Macrophages (ingest/kill microbes).
Dendritic Cells: Ingest fragments via endocytosis; bridge to adaptive immunity.
Natural Killer (NK) Cells: Recognize cells lacking MHC I (cancer/infected cells); release perforins (form pores) and granzymes to induce lysis.

Recognition (PAMPs and PRRs): Innate cells detect Pathogen-associated Molecular Patterns (PAMPs), such as Lipopolysaccharides (LPS), Flagellin, or double-stranded RNA (dsRNA). These are recognized by Pattern Recognition Receptors (PRRs) like Toll-like Receptors (TLR4 for LPS, TLR5 for Flagellin). Binding triggers signaling for inflammation.

Inflammation Mechanism

Inflammation is triggered by macrophages and mast cells. Key processes include:

Vasodilation: Increases blood flow (redness/heat).
Increased vascular permeability: Plasma leaks into tissue (swelling).
Extravasation: White blood cells exit capillaries into infected tissue.

Mast cells release histamine, and endothelial cells/macrophages produce Nitric Oxide (NO). Cytokines are released to coordinate the reaction and eventually tissue repair.

Obstetrics and Gynecological Disorders: PMS and Dysmenorrhea

Premenstrual Syndrome (PMS): Physical/behavioral changes occurring near the end of the menstrual cycle. Symptoms include bloating, breast soreness, headache, depression, and irritability. It must repeat for at least two cycles and disappear after menstruation. Treatments include hormonal treatments (estrogen/progesterone), stress reduction, or vitamins (B6).

Dysmenorrhea: Painful menstruation (cramps).

Primary: No underlying illness; affects women 15–25; caused by high levels of Prostaglandin $F2\alpha$ ( $PGF2\alpha$ ) which causes vasostriction and myometrial spasms.
Secondary: Caused by medical problems like endometriosis; affects women > 30.
Treatment: Oral contraceptives (stop ovulation) or NSAIDs (Aspirin/Ibuprofen) which inhibit prostaglandin synthesis.

Menopause

Menopause is the end of menstruation, typically occurring between ages 50 and 52. Perimenopause (ages 40–50) involves declining hormone production. Pathophysiology involves a decrease in ovarian follicles and receptor sites for FSH (Follicle-stimulating hormone) and LH (Luteinizing hormone). Symptoms include hot flushes (due to hypothalamus thermostat confusion), vaginal dryness (mucosa thinning), urinary incontinence, and osteoporosis (decreased bone resorption due to low estrogen). Treatment includes Hormone Replacement Therapy (HRT).

Vaginitis and Sexually Transmitted Diseases (STDs)

Vaginitis: Inflammation of the vagina.

Yeast Infection ( $Candida\,albicans$ ): Thick, white, odorless discharge; often follows antibiotic use.
Bacterial Vaginitis ( $Gardnerella$ ): Thin, milky discharge with a "fishy" odor.
Trichomonas: Frothy, greenish-yellow, foul-smelling discharge; caused by a protozoan.
Non-infectious: Allergic reaction to sprays or soaps.

STDs: Transmitted via venereal fluids, saliva, or skin lesions. Incidence is rising due to earlier sexual activity and multiple partners. Many are asymptomatic but still infectious. They can spread horizontally (person to person) or vertically (mother to child). Examples include Chlamydia, Gonorrhea, Syphilis, Hepatitis B, HIV, and HPV. Prevention focuses on abstinence, condoms, and vaccinations.

Psychiatric Disease: Neurotransmission and Neurotransmitters

The brain contains ~100 billion neurons. Communication occurs at the synapse where Action Potentials trigger $Ca^{2+}$ influx, causing vesicle docking and neurotransmitter release.

Key Neurotransmitters:

GABA: Inhibitory; regulates anxiety and motor control.
Glutamate: Excitatory.
Dopamine (DA): Modulates mood, movement, and emotional control. Excess DA is linked to psychosis; deficiency is linked to movement disorders.
Acetylcholine (ACh): Muscle contraction, wakefulness, aggression.
Norepinephrine (NE): Attentiveness, sleep, dreaming; causes blood vessel contraction.
Serotonin (5HT): Regulates mood, appetite, sleep, and body temperature.

Sleep Disorders

Sleep is regulated by the circadian rhythm via the suprachiasmatic nucleus.

Insomnia: Difficulty initiating or maintaining sleep. Acute is stress-related; chronic (> 30 days) is psychiatric or medical. Sleep hygiene involves regular wake times and bedroom restriction.
Narcolepsy: Autoimmune destruction of hypocretin-producing neurons; excessive daytime sleepiness.
Sleep Apnea: Central (brain respiratory center) or Obstructive (airway collapse/snoring).
Circadian Rhythm Disorders: Non-24-hour sleep-wake syndrome (common in the blind) or Jet-lag.

Schizophrenia and Bipolar Disorder

Schizophrenia: A neurodevelopmental disorder involving gray matter loss. The Dopamine Hypothesis suggests excess DA in the mesolimbic tract causes positive symptoms, while deficient DA in the mesocortical tract causes negative symptoms.

Positive Symptoms: Hallucinations (auditory), Delusions (persecution/grandeur).
Negative Symptoms: Anhedonia (lack of interest), Alogia (lack of speech), Avolition (lack of motivation), Affective flattening.
Treatment: Antipsychotics (block $D_2$ receptors), vocational rehab.

Bipolar Disorder: Characterized by shifts between mania (energized, decreased sleep, inflated self-esteem) and depression. Treatment includes mood stabilizers (Lithium), antipsychotics, and Electroconvulsive Therapy (ECT) for severe cases.

Depression, Anxiety, and ADHD

Depression: Major Depressive Disorder vs Dysthymia (chronic, less severe, > 2 years). The Monoamine Hypothesis posits a functional decrease in NE and 5HT activity. Antidepressants work by inhibiting reuptake or inhibiting monoamine oxidase breakdown.

Anxiety Disorders: Include Panic Disorder (sudden episodes of fear lasting 15–30 mins), GAD (prolonged excessive worry), OCD (obsessions and compulsions), and Social Phobia. Treatments involve Benzodiazepines (anxiolytics), SSRIs, and behavioral therapy.

ADHD: Characterized by inattention, hyperactivity, and impulsiveness. Implicates prefrontal noradrenergic (NE) and mesocortical (DA) pathways. Psycho stimulants (1st line) increase NE and DA to improve cognitive performance.

Pulmonary Pathology: Atelectasis and Edema

Atelectasis (Lung Collapse):

Resorption: Airway obstruction; $CO_2$ is reabsorbed without O2 exchange.
Compression: External lesion (pleural effusion) pushes air out.
Contraction: Chronic scarring causes lung contraction.

Pulmonary Edema: Fluid accumulation in alveoli, often due to left heart failure or lung injury (pneumonia). Leads to shortness of breath (SOB) and frothy sputum.

ARDS: Rapid reaction to injury; systemic inflammation leading to multi-organ failure from lack of $O_2$ .

Chronic Obstructive Pulmonary Disease (COPD) and Asthma

Emphysema: Destruction of alveolar walls and lung tissue around alveoli; decreased surface area for gas exchange and decreased lung compliance.

Chronic Bronchitis: Inflammation of large airways causing mucus hypersecretion and goblet cell increase; thickening and scarring narrowing the airway.

Asthma: Chronic inflammation of small airways; reversible; strong allergic role (IgE/eosinophils). Hallmark is wheezing (bronchospasm).

Bronchiectasis: Irreversible dilation of the bronchial tree due to muscle/elastic tissue destruction, often following necrotizing inflammation.

Pneumonia and Influenza

Pneumonia: Alveolar inflammation where sacs fill with fluid or pus.

Community-Acquired: Often bacterial ( $Streptococcus\,pneumoniae$ , $Haemophilus\,influenzae$ ).
Atypical: Viral; gradual onset; interstitial infiltration.
Aspiration: Entry of foreign material (gastric contents); common in unconscious patients.
Chronic: Persists > 6 weeks; often tuberculosis or autoimmune.

Influenza: Types A (pandemic-prone), B, and C (mild). Structure includes Hemagglutinin (HA) for adherence and Neuraminidase (NA) for release from host cells.

Antigenic Drift: Minor RNA mutations leading to small antigen changes (seasonal changes).
Antigenic Shift: Major genetic reassortment (usually in a "mixing vessel" like a pig), leading to pandemics (e.g., Spanish Flu 1918, H1N1 2009).
Treatment: Amantadine/Rimantadine (prevents uncoating); Zanamivir/Oseltamivir (prevents NA function). Vaccines take ~14 days to become effective.

H5N1 and H1N1 Viruses

H5N1 (Bird Flu): Typically carries a high risk of pandemic due to mutation. It can cross from birds to pigs or humans. Highly virulent strains can be cleaved by various human proteases, allowing spread throughout the body.

H1N1 (Swine Flu): A reassortment of four strains (human, bird, and two swine). Declared a pandemic in June 2009. Seasonal flu can also be H1N1, but the 2009 pandemic strain was "Novel" because it was a completely new mixture. Vaccines can be killed (injected) or live attenuated (nasal spray).