The Islets of Langerhans (endocrine pancreas) contain four main cell types: Beta cells (~65%) produce Insulin to lower blood glucose. Alpha cells (~25%) produce Glucagon to raise blood glucose. Delta cells (~5%) produce Somatostatin to inhibit insulin AND glucagon. PP cells (~1%) produce Pancreatic Polypeptide to inhibit pancreatic exocrine secretion. The islets are scattered throughout the pancreas (~1 million islets). They have a rich blood supply and are innervated by the autonomic nervous system. Insulin stimulants: High glucose, amino acids, GLP-1, CCK, and parasympathetic NS. Insulin inhibitors: Low glucose, somatostatin, and sympathetic NS (adrenaline). Glucagonoma: Alpha cell tumour causing excess glucagon causing hyperglycaemia, necrolytic migratory erythema (skin rash), and weight loss. Insulinoma: Beta cell tumour causing hypoglycaemia (Whipple's triad).

Chronic diabetes causes vascular damage through hyperglycaemia, oxidative stress, and advanced glycation end-products (AGEs). Microvascular (small vessels - specific to diabetes): Diabetic Retinopathy = Leading cause of blindness in working-age adults in developed countries. Background to Proliferative retinopathy (new vessel formation causing vitreous haemorrhage, retinal detachment). Diabetic Nephropathy = Leading cause of end-stage renal disease (ESRD) worldwide. Microalbuminuria to macroproteinuria to declining GFR to ESRD. Diabetic Neuropathy = Most common complication. Peripheral sensory neuropathy (glove and stocking distribution), autonomic neuropathy (erectile dysfunction, gastroparesis, postural hypotension, cardiac arrhythmia), Charcot's arthropathy. Macrovascular (large vessels - accelerated atherosclerosis): Coronary artery disease (MI - main cause of death in T2DM), Stroke (2-4 times risk), and Peripheral vascular disease causing diabetic foot, gangrene, amputation. Monitoring: HbA1c (glycated haemoglobin - reflects average blood glucose over 2-3 months).

Melatonin (N-acetyl-5-methoxytryptamine) produced by the pineal gland has multiple roles: Circadian rhythm regulation (primary role - promotes sleep onset and maintains sleep architecture), Seasonal reproductive cycles (photoperiodism - in many mammals, melatonin signals day length causing regulation of seasonal breeding - less prominent in humans), Antioxidant (directly scavenges free radicals - protects DNA, lipids, proteins from oxidative damage), Immune modulation (enhances T-cell and NK cell activity; anti-inflammatory effects), Pubertal timing (high melatonin suppresses GnRH causing delay of puberty. During puberty, melatonin levels naturally decline causing GnRH pulses increase causing puberty begins. Pineal tumours that secrete excess melatonin cause delayed puberty; tumours that destroy the pineal cause reduced melatonin causing precocious puberty), and Temperature regulation (core body temperature drops as melatonin rises at sleep onset).

Incretins are gut hormones released in response to food intake that amplify insulin secretion (the incretin effect explains why oral glucose raises insulin more than IV glucose). GLP-1 (Glucagon-Like Peptide-1): Produced by L-cells of the distal small intestine and colon. Actions: Stimulates insulin secretion (glucose-dependent - only works when glucose is elevated causing low hypoglycaemia risk), Suppresses glucagon, Slows gastric emptying (reduces post-meal glucose spike), Reduces appetite (acts on hypothalamus causing weight loss), and Promotes beta cell survival. GIP (Glucose-Dependent Insulinotropic Polypeptide): Produced by K-cells of duodenum/proximal small intestine - mainly stimulates insulin secretion. Clinical exploitation: GLP-1 receptor agonists (Semaglutide/Ozempic, Liraglutide/Victoza, Exenatide) treat T2DM, promote weight loss (now used for obesity - Wegovy/Semaglutide), and reduce cardiovascular risk. DPP-4 inhibitors (Sitagliptin/Januvia, Alogliptin) inhibit DPP-4 enzyme that breaks down GLP-1 causing increased GLP-1 levels to treat T2DM.

HbA1c (Glycated Haemoglobin) forms when glucose irreversibly binds to haemoglobin in red blood cells. Since RBCs live ~120 days, HbA1c reflects average blood glucose over 2-3 months (weighted toward the last month). Values: Normal = <42 mmol/mol (=48 mmol/mol (>=6.5%) on two occasions (or once with symptoms). Good diabetes control target = <53 mmol/mol (<7.0%). Advantages: No fasting required, reflects long-term control, not affected by acute illness. Limitations: Inaccurate in haemolytic anaemia, sickle cell disease, haemoglobinopathies, and pregnancy (increased RBC turnover causing falsely low HbA1c). DCCT trial (T1DM) and UKPDS (T2DM) showed tight glycaemic control reduces microvascular complications.

Obesity and Hormones - complex bidirectional relationship: Insulin resistance = Excess adipose tissue (especially visceral fat) releases free fatty acids and inflammatory cytokines causing impaired insulin signalling causing T2DM. Leptin resistance = Despite high leptin (proportional to fat mass), hypothalamus doesn't respond causing continuous appetite causing more weight gain. Sex hormones = Excess adipose tissue causes increased aromatase activity causing conversion of androgens to oestrogen. In males: gynaecomastia, reduced testosterone, impaired fertility. In females: PCOS, irregular periods. Cortisol = Obesity associated with increased cortisol (visceral fat has high cortisol receptor density causing visceral fat deposition). Adipokines = Adipose tissue produces hormones: Leptin (satiety), Adiponectin (anti-inflammatory, insulin-sensitising - reduced in obesity), and Resistin (promotes insulin resistance). Thyroid: Obesity associated with mildly elevated TSH (cause or effect debated).

Bone as an Endocrine Organ - a relatively new concept: Osteocalcin = A protein produced by osteoblasts that circulates as a hormone. It acts on: Pancreas (stimulates insulin secretion and beta cell proliferation), Muscle (promotes glucose uptake and exercise capacity), Liver (reduces hepatic glucose production), Testes/Leydig cells (promotes testosterone synthesis causing male fertility - mice lacking osteocalcin are infertile), and Brain (may promote memory and reduce anxiety). FGF-23 (Fibroblast Growth Factor 23) = Produced by osteocytes and acts on kidney to increase phosphate excretion and reduce calcitriol production causing maintenance of phosphate homeostasis. Elevated FGF-23 in X-linked hypophosphataemia (rickets) and CKD (contributes to renal osteodystrophy). This demonstrates that the skeleton actively participates in regulating whole-body metabolism - not just a passive structural tissue.

The Placenta is a major temporary endocrine organ during pregnancy, producing: HCG (Human Chorionic Gonadotrophin) = Maintains corpus luteum early in pregnancy (until ~8-10 weeks). Progesterone = Takes over from corpus luteum at ~8-10 weeks - maintains endometrium, prevents uterine contractions, thickens cervical mucus. Oestrogen (Oestriol - E3) = Promotes uterine growth, breast development, prepares for labour. HPL (Human Placental Lactogen/Chorionic Somatomammotrophin) = Similar to GH and prolactin - promotes fetal growth, causes maternal insulin resistance (ensures glucose available for fetus - can cause gestational diabetes in susceptible women). CRH (Corticotrophin-Releasing Hormone) = Rises late in pregnancy - may trigger labour initiation. Relaxin = Relaxes pelvic ligaments and pubic symphysis for delivery.

The HPG (Hypothalamo-Pituitary-Gonadal) Axis controls reproduction: 1) GnRH (Gonadotrophin-Releasing Hormone) = Released pulsatily from hypothalamus - continuous GnRH suppresses the axis (basis of GnRH analogue therapy). 2) FSH + LH = Released from anterior pituitary and act on gonads. 3) Sex hormones = Oestrogen/Progesterone (females) or Testosterone (males) causing negative feedback on hypothalamus and pituitary. In Females: Monthly cyclical changes causing menstrual cycle causing ovulation causing potential pregnancy. In Males: Tonic (continuous) stimulation causing continuous testosterone and sperm production. HPG axis disruption causes Hypogonadism (low sex hormones, infertility). Functional hypothalamic amenorrhoea: Stress, weight loss, excessive exercise cause suppress GnRH causing amenorrhoea (low FSH/LH/oestrogen). Anorexia Nervosa: Classic HPG axis suppression. GnRH analogues (leuprorelin): Initially stimulate then down-regulate causing suppress HPG axis - used in prostate cancer, endometriosis, and precocious puberty.

Conn's Syndrome (Primary Hyperaldosteronism) is caused by autonomous excess aldosterone from the adrenal gland - independent of the RAAS. Causes: Adrenal adenoma (Conn's adenoma - 35%) = unilateral, benign. Bilateral adrenal hyperplasia (65%) = most common overall cause. Features of excess aldosterone: Hypertension (often resistant to multiple drugs) - due to Na+ and water retention, Hypokalaemia (K+ lost in urine) causing muscle weakness, cramps, constipation, polyuria (nephrogenic diabetes insipidus), cardiac arrhythmias, Hypernatraemia (mild), Metabolic alkalosis (H+ also lost in urine), and Low plasma renin (renin suppressed by volume expansion). Investigations: Aldosterone:Renin ratio (elevated), CT adrenals, and adrenal vein sampling (differentiates unilateral from bilateral). Treatment: Unilateral adenoma = laparoscopic adrenalectomy (surgical cure). Bilateral hyperplasia = Spironolactone (aldosterone antagonist).