Cases 15 and 16 Flashcards
Functions of insulin
Increase glucose uptake Increase protein synthesis Increase fat deposition Increase potassium uptake into cells Decrease glycogenolysis and gluconeogenesis
Ketone synthesis
During fasting or high fat low carb diet
Glucagon/insulin ratio high
Excess acetyl CoA from B oxidation of fatty acids
Converted to ketones in liver mitochondria
And
Oxaloacetate converted to malate and exported from mitochondrion for gluconeogenesis
Less oxaloaxetate in TCA cycle, therefore AcetylCoA levels rise
Excess acetyl CoA converted to ketones in liver mitochondria
Effects of the glucose counter regulatory hormones
Glucagon: glycogenolysis and gluconeogenesis
Adrenaline: lipolysis and glycogenolysis
GH: lipolysis and glycogenolysis
Cortisol: proteolysis and gluconeogenesis
Clinical features type 1 diabetes
Usually less than 30 years old Usually lean Acute onset Almostalways symptomatic Usually unequivocal hyperglycaemia Insulin necessary for survival Otherwise healthy
Clinical features type 2 diabetes
Usually older Overweight or obese Insidious onset Often asymptomatic Not prone to ketosis Usually controlled with non-insulin therapies Often have comorbidities
Symptoms of diabetes mellitus
Weight loss
Polyuria
Polydipsia
Polyphagia
Complications of diabetes
Acute: DKA, HONK
Macrovascular:
CAD
Peripheral vascular disease
Stroke
Microvascular:
Retinopathy
Nephropathy
Neuropathy
What is HbA1c?
Haemoglobin with a glucose attached to the N-terminal valine of the beta chain
Factors interfering with HbA1c interpretation
Shortened RBC lifetime: Haemolytic disease Sickle cell disease Pregnancy Chronic blood loss
Increase RBC lifetime: Fe deficiency Pregnancy Splenectomy Aplastic anemia
Haemoglobinopathies
Diagnosis of diabetes
Fasting glucose >7 mmol/l. (11.1 mmol/l and symptoms of hyperglycaemia
HbA1c >6.5%. (<6%)
Pathogenesis of DKA
No insulin
Gluconeogenesis, glycogenolysis
Hyperglycaemia, glycosuria
Osmotic diuresis
Dehydration
Lipolysis
Ketones
Acidosis and vomiting
Dehydration
HONK pathogenesis
Hyperglycaemia due to low insulin
Glycosuria causes osmotic diuresis
Dehydration and hyperglycaemia cause increased plasma osmolarity.
Cerebral dehydration, increased viscosity and thrombosis
Mechanism of hypokalaemia in DKA
Depletion of glycolytic intermediates causes fewer K+ binding sites
Accumulating H ions displace K from intracellular proteins
Excess plasma K is cleared by the kidneys, giving a high normal level at presentation obscuring profound intracellular depletion
Treatment of DKA
Rehydration, avoid cerebral oedema Monitor and replace electrolytes (K, Mg and Phosphate) Insulin until normal pH (Bicarbonate) Look for and treat underlying cause
Features of hypoglycaemia
Blood glucose <2.2 mmol/l
Neuroglycopaenia: faintness, weakness, headache
Sympathetic stimulation: paplitations, tachycardia, sweating
Changes in behaviour, confusion, seizures, coma
Causes of hypoglycaemia
Drugs: insulin, alcohol
Neoplasms: insulinoma, IGF secreting tumours
Liver disease
Endocrine disease: addison’s, GH deficiency
Sepsis
Hypoglycaemia investigations
Insulin C peptide Ketones Cortisol Growth hormone
Causes of hypoglycaemia in diabetes
Exercise Missed meals Innapropriate insulin or secretagogue Progressive renal failure causing decreased renal insulin clearance Alcohol
Mini ethnography
Ethnic identity What is at stake Illness narrative Psychosocial stressors Influence of culture on the clinical relationship Is this schema useful here?
What is kinship?
Relationship between entities that share a genealogical background, inclusive of descent and marriage
What is stigma?
Linking a person to a set of undesirable characteristics that may lead to prejudice and discrimination
Critical elements of cultural competency
Communication repertoire: build relationships, gather information, manage patients in distress
Situational awareness: patient cues, conecting
Adaptability to different cultural divides
Knowledge of core cultural issues
Pancreatic islet cells
Alpha: produce glucagon
Beta: insulin
D cells: secrete somatostatin which inhibits insulin and glucagon
Stimuli for insulin secretion
Hyperglycaemia
Amino acids
Gastrin, secretin
Parasympathetic stimulation
Stimuli for glucagon secretion
Hypoglycaemia
NE and E
Amino acids
Mechanism of insulin secretion
Glucose enters beta cell via GLUT 2
Glycolysis and mitochondrial metabolism produce ATP
ATP dependent K channels close causing depolarisation
Ca channels open
Ca induces insulin granule exocytosis
Energy balance signals
Insulin crosses BBB and binds to insulin receptors in the hypothalamic arcuate nucleus, reducing food intake.
The adipocytokine leptin conveys the status of the peripheral fat stores in a similar fashion. It suppresses appetite, increases energy expenditure and promotes fecundity.
Gut satiety peptides
GLP-1 is made by L type enterocytes in the ileum. Glucose and FFAs bin to the apical poles of these cells, stimulating GLP release. GLP inhibits gastric secretion, stimulates insulin release and has a small anorexigenic effect.
Oxyntomodulin is released in by the same cells inr esponse to the same stimuli but is potently anorexigenic.
PYY binds to and inhibits NPY producing neurons which normally stimulate appetite
Ghrelin
Secreted by enteroendocrine cells int he fundus of the stomach. Stimulates orexigenic NPY neurons in the arcuate nucleus. Levels rise with fasting
Pathogenesis of primary diabetes
Type 1: inheritable with HLA associations. Autoimmune damage to pancreatic beta islet cells following environmental trigger in susceptible individual.
Type 2: obesity,insulin receptor or post-receptor defects
Secondary diabetes
Endocrinopathies
Gestational diabetes
Drugs
Pancreatic damage
Mechanism of diabetic complications
Advanced glycation end products lead to inflammatory changes leading to atheroma and thickened BM with increased matrix deposition
Activation of protein kinase C leads to angiogenesis, inflammation
Sorbitol and fructosed decrease myoinositol levels lead to schwann cll and pericyte injury
Increased 02 free radicals
Pancreatic polypeptide
Secreted by F islet cells
Inhibits somatostatin secretion
Inhibits pancreatic enzyme and and bile release
Histology of the adenohypophysis
No BBB
Cellular cords surrounding fenestrated capillaries
Acidophils: peptide hormones GH and prolactin
Basophils: glycoproteins. FSH, LH, TSH, ACTH
Chromophobes
Blood supply to the pituitary gland
The superior hypophysial artery forms the primary capillary plexus in the infundibulum where it collects hypothalamic secretions. E primary plexus is drained by portal veins which go on to form the secondary plexus in the adenohypophysis.
The inferior hypophysial artery supplies the pars nervosa, forming a plexus which collects oxytocin and ADH secretions.
The superior and inferior hypophysial arteries are linked by the trabecular artery
What are the secretory granules found in the pars nervosa called?
Herring bodies
Thyroid hormone synthesis
Exocrine phase:
Uptake of iodide by STP driven iodide pump in the basal membrane of follicular cells, concentrating iodide within the cell. Iodide diffuses into the colloid.
Thyroglobulin is synthesised at the rER and Golgi apparatus. Thyroglobulin and thyroid peroxidase are present in the same secretory vesicle. Thyroid peroxidase is activated at the apical membrane and converts iodide to iodine. Iodination of thyroglobulin takes place in the colloidal lumen.
Endocrine phase:
Colloid droplets containing iodinated thryoglobulin are endocytosed by apical pseudopodiaa and guided to a lysosome where proteolytic enzymes cleave thyroglobulin to release T3 and T4.
T3 and T4 are released into the bloodstream across the basal membrane.
Distinguishing active and passive thyroid gland on histology
Active: columnar follicular epithelium, colloid droplets within follicular cells, large apical pseudopodia and microvilli
Passive: enlarged colloid, cuboidal follicular epithelium
Parathyroid gland histology
Cord like arrangement of cells surrounding sinusoidal capillaries
Chief cells: secrete PTH, glycogen inclusions may be visible
Oxyphil cells: contain abundant mitochondria. May represent a transitional form of chief cells
PTH functions
Stimalates bone resorption by stimulating osteoclastogenesis via M-CSF and RANK ligand expression
Acts on the kidney to stimulate Ca reabsorption and stimulates vitamin D release
Histology of the adrenal gland
Fibrous capsule
Zona glomerulosa: concentrically arranged cells containing a few lipid droplets. Thinnest layer. Aldosterone under angiotensin II control.
Zona fasciculata: polygonal cells arranged in columns separated by capillaries. Vacuolated. Thickest layer. Cortisol under ACTH control
Zona reticularis: darker staining anastamosing cells arranged in a network surrounded by capillaries. Sex steroids under ACTH control
Medulla: epinephrine and norepinephrine secreting cells surrounded by venous sinusoids
Mechanisms of action of metformin and sulfonylureas
Metformin (biguanide): decreases hepatic gluconeogenesis and enhances peripheral GLUT 4 deployment
Sulfonylureas: insulin secretagogue. Bind to ATP dependent hyperpolarising K channels in beta cells causing increased membrane fusion of insulin vesicles
Insulin action on the cell
Insulin bands to the alpha subunit of the insulin receptor
This causes a conformational change and phosphorylation of the insulin response substrate IR by protein kinases causing a cascade of cellular responses including GLUT 4 deployment
