Please enable JavaScript.

Coggle requires JavaScript to display documents.

Endocrine System (General Concepts (Homeostatic control (Endocrine cell…

- - - - Low conc. in plasma, high affinity, binds and stays (effects for a period of time)
    - - Synapse is a tiny space, with high conc. of neurotransmitters, low affinity with quick control
    - - Local Control
    - - Self Control
    - - Contact Control
  - - - Na and H2O balance
      - Ca balance
      - Energy Balance
      - Processes that cope with stress
      - Growth and development
      - Processes associated with Reproduction
  - - - Hyper secretion, hormone excess
      - Can also be turned off
    - - Hypo secretion, hormone insufficiency
    - - Unresponsive to hormone
    - - Just nice
    - - Rate of production
        
        mediated by + and - feedbacks
      - Rate of delivery: dependent on perfusion and mass action law
        
        Mass action law: Hormones bound to carriers that are of lower affinity than receptors -> net transfer of hormones from carriers to receptors
        
        Bound hormones to carriers have longer half life
      - Rate of excretion/ degradation: half life in circulation
  - - - Pre-prohormone in RER , cleaved to prohormone in GA, Cleaved to hormone in secretory vesicle
      - Same synthesis and processing as secretory proteins, stored in secretory vesicle, soluble in plasma and usually not bound to carrier, short half life
    - - Cholesterol -> Pregnenolone -> steroid hormones (different types)
      - Insoluble in plasma, transported via carrier proteins, synthesized and secreted on demand (cannot be stored), conversion in target tissues
      - Secreted by adrenal glands, gonads and placenta
    - - Epinephrine
        
        soluble in plasma, short half life, in medulla of adrenal gland
      - Throxine (Thyroid hormones)
        
        Insoluble in plasma, transported via carrier, long half life, conversion in target tissues
    - - Synthesized by liver
      - Extend half life in circulation
      - Sequesters hormone from target cell receptor
      - Total concentration = bound + free (active)
      - Mass action law
  - - - e.g. tyrosine kinase linked, inherent tyrosine kinase, Gprotein coupled
      - Secondary messenger signaling -> rapid metabolic changes
    - - Able to cross plasma membrane
      - Intracellular/nuclear receptor
      - Affect DNA transcription, change phenotype of cells, takes longer to change but have longer effects
    - - Affinity
        
        Conc. of hormone for half maximal response
        
        High affinity -> low conc needed
      - Receptor no.
        
        Cells with more receptors are more sensi to hormone
        
        remove hormone -> increase receptors to increase sensitivity due to less available hormone -> give hormone -> huge effect (rebound)
      - Competition
        
        Binding by other agonist( or antagonist) reduces sensitivity
        
        e.g. cortisol vs aldosterone
      - Saturation
        
        Hormone conc. when all receptors are bound
  - - - Increase [osmol] (stimulus) -> neuron -> ADH release -> kidney (target cell)
    - - Lower glucose (S) -> Hypothalamus -> GHRH (H1) -> AP -> GH (H2) -> LIVER (IGF-1)
    - - decrease [Ca] -> parathyroid -> PTH -> Bone (release Ca and PO4
  - - - Use stimulation test to evaluate dysfunctional site leading to low cortisol
      - Give ACTH to promote cortisol secretion, assay cortisol levels after 60-90 minutes
      - If cortisol remains low -> adrenal dysfunctional (primary)
      - If cortisol increases -> either pituitary or hypothalamus is dysfunctional
    - - Use suppresion test to evaluate site leading to high secretion of cortisol
      - give Dexamethasone to inhibit ACTH secretion, assay cortisol levels after 60-90 mins
      - If cortisol remains high, adrenal gland dysfunctional
      - If cortisol decreases, either pituitary or hypothalamus is dysfunction
- - - - Na+-K+ ATPase transports Na+ out in exchange for 1 K+ in
      - Na+ iodide cotransporter moves in one iodide with 1 Na+
      - Iodide then converted to iodine
      - Thyroglobulin produced by RER of follicle cells and secreted into the lumen of the follicles for storage as colloid
      - Luminal membrane bound peroxidase conjugates adjacent pairs of tyrosines and adds iodine to the tyrosine residues
      - Resultant iodinated thyroglobulin in the preprohormone (2-3 months of supply)
      - In the absence of iodide, TH is not made
  - - - Cold and feeding increase TRH production
  - - - Peripheral tissues, on plasma membrane, converts T4 to T3 + rT3
      - Determine T3 pool in hyperthyroidism, inhibited by propylthiouracil
    - - some peripheral tissues, fetus and placental unit
      - On plasma membrane
      - T4 converted to rT3
      - For clearance to clear body of T3 and T4
    - - In CNS, skeletal muscles, fat, heart, bone and thyroid gland
      - Activity increased by TH depletion and by increase sympathetic NS stimulation
      - determines 50% or more of T3 levels in eu and hypothyroid states, active in development and thermiogenesis
        
        skeletal muscle and brown fat
      - Perinuclear ER
    - - Activate Na-K-ATPase, beta adrenergic receptors (increase HR), Glut 4 (increase glucose entrance into muscle) and others
      - TR saturation maximal in cells expressing D2
      - TR saturation minimal in cells expressing D3
  - - - Burns ATP, muscle and fat
      - Increase GLUT 4 in skeletal muscle
      - Increase rate of lipolysis and lipogenesis (to replace stores)
    - - Adrenergic receptor upregulates uncoupling proteins (UCP) which is driven by free fatty acids fromlipolysis
      - In brown fat of fetus (UCP1)
      - In skeletal muscle of adult (UCP3)
    - - Free T4, Free T3 and TSH should decrease (with T3 decreasing to a greater extend)
      - D1 down regulated during fasting (T4 will thus be primary active form, lowering BMR)
      - D2 doesnt change in CNS, heart, thyroid gland and skeletal muscle to preserve activity, mediates feedback regulation in pituitary
      - leptin levels modulate TRH and TSH in starvation
        
        High leptin will increase levels of TRH and on (fed state)
        
        Will also activate melanocortin receptors, which inhibits feeding
  - - - Hyper: increase HR, contractility and cardiac output, vasodilation
      - Reflects upregulation of beta adrenergic receptors
    - - Hypo: mental Fog, lethargic, fatigue
      - Hyper: anxious, hand tremors, anxiety, weakness
    - - Hypo: infertility, decrease LH secretion, retarded growth
    - - Hypo: dry and puffy skin, hair loss, cold intolerance
      - Hyper: sweaty skin, heat intolerance, dryness or bulging of eyes
  - - - Goiters
        
        One of the most acquired endocrine disorders
        
        Can occur with dietary iodine deficiency
        
        Can also happen in hyperthyroidism
      - Hashimoto's thyroiditis
        
        autoimmune disease that triggers apoptosis in thyroid follicular cells
        
        Gland overstimulated
      - Congenital hypothyroidism (Creinism)
        
        Partially reversible growth retardation
        
        Irreversible mental retardation
    - - present with exophthalamus (bulging eyes)
      - Grave's disease
        
        Autoimmune disease in which circulating antibodies mimic TSH activity
        
        T3 and T4 levels are high, TSH low
        
        Goiters form due to overstimulation
      - Thyroid storm
        
        True Emergency: Tachycardia, sweating, high fever
        
        Treat with beta blocker, propylthiouracil (PTU) to inhibit iodination of thyroglobulin and D1 activity
        
        Glucocorticoids to stimulate D3 activity
- - - - Act directly on non-endocrine tissues (GH, PRL, ADH AND OT)
      - Act to modulate other endocrine glands (ACTH, TSH, FSH AND LH) and are called tropic peptides
        
        increase in size and no. of cells
  - - - When the diencephalon (brain) extends caudally
      - Joins with anterior pituitary, forming the median eminence (closest to brain), infundibulum (stalk) and pars nervosa
      - Consists of neural tissue
    - - Root of mouth loops up, forming Rathke's pouch
      - cuff formed around infundibulum -> pars tuberalis
      - Pars distalis (glandular tissue, forming anterior pituitary)
      - Unsealed loops of the pouch forms cysts and pars intermedia (between the two laeyers, consisting of glandular cells protruding into neural tissue)
  - - - Superior hypophyseal artery -> median eminence (receive releasing factors) -> long portal vessels -> anterior
    - - Inferior hypophyseal artery -> posterior (receive ADH) -> short portal vessels -> anterior
  - - - Terminate in median eminence and secrete releasing factors (+ and -)
    - - Secrete OT and ADH into capillaries of posterior lobe
      - Supraoptic -> ADH
      - PVN -> OT and abit of ADH
    - - Called releasing factors (or inhibiting factors)
      - Secreted in episodic (perhaps circadian) and pulsatile manner
        
        Pulsatile to prevent down regulation from over secretions
      - Present at high conc. at target cell
      - Present in very low conc. in systemic blood
      - Releasing factors bind to plasma membrane receptors in pituitary target cells, release stored target hormone by exocytosis (short term) and increase transcription of target hormones
        
        will cause increase in size (hypertrophy) and number (hyperplasia) of target cells
      - Modulates own receptor activity (up/down regulation)
      - Feedback and chart
  - - - TRH-TSH-T4/T3
    - - CRH-ACTH-Cortisol
    - - Kisspeptin-GnRH-LH/FSH-gonad
  - - - Regulated by sucking and cry of infant
      - Increases myoepithelial contraction in breast and increases bonding (also contraction of uterin lining)
      - For both genders: sexual climax, stroking or hugging the baby for bonding
    - - Regulated by osmotic and volume stimuli
        
        rise in plasma osmolarity
        
        Decrease of 15-20% in total blood vol, cardiac output or blood pressure
        
        Act to raise blood vol by increasing reabsorption of water
    - - ADH and CRH secreted into median eminence enter anterior lobe by long portal vessels
      - ADH from posterior love enters anterior lobe by short portal vessels
      - Cosecretion of ADH with CRH potentiates ACTH secretion from anterior lobe
  - - - Central lesion due to trauma, inflammation or tumor
      - Nephrogenic lesion
        
        X-linked (defective vasopressin receptor)
        
        Autosomal: defective aquaporin-2 channels
        
        Acquired: lithium treatment, hypokalemia and post-obstructive polyuria
        
        Excess water intake
- - - - negatively charged plasma proteins have anionic sites that bind H+ or Ca2+
      - As pH rises, H+ dissociate from these sites and Ca2+ ions take its place, lowering plasma Ca2+
      - Patient with acute alkalosis is more susceptable to tetany (intermittent muscular spasms)
    - - PTH and Vit D govern movement of Ca2+
      - positive balance (growing child), net Ca2+ absorption from GI tract exceeds urinary excretion, difference is deposited in the bone
      - Negative Ca2+ balance (lactating mother), Ca2+ absorption from GI tract is insufficient and difference comes from bones
  - - - Primarily to kidney and bone, where it binds to cells expressing PTH receptor (PTHR)
      - Bone
        
        Affects all three cell types: osteocytes, osteoclasts and osteoblasts
        
        occurs in phases
        
        Rapid absorption of Ca2+ into blood from fluid within bone canaliculli
        
        Slower reabsorption of Ca2+ into blood due to osteoclast degradation of mineralized bone which releases Ca2+ and phosphate into the ECF and degrades organic matrix of bone
        
        Late inhibition of osteoblasts prevent bone formation
        
        doesnt directly affect osteoclasts (no receptors), could be paracrine signals from osteoblasts and osteocytes
      - Kidney
        
        Promote phosphate excretion into urine by decreasing phosphate reabsorption in proximal renal tubules
        
        prevent deposition of Calcium Phosphate, an insoluble precipitate, within tissues and blood
        
        Stimulate Ca2+ reabsorption in the distal renal tubules
        
        PTH also increases conversion of VitD to its active form, calcitriol which acts on GI tract to promote uptake of Ca2_
  - - - Primary: tumors (adenoma) that secrete excess PTH, blood Ca2+ elevated, PTH is high, surgery needed
      - Secondary: because of hypocalcemia due to chronic renal failure or Vit D deficiency, blood Ca2+ low but PTH high
    - - Consequence of thyroid or parathyroid surgery
      - Low circulating levels of PTH, decreased bone resorption and decrease Ca2+ reabsorption
      - Plasma Ca2+ low and phosphate is high
- - - - mineralcorticoid (Aldosterone) on the outer layer (zona glomerulosa)
      - Glucocorticoid (cortisol) in zona fasciculata)
      - Sex Hormone (DHEA) in zona reticularis
    - - epinephrine and norepinephrine
  - - - Maintains electrolyte and fluid balance
      - Affected by 21 and 11-hydroxylase (deificiency will cause no production of aldosterone)
    - - Mobilize fueal depots, increasing plasma glucose
      - deficiency in 17,11 and 21 hydroxylase will cause no cortisol in system
    - - weak ANDROGEN
      - Deficiency is 17 hydroxylase will cause no DHEA in system
  - - - Elevated angiotensin II due to low blood volume
      - elevated plasma K+
      - decrease inm serum K inhibits ANGII -stimulated release of aldosterone to prevent severe hypokalemia
      - elevated Na+ inhibits aldosterone release and activation of renin-angiotensin II by kidney
    - - Excess secretion leads to retention of Na, expansion of ECF vol, decreased K (Hypokalemia) and alkalosis
      - Deficiency leads to Na wasting, contracting of ECF vol, increase blood K+(hyperkalemia) and acidosis
      - aldosterone elevated and renin low -> primary pathology
        aldosterone elevated and renin elevated -> secondary
  - - - Physical
        
        Hypoglycemia
        
        Trauma
        
        Heavy exercise
        
        Dehydration
      - Psychological
        
        Acute anxiety
        
        Chronic anxiety
    - - hypothalamus releases Corticotropin Releasing Hormone, which stimulates pituitary to secrete a large transcript called ProOpioMelanoCortin, which is cleaved to yield ACTH and endorphin (acts within CNS as an endogenous opoid)
      - ACTH (adrenocorticotrophin) stimulates cells of zona fasiculata to take up cholesterol and synthesize and release cortisol
      - As plasma cortisol rises, -ve feeddback to inhibit further secretion of ACTH and CRH
      - Breakdown of PROMC also produces melanin stimulating hormone (MSH), causing darkening of skin
      - ADH potentiates secretion of ACTH in presence of CRH
    - - Catabolic hormones, promte mobilization of fuel stores (protein in skeletal muscle, fatty acids and glycerol from adipose tissue)
      - Amino acids and glycerol converted by liver to glycogen, which is released into blood as glucose
      - Liver convert free fatty acids to ketones
      - combined effect of cortisol on three target organs is REINFORCEMENT
      - metabolic effects
        
        Basal: increase gluconeogenesis in liver and lipolysis of fat
        
        Excess (or pharmalogical doses) increase gluconeogenesis in liver, anti-inflammatory, immuno-suppressive, degradation of muscle, bone and skin, lipolysis of peripheral fat but deposition of visceral fat
        
        inhibits GH, thyroid hormone, insulin and sex steroids on target tissues
        
        Still used against asthma and rejection of transplants or inflammation
        
        Mobilization of fuel stores, increased visceral fat and insulin resistnace
      - During stress, adrenal medulla also receive stimulation by sympathetic nervous system, releasing epinephrine
        
        inhibits insulin secretion from pancreas and moblization of triglycerides (lipolysis) from fat, thus keeping blood glucose levels high
      - Net effect of cortisol and EPI increases blood glucose, wasting of bone and muscle, loss of peripheral fats and deposition of omentum fats (neuropeptide Y upregulated, promoting growth)
      - insufficient cortisol -> increased resistance to insulin and poor capacity to generate substrate for gluconeogenesis -> hypoglycemic
      - molecular mechanism of action
        
        Diffuse across plasma membrane and bind to intracellular receptors (GR), which was maintain in an inactive state by a chaperone
        
        glucocorticoid displace chaperone and steroid-GR complex moves to the nucleus
        
        In nucleus, GR bind to glucocorticoid binding element (GRE) to control transcription, response time 60-90 mins
        
        Cortisol similar in structure to mineralcorticoid, can bind to the receptor (MR)
        under normal circumstances, specificity to mineralcorticoid is maintained through
        
        carrier CBG has higher binding affinity for cortisol, lowering free cortisol in blood
        
        Tissue sensitive to mineralcorticoids express enzyme 11,B-hydroxysteroid dehydrogenase type 2(11BHSD-2) which converts cortisol to cortisone (inactive) and cant bind to MR
        
        type 2 found in peripheral tissues
        
        type 1 coverts inactive cortisone to active cortisol in target tissues, leading to lipolysis
      - adrenal Pathophysiology
        
        Addisons disease
        
        entire adrenal gland destroyed or dysfunctional
        
        Absence/lack of mineralcorticoid and blucocortic steroids
        
        low serum Na and elevated serum K, low BP and increased skin pigmentation (no feedback from cortisol, excess ACTH)
        
        unless mineralcorticoid is administered, K levels increase markedly with daily diet intake, could lead to cardiac arrest
        
        Primary hyperaldosteronism (or Conn syndrome)
        
        Excess aldosterone due to tumor in zona glomerulosa or bilateral hyperplasia of zona glomerulosa
        
        decrease in K+ (hypokalemia), which can lead to arrhythmias and muscle weakness
        
        Water retension an dhypertension
        
        Renin should be decreased
        
        Cushing's syndrome/disease
        
        excess cortisol may be ACTH dependent (disease) or ACTH independent(syndrome, primary)
        
        Mobilize glucose, hyperglycemia not correctde by insulin secretion (insulin resistant diabetes)
        
        redistribution of fat from periphery to omentum fats
        
        tanned in areas that receive no sunlight (due to excess ACTH)
        
        thinning of skin as cortisol degrades the skin
        
        Congenital bilateral adrenal hyperplasia
        
        growth of cortex due to insufficiency of cortisol and consequent loss of -ve feedback on pituitary
        
        DHEA does not feedback
        
        congenital deficiencies occur in 17,21 or 11 hydroxylase
  - - - begins with tyrosine, taken up by chromaffin cells in medulla and converted to NorEpi or Epi, which are then stored in granules
      - Secretion is stimulated by activation of sympathetic fibers of autonomic nervous system
      - Activated by stress, including exercise, hypoglycemia and trauma
    - - bind to adrenergic receptors (a and B) on surface of target cells
      - Coupled to G proteins, which either stimulate or inhibit intracellular signalling pathways
      - involve changes in cAMP and free Ca
    - - Same effect on organs as direct stimulation by sympathetic nerves, although effect is more longer lasting
      - Can affect tissues and cells that are not innervated
      - effects
        
        Increase HR and contraction of heart muscle
        
        Vasoconstriction, increasing resistance and arterial blood pressure
        
        Dilation of bronchioles to assist pulmonary ventilation
        
        increased metabolic rate, oxygen consumption and heat production
        
        Stimulation of liplysis in adipose cells and lactate from muscle to provide additional sources of energy in fight or flight response
        
        Inhibit insulin release from pancrease to main elevated blood glucose
- - - - Increase size and function of internal organs
        
        e.g. lung, heart, kidney
      - Lengthening of bones (together with GH directly)
  - - - Amino acid
        
        Insulin: yes
        
        GH: yes
        
        Effect: increase growth of muscle (seen with anaerobic training, not with aerobic
      - Glucose
        
        Insulin: Yes
        
        GH: No (Due to glucose intake)
        
        Increase muscle glycogen (store)
      - Low glucose
        
        Insulin: No
        
        GH: yes (due to low glucose)
        
        Effect: burn fuel from fat
  - - - Gigantism
      - Overall increase in height in size as epiphyseal plate of bones are not closed yet
    - - Coarsening of facial features, widening of fingers, toes, hands, feet
      - Prominent eyebrow ridge and jaws
      - All organs increase in size
        
        Not good if it doesnt grow with axis of the body -> internal organ failure
        
        no lengthening of body due to mature epiphyseal plate
      - Give somatostatin or ablate pituitary tumor
      - IGF-1 will increase
- - - - Immediately following a meal
      - Energy of nutrient molecules is transferred to high energy compounds for either immediate use or storage
    - - When available nutrients in blood decreases, stored reserves mobilized either to perform work or generate heat
    - - Plasma glucose closely regulated at 80-100 mg/dL
  - - - when blood glucose rise >80mg/dL, glucose enters B cells via GLUT 2
      - As glc enters, phosphorylated by glucose kinase to form G6P
      - G6P metabolized (glycolysis), small increase in cytosolic ATP conc.
      - Rise inhibits ATP gated K channels, which governs membrane potential
      - When K channel close, no more K+ efflux, cell membrane depolarizes, opening voltage gated Ca2+ channels and Ca2+ enters
      - influx activates phospholipase C, leading to production of diacylglycerol (DAG) and inositol phosphate (IP3)
      - IP3 triggers Ca2+ release from ER, lead to secretion of insulin
      - secretion terminated by activation of voltage gated K+ channels
    - - Initial burst (5-10mins) of stored insulin
        
        Requires expression of insulin receptors on B cells
      - Second prolonged (30mins) phase of newly synthesized insulin
        
        Requires cell to cell contact between B cells and paracrine signalling
    - - Hyperglycemia, elevated plasma amino acids and long chain fatty acids, as well as signals from autonomic nervous system and the GIT
      - e.g. consumption instead of IV glucose results in higher secretion of insulin due to incretin effect in response to carbs within the intestinal lumen
      - short chain fatty acids inhibit insulin secretion, somatostatin and catecholamines
      - Sulfonylurea drugs close ATP gated K+ channels, increasing insulin secretion from B islet cells in a subclass of DMTII individuals
    - - Promtoes uptake of glucose from blood into cells
      - Enters all cells by GLUT 1 OR GLUT 2
      - in skeletal muscles and adipocytes, act to enhance by moving GLUT 4 to cell surface, glucose in cells kept low by rapid phosphorylation to G6P
      - Inactivation due to aggregation and endocytosis of insulin receptors, destruction in endosomes, degraded in liver and kidney
      - Promotes glycogen synthesis, inhibit glycogen degradation (improve glucose storage)
      - Stimulate lipogenesis and suppres lipolysis in adipose tissue, skeletal muscle and liver, inhibit hormone sensitive lipase resulting in accumulation of triglycerides and increase uptake of fatty acids from blood into adipose tissue and stored as triglycerides
      - stimulates amino acid transport into liver, skeletal muscle and fats, increase protein synthesis and inhibit protein degradation
    - - reduce flucose uptake into fat and muscle, excess glucose in blood and added production of glucose by liver
      - catabolism of protein, fat and glycogen and insufficient storage
      - Secretion of glucagon elevated, increasing lipolysis and gluconeogenesis
      - First consequence is protein deficiency, then overload of catabolic pathways wtih free fatty acids and triglycerides, which the liver converts to ketone bodies
      - As circulating levels of kotene rise, pH drops
      - Glucose excreted in urine
    - - Type 1 (insulin dependent diabetes mellitus, IDDM)
        
        inability of pancreatic B cells to produce insulin
        
        Must be injected with insulin daily
        
        Long term control depends on maintaining balance between 3 factors: diet, exercise and insulin
      - Non-insulin-dependent diabetes mellitus (NIDDM or type 2)
        
        Relative failure of pancreatic cell and/or by insulin resistance in muscle, fat and liver
        
        rough stages
        
        Skeletal muscle first develops insulin resistance, leading to reduced GLUT 4 activity
        
        increased secretion of insulin followin gglucose ingestion -> increased insulin levels with normal glucose
        
        progression to pre-diabetic state characterized by loss of first phase of glucose dependent insulin secretion by pancreatic B cells as well as prolonged hyperinsulinemia and hyperglycemia
        
        High circulating levels of insulin diverts liver metabolism away from glycogen synthesis to glucose and fatty acid synthesis in response to glucose ingestion -> elevated plasma fatty acids, hyperglycemia and hyperinsulinemia
        
        Dietary restriction supplemented with sulfonylurea drugs to enhance response of pancreatic B cells to glucose, with glitazone to reduce peripheral insulin resistance
        
        In obesity related NIDDM, impaired capacity to switch between fed and fasting, leading to ectopic accumulation of fat in muscle and liver, leading to down regulation of insulin receptor and impaired GLUT 4 translocation to cell surface
        
        aerobic exercise and weight loss recomended, correcting islet B cell abnormalities and increasing insulin stimulated glucose uptake in skeletal muscles
        
        In Maturity Onset Diabetes in the Young (MODY), mutations of glucokinase gene is the cause
        
        pt mutations in glucokniase gene alter sensitivity of islet B cell, requiring higher glucose levels to trigger insulin release
        
        Gestational DM, during pregnancy
      - Acute complications
        
        Ketoacidosis (metabolic) -> reduce blood vol, renal failure, coma and death
        
        Hyper glycemia lead to fluid loss and dehydration (glucose in urine, increased urine output, loss of electrolytes)-> hyperosmolar coma
        
        Corrective measuresL administration of base, fluids and insulin
      - Chronic Complications
        
        circulatory and nervous systems
        
        Deterioration of
        
        Blood flow to retina of eye, causing retinopathy and blindness
        
        BLood flow to extremities, causing need for amputation
        
        Glomerular filtration in kidneys -> renal failure
        
        Diminished sensation in extremities, impaired bladder and bowel functions
        
        C-peptide replacement along with insulin may prevent development or retard progression of chronic complications in Type I disease
  - - - rise in plasma glucose levels >80mg/dL, enters cell, metabolized and glycolysed to form ATP, close K-ATP channel, leading to depolarization of cell
      - depolarization open voltage gated Ca2+ and Na+ channel, inhibition of glucagon secretion
      - Also regulated by insulin, where its presence potentiates suppressive effects of high glc
      - depolarization of B cell and entry of Ca2+ leads to depolarization of adjacent d-cell (gap junction) and secretion of somatostatin, which acts to hyperpolarize neighbouring a cell, inhibiting glucagon secretion
      - in Type I and type II diabetes (insulin resistance), no regulation of glucagon, thus baseline elevated
      - Stress increases glucagon secretion, mediated by sympathetic system to alpha adrenergic receptors and a and B islet cells, inhibiting insulin secretion, and promoting glucagon secretion