Pathophys Exam 2

L9 - liver

macrostructure of liver

• liver is the largest visceral organ in the body

  • high capacity for regeneration

• right lobe is the largest lobe

• 75% - 85% of blood supply is from the portal vein

liver metabolic functions

• carb metabolism

  • gluconeogenesis

  • glycogenolysis and glycogenesis

• synthesis of fatty acids, lipoproteins, cholesterol

• ketogenesis (breakdown of fatty acids to ketones)

• protein metabolism

• synthesis of plasma proteins (albumin, globulin, fibrinogen)

• urea synthesis (ammonia to urea)

• hormone metabolism

• RBC production (in fetal livers during the first trimester of pregnancy)

liver storage functions

• glycogen (broken down into glucose for E)

• vitamins

  • A, D, E, K (lipid soluble)

  • B12 (water soluble)

• iron

• copper

liver excretory/secretory functions

• bile

  • water

  • cholesterol

  • bile pigments (bilirubin and biliverdin)

  • anions of the bile acids

  • phospholipids (mainly lecithin)

  • bicarbonate and other ions

• insulin-like growth factor 1 (IGF-1)

• most blood proteins

• cholesterol, fatty acids

liver protective functions

• purification, transformation, and clearance

  • endogenous (hormones, ammonia)

  • exogenous drugs and chemicals

• Kupffer cells (residential macrophages)

  • bacteria and other foreign materials form the (portal) blood

liver circulatory functions

• antechamber of the heart

  • collecting portal blood from the GI tract

liver coagulation functions

• production of coagulation factors

  • fibrinogen I

  • prothrombin II

  • factors (V, VII, IX, X, XI)

  • protein C

  • protein S

  • antithrombin

transaminases

• from damaged/dead hepatocytes

• aspartate aminotransferase (AST or SGOT)

• alanine aminotransferase (ALT or SGPT)

cholestatic enzyme

• from injured biliary epithelial cells

• alkaline phosphotase (ALP)

• gamma-glutamyl transferase (GGT)

hepatic lobule

• portal triad

  • portal vein → brings deoxy blood + waste products from body into liver

  • hepatic artery → brings oxy blood from heart

  • bile duct → takes bile and waste products to intestine

• kupffer cells → resident macrophages; 20-25% of liver cells

• sinusoid → blood vessel where blood flows from portal vein to central vein

• endothelial cells → line sinusoid

• central vein → clean blood going to heart to get reoxygenated via interlobular vein to hepatic vein

• hepatocyte → 70% of cells; make bile components

• cholangiocyte → modifies bile

• stellate cells → store vit A

• bile canaliculi → lumen where bile is secreted

acute hepatitis

• cholestasis - cells filled w pigment

• fatty change/deposits - from hepatitis C

• contains any immune cells besides Kupffer cells

chronic hepatitis

• FIBROSIS

• bridging necrosis to many central veins

• fatty change - hepatitis C

viral hepatitis - HAV & HEV

• HAV & HEV → direct disruption of hepatocytes

  • acute

viral hepatitis - HBV & HCV

• HBV & HCV → immuno-attack of hepatocytes

  • HCV - 75% asymptomatic

• HBV - prevalence is lower due to vaccine administration

• HCV - treated w direct-acting antiviral meds, which are oral drugs that cure the virus in most ppl within 8-12 weeks

  • pibrentasvir (Mavyret)

  • velpatasvir (Epclusa)

  • ledipasvir (Harvoni)

drug-induced liver injury

• high incidence

• 10% adverse drug reactions

• 2 types

  • hepatocellular (tylenol) - hepatocyte death

  • cholestatic (methyl testosterone) - cholangiocyte injury

• most common drugs

  • augmentin

  • diclofenac

  • azathiopurin

  • infliximab

  • nitrofurantoin

• bile plug and feathering changes

• central lobular necrosis

chronic liver injury; -hepatitis, fibrosis, cirrhosis, HCC etiology

• hepatitis (most to least common)

  • obesity

  • alcohol

  • drugs

  • viral

  • autoimmune

• less critical etiologies

  • iron overload

  • copper overload → Wilson’s disease (hepatolenticular degeneration)

  • alpha1-antitrypsin deficiency

  • autoimmune-biliary

    • PSC - progressing sclerosing cholangitis

    • PBC - progressing biliary cholangitis

global MASLD/NAFLD prevalence

• MASLD: metabolic dysfunction-associated steatotic liver damage

• NAFLD: non-alcoholic fatty liver damage

quite common in US

MASH

metabolic dysfunction associated steatohepatitis

NASH

non-alcoholic steatohepatitis

ASH

alcoholic steatohepatitis

North american incidence of MASLD, MASH ± fibrosis

• MASLD (by ultrasonography) - 25.2%

• MASH among MASLD patients - 21%

• MASH patients who experience fibrosis (global) - 41%

North american incidence of MASLD - NAFLD and NASH ± fibrosis

• N American prevalence of NASH + fibrosis - 2.1%

• # of individuals in US with or will have NASH + fibrosis → 7,078,411

epidemiology

• fatty liver diseases - most common cause of abnormal liver enzyme tests

• liver steatosis affects 30-40% pop. in developed countries

  • fibrosis, cirrhosis, hepatocellular carcinoma % of children (35-50% of obese children)

• affects 2-3% of children (35-50% of obese children)

ASH and MASH/NASH

• histologic features - NASH

  • steatosis

  • lobular inflammation

  • hepatocyte ballooning

• risk factors

  • female

  • obesity

  • dietary factors

  • polymorphisms

  • drinking pattern

  • smoking

• comorbidity

  • viral hepatitis

  • hemochromatosis

  • HIV

characteristics

• macrovesicular steatosis + inflammation

• infiltration of both lymphocytes and Kupffer cells

• ballooned hepatocytes that also contain Mallory-Denk bodies

• perivenular/pericellular (“chicken wire”) fibrosis

NAFLD spectrum

• fatty liver

  • fat accumulates in liver

• NASH

  • fat plus inflammation and scarring

• cirrhosis

  • scar tissue replaces liver cells

liver lipid homeostasis

HUHHH

molecular mechanism of MASH/NASH

two-hit (multi-hit) theory

• first hit → fat accumulation in the liver

  • obesity

  • long-term fasting

• additional/parallel hit → injury leads to inflammation

  • drugs

  • pathogens

  • leaky gut (LPS)

  • genetic abnormalities (PTEN, FXR, or other deficiency)

  • oxidative stress

ASH pathophysiology

• hepatic fat storage

• inflammation → inc hepatic uptake of gut-derived endotoxins triggering Kupffer cell activation and release of proinflammatory factors

• oxidation → induction of cytochrome P4502E1 producing toxic acetaldehyde and ROS

• ER stress → ethanol-mediated ER stress, protein mis-folding

alcohol inc hepatic lipid contents

ALD - inflammation mechanism

• activation of innate immunity

• inc pro-inflammatory cytokine production in all cells in the liver

• inc adaptive immunity

liver fibrosis

• persistent HSC activation → lots of connective tissue → collagen

• fibrosis potentially irreversible

• dec hepatic blood flow

• numerous sequelae

• no therapeutic agents

• req liver transplantation

cirrhosis induced by MASH/NASH

NASH histologic features may no longer exist - “burnt out NASH”; the characteristic perivenular/pericellular fibrosis may still be present

HBV pathology

• nodules of damaged and regenerating hepatocytes

• fibrous bands w chronic inflammatory cell infiltrates (dark purple dots)

• micronodular (<3 mm) vs macronodular (>3 mm) cirrhosis

• leads to hepatocellular carcinoma (HCC)

• ground-glass cytoplasm (light colored surface Ag particles)

• bile pigment accumulation (dark brown)

Hepatitis B viruses

DNA virus structure

• HBsAg - surface antigen

  • most abundant antigens, detectable at onset of clinical symptoms

• HBcAg - core antigen

  • marker of viral replication

• HBeAg - antigen between nucleocapsid and lipid envelope

  • marker of viral replication

• anti-HBc IgM

  • acute infection or disease flare

• anti-HBc IgG

  • chronic infection

phases of chronic HBV infection

• proliferative phase

  • more HBeAG

  • virus proliferates

  • peak in HBV DNA causes peak in ALT → signals liver damage

• dormant phase

  • ??? dont know why

  • more anti-HBe → no replication

  • lays dormant in DNA

• reactivation causes

  • mAb therapy

  • organ transplant

  • HIV co-infection

  • treatment resistance

  • stopping treatment

hepatitis C virus

RNA virus structure

• positive-sense

• single-stranded RNA virus from Flavivirdae family

  • each viral particle contains a single RNA strand

• does not have its own proteins

HCV pathophysiology

• HCV life cycle tightly linked to hepatocyte lipid metabolism

  • HCV assembly/release connected to fatty acid pathways and biogenesis of VLDL

• spontaneous resolution of acute infection in 15-45% ppl

• chronic infection if not treated//clinically undetected

  • predominantly immune response mediated injury

  • direct viral cytotoxic effect uncertain

innate immune system response to HCV infection

type I or type III interferon driven response

• interferon stimulated genes and NK cells partially control viral replication but does not eliminate infection

adaptive immune system response to HCV infection

• neutralizing antibodies target hypervariable envelope glycoproteins E1 and E2

  • short lived and nonpersistent in chronic infection

• HCV specific CD8+ T lymphocytes mediate viral clearance thru cytolytic and noncytolytic functions

• primed by HCV specific CD4+ T lymphocytes

• vigorous, sustained cytotoxic T lymphocyte response needed for resolution of acute infection and permanent clearance

chronic Hep C infection

• cord of liver parenchyma w a patchy distribution of chronic inflammation - lymphoid aggregates

• prominent chronic inflammatory infiltrate of the portal tracts and the periportal region

  • comprised of lymphocytes w occasional plasma cells

• interface hepatitis

• scattered acidophil bodies - Councilman bodies

• sinusoidal pattern of lymphocytic infiltrate

• mild degree of steatosis

gall bladder ductal system

diseases of gall bladder

• cholelithiasis (gallstone)

• carcinoma of the bile duct

• carcinoma of the gall bladder

• biliary obstruction

cholelithiasis (gallstone)

• gallstones can result from

  • excess of cholesterol

  • deficit of bile salts

• cholesterol stones may form if

  • imbalance between ratio of cholesterol and bile salts

  • form micelles which have hydrophilic exterior enclosing and hydrophobic cholesterol

risk factors for gallstone disease

• female

• forties

• fat

• fertile

• FXR mutation?

liver tumors - benign

• liver cell adenoma

• angioma

• bile duct hamartoma

• focal nodular hyperplasia

liver tumors - malignant

primary

• hepatocellular carcinoma (HCC)

• cholangiocarcinoma (adenocarcinoma of bile ducts)

• angiosarcoma (malignant neoplasm of vascular endothelium)

• hepatoblastoma (primary liver tumor in childhood)

secondary

• metastases from the GI, lung, and breast cancers

• colon cancers metastasize to liver

• highly common in east Asia and central/south Africa

hepatocellular carcinoma mechanism

heterogenic → many diff pathways result in HCC

• well differentiated

  • tumor cells resemble hepatocytes

  • form trabeculae, cords and nests

  • may contain bile pigment in cytoplasm

• poorly differentiated

  • malignant epithelial cells are discohesive

  • pleomorphic

  • anaplastic

  • giant

NAFLD → HCC progression

fatty liver → NASH → Cirrhosis → HCC

• abt 25% of patients never develop cirrhosis

cholangiocarcinoma

malignant tumors in the bile duct

L10 - GI

GI functions

• ingest and prepare food for digestion

• mechanical and chemical digestion

• regulated absorption of nutrients

• metabolism of endogenous and exogenous chemicals

• immune surveillance

• regulated secretion of hormones, enzymes, lubricants, and water

• microbiome functions

• propulsion of waste

• regulated defecation

regions of GI

• upper GI tract

  • mouth - mechanical & chemical digestion

  • esophagus

  • stomach

• middle GI tract (small bowel)

  • duodenum - 9'“

  • jejunum - 2.5 m

  • ileum - 3 m

• lower GI tract (large bowel)

  • cecum

  • colon

    • ascending

    • transverse

    • descending

  • rectum

• sphincters between segments

• accessory structures

  • salivary glands - release amylase

  • liver

  • pancrease

  • gall bladder - can live without it

sphincters of the GI

small bands of smooth muscle that constrict and dilate; most under involuntary control

• upper esophageal sphincter (pharyngoesophageal)

  • moves food down esophagus

• lower esophageal sphincter (gastroesophageal)

  • regulates food entry into stomach

• pyloric sphincter (gastroduodenal)

  • regulates food going from stomach to small intestine (duodenum)

• ileocecal valve/sphincter

  • ileum to cecum

• internal anal sphincter

• external anal sphincter

  • can be controlled to a certain point

gross anatomy of the GI tract

stomach

has extramuscular layer to aid in lots of mechanical digestion

• first place of protein digestion

• acidity helps denature

layers of the GI tract

for protection of tissues

• serosa

• longitudinal muscle

• myenteric (Auerbach’s) nerve plexus

• circular muscle

• submucosa

• submucosal (Meissner’s) nerve plexus

• muscularis mucosae

• mucosa

• epithelial lining

GI cross section

muscles move food up & down, side to side, twisty

• enteric nervous system “second brain of body”

  • myenteric nerve plexus

  • meissner’s nerve plexus

  • submucosal gland

• muscles - prevent food from going backward; keep propelling bolus forward

  • longitudinal muscle - accordion; pinches and helps move by shortening & lengthening

  • circular muscle - rings; regulates diameter of lumen

enteric nervous system (ENS)

connects gut to brain via vagus nerve

• location - gut wall from esophagus to anus

• composition - cell bodies, axons, dendrites, nerve endings

• innervation - gut cells, sensory nerves, other neurons

• integration - can occur entirely within ENS; can function independent of ANS

• transmitters - many excitatory and inhibitory

intrinsic control

ENS

• myenteric (Auerbach’s) plexus

  • muscle

  • coordination of smooth muscle

• submucosal (Meissner’s) plexus

  • regulates secretion and in turn absorption

extrinsic control

autonomic NS

• in gut specifically; kinda opposite in rest of body

  • parasympathetic - mainly stimulates (ACh)

  • sympathetic - mainly inhibits (NE)

gastric mucosal barrier

protects the stomach from low pH

• affect gut microbiome and happiness of gut bacteria

• goblet cells → make mucus

• NO and prostaglandins → control blood flow to stomach and help protect lining

• sensory nerves → help chyme move around via peristalsis

basic major diseases of GI tract

• constipation

• diarrhea

• gastroesophageal reflux disease

• nausea and vomiting

  • acute viral gastroenteritis

  • overindulgence

  • motion sickness

constipation

infrequent passage of hard stools

causes

• git (gastrointestinal tract) disorders

  • lack of dietary fiber and/or fluid intake

    • fiber → OTC (osmotic-based and stimulant based laxatives) and fruits and veggies (beans)

  • lack of motility

  • structural → carcinoma colon, diverticular disease

• non git disorders

  • drugs: opioides, anticholinergics, aluminium salts

  • neurological: MS, Parkinsonism

  • metabolic/endocrine: DM, hypothyroidism

diarrhea

passage of loose or watery stools; greater 200 grams per day

• causes deaths of children mostly in areas of poor water quality

• common symptoms of many intestinal diseases including those due to infection, inflammation, ischemia, malabsorption, and nutritional deficiency

4 major categories of diarrhea

• secretory diarrhea

  • isotonic stool and persists during fasting

  • problems w intestinal wall due to inc contractions

• osmotic diarrhea

  • occurring w lactase deficiency

  • due to osmotic force exerted by unabsorbed luminal solutes

  • diarrheal fluid is at least 50 mOsm more conc than plasma

  • condition resolves with fasting

• malabsorptive diarrhea

  • inadequate nutrient absorption is associated w steatorrhea (stinky stool cuz it pulls fat) and relieved by fasting

• exudative diarrhea

  • due to inflammatory disease

  • characterized by purulent, bloody stools that continue during fasting

GERD (gastroesophageal reflux disease)

when acid comes up the relaxed lower esophageal sphincter

• lower esophageal sphincter

  • dec esophageal clearance of acid - lying flat, alcohol, coffee

  • impaired mucosal defense - can erode lining of esophagus

  • impaired LES

    • transient LES relaxaations

    • hypotensive LES

    • hiatus hernia - upper part of stomach goes above diaphragm

• stomach

  • inc acid output - smoking, coffee

  • H. pylori - protective effect

  • inc intragastric pressure - obesity, lying flat

  • dec gastric emptying - fat

  • inc bile reflux

meds for GERD

• antacids → neutralizes acids as it comes down; ex: Tums

• histamine blocker → 50% effective

• PPI → very effective; inhibits H+ pumps

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nausea and vomiting

higher centers:

• hypothalamus

• cerebellum

• labyrinth

• area postrema

vomiting center causes

• closure of epiglottis - closes trachea & stops respiration

• LES relaxation - releases acidity

• somatomotor signals → inc abdominal P → wrenching of stomach; stomach squeeze; antiperistalsis

medications for nausea and vomiting

neurokinin1 antagonist

ex: serotonin, histamine, anti-emetics

complex major diseases of the GI tract

• gastritis

• inflammatory bowel disease (Crohn disease, ulcerative colitis)

• irritable bowel syndrome

• nausea & vomiting → complex; postoperative, chemotherapy-induced

• peptic ulcer disease - including stress-related mucosal injury, GI bleeding

clinical manifestations of gastric disease

• pain and dyspepsia

• loss of appetite

• bloating and distension

• bleeding/vomiting

  • slow → black ‘coffee grounds’ vomit

  • rapid → bright red blood

• ‘mass’ effect mimicking satiety

• outlet obstruction (pyloric stenosis) w profuse vomiting

  • hypokalemic alkalosis

  • change in pH

chemotherapy-induced emesis

chemotherapy → stimulates enterochromaffin cells of GI tract which release serotonin → attach to 5HT3 receptors and stimulate chemoreceptor trigger zone → stimulates vomiting center → controls vomiting

chemoreceptor trigger zone

• 5HT3 receptors

• NK1 receptors

• dopamine receptors

vomiting center

• 5HT3 receptors

• NK1 receptors

• dopamine receptors

gastric inflammations

• gastritis (acute and chronic)

• associated w enhanced gastric secretion and/or impaired gastric defenses

  • alcohol, smoking, infections (Helicobacter pylori, Herpes, Salmonella), corticosteroids, NSAIDs, stress, CNS trauma, shock, serious illnesses

• chronic gastritis associated w anemia; common in elderly patients

  • H. pylori is most common cause

  • 90% of patients w chronic gastritis are infected

  • autoimmunity

  • anemia → stomach produces factors for vit B absoprtion; B vit-linked anemia

  • degradation of wall which may cause bleeding

H. pylori

produces urease, inc ammonia production; basis of urea breath test

• toxic to mucosal cells

• hides in mucous layer

• diagnosed thru biopsy

• stimulates gastric emptying - overwhelming bicarbonate buffering

mechanisms of gastritis

healthy

• damaging forces

  • gastric acidity

  • peptic enzymes

• defensive forces

  • surface mucus secretion by goblet cells

  • bicarb secretion into mucus

  • mucosal blood flow

  • apical surface membrane transport

  • epithelial regenerative capacity

  • prostaglandin synthesis

injury

• H. pylori infection

• NSAIDs

• aspirin

• tobacco

• alcohol

• gastric hyperacidity

• duodenal-gastric reflux

• delayed gastric emptying

• ischemia

• shock

ulcer

• accumulation of dead tissue

• hole in stomach

• fibrosis

• acute inflammatory cells

peptic ulcer disease

occurs anywhere mucosa is exposed to acid gastric juice

• often chronic, frequently reccurent

• most common site → duodenum

• extremely common

• duodenal ulcers most common age 20-40

• most common in patients w blood type O

• resemble carcinomas

signs/symptoms

• burning or gnawing epigastric pain w transient reduction of pain upon eating, bleeding, belching

• pain worse 1-3 hrs after eating

• at night

• infection w H. pylori

• genetic factors can contribute

clinical manifestations of intestinal disease

• malabsorption

• obstruction/constipation

• ‘paralytic’ bowel

• ischemia

• perforation

• hemorrhage → tears and bleeds

• diarrhea-rapid movement, often high volume, extremely dangerous in young and old

• dysentery-blood and mucous

• steatorrhea

IBS - inflammatory bowel syndrome

• very varied

• brain-gut dysregulation

• altered motility

causes

• neuronal plasticity

• altered endocrine metabolism (serotonin)

• transient infection

• altered GI microbiome

• genetic polymorphisms

• inc mucosal permeability

• bile acid malabsorption

• altered mucosal immune function

• food hypersensitivity

IBD - inflammatory bowel disease

• idiopathic colitis

• crohn disease

  • common in female teens

• ulcerative colitis

  • common in female teens

• GI issues are common among GLP-1 users

• IBDs are usually idiopathic w multi-factorial origins

• arise from mucosal immune activation and interaction between gut microbiome

• both Crohn and UC

  • more common in females

  • often presenting in teens and 20s

  • inc long-term risk of Ca??

hygiene hypothesis for IBD

• 70% of lymphoid tissue is in GI → GALT

• tm hygiene is skipping away normal bacteria needed to keep our immune system well

  • inc risk for more disease

Crohns disease

autoimmune related disease; US has highest IBDs per capita; lesions may occur anywhere (mouth to anus), but most common in terminal ileum

• F > M; rare in young children; common in whites

• etiology → unknown; can be triggered by stress

• clinical signs → highly variable

  • acute → pain, diarrhea, fever

  • chronic → relapse and remission, weight loss, obstruction, malabsorption

  • anatomic → full thickness inflammation, ‘skip’ lesions, luminal narrowing (‘lead-pipe’ bowel, string-sign on X-ray)

• multiple surgeries req leading to ‘short bowel syndrome’

• suppression of inflammatory response used but has side-effects, particularly activation of Herpes virus

Ulcerative Colitis

inflammation of mucosa in the rectum and moving up the large intestine

• most common in F>M, 20-30 years, US and Western Europe

• etiology → unknown; episodes may be precipitated by psychological stress

• ‘sloughing’ of contiguous sheets of mucosa w bleeding

• clinical presentation → pain, bloody diarrhea, pain and fever, exacerbations, remissions

• inc risk of aggressive rectal adenocarcinoma after 8-10 years of disease

antacids

• neutralizes gastric acids, inc serum bicarbonate (raises pH), or binds to intestinal phosphates

• raises pH in GI tract by either inc HCO3 from kidneys or dec/neutralizing HCl acid released by stomach

• ex: Al(OH)3, CaCO3, tums, sodium bicarbonate

PPI (proton pump inhibitors)

• inhibits gastric acid production and secretion at the level of parietal cells in the stomach

• reduces acid secretion in the stomach therefore helps ulcers heal and prevents further gastric ulcer formation

• ex: omeprazole, pantoprazole

antisecretory agent prostaglanding E analog

• inhibits gastric acid secretion and protects gastric mucosa

• eliminates gastric acid and protects mucosa from damage

• ex: misoprostol

gastric mucosal protectant

• adhered to site of ulcerations in order to prevent further breakdown

• helps to heal and protect gastric mucosa by adhering to surface

• ex: sucralfate

histamine blockers (H2)

• selectively antagonizes histamine H2 receptors to block gastric acid secretions

• reduces gastric acids by blocking histamine receptors (histamine is normally released to block unwanted invaders, and inc acidity)

• ex: ranitidine, famotidine

aminosalicylates

• reduces prostaglandin synthesis to reduce inflammation

• helps reduce inflammation in teh GI tract and elsewhere, thereby helping prevent flare-ups in diseases such as Crohn’s and UC

• ex: sulfasalazine, mesalamine, olsalazine

emetics

• stimulates the CNS to induce vomiting

• induces vomiting for therapeutic benefit

• ex: sorbitol, ipecac

L11 - diabetes

discovery of pancreatic diseases

Oskar Minkowski

• found that pancreas is impt for glucose regulation

• took pancreas out of dog and within 15 hrs it died of hyperglycemia

timeline of diabetes

• 1921 - discovery of insulin

• 1922 - first person treated w insulin - not recombinant & derived from dogs or cattle

• 1936 - type 1 and type 2 diabetes

• 1969 - structure of insulin found

• 1974 - monogenic forms of diabetes - immune-modulated

• 1982 - recombinant human insulin - more available for patients

• 1992-2018 - better understanding of diabetes thru genes

normal vs defective beta cells

T2DM - have insulin that is defective

• dec islet number of beta-cell mass

islet of langerhans

reduced beta cell number

• naturally smaller beta cell mass

• defective beta cell proliferation

• beta cell death

dysfunction

• ER stress

• oxidative stress

• no insulin secretion → hyperglycemia

compromised identity

• dedifferentiation (Ngn3+) - abnormal proportions

• loss of identity

• transdifferentiation

beta cells

• in islet of Langerhans

• secrete insulin

alpha cells

• in islet of Langerhans

• secrete glucagon

insulin structure

• synthesized by INS gene in beta cells of islets of Langerhans

• insulin and c-peptide (connecting peptide) are connected at 2 sites via dipeptide links (green dashes in pic)

• half-life of abt 5 mins

• 1:1 ratio of breaking

  • 1 - insulin

  • 1 - c-peptide

  • can be used to measure both

  • tm insulin → insulin poisoning

insulin release

1. glucose enters cell via GLUT2 - passive movement of glucose

2. glucose is oxidized to generate ATP via mitochondrial oxidative phosphorylation

3. ATP inhibits the KATP channel which leads to membrane depolarization

4. membrane depolarization causes opening of Ca channels

5. Ca triggers the fusion of insulin-containing secretory vesicles w plasma membrane and release of insulin to circulation

insulin functions

• transport glucose and amino acids

• glycogen formation in liver and skeletal muscle

• glucose transformation to triglycerides

• nucleic acid syntheis

• protein synthesis

• dec degradation of glycogen, lipid, and protein

• major anabolic hormone