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_______ refers to excessive discharge of urine
_______ refers to the observation made by ancient Greeks, Indians, Egyptians, Chinese and Persian physicians that the urine of diabetic patients tasted sweet
Diabetes is characterized by ___________, and is the leading cause of adult blindness, amputation, and a major cause of renal failure, nerve damage, heart attacks and strokes.
an elevated fasting blood glucose
Most cases separated into _____
type 1 and 2
Biosynthesis of insulin
- 1. transcription of insulin gene in nucleus
- 2. mRNA moves to cytosol and translating the N-terminal signal sequence on ribosome. The signal helps the complex to move on to RER.
- 3. complete translation of mRNA, preproinsulin produced
- 4. signal sequence cleaved off preproinsulin, forming proinsulin in RER lumen
- 5. proinsulin transferred to Golgi, where it is further cleaved into insulin and C-peptide.
- 6. insulin and C-peptide packed into vesicles.
- 7. insulin and C-peptide are released via exocytosis.
Time course of glucose, insulin, and glucagon before and after a carbohydrate-rich meal
- glucose and insulin are both at the lowest level before the meal, rise to the peak shortly after the meal, and then slowly fall back to the base level.
- glucagon is at high level before meal, peaked during meal, then drops to the lowest level.
- inverse relationship between insulin and glucagon
regulators for pancreatic β-cell insulin release
- Glucose (++)
- FAs, AAs (+)
- Epinephrine (-)
Insulin-mediated glucose receptor recycle
- insulin binds to membrane receptor
- binding stims a cascade of actions, resulting in the recruitment of GLUT-4 from intracellular pool to membrane
- insulin-mediated GLUT-4 increases blood glucose uptake
- when glucose level drops, GLUT-4 move away from membrane to intracellular space
- vesicles containing GLUT-4 fuse to form storage organ, endosome
intertissue relationship in type 1 diabetes
- Glucose (hyperglycemia; gluconeogenesis + decreased glucose uptake)
- ketone bodies (ketosis: adipose tissue fatty acid-> hepatic ketogenesis)
Diagnosis of type 1 diabetes
- Hb A1C > 6.5 mg/dL
- fasting blood glucose > 126 mg/dL
- when blood glucose>180mg/dL, glucose can be found in urine with loss of water
Type 2 diabetes characteristics
- resistance to insulin in tissues (low glucose take up, high gluconeogenesis)
- β-cells produce inappropriate amount of insulin
- later on β-cell failure
Development of T2D, when untreated
- Years before diagnose, obese and developing insulin resistance.
- When diagnosed, hyperglycemia and compensatory hyperinsulinemia.
- Years after, β-cell disorder, dramatic decrease in insulin production and worsening of hyperglycemia.
_______ eventually lead to T1D and T2D, respectively.
autoimmune destruction of b-cells
obese, inflammatory factors, insulin resistance
consequence of diabetes
- metabolism: hyperglycemia, ketoacidosis.
- long term complications:
- - macro-vascular
- - cardiovascular disease, stroke
- - micro-vascular
- - neuro-, retino-, and nephro-pathy
Structure of glycophorin A
- integral protein
- transmembrane part: coiled-coil dimer stabilized by Van der Waals interaction
- cytosolic part: basic AA, positive charges stabilized by intracellular negativity
lipid anchored proteins vs. peripheral proteins
- lipid anchored proteins bind to membrane lipid via covalent bonds
- peripheral proteins attach to transmembrane proteins via protein-protein interaction. no covalent bond, weaker interaction
Synthesis and positioning of type 1 transmembraneproteins in the endoplasmic reticulum
- signal sequence peptidase
- stop-transfer anchor sequence
10 essential amino acids
- phenylalanine Phe
- valine, Val
- threonine, Thr
- tryptophan, Trp
- methionine, Met
- leucine, Leu
- isoleucine, Ile
- lysine, Lys
- histidine, His
- *arginine, Arg
Ubiquitin-proteosome degradation pathway
- protein + ubiquitin + ATP -> ubiquitined-protein (UP) + AMP + PPi
- proteosome unfolds UP, de-ubiquitins it, and breaks it down to polypeptide fragments, at the cost of ATP
- polypeptides are further degraded by nonspecific proteases into AAs
Digestion of proteins -> AAs
- ↓ pepsin
- polypeptides and AAs
- ↓ trypsin/chymotrypsin/elastase/carboxypeptidase
- oligopeptides and AAs
- ↓ aminopeptidase, di-/tri-piptidases
hormonal control of digestion
CCK and secretin
both stimed by dietary lipids and proteins
- CCK stims
- gallbladder -> bile,
- pancreas -> enzymes;
- inhibits gastric motility
- secretin stims
- pancreas -> bicarbonate
___ AA transporters exist
deficiency of the transporter for _____ affect ____________, eventually causing ______. The condition is named _________.
- Cynstine, Ornithine, Arginine, Lysine (last 3 dibasic)
- the resorption of the AA, esp cystine at the proximal convoluted tubule
- cystine percipitates in acidic urine, forming stones (calculi)
Dermatitis, diarrhea, dementia, death
deficiency of niacin -> NADP+
- deficiency in tryptophan absorption
- try ->... -> NADP+
- results in pellagra
Corn based diet is low in _______ and can cause __________.
niacin and tryptophan
- ________ nitrogen balance
- protein malnutrition
- mental: lethargy, apathy, irritability
- final stages
remove of nitrogen from amino acid
amino group receiver: ______
- aminotransferase / transaminase
- α-keto acid + glutamate
liver function test
- ALT (alamine transaminase)
- AST (aspartate transaminase)
amino group transfer
Alanine->_____? aKG forming _____
oxaloacetate->______? reproducing ________
- pyruvate, donate; glutamate
- aspartate, receiver; aKG
- PLP: pyridoxal phosphate
oxidative deamination of glutamate
- allosteric modulators
- coenzyme in reverse reaction
- the reverse reaction is also an important pathway for ___________.
- glutamate-> aKG
- glutamate dehydrogenase
- NAD+ -> NADH
- ADP stim; GTP inhibits
- NADPH -> NADP+
- removing NH3 when urea production can't deplete NH3 in time
D-serine is present in the diet and is also made in ____ by serine racemase from ______.
D-serine modulates ______ receptors, and plays roles in synaptic plasticity, development, and is involved in aging, neruodegeneration, and schizophrenia. N-methyl-D-aspartate (NMDA)-type glutamate
D-amino acid oxidase (DAO) is a ___-dependent peroxisomal enzyme that catalyzes the ___________’s producing ________.
- oxidative deamination of D-AA
- a-keto acids, ammonia, and hydrogen peroxide
Increased DAO activity has been linked to increased susceptibility to _______.
Two NH3 transport mechanisms
- Free NH3 + glutamate -> glutamine; E: glutamine synthetase; ATP required.
- Glutamine-> blood->liver->glutamate + Free NH3; E: glutaminase
- NH3-> -> urea
- Free NH3 + aKG -> glutamate; E: glutamate dehydrogenase
- glutamate + pyruvate -> aKG + alanine; E: ALT; pyruvate comes from glycolysis and metabolism of AAs w/ branched side-chain
- alanine->blood->liver->pyruvate while aKG->glutamate w/ALT
- glutamate->aKG+NH3; E: glutamate dehydrogenase
- pyruvate->->glucose->blood->peripheral tissue such as muscle
Summary of Two NH3 transport mechanisms
glutamine carries nitrogen from tissue to liver, then gives up NH3 directly
alanine carries nitrogen from tissue to liver, alanine-glucose cycle involved, nitrogen is transferred to gKG->glutamate, from which NH3 is released.
- 1. HCO3-, NH3, ATP -> carbamoyl phosphate (C1N1); E: CPSynthetase I
- 2. ornithine+CP (C1N1)->citrulline (C1N1)+Pi
- citrulline: mitochondria->cytosol
- 3. oxaloacetate + glutamate -> aspartate(N) + aKG
- 4. citrulline(CN)+aspartate+ATP -> arginosuccinate (CN2)
- 5. arginosuccinate(CN2)->fumarate + arginine (CN2)
- 6. arginine+H2O->ornithine+CO(NH2)2
- ornithine: cytosol->mitochondria
Patients with urea cycle defects have excessively high level of ammonia, which is fatal. The condition can be treated with _______.
- phenylbutyrate -> phenylacetate
- phenyacetate binds with glutamine, the common NH3 carrier, and the product is excreted via urine
Carbon side chains of AAs can be utilized in _______ pathways.
- ketogenic: Leu, Lys
- glucogenic and ketogenic: Tyr, Phe, Try, Ile
- glucogenic: all the others
Seven intermediates generated in AA carbon side chain catabolism
- acetyl CoA
- succinyl CoA
Asn /Asp metabolism
what is used in treating leukemia? Why
- Asn - asparaginase -> Asp - AST -> oxaloacetate
- asparaginase, breaks down any systemically generated Asn, so there is no Asn supply in leukemia cell, which will be starved to death.
synthesis of catecholamines from tyrosine
what inhibits their uptake by the brain?
tyrosine - hydroxylase + BH4 - - decarboxylase -> dopamine - hydroxylase -> norepinephrine - methyltransferase -> epinephrine
metabolism of catecholamines involve: __
first generation antidepressant works by ___
- COMT and MAO
- inhibiting MAO
Serotonin synthesis and Prozac
tryptophan - BH4 and hydroxylase -> 5-OH tryptophan - decarboxylase -> serotonin
prozac inhibits the reuptake of serotonin, thus prolongs its action
- name comes from
- phenylketonuria or hyperphenylalanemia
- deficiency in the pathway of converting Phe to Tyr, which leads to Phe accumulation and entering alternate pathway, forming phenylpyruvate, phenylacetate, phenyllactate, high level in urine
- Reduction in tyrosine production reduce melanin formation -> depigmentation (hypopigmentation). Also has CNS symptoms.
- treatment: Phe free diet
Any deficiency in the enzymes involved in forming ____ or the reductase which convert ___ to ___ will lead to hyperphenylalanemia and ______ and _____ deficiency.
- BH4 (TetraHydroBiopterin)
- BH2 -> BH4
Maple syrup urine disease (MSUD)
- deficiency in the dehydrogenase (oxidatively decarboxylation) for the α-keto acid, the intermediate of branched chain
- AAs' (Leu, ILe, Val) metablism, results in blood and urine accumulation of these AAs and the α-keto acids, and a maple syrup odor in the urine (Ilu).
- Symptoms: feeding, muscle tone, CNS (Leu, a-Kic acid), can be fatal, treatment can be too late
- Treatment: limit the amount of branched chain AA
- deficiency in a copper-requiring tyrosinase
- depigmentation in skin, hair, eyes; lightphobic; skin susceptible to sun burn and skin cancer; impaired vision
- treatment: avoid UV exposure
- defects in homocystine (Hcy) metabolism
- symptoms: high blood and urinary level of Hcy and Met. lens dislocation, long limb and fingers, intellectual disability, risk of developing blood clots.
- treatments: limit Met in diet and supplement B6, B12, folate.
- deficiency in homogentistic acid oxidase, causing accumulation of HA (homogentistic acid), an intermediate of tyrosine degrading.
- symptoms: urine exposed in air oxidized to black; deposition of black pigment in cartilages and collagenous tissue; major joint arthritis
- treatment: diet with low Phe and Tyr.
the Ca/NO pathway for smooth muscle relaxation
- ACh binds to ACh GPCR->PLC->IP3->Ca-Camodulin->NO synthesis->NO release
- NO -> NO receptor, stims GTP-> cGMP + PPi, cGMP activates PKG -> -> stims smooth muscle relaxation
secretion of insulin in response to increase blood glucose level
- glucose enters cell via GLUT2
- glucose--glycolysis -->pyruvate + ATP
- ATP sensitive K chan closes
- cell depolarizes
- voltage-sensitive Ca chan open
- influx of Ca induce fusion of insulin-containing vesicle to cell membrane and release of insulin
signal transduction following insulin binding to its receptor
- insulin->insulin receptor
- activates the intracellular β-domain which has tyrosin kinase function
- tyrosin kinase auto-phosphorylate and becomes activated
- activated tyrosin kinase phosphorylates other tyrosine-protein (eg insulin receptor substrate, IRS)
- activated target protein further activates other pathways, cause
- increase in
- glucose uptake
- glycogen synthesis
- lipid synthesis
- protein synthesis
- and decrease in
- IP3 --IP3 kinase--> PIP2
- inactive PKB (Akt) binds to PIP2, becomes partially active
- PIP2 also binds to PDK1
- activated PDK1 and PDK2 together activate partially activated PKB to fully activated
adipose cell in response to insulin binding
insulin binds to ->insulin receptor activates -> IRS stims -> PI3K -> PIP2 -> PDK -> AKT -> phosphorylates AS160 ->AS160-P promotes -> RabGTP -> receptor containing endosomes fuse with membrane
effect of insulin and glucagon on glycolysis
- insulin stims / glucagon inhibits
- pyruvate kinase
regulation of glucagon release from pancreatic α cells
- epinephrine and AAs stim
- glucose and insulin inhibit
Action of glucagon
- glucagon->receptor->adenyl cyclase->cAMP-> PKA c unit -> phosphorylate various enzymes -> ->
- FA oxidation
- uptake of AA
- inhibit glycogenesis
hormonal regulation of adipose cells' degradation of lipids
epinephrine ->-> cAMP -> PKA -> active hormone-sensitive lipase -> diacylglycerol -> monoacylglycerol + FA
compensatory mechanisms in response to hypoglycemia
- gluconeogenesis: cortisol = glucagon
- glycogenolysis: (nor)epinephrine > glucagon