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68 Cards in this Set
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By action of hormone-sensitive lipase
triglycerides are broken into |
glycerol (G) and free FFA a process called lipolysis
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FFA move into the blood stream where they are bound by
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serum albumin. At target tissues, FFA enters beta-oxidation which is catalyzed by enzymes located in the mitochondria.
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Beta oxidation process
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two-carbon molecules acetyl-CoA are repeatedly cleaved from the fatty acid. Ac-CoA can then enter the citric acid cycle (TCA), which produces NADH and FADH2 used to produce ATP via oxidative phosphorylation (Ox Phosph). FFA can be produced from Ac-CoA and then FFAs are esterified to TG.
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Carbohydates are storage in the form of
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Glycogen. Glycogenesis is the process of glycogen synthesis, in which glucose molecules are added to chains of glycogen. In contrast, glycogenolysis is the conversion of glycogen to glucose monomers.
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In the cell, glucose enters glycolysis that converts glucose into
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pyruvate (10 reactions).
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The liver is
the major site of |
gluconeogenesis although during liver failure, the kidney can produce glucose.
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AcCoA may then be used in TCA cycle and coupled with Oxidatice Phosphilation. Pyruvate from glucose or amino acids
can be used to make sugars before it is converted to AcCoA, but PDC reaction is irreversible. This means |
that AcCoA, FFA, ketone and some Aac cannot be used to produce glucose.
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Ketone bodies are 4-carbon molecules (acetoacetate and beta-hydroxybutirate). Ketone bodies do not
exist in significant levels in the diet. Rather, ketone are synthesized by |
he liver from AcCoA and exported to the blood stream. Extrahepatic tissues convert ketone back into AcCoA and this can enter the TCA cycle and produce energy.
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During starvation, however, the brain can derive energy from
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ketone bodies which are converted to AcCoA.
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Transport of glucose across membranes is facilitated by specific transporters, called
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GLUT. GLUT facilitates
the diffusion of glucose this means that this transport is energy-independent. |
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Many mammalian tissues, such as the brain, have a constitutively high glucose requirement and have been
endowed with transporters that are constitutively targeted to the cell surface (for example, GLUTs 1–3). By contrast, certain tissues, such as muscle and adipose tissue, have acquired a highly specialized glucose- transport system, the activity of which can be rapidly upregulated to allow these tissues to increase their rate of glucose transport by 10–40-fold within minutes of exposure to a particular stimulus. This system is crucial during |
exercise, when the metabolic demands of skeletal muscle can increase more than 100-fold, and during the absorptive period (after a meal), to facilitate the rapid insulin-dependent storage of glucose in muscle and adipose tissue, so preventing large fluctuations in blood glucose levels. Dysfunctional glucose uptake into muscle and fat cells contributes to the onset of type II diabetes.
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the endocrine portion of the pancreas
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The islets of Langerhans
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β-Cells produce
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Insulin (predominate in the center of the islet in mouse not in humans)
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α-Cells produce
δ-Cells produce |
-Glucagon (predominate in the periphery in mouse not in humans)
-Somatostatin (predominate in the periphery in mouse not in humans) Somatostatin also known as growth hormone inhibiting factor. |
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n the islet, somatostatin inhibits
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both glucagon and insulin secretion.
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Insulin is synthesized on
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he microsomal membrane as a single chain called preproinsulin, which consists of a leading sequence, B-chain, C-chain and A-chain.
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Insulin: Formed in
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the Golgi apparatus where the C chain is removed. Granules containing insulin and the C- chain and some proinsulin move via microtubules to the β-cells membrane and are released by exocytosis.
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does insulin circulate bound or unbound?
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unbodun
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The main stimulus for insulin secretion from the β-cells is
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high levels of glucose in circulation.
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Glucose enters the pancreatic -cell by
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simple diffusion, facilitated by GLUT-2. GLUT2 activity is not affected by
insulin. |
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Glucose stimulation of insulin secretion involves
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the depolarization of the β-cell, generation of a membrane
potential, Ca++ influx and exocytosis. |
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How glucose levels are transduced into a membrane potential?
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The pancreatic β-cell obtains its energy supply
through aerobic glycolysis, using glucose as substrate. ATP synthesis is dependent upon the rates of glucose uptake and aerobic glycolysis. In β-cells, ATP has inhibitory actions on the KATP channel and therefore inhibits K+ efflux. |
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Once glucose enters the cells, it is phosphorylated to G-6-P by
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he low affinity hexokinase, Glucokinase
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Glucokinase in refer as the glucose sensor because
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rate of glucose entry is correlated to the rate of glucose phosphorylation.
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After phosphorylation G-6-P enters
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glycolysis and generated ATP. The glucose uptake augments ATP synthesis. ATP acts as a second messenger in these cells, informing the KATP channel of variations in blood glucose levels. Variations in ATP levels occur parallel to changes in blood glucose concentration
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Inhibition of the KATP channel results in
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depolarization of the membrane that will open voltage-gated calcium channels.
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Calcium stimulates calcium-dependent kinases (MLCK, PKC) leading to
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phosphorylation of microtubule proteins and microtubule-mediated exocytosis of insulin containing granules.
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the more glucose
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more ATP, increased INHIBITION of K+ transport, depolarization of the β-cell, more calcium, release of insulin.
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Glucose stimulates both
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synthesis and release of insulin.
The response to glucose is biphasic. First (early) phase is due to release of insulin from β-cells granules. Late phase 2 is due to de novo synthesis and release from granules. |
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Stimulation of insulin by glucose help to decrease
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glucose levels to normal levels after for example breakfast. Also notice that in the case of food insulin increases early that actual glucose this indicate that other stimulus for
insulin secretion. |
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the major AAc drivers of insulin secretion.
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Alanine, glutamine, leucine and arginine
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As with glucose metabolism of alanine and glutamine result in enhanced
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TCA cycle activity and generation of
metabolic secretion coupling factors including ATP, Ca2+ and glutamate |
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Leucine may enhance glutamine oxidation via
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activation of glutamate dehydrogenase (GDH). Arginine may depolarize the plasma membrane by net import of positive charge thus causing opening of voltage gated Ca2+ channels
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Activation of GPR40 by FFAs causes an
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increase in intracellular Ca levels, which is believed to be via activation of the Gq-PLC pathway with release of Ca from the endoplasmic reticulum. The capacity for FFAs to increase cytosolic Ca depends on glucose activation of L-type Ca channels and the presence of extracellular Ca.
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long-term exposure to FFA exerts
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lipotoxic effects and leads to blunted glucose stimulated insulin secretion and decreased cell viability.
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FFAs are also produce de novo form
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the excess of glucose.
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Malonyl CoA, an intermediate of lipogenesis, inhibits
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FFA transport into the mitochondria, and inhibits β-
oxidation. |
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Byproducts of lipogenesis such as ceramides and DAG stimulate
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signaling pathways that inhibit insulin
signaling. |
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Accumulation of TG leads to
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lipotoxicity.
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hyperinsulinemia, because of high glucose, leads to
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down-regulation of the insulin receptor.
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Parasympathetic input to the pancreatic β-cells stimulates
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insulin secretion
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Parasympathetic stimulation of
insulin secretion is part of what is known as |
cephalic phase stimulation of insulin secretion.
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Cephalic phase refers to
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ensory stimuli and neural inputs that are activated when food is first eaten
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There is activation of parasympathetic efferent in the vagus nerve that stimulates insulin secretion even before there is an increase in blood glucose. This is an example of
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feedforward regulation: insulin secretion is stimulated in anticipation of the rise in blood glucose. This can be demonstrated by inhibiting ganglionic activity.
A main characteristic of cholinergic islet effects is a synergistic action with glucose to augment insulin secretion. |
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Sympathetic input to the pancreatic β-cells
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inhibits insulin secretion.
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Sympathetic inhibition of insulin secretion is important during
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exercise. Muscle cells are utilizing glucose at much higher rates, and so the body needs
to activate fuel-producing (not storing) mechanisms, just as it does during fasting. |
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Glucose-stimulated insulin secretion is inhibited by activation of
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α2-adrenoceptors by norepinephrine (NE). α2- adrenoceptors inhibit insulin secretion through reduced formation of cAMP and through an inhibitory action on the distal exocytotic machinery.
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Epinephrine (E), also a cathecholamine, is secreted in high levels by the adrenal medulla inhibits
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cAMP and inhibits Insulin.
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Insulin stimulates entry of glucose into
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muscle and lower blood glucose leaving very little glucose for the brain that needs absolutely glucose. By preventing insulin secretion E prevents sugar to become too low in the circulation.
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5) Stimulation of Insulin by Incretin Hormones
“The incretin effect” designates the augmentation of insulin secretion observed after oral glucose intake compared with that observed |
after an intravenous infusion of glucose resulting in identical elevations of plasma glucose. In normal subjects the augmentation is three- to four-fold.
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ncretin hormones are peptide hormones secreted from
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the gut.
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mong the peptides released in response to oral glucose are
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glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP1).
GLP-1 is one of the most potent insulin-releasing substances known. |
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GLP-1 acts synergistically with glucose to close
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ATP-sensitive K (KATP) channels and thus facilitates membrane depolarization and the induction of electrical activity.
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GLP-1 stimulates all steps of insulin biosynthesis as well as
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insulin gene transcription. Most importantly, GLP-1 has been shown to have trophic effects on β-cells.
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Cholecystokinin(CCK), Secretin and gastric inhibitory peptide amplify
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he response of the β-cell to glucose by increasing cAMP.
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Glucagon is a single-chain protein, 29 amino acids, produced initially as
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re-proglucagon.
Proglucagon gene is expressed in α-cells and also in intestinal L cells of the GI tract. The processing of proglucagon differs in α-cells and L cells. |
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Primary glucagon target
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liver
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How much glucagon is degreaded in liver?
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about 80% and the rest is passed on to the circulation.
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A major stimulus for glucagon secretion is a decrease in
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glucose.
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Hypoglycemia stimulates and Hyperglycemia inhibits
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glucagon secretion.
Insulin inhibits glucagon secretion. Therefore, decrease in glucose will directly stimulate glucagon and indirectly by decreasing insulin. |
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Glucose is incorporated into α-cells by
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the transporter SLC2A1 (GLUT-1)
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At low-glucose concentrations, the
moderate activity of KATP allows the opening of voltage-dependent |
T- and N-type calcium channels and voltage dependent Na channels. Their activation triggers action potentials, Ca influx and exocytosis of glucagon granules.
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high-glucose concentrations elevate the intracellular ATP/ADP ratio blocking KATP channels, depolarizing the membrane and inactivating of voltage-dependent channels. This results in
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he inhibition of electrical activity, Ca influx and glucagon secretion.
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Both sympathetic and parasympathetic stimulation promote
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glucagon secretion.
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Somatostatin and insulin inhibit
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glucagon secretion.
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Amino Acids stimulate
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both glucagon and insulin.
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After a meal (Fed State), insulin secretion is stimulated leading to
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the uptake of glucose by almost every cell preventing an excessive increase in glucose levels in circulation.
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during fasting (metabolic state achieved after complete digestion and absorption of a meal, usually 8-12 h - overnight) glucose levels should
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be maintained. In this situation glucagon secretion is stimulated by the decreasing levels of glucose. Glucagon mainly stimulates liver glycogenolysis and liberation of glucose to circulation which prevent a dangerous decrease of glucose in circulation.
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