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Scientific Foundations > Lecture 47 > Flashcards

Lecture 47 Flashcards

Regulation of Blood Glucose

1
Q

normal blood glucose levels

A
  • glucose level must be in normal range to maintain healthy metabolism
  • too little OR too much glucose in blood is dangerous
  • hyperglycemia is common with diabetes -> not good, especially in long run
  • regulatory mechanism for metabolism to respond appropriately: epinephrine, glucagon, GH, and cortisol production increase
  • hypoglycemia adrenergic symptoms: anxiety, palpitation, tremor sweating
  • neuroglycopenia symptoms: headache, confusion, slurred speech, seizures, coma, death

pg 1204

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2
Q

blood glucose regulation in hepatocytes

A
  • 1st response to low glucose: activating glycogen phosphorylase -> only good as long as there is plentiful glycogen in liver
  • 2nd response to low glucose: gluconeogenesis forms glucose from smaller precursors (pyruvate from lactate from the Cori cycle)

pg 1205

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3
Q

role of liver and kidney in blood glucose regulation

A
  • ingested glucose gone within first 4 hours
  • gluconeogenesis takes longer to reach its peak
  • glycogenolysis usually done within 24 hours, but by the time this occurs, gluconeogenesis takes over
  • gluconeogenesis in the kidneys is important in long periods of fasting (60% in liver, 40% in kidneys)

pg 1206

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4
Q

blood glucose regulation timing

A
  • as dietary glucose increases, gluconeogenesis and glycogenolysis decrease
  • as dietary glucose decreases, gluconeogenesis and glycogenolysis increase

pg 1207

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5
Q

gluconeogenesis (GNG)

A
  • GNG is the pathway in which glucose molecules are built from non-sugar precursors
  • active in hepatocytes (and to a lesser extent, in cortical kidney cells)
  • does not oppose glycolysis
  • not simply a reversal of glycolysis
  • regulated in a reciprocal manner (when glycolysis is ON, gluconeogenesis is OFF)
  • glycolysis has 3 irreversible reactions which release energy, so gluconeogenesis needs energy and different enzymes to go backwards at these steps

pg 1208

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6
Q

hexokinase

A
  • 3 different isoforms in muscle and other tissues: hexokinase I, II, and III
  • liver expresses hexokinase IV or glucokinase

pg 1210

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7
Q

glucokinase (GCK)

A
  • hexokinase IV
  • found ONLY in: hepatocytes, pancreatic β-cells
  • first enzyme for glycolysis in the liver (irreversible step)
  • converts glucose to glucose-6-P

pg 1210

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8
Q

glucokinase activity

A
  • low affinity for glucose (higher Km)
  • higher maximum velocity (higher Vmax)
  • liver can use other substrates, so GCK is not saturated when other tissues need the glucose
  • regulated by hormones: insulin activates, glucagon inhibits

pg 1211

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9
Q

maturity-onset diabetes of the young-2 (MODY2)

A
  • very rare form of diabetes
  • caused by mutations in the glucokinase gene (deficiency)
  • autosomal dominant
  • results in mild and stable fasting hyperglycemia
  • usually requiring no specific treatment

pg 1211

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10
Q

glucokinase regulatory protein (GKRP)

A
  • nuclear protein that reversibly binds glucokinase and sequesters it in the nucleus (keeps it inactive)
  • regulation of GKRP: inhibited by glucose (promotes glucokinase release) and activated by fructose-6P (promotes GKRP-GK binding and nuclear sequestration)

pg 1212

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11
Q

phosphofructokinase-1 (PFK-1)

A
  • 2nd irreversible step of glycolysis in the liver
  • rate-limiting and committed step
  • most important control point
  • regulated by: ATP and citrate (inhibitors) and fructose-2,6-bisphosphate (activator when insulin is high)
  • fructose-6-P to fructose-1,6-bisP, uses ATP and releases ADP

pg 1213

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12
Q

PFK-2

A
  • activated by high levels of insulin
  • phosphorylates C-2 on fructose-6-phosphate to form fructose-2,6-bisphosphate

pg 1213

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13
Q

pyruvate kinase

A
  • 3rd irreversible step of glycolysis in the liver
  • inhibitors: ATP, glucagon
  • activators: fructose-1,6-bisphosphate
  • PEP to pyruvate, releases ATP

pg 1214

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14
Q

regulation of liver glycolysis by glucagon

A
  • glucagon increases levels of cAMP (a 2nd messenger)
  • cAMP activates protein kinase A (active PKA)
  • active PKA uses ATP to phosphorylate active pyruvate kinase (which is dephosphorylated)
  • releases ADP and inactive pyruvate kinase (which is phosphorylated)

Bottom Line: high levels of glucagon inactivates pyruvate kinase

pg 1215

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15
Q

liver glycolysis: short-term regulation

A
  • allosteric
  • covalent modifications -> phosphorylation/dephosphorylation of pyruvate kinase
  • insulin activates and glucagon inhibits: glucokinase, phosphofructokinase, and pyruvate kinase

pg 1216

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16
Q

liver glycolysis: long-term regulation

A
  • protein expression -> 10 to 20 fold increases in enzyme synthesis
  • transcriptional effects are mediated by transcription factors -> SREBP-1c (effect of insulin) and CRBP (effect of glucose)

pg 1216

17
Q

liver gluconeogenesis

A
  • 3 irreversible steps of glycolysis are overcome by using 4 alternate enzymes
  • pyruvate to oxaloacetate (in mt matrix) -> pyruvate carboxylase
  • oxaloacetate to phosphoenolpyruvate (in cytosol) -> PEP carboxykinase
  • fructose-1,6-bisP to fructose-6-P (in cytosol) -> fructose-1,6-bisphosphatase
  • glucose-6-P to glucose (in ER) -> glucose-6-phosphatase (removes phosphate group for glucose to enter circulation)

pg 1218

18
Q

liver gluconeogenesis substrates

A
  • pyruvate
  • glycerol (backbone of triacylglycerols)
  • glucogenic amino acids
  • lactate (from Cori cycle)
  • CANNOT use acetyl-CoA because humans do not have an enzyme to convert acetyl-CoA back to pyruvate

pg 1218

19
Q

steps 1 and 2 of liver gluconeogenesis

A
  1. CO2 from bicarbonate is activated and transferred by pyruvate carboxylase to its biotin prosthetic group
  2. The enzyme then transfers the CO2 to pyruvate, generating oxaloacetate
  3. Oxaloacetate cannot cross the mitochondrial membrane and it is reduced to malate that can
  4. Malate is reoxidized to oxaloacetate, which is oxidatively decarboxylated to PEP by the cytosolic isozyme of PEP carboxykinase

pg 1219-1220

20
Q

step 3 of liver gluconeogenesis

A
  • dephosphorylation of fructose-1,6-bisphosphate
  • enzyme: fructose-1,6-bisphosphatase
  • inhibitors: AMP, fructose-2,6-bisphosphate
  • activators: ATP

pg 1221

21
Q

regulation of liver PFK-2 by insulin

A
  1. high insulin/glucagon ratio causes decreased cAMP and reduced levels of active protein kinase A
  2. decreased protein kinase A activity favors dephosphorylation of PFK-2/FBP-2
  3. dephosphorylated PFK-2 domain is active, whereas FBP-2 is inactive, which favors formation of fructose-2,6-bisphosphate
  4. elevated concentration of fructose-2,6-bisphosphate activates PFK-1 which leads to an increased rate of glycolysis

pg 1222

22
Q

regulation of liver PFK-2 by glucagon

A
  1. high glucagon/insulin ratio causes elevated cAMP and increased levels of active protein kinase A
  2. increased protein kinase A activity favors the phosphorylated form of PFK-2/FBP-2
  3. phosphorylation of the PFK-2 domain inactivates it, allowing the FBP-2 domain to be active
  4. decreased levels of fructose-2,6-bisphosphate decrease the inhibition of FBP-1 which leads to an increased rate of gluconeogenesis

pg 1223

23
Q

step 4 of liver gluconeogenesis

A
  • dephosphorylation of glucose-6-phosphate to glucose
  • in the ER
  • enzyme: glucose-6-phosphatase
  • G-6-phosphatase has 3 transporter subunits and a catalytic subunit which is on the luminal side

pg 1224

24
Q

glycogen storage in liver

A

only the liver is capable of converting glycogen to glucose as it requires glucose-6-phosphatase which is only found in liver

pg 1226

25
Q

regulation of glycogen synthesis and degradation in liver

A
  • glycogen phosphorylase inhibited by glucose-6-phosphate and glucose
  • glycogen synthase activated by glucose-6-phosphate
  • glycogen phospharylase activated by glucagon and epinephrine, inhibited by insulin
  • glycogen synthase activated by insulin, inhibited by glucagon and epinephrine
  • synthesis increased in well-fed state, degradation increased during fasting

pg 1227

26
Q

Type I: Von Gierke disease

A
  • glucose-6-phosphatase deficiency
  • affects liver and kidney (kidney also does gluconeogenesis)
  • fasting hypoglycemia is severe (glucose cannot be dephosphorylated so glucose in liver is not released)
  • fatty liver, hepato- and renomegaly
  • progressive renal disease
  • growth retardation and delayed puberty
  • lactic acidemia, hyperlipidemia, and hyperuricemia
  • normal glycogen structure, increased glycogen stored
  • treatment: nocturnal gastric infusions of glucose or regular administration of uncooked cornstarch

pg 1229-1230

27
Q

Type VI: Hers disease

A
  • liver glycogen phosphorylase deficiency
  • mild fasting hypoglycemia (GNG still working)
  • hepatomegaly and cirrhosis: excessive buildup of glycogen in liver

pg 1229-1230

28
Q

acute liver disease

A
  • clinical presentation: CNS symptoms -> lethargy, confusion, coma
  • laboratory findings: low blood glucose level

pg 1231

Scientific Foundations (46 decks)

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