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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
- CO2 from bicarbonate is activated and transferred by pyruvate carboxylase to its biotin prosthetic group
- The enzyme then transfers the CO2 to pyruvate, generating oxaloacetate
- Oxaloacetate cannot cross the mitochondrial membrane and it is reduced to malate that can
- 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
- high insulin/glucagon ratio causes decreased cAMP and reduced levels of active protein kinase A
- decreased protein kinase A activity favors dephosphorylation of PFK-2/FBP-2
- dephosphorylated PFK-2 domain is active, whereas FBP-2 is inactive, which favors formation of fructose-2,6-bisphosphate
- 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
- high glucagon/insulin ratio causes elevated cAMP and increased levels of active protein kinase A
- increased protein kinase A activity favors the phosphorylated form of PFK-2/FBP-2
- phosphorylation of the PFK-2 domain inactivates it, allowing the FBP-2 domain to be active
- 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
