Carb Metabolism Flashcards
1
Q
Why is too much “fuel” in the blood bad?
A
Oxidation generates electrons, can lead to ROS
2
Q
Glycolytic
A
Glucose (6C) to pyruvate (2: 3C) or lactate via glycolysis
3
Q
Lipogenesis
A
Conversion of carbon of glucose and amino acids to fat (triacylglycerol)
Occurs in the liver in the well-fed state
Requires lots of glucose for glycolysis to make pyruvate and for the PPP to make NADPH (reducing agent)
Requires mitochondria for formation of CITRATE which carries acetyl groups from mito matrix space to cytosol for FA synthesis
4
Q
Lipogenic
A
Carbon of glucose and amino acids to fat via lipogenesis
5
Q
GLUT4
A
Stimulating glucose uptake into muscle and heart and adipose
Insulin-regulated
NOT in liver
6
Q
Locked in the fed state
A
Obesity
Over consumption of high energy fuels
Insulin very high
Glucagon low
High I:G ratio
Conditions are favorable for the synthesis and storage of fuel (fat)
BMI of 30+ is obese
7
Q
Heavy vs light calories
A
Glycogen 4x heavier than fat
Soaks up a lot more water
If you wipe out glycogen, you’d see a lot more weight loss
8
Q
Route of fuel in fed state
A
- Synthesis and storage of glycogen in skeletal muscle and liver
- Synthesis of fat in liver, release of fat into blood, uptake and storage of fat in the adipose tissue
9
Q
Route of fuel in starved state
A
4 hours: All of the glucose is gone from your gut
8 hours: Reached a peak in the rate at which glycogen is being made
30 hours: Out of glycogen
48 hours: Less gluconeogenesis because ketone bodies are getting into the brain
Gluconeogenesis is important or you die
Drops off due to production of ketone bodies
Body adapts, uses more ketone bodies and less glucose
Utilization of ketone bodies raises blood glucose, releasing insulin; signaling inhibition of proteolysis (conservation of protein of diaphragm and rest of body)
most important thing is to have glucose for your brain and RBCs
Pancreatic alpha cells: produce glucagon instead of insulin
Liver: makes ketone bodies but can’t use them; glycogenolytic, gluconeogenic, ketogenic, proteolytic
Anterior pituitary: produces GH
Brain: Uses ketone bodies but not FA
Adipose tissue: lipolytic
Adrenal: Cortex produces cortisol; medulla produces catecholamines
Muscle: Proteolytic
10
Q
Lipolysis during starvation
A
TAG + 3H2O»_space;> 3 FFAs + glycerol
Triacylglycerols are converted to free FA and glycerol
Glycerol (from adipose) is a good substrate for gluconeogenesis
Hepatic oxidation of FFA yields ATP for glucose synthesis
AND acetyl-coA which activates pyruvate carboxylase (which stimulates anaplerosis»_space; precursors for gluconeogenesis)
11
Q
Gluconeogenesis during starvation
A
Hepatic gluconeogenesis becomes important before the exhaustion of hepatic glycogen
Drop in need for gluconeogenesis is due to increases in production of ketone bodies by the liver and their use by other tissues
In liver and kidneys
Glucose is the primary energy source for the brain, the only source of energy for RBCs
12
Q
Glucose homeostasis
A
Role of glycogen and gluconeogenesis
13
Q
Ketogenesis during starvation
A
Fatty acids are converted to ketone bodies
The way the body adapts and conserves glucose for the tissues that need it most
14
Q
Relationship between liver, muscle, and adipose in lowering blood levels of fuel in fed state & maintaining in starved state
A
a
15
Q
Ketones
A
Water soluble fat calories
16
Q
Graph of glucose tolerance test (normal and diabetic)
A
Shows how effective the normal body is at clearing glucose from the blood
Rapid clearance in a normal person is due to glucose uptake and conversion into glycogen, especially in skeletal muscle and liver. Clearance from the blood depends on stimulation of glucose transporter GLUT4 in skeletal muscle
Low clearance in individuals with impaired glucose tolerance (IGT) and diabetes is due to lack of insulin and/or insulin resistance
17
Q
How does insulin promote glucose uptake in muscle?
A
Insulin opposes the effects of glucagon and epinephrine
Signals enzyme dephosphorylation
Inhibits glycogenolysis, gluconeogenesis
Stimulates glycolysis, glycogenesis, lipogenesis
18
Q
Fate of glucose in liver
A
- Bidirectional glucose transport by GLUT2
high km = low affinity; good because you don’t want it to take up all the glucose, only when it is in excess - Glucokinase (phosphorylates glucose)
- PPP
- Glycolysis (G6P to pyruvate)
- Lactate transporter
- Pyruvate dehydrogenase complex (pyruvate > acetyl coA) or gluconeogenesis (pyruvate > G6P)
- Lipogenesis (acetyl coA > Fat) and lipoprotein synthesis
- CAC (acetyl coA > CO2)
Also glycogenesis and glycogenolysis between G6P and glycogen
Glucuronide synthesis from G6P (formation of water-soluble substrates to be excreted)
19
Q
Fate of glucose in muscle and heart
A
- Glucose transport by GLUT4
- Hexokinase
- PPP
OR - Glycolysis (glucose 6 P to pyruvate or lactate)
- Pyruvate dehydrogenase complex (pyruvate > acetyl coA)
OR - Lactate transport
- CAC (acetyl coA > CO2)
Can also make glycogen from G6P via glycogenesis, or revert glycogen back to G6P via glycogenolysis but in small amounts
20
Q
Fate of glucose in adipose
A
Synthesizes & stores fat
- Glucose transport by GLUT4
- Hexokinase
- PPP
OR - Glycolysis (glucose > pyruvate)
- Pyruvate dehydrogenase complex (pyruvate > acetyl coA)
- Lipogenesis (acetyl coA > fat)
Can also make glycogen from G6P via glycogenesis, or revert glycogen back to G6P via glycogenolysis but in small amounts
21
Q
Gluconeogenesis
A
Formation of glucose from small molecules (when you’re starving)
22
Q
Metabolism in Starvation and Type 1 diabetes
A
a
23
Q
Why do metabolic adaptations in the starved state have pathological consequences in type 1 diabetes?
A
a
24
Q
Why is the liver the only organ that synthesizes significant amounts of ketone bodies? What is the purpose of these ketone bodies?
A
a
25
Why does ketoacidosis occur only in type 1 diabetes, not in starvation?
No insulin
Person with T1 diabetes is locked in starved state
Complete loss of the metabolic flexibility of a normal person
26
Phases of tissues using glucose
1. All
2 and 3. All except liver; muscle and adipose at diminished rates
4. Brain, RBCs, renal medulla. Small amount by muscle
5. Brain at diminished rate, RBCs, renal medulla
27
Why is the prevention of hyperglycemia important? (3)
1. Oxidative stress
Oxidation generates NADH and FADH2 > electrons
Electrons used by ETC to produce ATP
Too much fuel = too many electrons
Electrons react with oxygen to make ROS via mitochondria, peroxisomes, plasma membrane NADPH oxidase (NOX)
Oxidative damage to DNA, protein, and lipid
2. Glycation: addition of sugar to protein without an enzyme produces advance glycation age end products (AGEs). Cross-link collagen molecules to each other and other serum proteins; cross-link lens crystallins to produce cataracts. Glycated hemoglobin (HbA1c) is measured as a clinical marker for glycation
3. Increased hexosamine pathway, resulting in covalent modification of proteins with the addition of N-acetylglucosamine to serine and threonine residues. Termed O-GlcNAcylation. Reversible but can have negative effects on transcription factors and enzymes
4. Glucose > polyol pathway. Causes osmotic stress. Results in sorbitol, a sugar that accumulates in cells because it is poorly metabolized and impermeable to the plasma membrane. Cataracts, microvascular damage
28
Substrate and hormone levels in blood after 5 weeks starved
Insulin remains unchanged in a normal patient, not in diabetic
Glucose is well maintained, significant amount in blood- enough for the brain
FA/ketone bodies increase; can be used by so many tissues in the body
Caloric homeostasis: enough fuel in the blood to give you good production of ATP
29
Gluconeogenic
Conversion of lactate, glycerol, and AA to glucose via gluconeogenesis
30
Pentose phosphate pathway
a
31
Fate of glucose in brain tissue cells
```
1. Glucose transport by GLUT3
low km = high affinity, makes sense because brain needs glucose badly
2. Hexokinase
3. PPP
OR
4. Glycolysis to pyruvate
5. Pyruvate dehydrogenase complex (pyruvate > acetyl coA)
6. Citric acid cycle (produce CO2)
```
32
Ketone bodies and starvation, role of insulin
Most tissues use ketone bodies in preference to glucose during starvation
Utilization of ketone bodies conserves glucose during starvation
As long as ketone bodies are available, blood glucose levels are maintained high enough to promote release of some insulin from pancreatic B cells
33
Role of insulin
Released from pancreatic B cells
Major anabolic hormone
1. Upregulates insulin-dependent glucose transporter GLUT4 on skeletal muscle and adipose
2. Increased glucose uptake by tissues leads to increased glycogen synthesis, protein synthesis, and lipogenesis
Insulin inhibits proteolysis in skeletal muscle
Presence of insulin in blood is important for conservation of body protein during starvation
34
Ketoacidosis
(neutral fuels) FA/ketogenic AA >> (acid intermediates) Ketone bodies + H+ >> (neutral waste products) CO2 + H2O
Ketoacidosis occurs when rate of B hydroxybutyrate (ketone bodies) and H+ production by liver exceeds the rate they're being used by other tissues. (faster than they can be oxidized to CO2 and H2O in peripheral tissues)
Low pKas of acetoacetic acid and B hydroxybutyric acid allow them to be ionized to acetoacetate and B hydroxybutyrate in the blood. H+ released from acids lower the blood pH
Conversion of acetoacetate to acetone has a small but favorable effect on pH
B hydroxybutyrate and Na+ is excreted in urine, but H+ remains in the blood, resulting in acidosis
35
Major differences between diabetic and starved state
Diabetic consumes food
Body does not transition into fed state in response to consumption of food
Ability to maintain caloric homeostasis is lost in diabetes
Insulin is absent in T1 diabetes; insulin is low but still present in starved state
36
Type 1 Diabetes
Insulin is absent because pancreatic beta cells have been destroyed
Glucagon is still made and released by alpha cells, insulin glucagon ratio is 0
Locked in starved state
37
Glycation
One negative outcome of too much glucose
Irreversible, non-enzymatic
Addition of sugar to protein without an enzyme produces advance glycation age end products (AGEs).
Cross-link collagen molecules to each other and other serum proteins
Cross-link lens crystallins to produce cataracts
Glycated hemoglobin (HbA1c) is measured as a clinical marker for glycation
AGEs are a better measure of persistent hyperglycemia than normal plasma glucose. They provide an estimate of glycemic control over several months, based on a lifespan of a RBC (120 days) and is not affected by day-to-day variations in plasma glucose
AGEs are recognized by receptors on inflammatory cells leading to increased cytokine and TGF-beta secretion, increased ROS, increased procoagulant activity
Cross linking of ECM proteins decrease synthesis of ECM
38
Mechanisms for switching between fed and starved states (4)
1. Substrate supply (glucose, AA, FA, ketone bodies)
2. Allosteric effectors (glucose, citrate, acetyl coa, etc.)
3. Covalent modification (phosphorylation)
4. Induction-repression of enzymes (transcription, translation, degradation)
39
Substrate supply
Dietary glucose: needed for glycogenesis and lipogenesis
High serum FA: needed for ketone synthesis by liver
All 20 AA: needed for protein synthesis
High ketone body blood concentration: only way brain would use ketone bodies
40
Malonyl-CoA
```
Allosteric effector (important regulatory mechanism)
High in fed state
```
Inhibits FA oxidation (FOX) at the level of Carnitine palmitoyl-transferase I (CPT1)
Inhibited because if you're making FA, you don't want to immediately turn around and turn them into ketone bodies
41
Fructose 2,6 P2
Allosteric effector
High in fed state
Increased by insulin, decreased by glucagon
Blocks the "futile cycle"
ACTIVATES glycolysis and lipogenesis in liver (positive allosteric regulator of PFK1)
BLOCKS gluconeogenesis in liver (negative allosteric regulator of Fructose-1,6-bisphosphatase)
Kinase and phosphatase activities are located in the same bifunctional enzyme
42
Carnitine palmitoyl CoA Transferase I (CPT1)
Converts long-chain acyl CoA (from FA) to Fatty acylcarnitine which leads to acetyl coA
Transport of long chain fatty acids into the mito matrix requires Carnitine
Inhibited by malonyl coA
43
Glucose
High in fed state
| Promotes glycogen synthesis in liver
44
Conditions that favor FA synthesis would have an increase in what allosteric effector?
Malonyl coA
| Would inhibit FA oxidation (breakdown of FA) at the level of CPT1
45
Conditions that favor FA oxidation would result in an increase in what allosteric effector?
Long-chain acyl coA
| Would inhibit FA synthesis at level of Acetyl-CoA carboxylase
46
Covalent modification
Phosphorylation: the most important mechanism for switching between starved and fed states
```
Protein kinase phosphorylates enzymes (non phosphorylated > phosphorylated form, ATP > ADP)
Phosphoprotein phosphatase (phosphorylated form > non phosphorylated form, loses a P)
```
47
Induction-repression of enzymes
Mechanism for switching between fed and starved state
Ex. Insulin promotes synthesis of enzymes involved in lipid synthesis
48
Enzymes induced in fed state
Glucokinase (glucose > G6P)
G6P dehydrogenase (G6P > 6phosphogluconate)
Acetyl CoA carboxylase (acetyl coA > malonyl coa)
49
Enzymes induced in fasted state
G6 phosphatase (G6P>glucose)
PEP carboxykinase (Oxaloacetate>F16P2)
50
Glucokinase (Hexokinase IV)
Expressed by the liver
Glucose sensor in the liver
High Km allows it to sense the concentration of glucose in the blood
Low affinity
HIgh Vmax - high capacity, can handle a large workload
51
Glycogen phosphorylase as glucose sensor in liver
Glucose is a negative allosteric effector for glycogen phosphorylase
Binding of glucose makes glycogen phosphorylase A a better substrate for phosphoprotein phosphatase
52
Can we synthesize glucose from FA with even number of carbon atoms?
NO.
1. No pathway exists for conversion of acetyl Coa to glucose
2. The acetyl group of acetyl coa is completely oxidized to CO2 and water by CAC
53
Anaplerosis
Enzyme catalyzed reaction that results in net synthesis of gluconeogenic precursors
Anaplerosis provides CAC intermediate - PEPCK, Fructose 1,6 biphosphatase, glucose 6-phosphatase
Without insulin- pyruvate carboxylase (catalyzes anaplerosis) is stimulated by high levels of acetyl coA
Expression of PEPCK increases
Fructose 1,6 biphosphatase is active
Glucose 6 phosphatase is increased
With glucagon- pyruvate carboxylase activity is increased from increasing acetyl coA,
Decreasing fructose -2,6-biphosphatase
Increasing expression of PEPCK
Increasing glucose 6 phosphatase
54
Hypothesis that lead to discovery of insulin by Banting and Best
f
55
Role of SGLT2
Located on luminal surface of renal tubule cells
| Uses membrane potential and sodium gradient to actively transport glucose from blood filtrate across plasma membrane
56
Mechanisms by which hyperglycemia damages blood vessels
No cell in the body can survive without glucose, but too much is toxic
1. Damage from osmotic stress (most important)
2. Irreversible Glycation
3. Reversible Glycosylation
4. Oxidative stress and inflammation damage cellular components
57
Conversion of HbA1 to HbA1c
Glycation of HbA1:
Reactive glucose in L open chain aldeyhyde + amine > Shiff base > Shiff base rearrangement > Fructosamine
Fructosamine = HbA1c; irreversible covalent modification of protein
58
HbA1c
Useful marker for the blood glucose concentration over the past several weeks (6-8wks)
Hb turns over slowly due to concentration of RBCs
59
Metabolic interrelationships of liver, skeletal muscle, and adipose in Type 1 diabetes
Hyperglycemia: High sugar in blood, cannot get glucose to cells.
Gut:
Consumed food glucose contributes to hyperglycemia
```
Liver produces glucose through:
Lipolysis (glycerol)
Proteolysis (AA)
Glycogenolysis (glycogen)
Lactate (cori cycle)
```
Muscle:
Proteolysis (provides Alanine)
Adipose:
Lipolysis (provides glycerol)
Poor clearance of glucose from blood due to lack of insulin worsens hyperglycemia
60
Biochem regulatory mechanisms lost in liver, skeletal muscle, and adipose tissue in Type 1 diabetes
1. No transport of glucose into skeletal muscle and adipose due to lack of GLUT4 stimulation by insulin
2. No synthesis of glycogen in liver and skeletal muscle (due to lack of insulin)
3. No complete oxidation of glucose to CO2 by heart, liver, and skeletal muscle (due to lack of insulin)
4. No synthesis of fatty acids from glucose in the liver (due to lack of insulin)
5. No negative control of liver glucose synthesis, adipose lipolysis, or muscle proteolysis (due to lack of insulin)
No opposition to counter regulatory hormones (due to lack of insulin)
61
How does insulin promote glucose uptake in skeletal muscle, heart, and adipose tissue?
Insulin binding at insulin receptor on plasma membrane
Initiates signaling cascade
Fusion of cytoplasmic vesicles carrying GLUT4
GLUT4 wedged in membrane and activated
> leading to glucose uptake into the cells
**Happens in skeletal muscle, adipose, and heart cells, NOT in LIVER or PANCREATIC B CELLS
62
Why is insulin-promoted glucose uptake not operational/necessary in the liver?
f
63
How does insulin promote glycogen synthesis in the liver? Compare to glucagon
Insulin increases glucokinase expression,
Increasing availability of glucose-6-phosphate for glycogen synthesis
Dephosphorylates/activates glycogen synthase
Dephosphorylates/inactivates glycogen phosphorylase (enzyme in glycogenolysis)
vs. Glucagon inactivates glycogen synthase, activates glycogen phosphorylase
64
Why without insulin: Complete oxidation of glucose to CO2 and H2O is POOR in skeletal muscle, heart, and liver
Complete oxidation is the only way to clear glucose completely from the body
Requires:
1. Glucose uptake (poor without insulin)
2. Glycolysis (inhibited by low fructose26p2 without insulin)
3. Pyruvate dehydrogenase complex (without insulin-
inactivated through phosphorylation by pyruvate dehydrogenase kinase)
4. CAC
65
Why without insulin: Control of the rate of glucose synthesis by the liver is lost
*Without insulin, anaplerosis increases, providing necessary precursors for gluconeogenesis*
Synthesis of glucose from most gluconeogenic precursors requires anaplerosis
Anaplerosis provides CAC intermediate - PEPCK, Fructose 1,6 biphosphatase, glucose 6-phosphatase
Without insulin- pyruvate carboxylase (catalyzes anaplerosis) is stimulated by high levels of acetyl coA
Expression of PEPCK increases
Fructose 1,6 biphosphatase is active
Glucose 6 phosphatase is increased
With glucagon- pyruvate carboxylase activity is increased from increasing acetyl coA,
Decreasing fructose -2,6-biphosphatase
Increasing expression of PEPCK
Increasing glucose 6 phosphatase
66
Why without insulin: Fatty acid synthesis by the liver is inhibited and fat storage is reduced
FA synthesis requires
1. Glucokinase (downregulated without insulin)
2. Glycolysis (inhibited for want of fructose 2,6 p2 without insulin)
3. Pyruvate dehydrogenase complex (inactive due to upregulation of pyruvate dehydrogenase kinase without insulin)
4. Acetyl-coa carboxylase (downregulated and inhibited by phosphorylation without insulin)
5. FA synthase (downregulated without insulin)
Glucagon inhibits FA synthesis by:
1. Reducing the level of fructose 2,6 p2 (needed for glycolysis) and
2. Promoting the phosphorylation/inactivation of acetyl-coA carboxylase
67
Why without insulin: Control of lipolysis in the adipose tissue is not kept in check
Without insulin, Hormone sensitive lipase (HSL) is phosphorylated and active by unopposed activation of protein kinase A signaling cascade
HSL catalyzes lipolysis
Without insulin, Glucagon and epinephrine signal phosphorylation/activation of HSL
Lipolysis: TAG + H2O >>> 3FFA + glycerol
Glycerol (from adipose) is a good substrate for gluconeogenesis
FFA provide substrate for FA oxidation and ketogenesis
Hepatic oxidation of FFA yields ATP for glucose synthesis
AND acetyl-coA which activates pyruvate carboxylase (which stimulates anaplerosis >> precursors for gluconeogenesis)
68
Why without insulin: Proteolysis in skeletal muscle is not kept in check
Insulin inhibits proteolysis. Without insulin, proteases in skeletal muscle are activated, resulting in ketogenic AA that travel through the blood and act as substrates for ketogenesis and gluconeogenesis.
Protein >>> AAs
Muscle wasting in type 1 diabetes
AA are substrates for gluconeogenesis, therefore AAs released by proteolysis contribute to the hyperglycemia in type 1 diabetes
Proteases: Protein + H2O >>> AA
Insulin > mTOR > Autophagy/lysosome OR ubiquitination/proteosome
69
Ketone bodies (3)
Acetoacetic acid
B Hydroxybutyric acid
Acetone
70
Complete FA oxidation via citric acid cycle
Palmitate + O2 > CO2 + H20
| no acid, no base production
71
Incomplete FA oxidation via Ketogenesis
Palmitate + O2 > B hydroxybutyrate + H
| acid production
72
Ketolysis of B hydroxybutyrate by peripheral tissues
B hydroxybutyrate + H + O2 > CO2 + H20
| acid utilization
73
Sum of FA oxidation, ketogenesis and ketolysis
Palmitate + O2 > CO2 + H2O
no acid, no base production
*when ketone bodies produced from fatty acids by liver are oxidized to CO2 and H2O, there is no metabolic ketoacidosis*
All balanced
Ketogenesis by liver produces acid
Could lower blood pH and cause ketoacidosis BUT
Ketolysis of the ketone bodies utilizes the acid that ketogenesis produced, subsequently preventing ketoacidosis
74
Lactic acidosis
(natural fuel) glucose, glucogenic AA >> (acid intermediates) Lactate + H+ >> (natural waste) CO2 + H2O
When rate of glycolytic pathway is not balanced by the rate of the pyruvate dehydrogenase complex + CAC
Since the glycolytic pathway does not require oxygen whereas PDC and CAC do, hypoxia is a common basis for lactic acidosis
75
Range of [H+] and pH seen in clinical conditions
Acidosis
Life threatening [H+] >100 ; pH < 7.0
Clinically significant [H+] 50-80 ; pH 7.1-7.3
Normal
Normal [H+] 40 ; pH 7.4
Alkalosis
Clinically significant [H+] 25-30 ; pH 7.5-7.6
Life threatening [H+] <20; pH >7.7
76
Why without insulin: Proteolysis in skeletal muscle is not kept in check
Insulin signals proteolytic mechanisms that hydrolyze
Protein >>> AAs
Muscle wasting in type 1 diabetes
AA are substrates for gluconeogenesis, therefore AAs released by proteolysis contribute to the hyperglycemia in type 1 diabetes
Proteases: Protein + H2O >>> AA
Insulin > mTOR > Autophagy/lysosome OR ubiquitination/proteosome
77
Anion gap
+ charged ions must = # - charged ions
```
Measured cations (Na) + unmeasured cations (K, Mg, Ca) =
Measured anions (Cl- + HCO3-) + unmeasured anions (albumin + organic anions)
```
Na - (Cl + HCO3) = 12 +/- 2 is normal
Albumin accounts for almost all of the normal anion gap
Rise in anion gap determined mainly by a rise in the organic anions of lactic acid and ketone bodies
If pH is low and anion gap is high, patient likely has metabolic acidosis
78
The most important buffering system in our blood
HCO3-/CO2
Metabolic acidosis lowers [HCO3] by acid titration:
HCO3 + H >>> H2CO3 >>> H2O + CO2
pCO2 is reduced because it's blown off by lungs during hyperventilation
HCO3 is most often what is affected because of titration with protons originating from ketone bodies
79
Hormonal bases for ketoacidosis in type 1 diabetes
Insulin, the most important hormone in preventing ketoacidosis, is ABSENT
Glucagon, catecholamines, growth hormone, and glucocorticoids, the most important hormones for raising blood ketone bodies, are PRESENT
80
Biochemical bases for ketoacidosis in type 1 diabetes
1. Negative control of lipolysis in adipose tissue requires insulin
2. Negative control of proteolysis in skeletal muscle requires insulin
3. Negative control of FA oxidation and ketogenesis in liver requires insulin
81
Without insulin, negative control of FA oxidation and ketogenesis is lost in the liver
FA oxidation and ketogenesis are increased in absence of insulin because carnitine palmitoyl transferase 1 (CPT1), the rate limiting enzyme for FA oxidation, is active
FA released from adipose and ketogenic AA are released from muscle
CPT1 is active because malonyl-coa, the negative allosteric effector, is greatly reduced in amount
Malonyl-coa levels are reduced because acetyl-coa carboxylase is...
Inhibited by long-chain acyl-coa esters produced from FFA
Downregulated because of the absence of insulin (reduces amount of enzymes)
Phosphorylated/inactivated by action of glucagon/protein kinase A
82
Urine protein:creatinine ratios
Early diabetic nephropathy: 30-300mg/g
| Advanced diabetic nephropathy: >300mg/g
83
EGFR
| And serum creatinine
<15: end stage renal disease
Serum creatinine used to estimate GFR, values less than 1.0 are likely associated with renal dysfunction
84
HbA1c measurement
>7% is aligned with advanced renal disease
Goal for diabetes is <7%
Normal: between 4 and 5.6%
85
Measurement of TSH for thyroid function
Only recommended for Type 1 DM
86
Persistent hyperglycemia causes:
```
Increased proteoglycan synthesis
Non-enzymatic glycosylation
Decreased NADH
Decreased reduced glutathione
Increased diacyl glycerol
Increased F6P
```
87
Early indicator of diabetic nephropathy?
Low amounts of albumin in urine
88
What test is helpful in evaluating long-term control of diabetes?
Hemoglobin A1c
89
Vascular proliferation in response to overexpression of VEGF is important in the pathogenesis of which diabetic complication?
Retinopathy
90
Complications of DM in Type 1 and Type 2 (order)
Some type 2 DM is initially asymptomatic; it usually is discovered several years after onset. Complications of DM may be present at diagnosis. Whereas the complications of type 1 DM predictably appear after diagnosis.
91
Pathologic abnormalities caused by hyperglycemia
1. Forming advanced glycation and products that damage cells, produce cytokines, promote vascular proliferation and increase ECM synthesis
2. Activate protein kinase C by increasing intracellular diacyl glycerol (2nd messenger) with subsequent production of cytokines and growth factors
3. Increasing oxidative injury by decreasing NADPH (needed for generation of reduced glutathione, a potent anti-oxidant)
4. Increasing the production of fructose-6-phosphate that generates excess proteoglycans
```
Non-enzymatic glycosylation
Decreased NADH
Decreased reduced glutathione
Increased diacyl glycerol
Increased F6P
```
92
Serum creatinine (and calculated estimate of GFR) and urine albumin/creatinine ratio
Helpful in evaluating renal function
Serum creatinine: marker of renal FUNCTION, can be used to estimate GFR; takes into account patient's age/race/sex
Increased excretion of albumin by kidney provides a sensitive marker of renal DAMAGE
Preferred strategy for detecting kidney damage: Simultaneous quantitative measurement of albumin and creatinine in a random urine sample (rather than performing a 24 hour urine collection) and measuring the albumin/creatinine, which overcomes issues related to urine concentration.
Urine albumin/creatine ratio of 30-300mg/g corresponds to urine albumin excretion of 30-300 mg/day
93
Co-morbidities of DM
Hypertension: need strict blood pressure control
Hyperlipidemia: need to raise HDL, lower LDL, lower triglycerides
Atherosclerosis
Obesity and smoking
Increase physical activity, lifestyle, and pharmacological changes
94
Patients who benefit from more aggressive glycemic control targets
Targets for glycemic control depend on patient specific and disease specific factors
```
Patient who is .....
motivated
with resources
no or early evidence of complications
long life expectancy
co-morbidities are well controlled
...will benefit from more aggressive control
```
vs. a patient with long-standing disease, established vascular complications, and extensive co-morbidities
95
Type 1 Diabetes Mellitus
1. Insulin deficiency leads to disorder characterized by hyperglycemia
2. Due to autoimmune destruction of beta cells by T lymphocytes
3. Early childhood manifestation
High serum glucose (decreased glucose uptake by fat and skeletal muscle)
Weight loss, low muscle mass, polyphagia (unopposed glucagon)
Polyuria, polydipsia, glycosuria
Treatment: lifelong insulin
4. Risk for diabetic ketoacidosis
96
Diabetic ketoacidosis
1. Excessive serum ketones
2. Often arises with stress (infection); epinephrine stimulates glucagon secretion increasing lipolysis (along with gluconeogenesis and glycogenolysis)
Increased lipolysis leads to inc. FFAs
Liver converts FFAs to ketone bodies
3. Results in hyperglycemia, anion gap metabolic acidosis, hyperkalemia
4. Treatment is fluids, insulin, and replacement of electrolytes (K)
97
Type 2 Diabetes Mellitus
1. End-organ insulin resistance leading to a disorder characterized by hyperglycemia
Most common type (90%) affecting 5-10% of population
2. Middle-aged, obese adults
Obesity leads to decreased number of insulin receptors
Strong genetic predisposition
3. Insulin deficiency due to beta cell exhaustion, amyloid deposition in islets
4. Polyuria, polydipsia, hyperglycemia, often silent disease clinically
5. Diagnosis by glucose levels
GTT with serum >200mg/dL
6. Treatment
Weight loss (diet and exercise)
Drug therapy to counter insulin resistance (sulfonylurea, metformin) or exogenous insulin after exhaustion of beta cells
98
Pancreas
1. Cluster of cells termed islets of Langerhans
| 2. Single islet consists of multiple cell types each producing 1 type of hormone
99
Glucagon
Secreted by pancreatic alpha cells
| Oppose insulin in order to increase blood glucose levels (in state of fasting) via glycogenolysis and lipolysis
100
Glucosuria
Glucose spills out into the urine when it's too high in the blood
Renal tubule is designed to salvage glucose from filtrate destined to become urine
SGLT2: on luminal surface uses membrane potential and Na+ gradient to ACTIVELY transport glucose back into blood
Hydrolysis of ATP will transport Na out of the cell by Na/K ATPase
GLUT2: after gaining access to renal tubule, glucose moves back into blood through passive transport by GLUT2
When SGLT2 is saturated and blood glucose levels are high enough to reach renal threshold for retaining glucose, glucose is shed into the urine
101
Sorbitol
A sugar that accumulates in cells because it is poorly metabolized and impermeable to the plasma membrane
Suggested that accumulation of this in the lens causes cataracts
Cataracts: swelling of the lens of the eye
Osmotic stress: resulting in water uptake and swelling of cells
102
Catecholamines
Produced by adrenal medulla
| Counter regulatory hormone (oppose insulin); raise glucose level; catabolic
103
Growth hormone
Produced by anterior pituitary
| Counter regulatory hormone (oppose insulin); raise glucose level; catabolic
104
Glucocorticoids
Produced by adrenal cortex
| Counter regulatory hormone (oppose insulin); raise glucose level; catabolic
105
Metabolic acidosis
Ketoacidosis (FA and ketogenic AA > CO2 + water)
Lactic acidosis (Glucose and glucogenic AA > CO2 and water)
Both caused by accumulation of carboxylic acids in the blood coupled with excretions of the corresponding anions along with Na+ in the urine
Oxidation of neutral fuels results in neutral waste with no change in pH
Accumulation of intermediates results in acidosis
106
Pathological findings with diabetes
Thickened basement membrane can be seen early on
Nodular glomerulosclerosis (Kimmelstiel-Wilson) specific for diabetes
Membrane thickening and mesangial expansion can also be seen in other etiologies like hypertension
Pyelonephritis is also not specific to diabetes (inflamed kidney)
107
Plasminogen activator inhibitor (PAI-1)
Inhibits fibrinolysis, increasing chance of thrombosis and end-organ ischemia
Bc decreased blood flow and ischemic tissue injury
108
Granulation tissue
Composed of fibroblasts, loose connective tissue, leukocytes and leaky capillaries
Abundance capillaries with increased permeability
109
Granuloma
A special form of chronic inflammation
Epitheloid histiocytes and giant cells
110
Atherosclerosis and DM
```
Increased and accelerated atherosclerosis due to diabetes is the primary underlying mechanism of macrovascular complications including
Peripheral vascular disease
Cardiovascular disease
(MI)
Stroke
```
111
Diabetic microangiopathy
Associated with increased basement membrane thickening and
Increased vascular permeability
More important with microvascular complications like
nephropathy
neuropathy
retinopathy
112
Erythropoietin
Hormone secreted by the kidneys that increases the rate of production of RBCs in response to decreased oxygen levels
Kidney plays an important role in RBC production and releasing erythropoietin to circulation
113
Hyperkalemia
As chronic kidney disease progresses, the distal nephron loses the ability to secrete potassium ions, leading to hyperkalemia
114
Mechanisms activated in metabolic acidosis
1. Activation of H/K-ATPase in collecting tubule caused by accumulation of ketoacids
2. Decrease epithelial Na channel bc of low pH
3. Increase Na/bicarbonate co-transport in proximal tubule to overcome acidosis
4. Activation of Na/H exchange in proximal tubule
115
Sodium
The extracellular cation that exerts a major osmotic role
Na retention drives water retention and edema
Presents with electrolyte disbalance with retention of Na in renal insufficiency secondary to DM
116
Hexokinase
Works in other tissues (not liver or B cells)
Low Km = high affinity
Low vMax = low capacity
Feedback inhibition by G6P
If you have a lot of glucose and the cell doesn't need anymore, then G6P will inhibit hexokinase
117
Synthesis vs Catalysis and NADPH/NADH
```
Synthesis = utilizing NADPH
Breakdown = utilizing NADH
```
118
Phosphofructokinase-1
Major control in glycolysis
| Rate limiting enzyme
119
Pyruvate carboxylase
Pyruvate > oxaloacetate
First step in gluconeogenesis
120
Pyruvate dehydrogenase
Pyruvate > Acetyl CoA
Requires 5 co factors (B1, 2, 3, 5, lipoic acid)
*nutritional deficiencies can be a problem
Activated by exercise
121
PGC1a
Transcription factor that increases biogenesis of mitochondria
Active when energy is low because you'd want to make more ATP and more mitochondria could do that
122
AMP and ATP
ATP low, AMP high
High AMP, High AMPK which increases catabolic pathways to compensate for low energy levels
