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Diabetes > Carb Metabolism > Flashcards

Carb Metabolism Flashcards

1
Q

Why is too much “fuel” in the blood bad?

A

Oxidation generates electrons, can lead to ROS

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2
Q

Glycolytic

A

Glucose (6C) to pyruvate (2: 3C) or lactate via glycolysis

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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

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4
Q

Lipogenic

A

Carbon of glucose and amino acids to fat via lipogenesis

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5
Q

GLUT4

A

Stimulating glucose uptake into muscle and heart and adipose
Insulin-regulated

NOT in liver

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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

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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

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8
Q

Route of fuel in fed state

A
  1. Synthesis and storage of glycogen in skeletal muscle and liver
  2. Synthesis of fat in liver, release of fat into blood, uptake and storage of fat in the adipose tissue
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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

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10
Q

Lipolysis during starvation

A

TAG + 3H2O&raquo_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&raquo_space; precursors for gluconeogenesis)

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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

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12
Q

Glucose homeostasis

A

Role of glycogen and gluconeogenesis

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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

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14
Q

Relationship between liver, muscle, and adipose in lowering blood levels of fuel in fed state & maintaining in starved state

A

a

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15
Q

Ketones

A

Water soluble fat calories

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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

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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

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18
Q

Fate of glucose in liver

A
  1. 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
  2. Glucokinase (phosphorylates glucose)
  3. PPP
  4. Glycolysis (G6P to pyruvate)
  5. Lactate transporter
  6. Pyruvate dehydrogenase complex (pyruvate > acetyl coA) or gluconeogenesis (pyruvate > G6P)
  7. Lipogenesis (acetyl coA > Fat) and lipoprotein synthesis
  8. CAC (acetyl coA > CO2)

Also glycogenesis and glycogenolysis between G6P and glycogen

Glucuronide synthesis from G6P (formation of water-soluble substrates to be excreted)

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19
Q

Fate of glucose in muscle and heart

A
  1. Glucose transport by GLUT4
  2. Hexokinase
  3. PPP
    OR
  4. Glycolysis (glucose 6 P to pyruvate or lactate)
  5. Pyruvate dehydrogenase complex (pyruvate > acetyl coA)
    OR
  6. Lactate transport
  7. CAC (acetyl coA > CO2)

Can also make glycogen from G6P via glycogenesis, or revert glycogen back to G6P via glycogenolysis but in small amounts

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20
Q

Fate of glucose in adipose

A

Synthesizes & stores fat

  1. Glucose transport by GLUT4
  2. Hexokinase
  3. PPP
    OR
  4. Glycolysis (glucose > pyruvate)
  5. Pyruvate dehydrogenase complex (pyruvate > acetyl coA)
  6. Lipogenesis (acetyl coA > fat)

Can also make glycogen from G6P via glycogenesis, or revert glycogen back to G6P via glycogenolysis but in small amounts

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21
Q

Gluconeogenesis

A

Formation of glucose from small molecules (when you’re starving)

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22
Q

Metabolism in Starvation and Type 1 diabetes

A

a

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23
Q

Why do metabolic adaptations in the starved state have pathological consequences in type 1 diabetes?

A

a

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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

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25
Q

Why does ketoacidosis occur only in type 1 diabetes, not in starvation?

A

No insulin

Person with T1 diabetes is locked in starved state

Complete loss of the metabolic flexibility of a normal person

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26
Q

Phases of tissues using glucose

A
  1. All
    2 and 3. All except liver; muscle and adipose at diminished rates
  2. Brain, RBCs, renal medulla. Small amount by muscle
  3. Brain at diminished rate, RBCs, renal medulla
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27
Q

Why is the prevention of hyperglycemia important? (3)

A
  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
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28
Q

Substrate and hormone levels in blood after 5 weeks starved

A

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

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29
Q

Gluconeogenic

A

Conversion of lactate, glycerol, and AA to glucose via gluconeogenesis

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30
Q

Pentose phosphate pathway

A

a

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31
Q

Fate of glucose in brain tissue cells

A 
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)
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32
Q

Ketone bodies and starvation, role of insulin

A

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

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33
Q

Role of insulin

A

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

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34
Q

Ketoacidosis

A

(neutral fuels) FA/ketogenic AA&raquo_space; (acid intermediates) Ketone bodies + H+&raquo_space; (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

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35
Q

Major differences between diabetic and starved state

A

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

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36
Q

Type 1 Diabetes

A

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

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37
Q

Glycation

A

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

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38
Q

Mechanisms for switching between fed and starved states (4)

A
  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)
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39
Q

Substrate supply

A

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

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40
Q

Malonyl-CoA

A 
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

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41
Q

Fructose 2,6 P2

A

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

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42
Q

Carnitine palmitoyl CoA Transferase I (CPT1)

A

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

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43
Q

Glucose

A

High in fed state

Promotes glycogen synthesis in liver

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44
Q

Conditions that favor FA synthesis would have an increase in what allosteric effector?

A

Malonyl coA

Would inhibit FA oxidation (breakdown of FA) at the level of CPT1

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45
Q

Conditions that favor FA oxidation would result in an increase in what allosteric effector?

A

Long-chain acyl coA

Would inhibit FA synthesis at level of Acetyl-CoA carboxylase

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46
Q

Covalent modification

A

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)
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47
Q

Induction-repression of enzymes

A

Mechanism for switching between fed and starved state

Ex. Insulin promotes synthesis of enzymes involved in lipid synthesis

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48
Q

Enzymes induced in fed state

A

Glucokinase (glucose > G6P)

G6P dehydrogenase (G6P > 6phosphogluconate)

Acetyl CoA carboxylase (acetyl coA > malonyl coa)

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49
Q

Enzymes induced in fasted state

A

G6 phosphatase (G6P>glucose)

PEP carboxykinase (Oxaloacetate>F16P2)

50
Q

Glucokinase (Hexokinase IV)

A

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
Q

Glycogen phosphorylase as glucose sensor in liver

A

Glucose is a negative allosteric effector for glycogen phosphorylase

Binding of glucose makes glycogen phosphorylase A a better substrate for phosphoprotein phosphatase

52
Q

Can we synthesize glucose from FA with even number of carbon atoms?

A

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
Q

Anaplerosis

A

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
Q

Hypothesis that lead to discovery of insulin by Banting and Best

A

f

55
Q

Role of SGLT2

A

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
Q

Mechanisms by which hyperglycemia damages blood vessels

A

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
Q

Conversion of HbA1 to HbA1c

A

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
Q

HbA1c

A

Useful marker for the blood glucose concentration over the past several weeks (6-8wks)

Hb turns over slowly due to concentration of RBCs

59
Q

Metabolic interrelationships of liver, skeletal muscle, and adipose in Type 1 diabetes

A

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
Q

Biochem regulatory mechanisms lost in liver, skeletal muscle, and adipose tissue in Type 1 diabetes

A
  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
Q

How does insulin promote glucose uptake in skeletal muscle, heart, and adipose tissue?

A

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
Q

Why is insulin-promoted glucose uptake not operational/necessary in the liver?

A

f

63
Q

How does insulin promote glycogen synthesis in the liver? Compare to glucagon

A

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
Q

Why without insulin: Complete oxidation of glucose to CO2 and H2O is POOR in skeletal muscle, heart, and liver

A

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
Q

Why without insulin: Control of the rate of glucose synthesis by the liver is lost

A

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
Q

Why without insulin: Fatty acid synthesis by the liver is inhibited and fat storage is reduced

A

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
Q

Why without insulin: Control of lipolysis in the adipose tissue is not kept in check

A

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&raquo_space;> 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&raquo_space; precursors for gluconeogenesis)

68
Q

Why without insulin: Proteolysis in skeletal muscle is not kept in check

A

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&raquo_space;> 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&raquo_space;> AA
Insulin > mTOR > Autophagy/lysosome OR ubiquitination/proteosome

69
Q

Ketone bodies (3)

A

Acetoacetic acid
B Hydroxybutyric acid
Acetone

70
Q

Complete FA oxidation via citric acid cycle

A

Palmitate + O2 > CO2 + H20

no acid, no base production

71
Q

Incomplete FA oxidation via Ketogenesis

A

Palmitate + O2 > B hydroxybutyrate + H

acid production

72
Q

Ketolysis of B hydroxybutyrate by peripheral tissues

A

B hydroxybutyrate + H + O2 > CO2 + H20

acid utilization

73
Q

Sum of FA oxidation, ketogenesis and ketolysis

A

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
Q

Lactic acidosis

A

(natural fuel) glucose, glucogenic AA&raquo_space; (acid intermediates) Lactate + H+&raquo_space; (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
Q

Range of [H+] and pH seen in clinical conditions

A

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
Q

Why without insulin: Proteolysis in skeletal muscle is not kept in check

A

Insulin signals proteolytic mechanisms that hydrolyze
Protein&raquo_space;> 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&raquo_space;> AA
Insulin > mTOR > Autophagy/lysosome OR ubiquitination/proteosome

77
Q

Anion gap

A

+ 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
Q

The most important buffering system in our blood

A

HCO3-/CO2
Metabolic acidosis lowers [HCO3] by acid titration:
HCO3 + H&raquo_space;> H2CO3&raquo_space;> 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
Q

Hormonal bases for ketoacidosis in type 1 diabetes

A

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
Q

Biochemical bases for ketoacidosis in type 1 diabetes

A
  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
Q

Without insulin, negative control of FA oxidation and ketogenesis is lost in the liver

A

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
Q

Urine protein:creatinine ratios

A

Early diabetic nephropathy: 30-300mg/g

Advanced diabetic nephropathy: >300mg/g

83
Q

EGFR

And serum creatinine

A

<15: end stage renal disease

Serum creatinine used to estimate GFR, values less than 1.0 are likely associated with renal dysfunction

84
Q

HbA1c measurement

A

> 7% is aligned with advanced renal disease

Goal for diabetes is <7%

Normal: between 4 and 5.6%

85
Q

Measurement of TSH for thyroid function

A

Only recommended for Type 1 DM

86
Q

Persistent hyperglycemia causes:

A 
Increased proteoglycan synthesis
Non-enzymatic glycosylation
Decreased NADH
Decreased reduced glutathione
Increased diacyl glycerol
Increased F6P
87
Q

Early indicator of diabetic nephropathy?

A

Low amounts of albumin in urine

88
Q

What test is helpful in evaluating long-term control of diabetes?

A

Hemoglobin A1c

89
Q

Vascular proliferation in response to overexpression of VEGF is important in the pathogenesis of which diabetic complication?

A

Retinopathy

90
Q

Complications of DM in Type 1 and Type 2 (order)

A

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
Q

Pathologic abnormalities caused by hyperglycemia

A
  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
Q

Serum creatinine (and calculated estimate of GFR) and urine albumin/creatinine ratio

A

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
Q

Co-morbidities of DM

A

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
Q

Patients who benefit from more aggressive glycemic control targets

A

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
Q

Type 1 Diabetes Mellitus

A
  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
Q

Diabetic ketoacidosis

A
  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
Q

Type 2 Diabetes Mellitus

A
  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
Q

Pancreas

A
  1. Cluster of cells termed islets of Langerhans

2. Single islet consists of multiple cell types each producing 1 type of hormone

99
Q

Glucagon

A

Secreted by pancreatic alpha cells

Oppose insulin in order to increase blood glucose levels (in state of fasting) via glycogenolysis and lipolysis

100
Q

Glucosuria

A

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
Q

Sorbitol

A

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
Q

Catecholamines

A

Produced by adrenal medulla

Counter regulatory hormone (oppose insulin); raise glucose level; catabolic

103
Q

Growth hormone

A

Produced by anterior pituitary

Counter regulatory hormone (oppose insulin); raise glucose level; catabolic

104
Q

Glucocorticoids

A

Produced by adrenal cortex

Counter regulatory hormone (oppose insulin); raise glucose level; catabolic

105
Q

Metabolic acidosis

A

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
Q

Pathological findings with diabetes

A

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
Q

Plasminogen activator inhibitor (PAI-1)

A

Inhibits fibrinolysis, increasing chance of thrombosis and end-organ ischemia

Bc decreased blood flow and ischemic tissue injury

108
Q

Granulation tissue

A

Composed of fibroblasts, loose connective tissue, leukocytes and leaky capillaries

Abundance capillaries with increased permeability

109
Q

Granuloma

A

A special form of chronic inflammation

Epitheloid histiocytes and giant cells

110
Q

Atherosclerosis and DM

A 
Increased and accelerated atherosclerosis due to diabetes is the primary underlying mechanism of macrovascular complications including
Peripheral vascular disease
Cardiovascular disease
(MI) 
Stroke
111
Q

Diabetic microangiopathy

A

Associated with increased basement membrane thickening and
Increased vascular permeability

More important with microvascular complications like
nephropathy
neuropathy
retinopathy

112
Q

Erythropoietin

A

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
Q

Hyperkalemia

A

As chronic kidney disease progresses, the distal nephron loses the ability to secrete potassium ions, leading to hyperkalemia

114
Q

Mechanisms activated in metabolic acidosis

A
  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
Q

Sodium

A

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
Q

Hexokinase

A

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
Q

Synthesis vs Catalysis and NADPH/NADH

A 
Synthesis = utilizing NADPH
Breakdown = utilizing NADH
118
Q

Phosphofructokinase-1

A

Major control in glycolysis

Rate limiting enzyme

119
Q

Pyruvate carboxylase

A

Pyruvate > oxaloacetate

First step in gluconeogenesis

120
Q

Pyruvate dehydrogenase

A

Pyruvate > Acetyl CoA

Requires 5 co factors (B1, 2, 3, 5, lipoic acid)
*nutritional deficiencies can be a problem

Activated by exercise

121
Q

PGC1a

A

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
Q

AMP and ATP

A

ATP low, AMP high

High AMP, High AMPK which increases catabolic pathways to compensate for low energy levels

Diabetes (4 decks)

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