M2C Unit 2 Lesson 10, 11, 12.5

What is Hyperglycemia?

chronically elevated levels of blood glucose

Hyperglycemia can lead to?

Polydipsia (elevated thirst)

• Polyuria (elevated urine production)

• Blurred vision

• Headache

• Nausea and vomiting

• Non-enzymatic glycosylation

• Hyperosmolar effects and coma

What is Hypoglycemia?

acutely reduced levels of blood glucose

Hypoglycemia can lead to?

• Dizziness

• Sweating and palpitations

• Red blood lysis, with concomitant

decreased O2 transport

• Coma and death

Insulin makeup

Consists of 2 polypeptide chains (A and B) connected by disulfide bonds

What is a good indicator of insulin production due to its longer half life?

C-peptide

Insulin gene is on what chromosome?

11

Initail insulin?

proinsulin

What happens to C-peptide?

removed from proinsulin by proteases within secretory granules and released in equimolar amounts with insulin but not removed from the circulation by the liver - thus found in higher concentrations than insulin (4:1)

Insulin binds to an __subunit of the Insulin Receptor activating the tyrosine kinase domain on its _ subunits

alpha; beta

The extent of insulin action is dependent upon:

a. Level of circulating "free" insulin

• b-cell secretory activity

• Clearance from circulation - degradation - “insulinases”

b. Number of cell surface insulin receptors

• Down regulation phenomenon - affinity and number

c. Presence of anti-receptor antibodies

Insulin increases?

glucose storage as glycogen

Insulin increases?

triglyceride synthesis

Insulin increases?

very low density lipoprotein formation

Insulin inhibits?

glucokinase and glycogen synthase

Insulin inhibits?

phosphorylase (increasing glycogen synthesis)

Glucagon is released in response to?

hypoglycemia

Epinephrine and cortisol are released in response to?

stress

Caffeine, theophylline, and other members of the methylxanthine group of compounds ____ phosphodiesterase, leading to _____ cellular levels of cAMP.

inhibit; increased

What are the major liver enzymes responsible for metabolizing alcohol?

alcohol dehydrogenase and acetaldehyde dehydrogenase.

In the cytosol, alcohol dehydrogenase converts ethanol into?

acetaldehyde

Then, in the mitochondria, acetaldehyde dehydrogenase converts acetaldehyde to?

acetate

What does Fomepizole inhibit?

Alcohol dehydrogenase

What does disulfiral inhibit?

acetaldehyde dehydrogenase

When is CYP2E1 activated?

when large amounts of alcohol are consumed

deficiency of acetaldehyde dehydrogenase results in what?

leading to accumulation of acetaldehyde; alcohol flushing

A high NADH-to-NAD+ ratio triggers activation of other reactions that convert NADH back to NAD+ like what?

Pyruvate to lactate, creates a state of lactic acidosis by preventing the oxidation of lactate to pyruvate.

A high NADH-to-NAD+ ratio triggers inhibition of what?

gluconeogenic dehydrogenase enzymes, resulting in fasting hypoglycemia. (DHAP → G3P)

G3P can combine with fatty acids to form what?

triglycerides and result in a state of hepatosteatosis, or fatty liver.

What are Mallory bodies?

The large amount of white space in the figure is representative of the high level of fat found in hepatosteatosis.

What is fasting hypoglycemia?

shunting of resources away from gluconeogenesis. preventing the the liver from making glucose in times of fasting (decreased gluconeogenesis)

Another name for methanol?

wood alcohol

Methanol toxicity effect

basal ganglia injury and other brain damage; and acidosis

Glyoxylic acid and oxalic acid have what toxic effects?

Lactic acidosis (which leads to multiple systemic metabolic derangements),

• Formation of calcium oxalate.

• Calcium oxalate crystals can precipitate in the proximal renal tubule, leading to

acute tubular necrosis and renal failure.

What is Glucose 6-Phosphate Dehydrogenase deficiency?

causes hemolytic anemia due to inability to detoxify oxidizing agents (owing to insufficient reduced glutathione)

In G6PDH deficiency, Oxidative damage to hemoglobin in the RBCs results in small inclusions within the cell body known as?

Heinz bodies

Another name for Glucose 6-P Dehydrogenase Deficiency?

favism

Homozygous mutation of G6PDH?

high hemolysis and anemia

heterozygous mutation of G6PDH?

Normally asymptomatic unless exposed to drugs (primaquine, anti-malarial drug) or compounds (fava beans) that produce ROS

What is the rate-limiting enzyme of fructose metabolism?

Aldolase B

What is hereditary fructose intolerance (HFI)?

deficiency of aldolase B, HFI is also known as Fructose Intolerance

Effect of hereditary fructose intolerance (HFI)?

accumulate much higher amounts of fructose 1-P in their livers.

What enzyme is inhibited in essencial/benign fructosuria (fructose in urine)?

fructokinase

Symptoms of Hereditory fructose intolerance

Causes severe hypoglycemia, vomiting, jaundice, hemorrhage, hepatomegaly, hyperuricemia, and lactic acidosis

Treatment for Hereditory fructose intolerance

Rapid detection and removal of fructose and sucrose from the diet

Accumulation of Fructose-1P and Galactose-1P leads to sequestration of Pi and increased production of?

uric acid

In Diabetes, Sorbitol Accumulates In Cells That Lack?

Sorbitol dehydrogenase

High sorbital concentrations result in?

cataracts (white spot in eyes)

What enzyme is inhibited in non-classical galactosemia?

Galactokinase

What enzyme is inhibited in Classical galactosemia?

Galactose-1 phosphate uridyltransferase

What is Galactokinase Deficiency?

①Causes elevation of galactose in blood (galactosemia) and urine (galactosuria)

②Causes galactitol accumulation if galactose is present in the diet.

③Elevated galactitol can cause cataracts.

What is CLASSIC GALACTOSEMIA & GALT DEFICIENCY?

①Causes galactosemia and galactosuria, vomiting, diarrhea, and jaundice.

②Accumulation of galactose 1-phosphate and galactitol in nerve, lens, liver, and kidney tissue causes liver damage, severe mental retardation, and cataracts.

• newborns should be screeened

Treatment for CLASSIC GALACTOSEMIA & GALT DEFICIENCY?

①Rapid diagnosis and removal of galactose (and therefore lactose) from the diet.

②Despite adequate treatment, at risk for developmental delays and, in females, premature ovarian failure.

What is Pyruvate Kinase Deficiency?

• •2^nd most common genetic cause of hemolytic anemia (G6PDH deficiency #1)

• RBCs have insufficient ATP for their membrane pumps

• Hemolytic anemia

• Inability to maintain membrane integrity leads to change in shape-spiculated cells (burr cells)

• Results in an increase in glycolytic intermediates (2,3-BPG etc.)

What is Pyruvate Dehydrogenase Complex disorder?

The brain depends on glucose as a fuel. PDCD degenerates gray matter in the brain.

Pyruvate accumulates, leading to alanine and lactate accumulation in the blood (lactate acidosis).

• Acidosis leads to:

  • Hyperventilation

  • Muscle pain and weakness

  • Abdominal pain and nausea