CFB 11: Maintaining Blood Glucose

What are the adrenergic (autonomic) effects of not having enough glucose?

Trembling

Palpitations

Sweating

Anxiety

Nausea

Hunger

Tingling

What are the neuroglycopenic effects of not having enough glucose?

Headache

Confusion

Weakness

Drowsiness

Vision changes

Difficulty speaking

Dizziness

Tiredness

Dental management of the hypoglycemic patient: mild and moderate stages

Recognize hypoglycemic signs and symptoms

Terminate the procedure

Give the patient anything containing sugar

Position the patient

Summon medical assistance if necessary and monitor the patient

Dental management of the hypoglycemic patient: severe stage

Unconscious patient

Stop the procedure

Position the patient

Summon medical assistance

Give 50% IV dextrose or 1mg glucagon IM

What hormones maintain blood glucose?

Insulin (when fed) and glucagon (when starving)

What is the signal of fasting vs. of feeding?

Fasting: glucagon

Feeding: insulin

Where is glucagon vs. insulin made?

Glucagon: alpha cells

Insulin: beta cells

How many chains are glucagon vs. insulin?

Glucagon: 29 amino acid chain

Insulin: 2 chains (A = 21 and B = 30)

What are the target tissues of glucagon?

Liver, adipose (NOT MUSCLE)

What are the target tissues of insulin?

Liver, adipose, skeletal muscle

What is the target metabolism of glucagon?

Carbohydrates, lipids

What is the target metabolism of insulin?

Carbohydrates, lipids, proteins

What experiment is this:

Dogs do not eat carbohydrate

Blood entering liver has low glucose concentration

Blood leaving liver has high glucose concentration

Claude Bernard's Experiment

What organ is the major source of glucose?

Liver

What organ becomes significant for glucose in starvation?

Kidney

What are the liver's 2 sources of glucose?

Glycogen

Gluconeogenesis

Glycogen, stored poly-glucose, sustains blood glucose for how long after a meal?

A few hours

Gluconeogenesis, de novo glucose synthesis, sustains blood glucose for how long in the absence of carbohydrate intake?

Many days/weeks

When does a crossover of sources occur?

16 hours

Glycogen is unimportant after a day

Poly-glucose is linked α____ with α____ branches.

Linked α1→4 with α1→6 branches

Why bother to make glycogen?

1. Glucose transport is facilitated, so a high concentration would leak out

2. High glucose would pose a major osmotic problem

3. High glucose would glycate proteins

4. Glucose reacts with metals to give ROS

Where do you find glycogen?

Liver (up to 10% WT) (100g)

Muscle (1-2%) (400g)

Why does muscle use glycogen for its own energy?

Lacks G6P'ase

T/F: Glycogen is a long-term glucose buffer.

False; short-term

What stimulates glycogen synthesis?

Glucose-6-phosphate

What decreases glycogen breakdown?

Glucose-6-phosphate

What inhibits glycogen breakdown?

Fructose-1-phosphate

What hormone stimulates glycogen synthase?

Insulin

What hormone decreases phosphorylase activities?

Insulin

What hormone leads to a decrease in blood glucose?

Insulin

What hormones promote glycogen breakdown?

Glucagon and epinephrine (stress hormone)

What hormones inhibit glycogen synthesis?

Glucagon and epinephrine (stress hormone)

Neuromuscular stimulation activates ____________ _____ via _____________ receptor and Ca++ promote breakdown.

Phosphorylase kinase via acetylcholine receptor

What enzyme carries out the limiting, regulated step of glycogen synthesis?

Glycogen synthase

Glycogen synthase elongates an existing __________ chain by one glucose -- from ___ ________ to the ____ of a glucose at the end of an already existing chain.

α-1,4 chain

From UDP Glucose to the 4'OH of a glucose at the end of a chain

Glycogen synthase requires a primer which can be made by __________.

Glycogenin

What transfers a terminal segment of growing chain to form a branch linked α1-6 to a different chain?

Branching enzyme

Steps of glycogen synthesis

1. Glycogen synthase elongates the chain by one glucose residue at a time (requires primer made by glycogenin)

2. Branching enzyme transfers a terminal segment of growing chain to form a branch linked α1-6 to a different chain

What cleaves one glucose residue at a time by phosphorolysis from the end of the chain?

Glycogen phosphorylase

What is the regulated step of glycogen breakdown?

Glycogen phosphorylase

What is the product of glycogen phosphorylase?

Glucose-1-phosphate

What transfers 3 residues of a branching chain to a different chain and then cleaves the remaining glucose by hydrolysis?

Debranching enzyme

How does debranching enzyme cleave the remaining glucose?

Hydrolysis

What is the product of debranching enzyme?

Free glucose

What are the steps of glycogen breakdown?

1. Glycogen phosphorylase cleaves one glucose residue at a time by phosphorolysis from the end of the chain *regulated step (G6P, ATP, AMP, Ca++)*

--> glucose-1-phosphate

2. Debranching enzyme transfers 3 residues of a branching chain to a different chain and then cleaves the remaining glucose by hydrolysis

--> free glucose

What regulates glycogen phosphorylase and synthase?

Insulin and glucagon in a coordinated way

What is the important distinction between liver and muscle?

Breakdown of glycogen in the liver provides glucose to the body

Muscle largely reserves glucose for its own use

Name the disease:

Enzyme: glucose-6-phosphatase

Location: liver, kidney

Glycogen: increased amount, normal structure

Type 1A

Von Gierke

What disease has severe hypoglycemia and hepatomegaly?

Type 1A

Von Gierke

Name the disease:

Enzyme: Glucose-6-phosphate transporter

Location: liver, kidney

Glycogen: increased amount, normal structure

Type 1B

Von Gierke

What disease has severe hypoglycemia, hepatomegaly, and severe dental issues?

Type 1B

Von Gierke

Name the disease:

Enzyme: α-1,4 glucosidase (lysosomal)

Location: everywhere

Glycogen: large increase, normal structure

Type II

Pompe

What disease has cardiorespiratory failure?

Type II

Pompe

Name the disease:

Enzyme: debranching enzyme

Location: muscle/liver

Glycogen: increased amount, short outer branches

Type III

Cori

What diseases are like Type 1 but milder?

Type III (Cori)

Type VI (Hers)

Name the disease:

Enzyme: branching enzyme

Location: liver

Glycogen: normal amount, long outer branches

Type IV

Andersen

What disease has hepatomegaly and can be fatal?

Type IV

Andersen

Name the disease:

Enzyme: phosphorylase

Location: muscle

Glycogen: increased amount, normal structure

Type V

McArdle

What disease causes exercise problems and cramps?

Type V

McArdle

Name the disease:

Enzyme: phosphorylase

Location: liver

Glycogen: increased amount, normal structure

Type VI

Hers

Name the disease:

Enzyme: PFK1

Location: muscle

Glycogen: increased amount, normal structure

Type VII

Tauri's

Which disease is like Type V?

Type VII

Tauri's

Gluconeogenesis starts how long after eating?

4 hours

What are the substrates of gluconeogenesis?

Lactate

Pyruvate

Alanine / any AA that is convertible to oxaloacetate

Glycerol

Can you use fatty acids that yield acetylCoA as substrates for gluconeogenesis?

No!

What is the tissue location of gluconeogenesis?

Liver (80-90%)

Kidney (10-20%, but more on starvation)

What is the subcellular location of gluconeogenesis?

Mitochondria: pyruvate carboxylase (use malate/aspartate shuttle OAA)

Cytoplasm: most reactions

ER: G6P

Gluconeogenesis looks like glycolysis in reverse except for what?

The 3 "irreversible" glycolytic steps use different enzymes

What enzymes does gluconeogenesis use?

Pyruvate carboxylase

PEP carboxylase

Fructose 1,6 bisphosphatase

Glucose 6 phosphatase

What upregulates pyruvate carboxylase?

Acetyl CoA

What upregulates fructose 1,6 bisphosphatase?

Citrate

What downregulates fructose 1,6 bisphosphatase?

AMP

F2,6BP

What downregulates liver gluconeogenesis?

Pyruvate kinase

What upregulates liver gluconeogenesis?

Glucagon/insulin

Is there G6 glucose 6 phosphatase in muscle?

No

Does glucocorticoid treatment increase or decrease gluconeogenesis?

Increase

What does fructose 1,6 bisphosphatase do?

Converts fructose 1,6-bisphosphate to fructose 6-phosphate

*A key target!*

Hormonal regulation of ____ coordinates glycolysis and gluconeogenesis.

PFK2

What is the Cori Cycle?

Process in the liver that regenerates glucose from lactate released by muscles

How is the Alanine/Cahill Cycle different from the Cori Cycle?

Alanine/Cahill uses alanine instead of lactate

Cori Cycle vs. Cahill Cycle

Glucose is obtained from gluconeogenesis in __________________ and glycogen breakdown in ________________.

Gluconeogenesis: kidney and liver

Glycogen breakdown: muscle and liver

Besides eating, glucose is available from glucose stored as glycogen or glucose synthesized de novo. As starvation proceeds, when does gluconeogenesis become the majority source of blood glucose and when are glycogen stores essentially depleted?

16 hours, 30 hours

In a glucose tolerance test, a patient ingests a large amount of glucose. What will happen in a normal patient?

Enhanced glycogen synthase activity in the liver

A patient has an infection by a bacterium that produces an endotoxin that blocks phosphoenolpyruvate carboxykinase (PEPCK). This causes an inhibition of glucose synthesis from:

Lactate

A diabetic forgets that he has taken his morning insulin, so he takes another dose. After several hours, he starts sweating and having a rapid heart rate. Somewhat later he became confused, had difficulty with speech, finally becoming comatose. Blood glucose was 1mM (quite low). Which mechanism is most likely at work?

F2,6 bisphosphate production inhibits F1,6 bisphophatase

What statement about the Alanine/Cahill Cycle is true?

Alanine is produced by the skeletal muscle and transported to liver for use as a gluconeogenic substrate