Energy Metabolism

What are the TWO major energy metabolism parameters evaluated on a general chemistry profile?

1. Glucose

2. Cholesterol

What can glucose concentration be sampled from? Cholesterol?

Glucose: serum, plasma, or whole blood

Cholesterol: serum and plasma

True or False: All living cells require energy to function and all mammalian cells metabolize glucose for energy.

True!

What are the THREE major molecules that can be used for energy?

1. Sugars (glucose)

2. Ketone (ketoacids)

3. Lipids

(Also proteins and fiber, but not as much)

Glucose concentration is a balance between ———————— and ——————-.

Glucose entry (diet)

Cellular energy utilization (tissue oxidation)

What FOUR major things are involved in the multifactorial regulation of blood glucose?

1. Dietary intake

2. Insulin to glucagon ratio

3. Liver function

4. Insulin antagonists (counter-regulatory hormones)

Where is glucose absorbed in monogastric animals?

Intestines

Where does MAJOR glucose production (gluconeogenesis + glycogenolysis) occur?

What organ has minor contributions to this?

Liver

Kidney

What is required to allow glucose to enter cells via a concentration gradient?

Glucose transport proteins (GLUT)

What stimulates cellular uptake of glucose in insulin dependent tissues and how?

Insulin via upregulation of GLUT to cell surface

Name THREE major insulin dependent tissues.

1. Liver

2. Muscle

3. Fat

Insulin is NOT necessary for glucose uptake in what FIVE major insulin independent tissues?

1. RBCs

2. Neurons

3. Renal tubular epithelial cells

4. Pancreatic beta cells

5. Lens of the eye

What do we call the rate at which glucose leaves the bloodstream and enters tissues?

Glucose disposal rate

True or False: Monogastric animals are less dependent on oxidation of glucose for energy than ruminants.

False! RUMINANTS are less dependent on oxidation of glucose for energy than monogastric animals.

What does fermentation in the rumen convert glucose to that are absorbed and used as energy production?

Volatile substances (acetic acid, propionic acid, butyric acid)

In ruminants, blood glucose is maintained primarily via —- in the —-.

Gluconeogenesis

Liver

True or False: Insulin:glucagon ratio determines physiologic status.

True!

What is the primary hormone when blood glucose concentration is high?

Insulin

What prevents hypoglycemia during fasting and only exerts effects when insulin concentrations are low or when stimulated by additional hormones?

Glucagon

What is the I:G ratio in a normal/fasted state? Normal/fed state? Starvation?

Normal/fasted: 4

Normal/fed: 30

Starvation: <1

True or False: Actions of insulin and glucagon together are needed to maintain CONSTANT blood glucose concentrations.

True!

Name the FIVE major factors that increase I:G ratio.

1. Nutrients (glucose, aa, lipids)

2. Acetylcholine

3. Gastric dilation (gastrin, CCK, secretin)

4. Gastric inhibitory polypeptide

5. Hypothalamic stimuli

What are the SIX major factors that decrease I:G ratio?

1. Glucocorticoids

2. Epinephrine

3. Norepinephrine

4. Growth hormone

5. Estrogen/progesterone

6. Somatostatin

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Tf

True or False: Pancreatic islets have a large capacity for regeneration when damaged, but have little functional reserve.

False! Pancreatic islets have a large FUNCTIONAL RESERVE, but little CAPACITY FOR REGENERATION WHEN DAMAGED.

What happens if you have substantial loss of pancreatic islet tissue (>70%)?

Hyperglycemia due to insufficient insulin production

1. Glucose enters through the GI tract and flows to the —-.

2. This responds via changes in —- and —- production.

3. Secretion of these things is coordinated with secretion of —- —— —-.

4. The blood involved then flows to the —- via —- circulation.

5. This organ then responds to drive either ————- or ——————-.

Pancreas

Insulin

Glucagon

Exocrine pancreatic enzymes

Liver

Portal

Glucose storage (glycogen)

Glucose release (glycogenolysis/gluconeogenesis)

True or False: Insulin release works differently when injected to a diabetic than it does in normal physiology.

True!

What is the primary hormone responsible for controlling the uptake, utilization, and storage of cellular nutrients?

What is the major source and the primary targets of this hormone?

Insulin

Source: B pancreatic cells

Primary targets: liver, muscle, fat

Name the major functions of insulin in terms of the liver, muscle, and adipose tissue.

Liver: promotes fuel storage

Muscle: promotes fuel storage and protein synthesis

Adipose: promotes fat storage

What TWO major ways does insulin promote fuel storage in the liver?

1. Stimulate glycogen production

2. Inhibit gluconeogenesis, beta-oxidation of ketones, and glycogenolysis

What TWO major ways does insulin promote fat storage in the adipose tissue?

1. Stimulates lipoprotein lipase (promotes storage of lipids)

2. Inhibits hormone sensitive lipase (prevents breakdown of lipids)

What is the primary hormone for maintenance of blood glucose during fasting?

What is the major source and target organ?

Glucagon

Source: alpha pancreatic cells

Target organ: liver

What are the TWO major effects of glucagon used to release glucose from storage?

1. Enhance glycogenolysis and gluconeogenesis (promote glucose output by liver)

2. Stimulate b-oxidation of fatty acid in liver leading to ketone body formation (alternative energy source)

The role of glucagon is to protect from —-.

Hypoglycemia

True or False: Neither insulin or glucagon function in a vacuum

True!

What is the major goal with insulin and glucagon?

Maintain plasma glucose within 80-150 mg/dL

Insulin is the overriding regulator because it prevents —— and promotes a state in which energy is —- and —-.

Hyperglycemia

Utilized

Stored

When is glucagon ONLY effective?

When insulin is low

Glucagon prevents —- and promotes a state where glucose is derived from what?

Hypoglycemia

Alternative fuel sources

What is the main source of glucocorticoids?

What is their function?

Adrenal cortex

Potentiate glucagon actions in the liver

What are the FOUR targets/abilities of glucocorticoids?

1. Inhibit glucose uptake by insulin-responsive cells

2. Promote hepatic gluconeogenesis

3. Promote lipolysis

4. Inhibit muscle protein synthesis

What are the TWO major results with glucocorticoid use?

1. Liver makes more glucose

2. Glucose use impaired, resulting in mild/moderate hyperglycemia

What TWO major blood changes occur with increased glucocorticoids?

1. Hyperglycemia

2. Hyperlipidemia

Does hyperadrenocorticism or hypoadrenocorticism lead to hyperglycemia? Hypoglycemia?

Hyperadrenocorticism: hyperglycemia

Hypoadrenocorticism: hypoglycemia

True or False: Hyperadrenocorticism can be caused by pituitary gland, adrenal gland, or exogenously.

True!

True or False: Hyperadrenocorticism may lead to hyperglycemia, but the blood glucose usually does not exceed the renal threshold.

True!

Is the hypoglycemia seen with hypoadrenocorticism in dogs mild, moderate, or severe?

Mild

What is the major source for catecholamines like epinephrine and norepinephrine?

Adrenal medulla

What are the THREE major functions of catecholamines?

1. Increase glycogenolysis in liver and muscle

2. Inhibit insulin secretion

3. Stimulate glucagon secretion

A high secretion of catecholamine in response to what can result in a temporary marked hyperglycemia that usually resolves within 30 minutes?

Stress/excitement

What is the source of growth hormone?

What is the net effect?

Hypothalamus

Decrease peripheral glucose use and increase hepatic glucose synthesis

What is the presence of excessive growth hormone called that clinically presents as a diabetes mellitus that is hard to regulate?

Acromegaly

True or False: Acromegaly causes marked peripheral insulin resistance and requires an usually low insulin dose.

False! Acromegaly causes marked peripheral insulin resistance and requires an usually HIGH insulin dose.

How does acromegaly differ between dogs and cats?

Dogs: induced by progesterone

Cats: functional pituitary adenoma

What is the source of progesterone?

Ovaries/uterus

What are the TWO function/targets of progesterone?

1. Increase GH release by hypothalamus -> hyperglycemia

2. Anti-insulin effects in late pregnancy/estrus/diestrus

What is the major clinical effect of progesterone in diabetic patients?

Increased serum progesterone causes preclinical diabetic to become overtly diabetic

What are the major clinical signs of hyperglycemia? Hypoglycemia?

Hyperglycemia: PU/PD

Hypoglycemia: weakness/behavior/seizures

Name FOUR known problems that interfere with glucose metabolism.

1. Hepatic/adrenal insufficiency

2. Sepsis

3. Pancreatitis

4. Patients given insulin/TPN

What is the difference between hyperglycemia and hypoglycemia?

Hyperglycemia: increased glucose in serum, plasma, blood, or interstitial tissues

Hypoglycemia: decreased glucose in serum, plasma, blood, or interstitial tissues

What are the FIVE general causes for hyperglycemia?

1. Post-prandial (transient)

2. Iatrogenic (glucose fluid, TPN, drugs)

3. Increased glucose production and release

4. Peripheral insulin resistance

5. Lack of insulin (type I DM)

True or False: Glucocorticoids, growth hormone, and progesterone all decrease cellular uptake and utilization of glucose.

True!

What does stress of disease increase and what does this cause?

How about for pain and excitement?

Stress of Disease: glucocorticoids -> gluconeogenesis

Pain/Excitement: catecholamines -> glycogenolysis

Name the THREE classifications of hyperglycemia and indicate if it is transient and persistent.

1. Physiologic hyperglycemia- transient

2. Pathologic hyperglycemia- persistent

3. Pharmacologic/toxicologic hyperglycemia- often transient

What is the most common form of diabetes amongst dogs? Cats?

Dogs: type I

Cats: type II

How does the major mechanism differ between type I and II diabetes mellitus?

Type I: destruction of pancreatic b-cells (absolute insulin deficiency)

Type II: b-cell exhaustion

Which form of diabetes is related to chronic pancreatitis and autoimmunity? Which is related to obesity?

Chronic pancreatitis/autoimmunity: type I

Obesity: type II

Which type of diabetes experiences peripheral insulin resistance, where there are changes in insulin receptor and insulin signaling?

Type II

Name another pathologic cause of hyperglycemia in dogs and cats involving the pancreas that is NOT diabetes.

Chronic pancreatitis

Name at least THREE endocrine/non-pancreatic pathological causes of hyperglycemia.

1. Acromegaly

2. Glucagonoma

3. Hyperadrenocorticism

4. Pheochromocytoma

5. Hyperthyroidism

6. Hypothyroidism

7. BVD in cattle

8. Pituitary macroadenoma in horses

9. Hyperammonemia in horses

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K

What is the fasting blood glucose concentration in hypoglycemia in small animals?

<60 mg/dl

What are the FOUR major physiologic causes of hypoglycemia?

1. Decreased glucose uptake from the gut

2. Decreased glucose production

3. Rapid/excessive glucose transport from blood into cells

4. Rapid/excessive glucose utilization by cells

What are THREE major causes of decreased glucose production?

1. Starvation/illness (toy breeds; neonates)

2. Hepatic insufficiency

3. Glycogen storage diseases

What are the TWO major causes of rapid, excessive glucose transport from blood into cells?

1. Iatrogenic (insulin overdose)

2. Insulin-producing tumor (insulinoma)

What are the THREE major causes of rapid, excessive glucose utilization by cells?

1. Severe septicemia (especially endotoxemia)

2. Large tumor burden

3. Extreme exertion (hunting dog hypoglycemia)

What is a potent stimulator of insulin release independent of glucose concentrations and can cause hepatic failure, commonly found in sugar-free foods like gum?

Xylitol

What TWO conditions involving counter regulatory hormones can lead to hypoglycemia?

1. Hypopituitarism: decreased GH or ACTH

2. Hypoadrenocorticism: addison's disease

What is the fasting blood glucose concentration in a hypoglycemic large animal?

<40 mg/dl

What do ruminants rely on to maintain their blood glucose concentration?

Gluconeogenesis

What TWO conditions are the most common causes for hypoglycemia in large animals and when do they occur in the animals lives?

1. Bovine ketosis- early lactation

2. Pregnancy toxemia in sheep and goats- late gestation

In what condition does milk production require a high glucose demand and causes mobilization of fat for energy to produce ketones?

Bovine ketosis

What condition has a high fetal demand for glucose and inadequate nutrition causes mobilization of fat for energy, causing ketone production with an occasional fatty liver?

Pregnancy toxemia (sheep + goats)

True or False: Whole blood glucose concentration is slightly higher than plasma.

False! Whole blood glucose concentration is slightly LOWER than plasma (12% lower with a normal PCV).

Why is venous blood glucose concentration slightly lower than arterial?

Peripheral glucose utilization

What kind of animals experience a postprandial increase in blood glucose concentration 2-4 hours after a meal, making fasted blood sample unless hypoglycemic a concern?

Monogastric animals

Should you fast ruminants?

No

True or False: Removal of serum or plasma from RBCs within 30 minutes of collection causes decreases in glucose concentration at 10%/hr at room temperature due to metabolism in the cells.

True!

What kind of tube can inhibit glycolysis in a sample, making separation of cells from plasma not critical?

What is one downside with using this tube?

Grey top (sodium fluoride)

Interfere with MANY assay methods

Blood glucose assay methods are based on enzymes that use glucose like —- or —-.

Glucokinase

Hexokinase

True or False: Blood glucose assays work by detecting color change or H2O2 production in the reaction, where lipemia/hemolysis/icterus may interfere with detection.

True!

Is normal urine glucose negative or positive on dipstick?

Negative

What is the amount of glucose entering the glomerular filtrate exceeding tubular capacity for resorption?

Renal threshold

True or False: Dipstick reagent pad is an enzymatic method for glucose detection, so urine should be at least room temperature.

True!

What is used to monitor diabetic animals receiving exogenous insulin?

Serial blood glucose curve

How is a glucose curve performed?

Blood glucose measured every 2 hours throughout a 10-24 hour period to assess response to insulin administration

What THREE things can be assessed in a serial blood glucose curve?

1. Response to insulin

2. Duration of effect

3. Glucose nadir (low point should NOT be too low)

Describe briefly what an ideal blood glucose curve should look like.

Negative bell-shaped curve from initial insulin administration to next adminsitration

What is an interstitial monitoring system initially developed for people as an alternative to traditional blood glucose monitoring methods?

Continuous glucose monitoring systems