Lesson 6a and 6B

Endocrine Pancreas/ Selected clinical signs of dysfunction and Pathogenesis and evaluation

What is the difference between fasting and starvation?

Fasting: BG levels are maintained largely via glycogenolysis, stimulated by glucagon and epinephrine

Starvation: Glycogen stores are empty causing gluconeogenesis by braking down amino acids.

What is the function of insulin?

Facilitates Glucose uptake using GLUT-4 and glucose utilization in muscles and fat

What happens if there is an insulin dysfunction causing an insulin deficiency?

Reduced Glucose uptake and utilization causing hyperglycemia

What can increase due to the lack of inhibition by insulin, contributing to hyperglycemia via glycogenolysis and glucomeogenesis?

Glucagon

What can increase due to hypothalamic insulin-receptor dysfunction and adipose tissue reactivating cortisone to active cortisol causing hyperglycemia due to gluconeogenesis and insulin-resistance?

Cortisol

What happens to the kidneys due to hyperglycemia in Diabetes?

Kidneys cannot handle the reabsorption of excess glucose.

What are the effects and clinical signs when renal glucose reabsorption becomes saturated?

Glucosuria

Polyuria/Polydipsia

How does Glucosuria lead to Polyuria?

Glucose in the urine inceases urine osmolarity

Glucose binds to excess water/absorbs more water which can lead to large volumes of diluted urine

How does polyuria lead to polydipsia?

Polyuria leads to dehydration with high plasma osmolarity and thirst

What is a renal threshold?

The blood glucose level which glucosuria will occur.

Dogs 180mg/dL

Cats 280mg/dL

How does hyperglycemia during diabetes effect the hypothalamic satiety center?

The Hypothalamic satiety center measure blood glucose levels which signal satiety when glucose levels are high. This center is insulin depended, which means that without insulin the center cannot register the glucose in the bloodstream causing Polyphagia.

What is the effect on WBCs during Hyperglycemia in DM?

WBCs have insulin receptors that are both insulin dependent and non insulin dependent. Therefore they can maintain their basic function without insulin but need insulin to do more advanced task such as phagocytic actions of neutrophils.

What are the metabolic effects of insulin deficiency on WBC function and subsequent clinical signs?

Effect: cannot fight infections, immune suppressed

Clinical signs: UTI, Dermatitis, Prostatis, Bronchopneumonia

How is the ocular lens effected during hyperglycemia in DM?

The lens tissue absorbs excess amounts of glucose, which causes an accumulation of sorbitol. Sorbitol attracts water, causing swelling and liquification of lens protein,s making a Cataract.

What is the effect on Proteins during hyperglycemia in DM?

Excess glucose can bind to plasma proteins and intracellular proteins, this causes proteins to lose their function.

Why is fructosamine diagnostically relevent?

Only accumulate a high number of fructosamine in long-standing hyperglycemia of >2-3 weeks.

What is the function of insulin in lipolysis and proteolysis?

Insulin is an anabolic hormone which inhibits lipolysis and proteolysis

What happens in an insulin deficiency to lipolysis and proteolysis?

Inhibition is lifted and lipolysis and proteolysis using cortisol to create a catabolic situation (breaking down lipids and amino acids to make energy)

What are the effects and clinical signs of increased lipolysis and proteolysis?

Muscle wasting and weight loss

What is Glucotoxicity?

• Glucose-dependent cells absorb excess glucose due to the steep concentration gradient causing the mitochondria to be overloaded.

• Increasing the blood acidity and inhibiting the ETC enzymes.

• Creating ROS causing mitochondrial injury and apoptosis

What are the consequences of glucotoxicity?

Neuopathies (reduced motor function)

Angiopathies (tissue damage/Increased BP)

Pancreatic Beta-cells destruction (worsening of DM signs)

What is lipotoxicity?

Uncontrolled lipolysis releases vast amounts of FFA, liver accumulates FFAs and converts them into ketone bodies.

Why is it harmful to have excess ketone bodies in the blood stream?

Ketone bodies increase in plasma beyond bodies capacity to metabolize them causing ketoemia and ketouria. This drops the blood pH causing Diabetic Ketoacidosis (DKA)

What is the treatment goals for all patients with DM?

• Maintain BG below renal threshold

• Control the clinical signs of DM

• Avoid hypoglycemia

• Avoid long term complications

What is type 1 DM in terms of Drug targets?

Mostly in dogs. Beta cells are destroyed, which causes them to be insulin dependent DM requiring insulin replacement.

What is Type 2 DM in terms of Drug targets?

Mostly in cats, often obesity-related insulin resistance.

Beta cells are viable in early stages and become destroyed in later stages creating insulin resistant DM.

When would you use insulin receptor agonist (substitution therapy)?

Type 1/ dogs

Type 2/ cats

Early stages of DM in cats to help bring them back into the insulin resistant stage without DM signs

Late stages of DM mandatory for cats

When would you use a renal sodium glucose cotransporter 2 inhibitor?

Early stages or stable phases of DM in cats without insulin therapy

How does a Renal sodium glucose contransporter 2 inhibitor work?

Blocks the renal reabsorption of glucose which increases glucosuria, but it can risk dehydration and electrolyte imbalance

When would you use an Insulin secretagogue?

For early stages of DM type 2

How does an insulin secretagogue work?

Blocks ATP-sensative K channels in beta cells causing insulin to be released

What are examples of physiologic hyperglycemia?

Mild Post-prandial (right after eating)

Stress

mid-mod Pregnancy

What are stress hormones that can cause physiological hyperglycemia? And what are the species they are most effected in?

Cortisol and Catecholamines

Cats and Cows

What is a Pregnancy hormone that can cause physiological hyperglycemia?

progesterone

What are two types of pathological hyperglycemia?

Sustained

Transient

What are examples substained pathological conditions that can cause hyperglycemia?

Diabetes

Hyperadrenocortism

Aergomealy

PPID (Equine cushings)

What are examples of transient pathological conditions that can cause hyperglycemia?

Pancreatitis

Hyperthyroidism

Sepsis

What is usually the number 1 finding in hyperglycemia?

Hyperadrenocortism

How can post-prandial increases be avoided?

Fasting

What is the main cause of Type 1 diabetes?

Beta cell destruction (immune mediated or idiopathic)

Which species is most effected by type 1 diabetes?

Dogs

Is type 1 diabetes insulin dependent?

Always

What are the key features of type 1 diabetes?

• Decreased insulin production

• decreased glucose uptake

• increased gluconeogenesis

• hyperglycemia

What is the pathiophysiology of type 1 diabetes?

perceived starvation causing an increase in glucagon production

What is the main cause of type 2 diabetes?

insulin resistance and/or pancreatic amyloidosis

What species is mainly effected by type 2 daibetes?

Cats (70%) and dogs

Is type 2 diabetes insulin dependent?

Yes and no

in early stages the b-cells still work but the tissues are not responding

What are the key features to type 2 diabetes?

• Poor tissue response to insulin

• Glucose toxicity

• Hyperglycemia

What is the pathophysiology of type 2 diabetes?

Increased glucagon production due to perceived starvation

What are the findings/abnormalities in the biochemistry for both types diabetes?

Persistent fasting

Hyperglycemia

What are the findings/abnormalities of fructosamine in the chemistry for both types diabetes?

Elevated in sustained hyperglycemia (diagnostic for DM)

What are some findings/abnormalities in the CBC for both types of DM?

Stress or inflammatory leukogram

Increased PCV and Proteins due to dehydration

Increased MCV

What are so findings/abnormalities that can be seen in the urine in both types of DM?

Glucosuria (act as an osmotic diuretic influencing USG)

Ketonuria

What are the liver enzymes that will change on the chemistry during DM?

Increased ALT, AST,ALP,GGT

Do cholesterol and triglycerides increase or decrease during DM?

Increase

Do bile acids or bilirubin increase or decrease during DM?

Less common but they increase

What is often secondary to hepatic lipidosis or other concurrent conditions such as hyperadrenocorticism?

Increased cholesterol and triglycerides

What is the primary difference between type 1 and type 2 diabetes in dogs and cats?

Type 1 involves the destruction of beta cells while Type 2 involves insulin resistance or insufficient insulin production

A 10 year old neutered male pothound presents PUPD and weight loss. BG are 300 mg/dL and urine reveals glucosuria. What is the most likely explanation or the urinalysis findings?

the dog has DM with blood glucose exceeding the renal threshold

What are the effects of steroids (glucosorticoids) and catecholamines (epinephrine) on glucose levels?

Steroids: promote glucose production and reduce glucose uptake by tissues causing hyperglycemia

Catecholamines: Stimulate the breakdown of glycogen in the liver and muscles rapidly increasing the glucose. Reduce insulin secretion and promote glucose release during acute stress.

What is insulin resistance?

The bodies cells don’t respond properly to a normal amount of insulin causing less effective Blood sugar control.

What are three ways that insulin resistance occur?

before the insulin binds to its receptor

At the receptor (Changing receptors shape)

After binding to receptor (affecting the steps that activate it)

Insulin resistance at the receptor and post the receptor in dogs and cats are linked in what three ways?

Hormonal causes

Obesity

Inflammation/inflection

What are some examples of hormonal changes that can cause insulin resistance at the receptor and post receptor?

Glucocorticoids

Acromegaly

Progestogens

Thyroid hormones

How does the amount of amyloid deposition correlate with the degree of glucose intolerance?

It directly correlates

The islet amyloid composed of what pancreatic hormone causes damage to beta cells and promotes insulin resistance?

Amylin

In 50% of obese cats what hormone sensitivity tends to decrease but is reversible?

Insulin

In cats beta cells integrity can tend to wax and wane which means what?

That a cat can go into remission and revert back to the DM state

What happens to obese cats with poor glycemic control?

They undergo severe weight loss

Cats that are hyperglycemic that are eating regular meals are diagnostic for what?

Diabetes

Animals that require > 1.5-2.5 U insulin a day or serum fructosamine >700umol/l should be evaluated for what?

Insulin resistance

Animals that require > 1.5-2.5 U insulin a day or serum fructosamine >700umol/l should be evaluated for insulin resistance. What concurrent issues could these animals be facing?

Cushings/Acromeagaly

What is the IV glucose tolerance test?

A test used to detect decreased tolerance in persistently hyperglycemic dogs

How do you perform the IV glucose test?

• Fast animal overnight

• Collect a baseline glucose

• Inject -.5g/kg of 50% dextrose IV over 30-60 secs

• Collect blood immediately after injection then again at 5, 15, 25, 35, 45, 60 minutes

• plot glucose concentration vs time

How do you interpret the results of the IV glucose tolerance test?

Glucose intolerance is prolonged >60 mins

Normal animals blood have normal BG by 60 mins.

What is the clinical use of insulin concentration?

Insulin levels most helpful in animals with hypoglycemia when assessed alongside glucose levels

What are some limitations to insulin concentrations?

RR may not be established for all species

Some testing methods are not validated for cats

How should you handle a sample for insulin concentration testing?

Harvest serum within 30min of blood clotting

immediately assay or freeze the sample

What cause increased insulin resistance/metabolic syndrome and diabetes?

Obesity

What 4 examples of metabolic syndromes that can be caused by obesity?

• insulin resistance

• Hypertriglyceridemia

• hypertension

• Increased laminitis risk in horses

What is the primary pathophysiological mechanism underlying equine metabolic syndrome?

Insulin dysregulation leading to hyperinsulinemia

What are the three most common conditions that can occur in llamas and alpacas?

Hyperglycemia

Hypernatremia

Hyperosmolarity

How does stress lead to hyperglycemia in crias?

Cortisol increases glucose production

How does a poor insulin response lead to hyperglycemia in crias?

Insulin resistance can lead to persistent hyperglycemia and osmotic diuresis

How does hypernatremia occur in crias?

Water loss from osmotic diuresis → dehydration

NA concentration increases as water is lost

Why is it important to watch out of hyperglycemia in crias?

Hyperglycemia worsens dehydration and hyperosmolality which can cause metabolic collapse.