Metabolic Disorders- Diabetes

Question 1

Type I Diabetes

Answer 1

• insulin-dependent (deficient)
• Insulin is not produced by the beta-cells in the pancreas, leading to inactivation of GLUT 4 and high blood glucose content (hyperglycemia) causing diabetes

Question 2

Type II diabetes

Answer 2

• non insulin-dependent (resistant)
• Cell is resistant to effects of insulin due to prolonged overproduction that desensitizes the insulin receptor. Leads to defective activation of GLUT 4 and hyperglycemia causing diabetes.

Question 3

Normal insulin and glucose physiology

Answer 3

Insulin binds to insulin receptor to activate GLUT 4 (muscle and adipose tissue) to facilitate removal of glucose from bloodstream and into cells

Question 4

Canine diabetes mellitus

Answer 4

• Mostly type I (hypoinsulinemia)
• On the rise 2/1000 in 1970, 6.4/1000 in 1999, 10/1000 2023
• Peak occurrence is 7-11 yrs; more than 70% of patients are older than 7yrs
  -Multifactorial causes
  (Genetic predisposition, Obesity, Pancreatic cell destruction (ex. repeated pancreatitis for inflammation), Endocrine disorders

Question 5

Feline diabetes mellitus

Answer 5

• Mostly type II (insulin resistant)
• 6x less sensitive to insulin, eventually progresses to type I
• Multifactorial- Genotype (DSH, Russian blue, Burmese, Siamese), Obesity (4-6kg overweight leads to a 50% decrease in insulin sensitivity), Inactivity

Question 6

How does feline type II DM progress to type I DM?

Answer 6

Need 6x the amount of insulin to trigger the desired response of GLUT 4. If untreated more and more insulin is produced, causing an overuse of pancreatic cells resulting in inflammation and destruction. This destruction results in the inability of insulin production. Leading to a switch to Type I diabetes.

Question 7

Conditionally- induced starvation

Answer 7

Starvation in the midst of plenty

An animal with diabetes is in a state of starvation due to believed carbohydrate deficiency because of a lack of insulin or an inefficiency of insulin.

Question 8

Diabetes effect on metabolism

Answer 8

1. glucose production
2. lipolysis
3. lipoprotein lipase
4. randle cycle
5. ketogenesis
6. Muscle breakdown

Question 9

Diabetes effect on lipolysis

Answer 9

Insulin suppress lipolysis in healthy conditions by activating phosphodiesterase (cAMP –> 5 AMP) and protein phosphatase-1 (dephosphorylates Hormone Sensitive Lipase) BUT in diabetic individuals, insulin deficiency/resistance results in an increased rate of lipolysis

Question 10

Diabetes effect on glucose production

Answer 10

1. Low levels of insulin or insufficient activity of insulin triggers the pancreas to make glucagon.
2. High levels of glucagon stimulate glycogenolysis and gluconeogenesis leading to an increase of glucose in liver which is transported back into blood further exacerbating hyperglycemia

Question 11

Diabetes effect on lipoprotein lipase (LPL)

Answer 11

Insulin deficiency/inactivity reduces lipoprotein lipase activity which leads to inadequate FFA transport into muscle and adipose tissue from VLDL’s of liver
Results in weight loss (poor transport and high lipolysis), Hyperlipidemia and steatosis

Question 12

Diabetes effect on the Randle cycle

Answer 12

Excess FFA blocks glucose oxidation. (FFA bound to albumin, not in VLDLs so no need for LPL and can be transported directly into cells through CD36)

Glucose transport impaired by lack of GLUT 4 activation caused by increased citrate. Also lipolysis creates high levels of acetyl-CoA which inhibits pyruvate dehydrogenase and stalls glycolysis. Results in excess lipolysis and exacerbates hyperglycemia

Question 13

Diabetes effect on Ketogenesis

Answer 13

Low levels of glucose in the cell (no GLUT 4 transport) and lack of insulin control of lipolysis. Glucagon stimulates gluconeogenesis which uses the oxaloacetate. This triggers excess acetyl-CoA to be used to make ketones

Can lead to Diabetic Ketoacidosis (diabetic individuals are always making ketones so can use ketone dipstick to determine diabetes)

Question 14

Diabetes effect on muscles

Answer 14

• Muscle proteins begin to breakdown as starvation signal persists. Protein synthesis requires insulin. Proteolysis increase substrates for gluconeogenesis (hyperglycemia) and ketogenesis (ketoacidosis)

Question 15

Cataracts

Answer 15

Opacity of the lens prevents light from being properly directed to retina
Common in dogs, rare in cats after diabetes diagnosis

Question 16

Metabolic cause of cataracts

Answer 16

1. Glucose is turned into sorbitol by aldose reductase
2. Sorbitol accumulates in the lens and hyperosmolarity (increase in solute concentration) sets in
3. Salty environment cause proteins to aggregate = cloudiness, AND causes an influx of water into the lens fibers causing swelling

Question 17

Aldose reductase levels normal vs. hyperglycemic

Answer 17

Normal: less than 5%
Hyperglycemia: 10-33%

Question 18

Why is cataracts less likely in cats?

Answer 18

Aldose reductase activity is much lower

Question 19

Glycation

Answer 19

Glucose spontaneously reacts with amino groups of protein, DNA, and lipid to form Amadori products. Increased rate during hyperglycemia.

Fructosamine= serum albumin + glucose

Question 20

Human equivalent of fructosamine

Answer 20

HbA1c

Question 21

Diabetes mellitus lipid toxicity

Answer 21

Reduced insulin or insulin activity results in decreases VLDL synthesis, reduced LPL activity, and uninhibited hormone sensitive lipase. Leads to hyperlipidemia, heptaomegaly and liver failure.

Liver failure results in decreased protein synthesis (serum albumin), glucose and glycogen synthesis, and lipid biosynthesis, uptake, and export.

Question 22

Pancreatitis caused by diabetes mellitus

Answer 22

Hyperlipidemia results in high levels of circulatory fat associated with immune cells which are thought to trigger inflammation events in the pancreas which can result in necrosis and cell death.

Decreased pancreas function can have impacts in both the endocrine system (insulin and glycogen), and the digestive system (secretion of digestive enzymes into small intestine)

Question 23

Diabetic ketoacidosis

Answer 23

High rate of ketoacidosis results in loss of bicarbonate, and metabolic acidosis

Metabolic acidosis has a huge effect on pH. Many enzymes are pH dependent so these changes can cause a loss of protein function and poor energy production.

Question 24

Diabetes effect on fluid/electrolyte imbalance

Answer 24

Imbalance occurs when the blood glucose and ketones exceed the renal threshold.

Steps:
1. Water, Ketones and glucose enter the nephrons of the kidney
2. The water, ketones, and glucose enter the kidney tubule which increases the tubule osmotic concentration. This reduces ability for water to be reabsorbed in the Loop of Henle. Leads to an increases urine rate (polyuria), increased thirst (polydipsia) and dehydration.

The significant decrease in blood volume (hypovolemia) results in circulatory shock, organ failure, and death