Blood Glucose Homeostasis & Concept of Glucose Tolerance

Question 1

Incretins […] insulin’s effects

Answer 1

Augment

Question 2

What effect does exercise have on skeletal muscle?

Answer 2

Insulin-dependent increase in # GLUT4 transporters –> increased glucose entry. The effect can persist for hours after exercise and if a person exercises regularly the result can be prolonged improvement in insulin sensitivity.

Question 3

What advice do you have to give to diabetic patients who want to exercise?

Answer 3

Because insulin makes muscle more sensitive to its effects, exercise will cause muscle to respond more to insulin and take in more glucose from the blood. As a result, diabetics should to reduce their insulin levels or take in extra calories prior to exercise to prevent becoming hypoglycemic due to the increased response to insulin that will result with exercise.

Question 4

Insulin […] hormone sensitive lipase in white fat.

Answer 4

Inhibits

Question 5

What hormones stimulate HSL in white fat?

Answer 5

Glucagon

Catecholamines

GH

Cortisol

Question 6

What are some of the bodily processes that white fat is involved in?

Answer 6

Question 7

How is adiponectin related to fat mass?

Answer 7

Inversely proportional –> high adiponectin = low body fat

Question 8

What factors reduce adiponectin?

Answer 8

Pro-inflammatory cytokines (TNF-alpha, secreted by fat)

Question 9

Low adiponectin puts one at risk for what diseases?

Answer 9

T2DM, Metabolic syndrome, Insulin resistance, coronary artery disease

Question 10

What does adiponectin do to glucose levels in blood and insulin?

Answer 10

Reduce blood glu

Increase insulin sensitivity via increased FA oxidation and inhibition of hepatic gluconeogenesis

Question 11

What is a normal fasting plasma glucose range?

Answer 11

60 - 100 mg/dL

Question 12

Plasma glucose must be > […] to see glycosuria

Answer 12

180mg / dL

Question 13

Why is it bad for plasma glucose to be too low?

To be too high?

Answer 13

Question 14

Oral Glucose Tolerance Test

• What does this test measure?
• What are the indications for doing the test?
• How do you peform this test?

Answer 14

Question 15

In a normal person, renal threshold for glucose is around 180 mg/dL. How does this change in someone who is:

• Pregnant
• Elderly

Answer 15

• Lower in pregnant women
• Higher in eldergy

RTG has to do with SGLT2 transporter. In elderly for example, transporter may be less efficient or may be less of them in membrane. This results in higher levels of glu needed in blood to see entry of glu into urine.

Question 16

Insulin resistance is almost always associated with […]

Answer 16

Hyper-insulinemia

Question 17

What is believed to be the mechanism of insulin receptor resistance?

Answer 17

Down regulation of insulin receptors in response to hyper-insulinemia

Question 18

Describe how the plasma glucose and plasma insulin levels would look in:

• Normal person
• Pre-diabetic person
• Type 2 diabetic person

Answer 18

Question 19

What is pre-diabetes?

Answer 19

Prediabetes is the stage before the onset of T2D. It is usually 5 - 10 years before T2D onset and it is characterized as a mildly hyperglycemic state which serves as a marker of patients at risk for developing T2D. Patients who are prediabetic exhibit impaired glucose tolerance (increased glucose levels 2 hours after meal), impaired fasting plasma glucose (increased fasting glucose levels), increased HbA1c (indication of glucose levels over time).

Question 20

What are the 3 predominant mechanisms underlying insulin resistance in type 2 diabetes suggested by research?

Answer 20

1) Lipid burden hypothesis that causes a dysfunction of adipose tissue 2) Inflammatory response that causes a dysfunction of adipose tissue 3) Dysfunction of mitochondria in liver and muscle

Question 21

What are the 3 predominant mechanisms underlying impaired insulin secretion in the pancreas / beta cell failure?

Answer 21

1) Pyruvate cycling 2) ER stress 3) Amyloid fibrils

Question 22

Describe the lipid burden hypothesis.

Answer 22

In obesity, the capacity of adipocytes to store TAGs is decreased and adipocytes become less sensitive to insulin which leads to adipocyte dysfunction. Expression of PPAR gamma is decreased in adipose tissue and increased in muscle and liver, which leads to increased storage of lipids in liver and muscle and decreased storage in adipose tissue.

Question 23

Describe the role that inflammation has in leading to adipose dysfunction.

Answer 23

In the overweight state, adipocytes increase in size due to increased TAG storage. This results in increased expression of TAG storage enzymes. Continual overloading of the adipose tissue results in increased burden on the adipose tissue. This results in release of MCP-1, which attracts macrophages which release TNF alpha and other cytokines that cause inflammation. This inflammation decreases insulin signaling and leads to impaired TAG storage, resulting in increased lipolysis and increased circulating FAs. This, combined with increased expression of PPAR gamma, leads to increased accumulation of lipid in the liver and muscle and this accumulation interferes with GLUT4 function leading to insulin resistance.

Question 24

What are the consequences of FA accumulation in the liver and how does this lead to insulin resistance?

Answer 24

Overnutrition leads to increased [FA] and increased [glucose] from the diet. Increased dietary FA results in increased uptake of FA in the liver. Increased glucose means that there is more glucose than is needed to meet cellular energy demands and so it is used for FA synthesis. This results in increased [malonyl coA] which inhibits beta oxidation in the liver resulting in increased TAG synthesis and increased accumulation of fatty acid metabolites such as diacylglyerol and ceremide. These metabolites activate stress induced kinases which inhibit insulin signaling and lead to insulin resistance.

Question 25

What are the consequences of FA accumulation in muscle and how does it lead to insulin resistance?

Answer 25

In muscle, over nutrition leads to increased FA being taken up in muscle from diet. Unlike the liver, this FA can be oxidized because the muscle cannot use the excess glucose to make FAs. So any increase in FAs results in increased FA oxidation. This increased demand for oxidation results in overload of the mitochondria such that the rate of beta oxidation surpasses that of the CAC and ETC. This high demand surpasses the capabilities of the mitochondria leading to incomplete oxidation products, such as acylcarnitines and reactive oxygen species. These byproducts activate stress induced kinases, which inhibit insulin signaling and decrease the [GLUT4] in the membrane of the cell leading to hyperglycemia.

Question 26

Describe the role that pyruvate cycling plays in a NORMAL BETA CELL.

Answer 26

Pyruvate can also be converted to OAA by pyruvate carboxylase (PC) in the mitochondria. Increased [OAA] produces increased intermediates of CAC. Some of these intermediates (malate, citrate) can exit the mitochondria into the cytosol via transporters. Once in cytosol, they can enter pathways that produce NADPH, alpha ketoglutarate, and GTP, which will result in amplification of insulin signaling, leading to increased insulin secretion.

Question 27

Describe the role that pyruvate cycling plays in a DYSFUNCTIONAL BETA CELL.

Answer 27

Overnutrition leads to increased FA uptake in beta cells as well as increased glucose uptake. Increased FA uptake results in increased FA oxidation producing lots of acetyl coA. Increased glucose uptake also results in increased glycolysis and production of acetyl coA. Build up of AcoA inhibits PDH and activates PC, converting pyruvate to OAA instead of AcoA. Increased [OAA] results in increased flux of pyruvate cycling, leading to hyper secretion of insulin that is independent of energy state (amount of ATP). Overtime, hyper secretion of insulin leads to decrease in responsiveness of beta cell to glucose and decrease in insulin release.

Question 28

Describe how ER stress plays a role in Beta cell dysfunction / reduced insulin secretion.

Answer 28

Insulin is a protein that folds in the ER. In over nutrition/T2D there is increased production of insulin. This means that the ER is overloaded with the amount of insulin protein it is processing. This chronic increase in workload due to increased demand leads to ER stress and protein misfiling, which stresses the cell and leads to apoptosis.

Question 29

IN NORMAL BETA CELLS, what is the role of amylin?

Answer 29

Amylin is co-secreted with insulin (in lower [conc.]). It slows gastric emptying (slows time nutrients and glucose are being absorbed by intestines to blood, keeping blood sugar levels from spiking), suppresses glucagon release, and suppresses appetite.

Question 30

IN DYSFUNCTIONAL BETA CELLS, what is the role of amylin?

Answer 30

In a state of insulin hyper secretion (early T2D), amylin is also co-secreted in elevated amounts. Amylin is a protein that tends to "clump" together into aggregates, so increased secretion of amylin increases amylin aggregate formation. Large clumps of amylin in the cell overload cellular machinery and lead to cell dysfunction and potential apoptosis.

Question 31

Weight Loss 1) Effect on adipose tissue? 2) Effect of treatment wrt lipid burden hypothesis? 3) Increases capacity for ___ \_\_\_ 4) Effect on insulin sensitivity

Answer 31

1) Decreased TAG content 2) Decreases lipid burden 3) TAG storage in adipose 4) Restores insulin sensitivity

Question 32

Exercise 1) What molecule is the target of exercise? 2) Effect on FA and cholesterol synthesis 3) ___ FA oxidation 4) ___ Glucose uptake 5) ___ gluconeogenesis

Answer 32

1) Activating AMPK (activated by increased [AMP]/[ATP], turns on catabolic pathways) 2) Decreases 3) Increases 4) Increases 5) Decreases

Question 33

How do sulfonylureas function to treat T2D? What are their limitations?

Answer 33

Sulfonylureas inhibit K+ channels that are ATP sensitive. This leads to accumulation of K+ inside the cell, leading to depolarization and insulin release. These drugs are more beneficial in late stage T2D when the patient has lost beta cell function and is lacking insulin secretion. They are completely ineffective if the patient is insulin resistant at the insulin receptor level.

Question 34

How do GLP-1 analogues function to treat T2D?

Answer 34

Endogenous GLP-1 is released from the intestines and it functions to increase insulin release. However endogenous GLP-1 has a very short half life, so it is quickly broken down. The analogue is able to resist degradation for a while longer to exert its effects.

Question 35

What effects does GLP-1 have on the brain?

Answer 35

Increased neuroprotection Decreased appetite

Question 36

What effects does GLP-1 have on the stomach?

Answer 36

Slows gastric emptying

Question 37

What effect does GLP-1 have on the pancreas?

Answer 37

Increases insulin secretion Increases beta cell neogenesis Decreases beta cell apoptosis Decreases glucagon secretion

Question 38

What effect does GLP-1 have on the muscle?

Answer 38

Increases glucose uptake

Question 39

What effect does GLP-1 have on the liver?

Answer 39

Decreases gluconeogenesis

Question 40

Biguanides (Metformin) 1) Through what protein does it work? 2) Effect on glucose metabolism in liver? 3) Effect on glucose uptake in muscle and adipose tissue? 4) Effect on lipid synthesis?

Answer 40

1) Metformin activates AMPK which in turn activates catabolic pathways and reduces flux through anabolic pathways. 2) Metformin also reduces hepatic glucose production by inhibiting gluconeogenesis. 3) It increases glucose uptake in skeletal muscle and adipocytes 4) It decreases lipid synthesis thus decreasing lipid burden.

Question 41

Thiazolidinediones 1) Through what protein does it work? 2) Effect on muscle and liver? 3) Effect on genes? 4) Effect of fat stores?

Answer 41

1) Activates PPAR gamme in adipose tissue 2) Increases insulin sensitivity 3) Effects transcription of genes involved in glucose/lipid metabolism and energy balance 4) Shifts fat storage from visceral to subcutaneous

Question 42

How do α-glucosidase inhibitors function to treat T2D?

Answer 42

In the small intestines, α-glucosidase is an enzyme that hydrolyzes polysaccharides into glucose monomers. Inhibitors of this enzyme reduce the digestion of polysaccharides from the diet and therefore reduce their absorption into circulation.

Question 43

Why is carrying a lot of fat around the waist (apple shape) particularly bad?

Answer 43

Associated with higher risk of CV related illnesses

Question 44

**Metabolic Syndrome** * Signs/symptoms * Consequences * When do you make dx?

Answer 44

* See slide * See slide * Make dx when pt had 3 of following: * High abdominal waist circumference * Hyper-triglyceridemia * Low HDL * HTN * Hyperglycemia

Question 45

What is diabetes?

Answer 45

Disorder characterized by impaired CHO, fat and AA metabolism

Question 46

What are the clinical signs/symptoms of diabetes?

Answer 46

Polyuria Polydipsia Hyperglycemia Ketonuria Ketoacidosis Weight loss (sudden, rapid) Polyphagia

Question 47

What are the chronic macro and microvascular complications of diabetes?

Answer 47

Question 48

What is hypoglycemia? Why is it so dangerous? What can cause it? How would a person present if they are hypoglycemic? How do dx and treat?

Answer 48