Lecture 12 - Diabetes

Question 1

What is diabetes mellitus?

Answer 1

A metabolic disorder characterized by elevated levels of blood glucose (hyperglycemia)

Question 2

Type 1 diabetes 1) Typical age at onset 2) Is it associated w/ obesity? 3) Describe plasma levels of insulin 4) What happens to islet cells? 5) Is ketoacidosis a concern? 6) What is the worldwide trend?

Answer 2

1) <30 years old (juvenile) 2) No 3) Low/undetectable 4) Beta cells are destroyed by immune system 5) Yes 6) Stable

Question 3

Type 2 Diabetes 1) Typical age at onset 2) Is it associated w/ obesity? 3) Describe plasma levels of insulin 4) What happens to islet cells? 5) Is ketoacidosis a concern? 6) What is the worldwide trend?

Answer 3

1) > 30 years old (adult) 2) Yes 3) variable 4) Loss of beta cells over time 5) No 6) Increasing rapidly

Question 4

In type 1 diabetes, what causes insulin deficiency?

Answer 4

Autoimmune destruction of pancreatic beta cells. The underlying cause of the autoimmune reaction is not known, but it is believed to be related to genetics or exposure to a certain virus that causes antibodies against proteins of the patient’s own beta cells

Question 5

How is glucose metabolism affected in type 1 diabetes?

Answer 5

Destruction of beta cells results in loss of insulin production and secretion. This decreases the uptake of glucose in tissues and decreases phosphorylation of glucose in the liver. This causes the liver to think that the body is deprived of glucose and so glucose output is increased. The liver accomplishes this by mobilizing glycogen and increasing gluconeogenesis. This constant production of glucose combined with dietary intake creates a state of constantly high plasma glucose.

Question 6

What are 4 common symptoms of type 1 diabetes?

Answer 6

• Glucosuria (loss of glucose in urine) - Polyuria (Glucose being excreted in urine pulls water with it, increasing the frequency of urination) - Polydipsia (Excessive thirst) - Polyphagia (increased appetite and food intake, body thinks it is starving all the time)

Question 7

How is lipid metabolism affected in type 1 diabetes?

Answer 7

Normally insulin signals to increase synthesis and storage of TAGs, but without insulin there is no synthesis of lipids in the liver and no storage of lipids in adipocytes. Because the body thinks it is starving, there is increased mobilization of TAGs from adipocytes, which leads to increased levels of plasma FAs and oxidation of FAs in tissues. This results in increased acetyl coA, but because gluconeogenesis is being run constantly by the liver there are not enough intermediates of CAC for acetyl coA to be used in CAC. There is no insulin to signal for lipid storage so the acetyl coA will be used to make ketone bodies.

Question 8

How is protein metabolism impacted by type 1 diabetes?

Answer 8

Because the body thinks it is starving, there will be increased protein catabolism to use for energy and increased [AAs] in blood.

Question 9

What causes ketoacidosis?

Answer 9

Ketone bodies are produced in large amounts in type 1 diabetics. These molecules are acidic so they lower the blood pH and the bicarbonate system cannot keep up to restore blood pH. This quickly becomes life threatening and can lead to coma and death.

Question 10

Type 1 diabetes is most commonly treated with an insulin pump to address hyperglycemia and lack of insulin. Why are type 1 diabetics also at risk for hypoglycemia?

Answer 10

If they administer too much insulin, then their blood sugar will dip too low. Insulin inhibits glucagon release so they will not be able to counter the drop in blood sugar. Thus, type 1 diabetics must very closely monitor their glucose, food intake, medication and insulin dose.

Question 11

Why is the prevalence of type 2 diabetes (T2D) increasing? (3)

Answer 11

1) More people are developing the disease due to over nutrition, obesity and inactive lifestyles 2) Treatments / therapies are getting better so people with the disease are living longer 3) Dangerous complications of the disease are also being treated better, which also leads to increased lifespan if one has the disease

Question 12

What is pre-diabetes?

Answer 12

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 13

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

Answer 13

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 14

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

Answer 14

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

Question 15

Describe the lipid burden hypothesis.

Answer 15

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 16

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

Answer 16

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 17

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

Answer 17

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 18

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

Answer 18

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 19

Describe how beta cells secrete insulin in a NORMALLY FUNCTIONING BETA CELL.

Answer 19

Glucose enters the beta cell via GLUT transporters and is converted to pyruvate via glycolysis. Pyruvate enters the mitochondria and is converted to AcoA by PDH. AcoA enters CAC. This leads to production of NADH and FADH2 which enter ETC and produce ATP. This increases ATP/ADP ratio. High ATP/ADP ratio inhibits ATP-sensitive K+ channels. This decreases the cell’s ability to maintain membrane potential (+ outside, - inside) by pumping K+ out of the cell, leading to depolarization (inside becomes more +). This leads to activation of voltage gated Ca2+ channels allowing Ca2+ to enter cell and trigger insulin release from insulin granules.

Question 20

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

Answer 20

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 21

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

Answer 21

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 22

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

Answer 22

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 23

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

Answer 23

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 24

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

Answer 24

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 25

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 25

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

Question 26

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 26

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

Question 27

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

Answer 27

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 28

How do GLP-1 analogues function to treat T2D?

Answer 28

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 29

What effects does GLP-1 have on the brain?

Answer 29

Increased neuroprotection Decreased appetite

Question 30

What effects does GLP-1 have on the stomach?

Answer 30

Slows gastric emptying

Question 31

What effect does GLP-1 have on the pancreas?

Answer 31

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

Question 32

What effect does GLP-1 have on the muscle?

Answer 32

Increases glucose uptake

Question 33

What effect does GLP-1 have on the liver?

Answer 33

Decreases gluconeogenesis

Question 34

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 34

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 35

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

Answer 35

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 36

How do α-glucosidase inhibitors function to treat T2D?

Answer 36

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.