Lecture 35: Coordinating metabolism: Diabetes (Type II)

Question 1

Diabetes: Biochemical Features and
Symptoms

Answer 1

• Fasting glucose >7.0 mmol/L or random >11.1 mmol/L.
• HbA1c ≥50 mmol/mol (6.7% HbA1C) is the main diagnostic criteria.
• Glycosuria, osmotic diuresis and dehydration.
• Ketoacidosis (ketonemia and ketonuria). More common in type I.
• Symptoms include thirst, frequent urination, fatigue, hyperventilation, blurred vision and coma.
• Associated with a number of complications i.e. vascular diseases.
• Associated with elevated blood triacylglycerol levels

Question 2

Explain why glycated haemoglobin is used for diabetes diagnosis.

Answer 2

When glucose builds up in your blood, it binds to the
haemoglobin in RBCs.

The HbA1c test measures how much glucose is bound.

As RBCs live for about 3 months, the test shows the average level of blood glucose for the past 3 months.

HbA1c ≥50 mmol/mol (6.7%) is indicative of diabetes

Question 3

What effects can sustained high blood glucose levels have on blood vessels?

Answer 3

Vascular pathologies can result from glycation of structural proteins in arteries, making the, less compliant,

AND

from the formation of advanced glycation end (AGE)
products, which promote inflammation and atherosclerosis.

Question 4

What does a glucose tolerance test show, what are some signs that a person might be diabetic or pre diabetic?

Answer 4

A glucose tolerance test sees how well the body handles glucose. An oral glucose load (75g) is given after an overnight fast and blood glucose levels are then monitored for 2 hours.

A prediabetic will show a slightly elevated fasting level (5.6 to 7) and an impaired lowering.

Diabetics have an elevated fasting blood glucose >7 mmol/L and a very impaired lowering i.e. not returning to pre-load value

Question 5

Explain insulin resistance and what this could indicate:

Answer 5

Reduced response to the same amount of insulin

Higher insulin levels are required to control blood glucose in the insulin resistant individual compared to normal levels.

• Early warning sign that an individual is heading towards diabetes
• Over time the hyperinsulinaemia diminishes the ability of B cells to respond to further increases in blood glucose and the individual becomes glucose intolerant (prediabetic) and eventually diabetic.

Question 6

Type two diabetes causes insulin to not work - what situation does this then become similar to?

Answer 6

It appears that insulin isn’t working and glucagon effects
are prominent i.e. gluconeogenesis,lipolysis and ketone production.

The body looks like it is starving

Question 7

Why does insulin resistance lead to an accumulation of TAGs in the blood?

Answer 7

Insulin resistance reduces the hydrolysis of TAGs in chylomicrons and VLDL by LPL. This leads to their accumulation and an increase in blood TAGs.

(can’t be transferred into tissues in the larger form)

Question 8

What are some prominent features of insulin resistance?

Answer 8

Decreased glucose uptake and increased gluconeogenesis are prominent features as is elevated blood FFAs.

Question 9

Do some type 2 diabetics require insulin shots?

Answer 9

Yes

The hyperglycaemia induced by IR causes the pancreas to produce more insulin but eventually the B cells response diminishes, and insulin levels drop (some type 2 diabetics can require insulin).

Question 10

What is really happening with insulin resistance: at a cell signaling level?

Answer 10

They don’t really know:

There is evidence of reduced levels of phosphorylation and mis-phosphorylations (i.e. pS instead of pY) in insulin signaling proteins which reduces GLUT4 translocation likely promoted by FFAs, inflammatory cytokines and oxidative stress.

Question 11

What are the treatments for diabetes type 2 generally aimed at?

Answer 11

Treatments are mainly aimed at promoting insulin
secretion and improving insulin sensitivity.

Question 12

Explain how exercise enhances insulin sensitivity?

Answer 12

Exercise enhances insulin sensitivity through:

GLUT4 Translocation:
Muscle contractions stimulate the translocation of GLUT4 to the cell membrane, increasing glucose uptake independently of insulin.

AMPK Activation:
Exercise activates AMPK, which enhances insulin signaling and decreases hepatic glucose production.

Reduction of Inflammation:
Regular physical activity lowers inflammatory cytokines that impair insulin signaling.

These mechanisms collectively improve insulin sensitivity and glucose metabolism

Question 13

Name a drug that enhances insulin sensitivity and describe how it works.

Answer 13

Metformin:

Both metformin and exercise increase AMP levels, which
activates AMPK, which reduces gluconeogenesis. This
reduces blood glucose levels

Question 14

Name two drugs that promote insulin secretion and describe how they work:

Answer 14

Sulfonylureas promote insulin secretion by closing ATP-sensitive potassium channels in beta cells, leading to increased calcium influx and insulin release.

GLP-1 agonists enhance insulin secretion in a glucose-dependent manner, slow gastric emptying, and reduce glucagon secretion, helping to improve blood glucose control.

Question 15

What is the new drug for managing diabetes? How does it work?

Answer 15

SGLT2 inhibitors (Empagliflozin)

SGLT2 is expressed in the kidney proximal tubule where
it reabsorbs glucose back into circulation.

Inhibiting it allows glucose to remain in urine for excretion and hence lowers blood glucose levels.