Diabetes

Question 1

What is type 1 diabetes mellitus?

Answer 1

Type 1 diabetes mellitus
Insulin-dependent diabetes (IDDM)

• Patients who lack insulin. Treatment – insulin injections
• Mainly young (Juvenile onset)

Question 2

What are the symptoms of type 1 diabetes?

Answer 2

•Classic symptoms- Thirst, Tiredness, Weight loss

Polyuria (containing glucose + ketone bodies)

Ketoacidosis

Hyperglycaemic coma

Question 3

What causes type 1 diabetes?

Answer 3

• Results from autoimmune destruction of the β-cells of the islets of Langerhans. Sometimes follows viral infection such as mumps, rubella, or measles.
• As there is no feedback inhibition by insulin on α-cells, glucagon levels remain high, therefore also a disease of glucagon excess

Question 4

What are the metabolic consequences of diabetes?

Answer 4

• Blood insulin levels low despite high blood glucose, whereas glucagon levels are raised
• Insulin:glucagon ratio cannot increase even when dietary glucose enters from the gut. Metabolism stuck in the starved phase
• Low insulin:glucagon ratio leads to induction of catabolic enzymes and repression of anabolic enzymes

Question 5

What is the type 1 diabetic state in the liver?

Answer 5

• Despite high blood glucose, liver remains gluconeogenic because of high glucagon. Lactate and amino acids such as alanine from protein breakdown are main substrates for glucose production hence muscle wasting.
• Glycogen synthesis and glycolysis also inhibited; therefore liver cannot adequately buffer blood glucose.
• Fatty acids from lipolysis enter liver and provide energy to support gluconeogenesis while excess fatty acids are converted to TAGs and VLDL.
• Excess acetyl CoA from fatty acid oxidation converted to ketone bodies and if not used sufficiently rapidly can lead to ketoacidosis due to accumulation of ketone bodies and H+ ions in the blood.

Question 6

What is the effect of type 1 diabetes on ketone bodies?

Answer 6

Occurs normally under all conditions but increases dramatically during starvation

Prolonged low insulin:glucagon ratio result in:

• increased mobilisation of fatty acids from adipose tissue
• increased amounts of the enzymes required to synthesize and utilize ketone bodies

Question 7

Why does increased lipid mobilization stimulate ketone body formation?

Answer 7

• In the liver, the increased demand for gluconeogenesis results in depletion of oxaloacetate
• This decreases the capacity of the TCA cycle which increases the levels of acetyl-CoA present
• Acetyl-CoA is the substrate for production of ketone bodies

Question 8

How do ketone bodies form?

Answer 8

Question 9

What is the type 1 diabetic state in muscle?

Answer 9

• Relatively little glucose entry into muscle and peripheral tissues because of insulin lack. This contributes to hyperglycaemia
• Fatty acid and ketone body oxidation used as the major source of fuel
• Proteolysis occurs to provide carbon skeletons for gluconeogenesis leading to muscle wasting

Question 10

What is the type 1 diabetic state in adipose tissue?

Answer 10

• Despite the high glucose concentrations in the plasma, uptake of glucose is diminished by loss of insulin
• Low insulin:glucagon ratio enhances lipolysis leading to continuous breakdown of triacylglycerol and release of fatty acids and glycerol into the blood stream to support energy production in peripheral tissues and gluconeogenesis in the liver

Question 11

What is the type 1 diabetic state in plasma and urine?

Answer 11

• Constant production of excess glucose while utilising less leads to hyperglycaemia
• Glucose concentration exceeds renal threshold and is excreted in the urine (glycosuria) with loss of water and development of thirst
• Fatty acid synthesis greatly diminished in the diabetic state; VLDL secreted by the liver and chylomicrons entering from the gut cannot be metabolised properly as expression of lipoprotein lipase is regulated by insulin. Results in hypertriglyceridaemia and hyperchylomicronaemia and susceptibility to cardiovascular events.

Question 12

What are the short-term Possible life-threatening consequences of diabetes?

Answer 12

•Hyperglycaemia and ketoacidosis

Characteristic of type 1 diabetes

•Hyperosmolar hyperglycaemic state (Non-ketotic hyperosmolar coma)

Characteristic of type 2 diabetes

Question 13

What are the long-term Possible consequences of diabetes?

Answer 13

1. Predisposition to CV disease and organ damage
2. Retinopathy – cataracts, glaucoma and blindness
3. Nephropathy
4. Neuropathy

Question 14

Why is Glucose toxic in excess?

Answer 14

High concentration of glucose results in:

• generation of ROS
• osmotic damage to cells
• glycosylation leading to alterations in protein function
• formation of advanced glycation end products (AGE) which increase ROS and inflammatory proteins

Question 15

What are the 2 major tests for diagnosing diabetes?

Answer 15

Fasting blood glucose levels (WHO criteria)

After an overnight fast a blood glucose value of 126mg/dl (7.0mM) and above on at least two occasions indicates diabetes (normal range are between 70-110 mg/dl, i.e. less than 6.1mM)

Glucose tolerance test (WHO criteria)

Performed in morning after an overnight fast. Fasting blood sample is removed and subject drinks ‘glucola‘ drink containing 75g of glucose. Blood glucose is then sampled at 20 min, 1 hr and 2 hr.

Question 16

What test result indicates diabetes?

Answer 16

Diabetic: glucose remains >11.1 mM at 2 hr

Question 17

What is HbA1c?

Answer 17

HbA1c – glycated haemoglobin

Lifespan of RBCs is 8-12 weeks, so HbA1c measurements can be used to reflect average blood glucose levels over that duration, providing a useful longer-term gauge of blood glucose control.

Question 18

What is the HbA1c target for diabetics?

Answer 18

Question 19

How is type 1 diabetes treated?

Answer 19

Aim – mimic normal daily insulin secretion. Endogenous insulin secretion normally peaks within one hour after a meal with insulin secretion and plasma glucose levels returning to basal levels within two hours of the end of the meal-induced hyperglycaemia.

Question 20

Complete the table with types of insulin used to treat type 1 diabetes

Answer 20

Question 21

What is type 2 diabetes?

Answer 21

Type 2 diabetes mellitus (Non-Insulin-dependent diabetes mellitus (NIDDM)

Disease where there is not enough insulin to keep the blood glucose normal

It is a combination of:

• Impaired insulin secretion
• Increased peripheral insulin resistance
• Increased hepatic glucose output

Question 22

What are the causes of type 2 diabetes?

Answer 22

Failure of the body to respond properly to insulin:

1. Insensitivity of target cells to insulin (defects in receptors and cell signalling)
2. Impaired insulin secretion (amyloid deposits reducing β-cell mass)

Linked to obesity

Question 23

What are the mechanisms of insulin resistance?

Answer 23

Can be caused by a number of possible defects

• Mutations in insulin receptor gene (very rare)
• Most important are defects in insulin signalling pathway

Question 24

Peripheral insulin resistance is induced by…

Answer 24

• presence of excess fatty acids - inhibit peripheral glucose disposal and enhance hepatic glucose output
• dysregulated adipokines from adipose tissue
• also induced by defects in cellular translocation of Glut-4 (and glucose uptake). This has been observed in adipocytes (but not skeletal muscle) in both obesity and diabetes.

Question 25

What are the features of type 2 diabetes?

Answer 25

• Develops over many years, 2-6% of adults affected.
• Approx 90% of diabetic population are type 2
• Patients can survive long term without insulin and are often older and obese, but being increasingly observed in adolescents
• Associated with macrovascular disease, stroke and atherosclerosis (increased VLDL and LDL)
• May be asymptomatic, but may have classical hyperglycaemic symptoms (thirst, polyuria, weight loss)
• Ketone bodies present in low concentrations

Question 26

What changes to metabolism occur as a result of type 2 diabetes?

Answer 26

• Glucagon levels not raised to same extent as in Type 1, as some insulin present to suppress glucagon secretion
• Therefore, uncontrolled lipolysis and therefore ketone body formation are not a feature of Type 2 diabetes.
• Hyperglycaemia arises mainly from lack of glucose uptake.
• Hypertriglyceridemia and macrovascular disease is characteristic due to increased VLDL synthesis in liver from glucose and fatty acids from diet and fatty acids from adipose tissue

Question 27

How is type 2 diabetes treated?

Answer 27

• Diet and exercise (effect on glut 4)
• Oral hypoglycaemic agents – various mechanisms of action:

ØSulphonylureas increase insulin secretion (hypoglycaemia is a side-effect)

ØBiguanides (e.g. Metformin) or Thiazolidinediones (e.g. Pioglitazone) increase tissue insulin sensitivity

ØGlucosidase inhibitors (e.g. acarbose) reduces the absorption and digestion of carbohydrates

Question 28

A 10-year-old girl started to lose weight fast, and pass large volumes of urine, while eating and drinking excessively.

1. What is the most likely cause of these symptoms?
2. What is the likely underlying cause of the disease?
3. Why did this girl lose weight so quickly while eating excessively?
4. Why did this girl pass large volumes of urine?

Answer 28

1. These are the classic signs of Type 1 insulin-dependent diabetes mellitus. Why Type 1 diabetes? Age of the child, rapid weight loss, no evidence of obesity
2. In a normal person, release of insulin is matched, minute-by-minute, to the concentrations of glucose in blood. Disease arises because the β-cells of the pancreas can no longer release the proper amount of insulin in response to a given concentration of glucose in the blood. The body reacts as if it were in uncontrolled starvation, irrespective of dietary intake or the concentrations of fuels in the circulation.
3. This patient lost weight quickly because of the catabolism of muscle protein, which is stored with water in cells (heavy calories).
4. Stores of fat and protein are rapidly broken down, causing high concentrations of fatty acids, ketoacids and glucose in the blood. Amino acids are made into glucose, and fatty acids into ketoacids. Glucose and ketoacids appear in urine, requiring excretion of water and salts. Loss of water and salts in the urine will make her very thirsty and therefore she will be drinking excessive amounts of water

Question 29

Patients with untreated Type 1 diabetes continually undergo catabolism of triacylglycerols in adipose tissue yet hyperchylomicronaemia and hypertriglyceridaemia are commonly associated with this disease. Why?

Answer 29

·The low insulin:glucagon ratio results in high rates of triacylglycerol hydrolysis and release of free fatty acids into the bloodstream

·More free fatty acids enter the liver than can be metabolised by the TCA cycle and ketone body formation and hence the fatty acids are directed into triacylglycerol and VLDL formation which are secreted into the bloodstream.

·Lipoprotein lipase is induced by insulin and therefore in the absence of insulin the levels of LPL on the endothelial cells is reduced, therefore the metabolism of both chylomicrons and VLDL is reduced leading to hyperchylomicronaemia and hypertriglyceridaemia.

Question 30

How does ketogenesis differ between untreated type 1 AND type 2 diabetes

AND why does this occur?

Answer 30

Ketogenesis is a feature of type 1, but not type 2 diabetes.

Ketogenesis does not occur in type 2 diabetes as glucagon secretion is normal in this condition therefore there is no uncontrolled lipolysis

Question 31

With respect to Type1 diabetes, identify the missing components (A, B, C, D) in the Figure below.

Answer 31

A = Increased plasma amino acids

B = Increased ureagenesis

C = Glycosuria

D = Ketoacidosis