Diabetes

Question 1

Describe Insulin dependent diabetes (Type 1)

Answer 1

Patients who cannot survive without insulin

Mainly young (Juvenile onset), but increasingly observed in later life

Ketosis may lead to death

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 disease of glucagon excess

Treatment – insulin injections

Question 2

Give the classical symptoms of Insulin dependent diabetes

Answer 2

Classical symptoms- Thirst, Tiredness, Weight loss Polyuria (glucose + ketone bodies )
Hyperglycaemic coma

Question 3

List some major consequences of type 1 diabetes

Answer 3

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 4

Describe the IDDM state of the liver

Answer 4

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 5

Describe the IDDM state of the muscle

Answer 5

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 6

Describe the IDDM state in the adipose tissue

Answer 6

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 7

Describe the IDDM diabetic state of the plasma and urine

Answer 7

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 8

State the possible life-threatening short term consequences of diabetes

Answer 8

Hyperglycaemia and ketoacidosis
- characteristic of type I diabetes

Hyperosmolar hyperglycaemic state (Non-ketotic hyperosmolar coma)
- Characteristic of type II diabetes

Question 9

State the possible life-threatening long term consequences of diabetes

Answer 9

Predisposition to CV disease and organ damage

Retinopathy – cataracts, glaucoma and blindness

Nephropathy

Neuropathy

Question 10

Whys is glucose toxic in excess?

Answer 10

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 11

How do the long term consequences of type 1 and type 2 differ?

Answer 11

They are the same since they are caused by hyperglycemia

Question 12

How is diabetes diagnosed?

Answer 12

TWO MAJOR TESTS:
Fasting blood glucose levels
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
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. Diabetic : glucose remains >11.1mM at 2hrs. Can determine pre-diabetic patients too.

Question 13

How is type 1 diabetes treated?

Answer 13

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 14

What are insulin treatment regimes?

Answer 14

Premixed insulin
Requires less injecting
Timing of meals may be critical
Insulin and food taken at the same time
Provides greater flexibility for those doing shift work etc. Potential nocturnal hypoglycaemia
Rapid acting with short half life, reduces the potential for nocturnal hypoglycaemia.
More expensive

Question 15

What is non-insulin dependent diabetes?

Answer 15

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
Failure of the body to respond properly to insulin:
Insensitivity of target cells to insulin (defects in receptors and cell signalling)
Impaired insulin secretion (amyloid deposits reducing β-cell mass)
Link to obesity
Glucagon secretion not increased

Question 16

Give some mechanisms of insulin resistance

Answer 16

Can be caused by a number of possible defects

Mutations in insulin receptor gene (very rare)

Most important are defects in insulin signalling pathway

These include defects in cellular translocation of Glut-4 (and glucose uptake) e.g. this has been observed in adipocytes (but not skeletal muscle) in both obesity and diabetes.

Peripheral insulin resistance is induced by presence of excess fatty acids - inhibit peripheral glucose disposal and enhance hepatic glucose output

Question 17

List some features of type 2 diabetes

Answer 17

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

Question 18

Describe metabolism in type 2 diabetes

Answer 18

Glucagon levels not raised to same extent as in Type 1, as some insulin present and suppresses glucagon secretion

Hyperglycaemia arises mainly from lack of glucose uptake. Glycogen stored normally in liver and liver continues to produce VLDL from glucose and amino acids

Uncontrolled lipolysis and therefore ketone body formation are not a feature of Type 2 diabetes as insulin release suppresses glucagon secretion.

Hypertriglyceridemia and macrovascular disease is characteristic due to increased VLDL synthesis in liver

Question 19

What treatment is given for type 2 diabetes?

Answer 19

Diet and Exercise (effect on glut 4)
Oral hypoglycaemic agents – various therapeutic targets:

Insulin secretion e.g. sulphonylureas (hypoglycaemia is a side-effect)

Tissue insulin sensitivity e.g. Biguanides (Metformin) or Thiazolidinediones (Pioglitazone)

Absorption and digestion of carbohydrates e.g. glucosidase inhibitors (acarbose)

Question 20

How does Sulphonylureas (Gliclazide) work?

Answer 20

Glucose (>7mM) depolarizes the membrane by ATP-dependent closing of K+ channels
Depolarization of the membrane opens voltage-dependent Ca2+ channels with influx of Ca2+ causing secretion of insulin
Sulphonylureas interact with receptor closing K+ channel

Question 21

How does Metformin (Biguanides) work?

Answer 21

1st choice hypoglycaemic agent
Does not produce hypoglycaemia
Suppresses appetite – useful if overweight
Only effective in the presence of insulin
Increases insulin sensitivity
Reduces LDL and VLDL and CV risk.

Question 22

How does Thiazolidinediones (glitazones) - Pioglitazone) work?

Answer 22

Slow onset, effect achieved after 1-2 months
of treatment

Reduce hepatic glucose output and increase
glucose uptake into muscle, enhances
effectiveness of endogenous insulin and reduces
the amount of exogenous insulin needed

Reduction in glucose may be accompanied by reductions in circulating insulin, free fatty acids, triglycerides and small dense LDL particles (most atherogenic)

Bind to nuclear receptor, the peroxisome proliferator-activated receptor-gamma (PPARgamma) regulating gene expression, particularly in adipose tissue

Question 23

Describe the Targeting Glucagon-like Peptide (GLP-1 )

Answer 23

GLP-1 and GIP (Glucose-dependent insulinotropic peptide) produced by endocrine cells of the intestine following ingestion of food and stimulate insulin secretion. Have a very short half-life in vivo so ineffective as therapeutic
Exendin-4: 39 amino acid peptide hormone found in the saliva of the poisonous Gila monster. It is a powerful stimulator of the GLP-1 receptor.
Exenatide (Byetta) – synthetic version of exendin-4, with longer half-life in vivo. Stimulates insulin secretion, inhibits glucagon secretion, and glucose production by the liver.
Can be used in conjunction with other oral hypoglycaemic agents to achieve maximal effect. Downside: requires injection
Vildagliptin (Galvus) inhibits the inactivation of GLP-1 and GIP allowing increased activity of GLP-1. Can be used in combination with oral hypoglycaemics – danger of hypoglycaemia!