Glucose Metabolism 2

Question 1

(briefly) describe the pancreas

Answer 1

The pancreas is a pinkish- grey sponge-like organ that is connected to the duodenum and sits behind the stomach
It is composed of exocrine and endocrine components
The exocrine component secrete digestive juices and the endocrine component (or Islets of Langerhans) secrete hormones involved in glucose homeostasis

Question 2

describe insulin synthesis

Answer 2

B-cells are stimulated to release insulin by high blood glucose levels
Pre-insulin is split into insulin and C-peptide
Both insulin and C peptide are packaged into secretary granules in the glogi and are released together.
C peptide exploited diagnostically to examine cell function in diabetics.

Question 3

describe control of insulin secretion

Answer 3

Released mainly in response to HIGH blood glucose levels
Neural signals also contribute to secretion (eg sight and taste of food)
High concentrations of other metabolites eg amino acids and fatty acids also stimulate secretion

Question 4

what is the role of insulin in glucose metabolism

Answer 4

• Increases permeability of cells to glucose
• Increases glycolysis by activating key enzymes:
a) Glucokinase (liver and pancreas)
b) Phosphofructokinase (PFK)
• Increases glycogen synthesis
(glycogenesis) by activation of Glycogen synthase
• Decrease in glycogen breakdown and gluconeogenesis

Question 5

what are physiological effects of insulin

Answer 5

• Insulin plays a key role in control of metabolism 
• Insulin organises fuel for storage or oxidisation
• Insulin profoundly effects carbohydrate metabolism 
• Insulin also effects protein, lipid and mineral metabolism
Any disturbances in Insulin signalling have profound implications for organs and tissues

Question 6

Role of insulin in carbohydrate metabolism?

Answer 6

Glucose rises which increases glucokinase activity and therefore glycolysis in the pancreatic B cells which causes increase in Insulin secretion and synthesis
Increased blood insulin levels cause increased insulin sensitive GLUTs at the membrane of cells such as skeletal and cardiac muscle which means more glucose uptake and increased glycolysis
In the liver increased activity of glucokinase means more glucose trapped for glycogen synthesis and gluconeogenesis and glycogenolysis are inhibited.
As glucose levels decrease - insulin secretion decreases
INSULIN DECREASES BLOOD GLUCOSE CONCENTRATION!

Question 7

Role of insulin in lipid metabolism?

Answer 7

Insulin promotes fatty acid synthesis
• As glycogen stores become saturated, glucose is taken up by the liver and converted to fatty acids which are then transported to adipose tissue as lipoproteins
Insulin inhibits fat breakdown in adipocytes
• Inhibits lipase which hydrolyses triglycerides to fatty acids
Insulin increases glucose uptake into adipocyte
• Converted to glycerol and these +FA TG
DECREASED BLOOD FATTY ACID AND KETONE CONCENTRATIONS

Question 8

Role of inulin in Protein Metabolism?

Answer 8

• Increases amino acid uptake 
• Increases protein synthesis 
• Inhibits protein degradation
DECREASES BLOOD AMINO ACID CONCENTRATION

Question 9

what are physiological effects of glucagon

Answer 9

Glucagon has two major effects in the liver:
1. Stimulates glycogenolysis –
a) inh glycogen synthase
b) Stim glycogen phosphorylase
2. Stimulates gluconeogenesis
a) Inh PFK
b) Stim glucose-6-phosphatase and fructose 1,6 bisphosphatase 
Glucagon does not act on skeletal muscle (no receptors)
GLUCAGON ACTS TO INCREASE BLOOD GLUCOSE LEVELS
• Increased blood fatty acid and ketone concentrations
o Increased lipolysis in adipocytes
o Ketones produced from acetyl CoA resulting from increased FA breakdown

Question 10

how does Energy (ATP) levels in the cell regulate enzymes involved in Gluconeogenesis and Glycolysis

Answer 10

•  high energy levels (ATP) inhibit PFK and decrease glycolysis,
•  low energy levels (ATP) inhibit F-1,6-bisP activity and decrease gluconeogenesis

Question 11

how do hormones effect the enzymes involved in Gluconeogenesis and Glycolysis

Answer 11

• Low blood glucose = release of glucagon
• Increase gluconeogenesis (activates F1,6BisP), decreases glycolysis ( inhibits PFK)
• High blood glucose levels = release insulin
• Increase in glycolysis (activates PFK), decreases gluconeogenesis (inhibits F1,6 BisP)

Question 12

Why is glucose homeostasis important? What happens if blood glucose is not controlled?

Answer 12

If levels fall below 3 mmol /l (hypoglycaemia) this would lead to a loss of consciousness (coma).
If level goes above 10 mmol /l (hyperglycaemia) glucose will appear in the urine, the pH of the blood would fall and this also leads to coma.
Both conditions are a feature of diabetes mellitus.

If blood glucose levels rise too high the water content of the body will be affected.
Glucose is filtered through the kidneys and reabsorbed if glucose levels exceed the amount the kidneys are able to reabsorb then glucose appears in the urine (glycosuria)
Glucose is retained in the lumen of the tubule and causes water retention in the tubule leading to increased urine flow
Increased osmotic pressure of the blood causes water to be drawn from tissues leading to dehydration and decreases the blood circulation

Question 13

What is the role of the liver in glucose homeostasis?

Answer 13

The liver is the control centre for glucose homeostasis.
Its primary role is to transport glucose to peripheral tissues for use as metabolic fuel.
It is also critical in maintenance of blood-glucose levels.
It is the centre of glycogen synthesis and storage, glycogenolysis and gluconeogenesis.

Question 14

How is glucose homeostasis maintained?

Answer 14

Controlled by glucose release into the blood stream and also by storage of glucose as glycogen or fat.
The main hormonal control is by:
• Insulin
• Glucagon
• Epinephrine (is also important in a fight or flight situation)

Question 15

what is secret when blood glucose levels are high

Answer 15

Insulin is secreted and controls decreases in blood glucose levels

Question 16

what is secret when blood glucose levels are low

Answer 16

Glucagon is secreted and controls the increase of blood glucose levels

Question 17

After an approx. 14-16 h overnight fast (post- absorptive state) the metabolic situation is fairly stable.
what happens in this fasting state?

Answer 17

• Insulin secretion decreases and glucagon secretion increases
• Plasma glucose concentrations average around 5mmol/l 
• Glucose production comes from mainly glyogenolysis with some coming from gluconeogenesis i.e. catabolic.
• Glucose production and utilisation are approximately equal.

Question 18

Where does metabolic fuel come from in prolonged periods of starvation?

Answer 18

• Fat - triacylglycerols in adipose tissue which is sufficient to prolong life for 3 months
• Protein – provides approx 14 days worth of energy but is spared for as long as possible to permit mobility.

Question 19

describe adaptation to starvation

Answer 19

To adapt to conditions of near starvation conditions the body alters the flux of metabolites between various tissues in order to:
• provide enough glucose for the brain, the brain cannot use fatty acids for metabolic fuel because they cannot cross the blood-brain barrier so are dependent on glucose.
• Provide glucose for Red blood cells (erythrocytes) as these lack mitochondria and are not able to utilize fatty acids for energy because fatty acid oxidation takes place in the mitochondrial matrix.

Gluconeogenesis is the long-term mechanism for maintaining blood glucose concentrations during starvation.
It becomes more and more important as starvation progresses and liver glycogen stores are depleted

Question 20

describe glucose homeostasis in the refed state

Answer 20

Liver initially does not absorb glucose, lets glucose go to peripheral tissues, and stays in gluconeogenesis mode.
Newly synthesized glucose goes to replenish glycogen stores
As blood glucose levels rise, liver completes replenishment of glycogen stores.
Excess glucose goes to fat production.

Question 21

what are the four major adaptations from well fed to starving

Answer 21

• Increased triacylglycerol hydrolysis in adipose tissue.
• Increased gluconeogenesis in liver and kidney cells.
• Increased ketogenesis in liver cells.
• Protein degradation in skeletal muscle tissue.

Question 22

give background info on diabetes

Answer 22

• Diabetes mellitus is one of the most common chronic diseases in both western and developing countries
• A chronic and progressive disease impacting on most aspects of life
• The incidence of diabetes continues to rise throughout the world. Indeed, by 2010 it has been estimated that the diabetic population will increase to 221 million from 110 million in 1994
• Estimated 2.35 million people with diabetes in England (more than 200,000 in Scotland 4.1% population) with 0.5 mill thought to be undiagnosed
• Life expectancy is reduced by at least fifteen years for someone with Type 1 diabetes. In Type 2 diabetes life expectancy is reduced by up to 10 years
• Around five per cent of total NHS spend (and up to 10 per cent of hospital in-patient spend) is used for the care of people with diabetes
• Common worldwide with the rise in incidence predicted to come from increases in type 2 diabetes and with much occurring in China, the Indian subcontinent and Africa

Question 23

what are the 5 major categories of diabetes

Answer 23

• Type 1 diabetes
• Type 2 diabetes
• Gestational diabetes
• Impaired glucose tolerance/impaired fasting glucose
• Other rare forms include maturity-onset diabetes of the young (MODY), pancreatic diseases

Question 24

describe type 1 diabetes

Answer 24

• Normally presents before the age of 40
• Destruction of pancreatic Islet of Langerhans b cells normally leading to complete deficiency of insulin
• Usually autoimmune with 80% patients having antibodies to islet cells and glutamic acid decarboxylase
• Genetic with siblings of diabetics having 10% chance of developing diabetes by the age of 50
• Presence of ketonuria is a good indication of type 1 diabetes
• Requires insulin injections and careful monitoring of blood glucose levels for life before insulin discovery in 1921 avg life expectancy of person with type 1 diabetes was weeks to years

Question 25

describe type 2 diabetes

Answer 25

* Typically presents in middle or old age * Is associated with obesity and family history * Insulin synthesis is preserved with insulin resistance and impaired b cell function being hallmarks * >90% cases of diagnosed diabetes are type 2 * Often undiagnosed as can be asymptomatic apart from impaired glucose tolerance

Question 26

describe treatment of type 2 diabetes

Answer 26

* Treated initially with diet and increased activity which can reverse insulin resistance * If dietary and lifestyle changes not successful then metformin is now the drug of choice in overweight patients, once this is maximised then sulphonylureas or thiazolidiendiones may be added to optimise control

Question 27

describe Type II diabetes in childhood

Answer 27

* Has been recognised for over 30 years that type II diabetes can occur in childhood * Increasing prevalence associated with increasing obesity especially in specific ethnic groups (e.g. American Hispanics and indigenous American Indians) and those with family history * Distinct from MODY * Often children also have other symptoms linked to cardiovascular risk such as central obesity, higher blood pressure than peers and dyslipidemia

Question 28

describe Gestational Diabetes

Answer 28

• Carbohydrate intolerance first resulting in hyperglycaemia which is first recognised in pregnancy - occurs in 2-5% pregnancies • Most occurrences reverse after birth • More common in certain ethnic groups e.g. African Americans, Hispanic/Latino Americans and American Indians • Increased where there is a family history also associated with obesity • Women with gestational diabetes have increased risk of developing diabetes later in life • Unmanaged may cause problems in pregnancy with association with large-for-date babies • Managed by careful medical supervision to maintain blood glucose levels

Question 29

describe Impaired glucose tolerance/ impaired fasting glucose

Answer 29

* A stage between glucose homeostasis and diabetes  * Thought to be indicative of risk of diabetes and/or cardiovascular disease * Impaired glucose tolerance affects approx 17% 40-65 year olds in UK population (2004) * Impaired fasting glucose levels is a more recent measure of impaired glucose tolerance (6.1- 6.9mmol/l fasting blood glucose levels). * Its significance is as yet unknown.

Question 30

describe other forms of diabetes

Answer 30

A number of rare genetic, endocrine and infectious processes affecting the exocrine pancreas e.g. • MODY – results from a number of mutations in genes e.g. glucokinase (2), hepatic transcription factors (1 &3)- no insulin resistance and rarely obese • Insulinoma – tumor of the pancreas

Question 31

what laboratory tests are commonly used in the diagnosis or monitoring of diabetes

Answer 31

* Fasting Blood Sugar or Glucose test (FBS)  * Urine Glucose test * Oral Glucose Tolerance test (OGTT)  * Intravenous Glucose Tolerance test (IVGTT)  * Glycosylated Hemoglobin (HbA1C)  * Self-monitoring of Glucose level via Home Kits

Question 32

describe complications of diabetes

Answer 32

• Tissues with insulin dependent transport ie adipose tissue, lens and myocytes have no supply of glucose • Glycolysis and lipogenesis decrease • Gluconeogenesis, lipolysis, ketogenesis and glycogenolysis increase Increased glucose production + impaired transport hyperglycaemia

Question 33

what does hyperglycaemia cause

Answer 33

Disturbed water balance - Saturation of renal ability for reabsorption – glucose in urine - Body compensates for high glucose levels by increasing water loss (osmotic diuresis) - Leads to polyuria and polydypsia and dehydration ketoacidosis -Increased lipolysis leads to increased acetyl coA -Increased CoA leads to ketogenesis -Leads to ketonemia and ketonuria -Increased ketones diabetic ketoacidosis

Question 34

describe diabetic ketoacidosis

Answer 34

``` Causes: -Hyperglycemia -Ketonuria -Dehydration -Diabetic acidosis Occurs mainly in type 1 diabetes Very similar to the fasting state – ‘starvation in the midst of plenty’ ```

Question 35

describe hypoglycaemia

Answer 35

o Most common acute complication of diabetes o Occurs in type 1 and type 2 diabetes o Imbalance of insulin, carbohydrate and exercise o Is often a psychological barrier to compliance o Mild hypoglycaemia treat with sweet drink o Severe hypoglycaemia needs intravenous injection of glucose or intramuscular injection of glucagon

Question 36

what does diabetes increase risk of

Answer 36

Macrovascular disease: (2nd only to smoking in risk of atherosclerotic vascular disease), CHD stroke peripheral vascular disease Microvascular disease: (short term – reversible Long-term – irreversible) diabetic retinopathy diabetic nephropathy diabetic neuropathy Leading cause of blindness, renal failure and neuropathy in UK

Question 37

describe recent advances in treatments of diabetes

Answer 37

* Human insulin – advantages as compared to porcine and bovine not obvious * Modified human insulin – allowing for better management of condition there are 3 preps, two are short-lasting allowing them to be given just before or after eating, one is long-lasting giving slower release * Pancreatic transplant – select group of type 1 diabetics in UK usually patients with end stage diabetic nephropathy who require simultaneous pancreas and kidney transplantation * Islet transplantation – technically difficult due to isolation and purification of islets * Stem cell islet transplants - Production of functional beta cells for transplantation is the goal of many research laboratories, but clinical application remains uncertain.