What are the functions of glucose?
A universal energy source in that it can be used by all tissues in the body to generate adenosine triphosphate (ATP) via glycolysis, the tricarboxylic acid cycle (Krebs cycle, citric acid cycle) and oxidative phosphorylation.
What are dietary sugars and starchs digested to produce?
Monosaccharides, mainly glucose, fructose and galactose.
Fructose and galactose are converted to glucose by the liver.
Glucose being synthesized from lipids and amino acids in the liver is given what name?
(Lactate produced by glycolysis can also be converted to glucose in the liver by this process)
Give an overview of carbohydrate metabolism
What is the normal range for blood glucose?
What hormonal control is it under?
4.5 – 6 mM
Too high = it is brought back down by insulin.
Too low = it is brought back up by glucagon.
Adrenaline, noradrenaline, cortisol and growth hormone also raise blood glucose.
What can act to raise blood glucose levels?
Where is glucagon secreted from?
Where is insulin secreted from?
Glucagon is secreted by the alpha-cells in the pancreas.
Insulin is secreted by the beta-cells in the pancreas.
What are the 'glucose sinks'
Take up glucose to prevent hyperglycaemia
Thus there is a negative feedback relationship between blood glucose and insulin
How can the relationship between blood glucose and insulin be demonstrated?
By the glucose tolerance test.
Drinking a solution of glucose causes a rise in blood glucose which is soon followed by a sharp peak in insulin secretion, then a slower phase of insulin release. This causes blood glucose to fall, which in turn causes insulin to fall. Both eventually return to baseline levels.
What is insulin made up of?
What is it's release stimulated by?
A large molecule comprising 2 peptide chains
raised blood glucose concentration
sulphonylureas (drugs used to stimulate insulin release)
e.g. gliclazide, glimepiride, and glipizide.
What is the mechanism of insulin release?
- B cells have a large number of glucose transporters (GLUT2) that permit a rate of glucose influx that is proportional to the blood concentration in the physiological range.
- Once inside the cells, glucose is phosphorylated to glucose-6-phosphate by glucokinase. (rate limiting step for glucose metabolism in the beta cell and is considered the major mechanism for glucose sensing and adjustment of the amount of secreted insulin to the blood glucose levels)
- G6P is subsequently oxidized to form adenosine triphosphate (ATP), which inhibits the ATP-sensitive potassium channels of the cell.
Closure of the potassium channels depolarizes the cell membrane, thereby opening voltage-gated calcium channels, which are sensitive to changes in membrane voltage.
- This produces an influx of calcium that stimulates fusion of the docked insulin-containing vesicles with the cell membrane
- Secretion of insulin into the extracellular fluid by exocytosis.
Other nutrients, such as certain amino acids, can also be metabolized by the beta cells to increase intracellular ATP levels and stimulate insulin secretion.
What does Insulin stimulate?
- glucose uptake - insulin dependent (Binding of insulin to receptors on such cells leads rapidly to the insertion of glucose transporters into the plasma membrane, thereby giving the cell an ability to efficiently take up glucose)
- amino-acid uptake
- glycogen and lipid synthesis of AAs in the liver
- K+ uptake - important in insulin therapy
Overall, has an ANABOLIC EFFECT
How to Sulfonylurea drugs act?
What are they used for?
Stimulate insulin secretion by binding to the ATP-sensitive potassium channels and blocking their activity. This results in a depolarizing effect that triggers insulin secretion.
Stimulating insulin secretion in patients with type II diabetes
What does insulin inhibit?
How can an injection of insulin kill a patient?
Because of its ability to acutely suppress plasma potassium concentrations.
Summarise the mechanism of insulin action
Insulin binding to the insulin receptor induces a signal transduction cascade which allows the glucose transporter (GLUT4) to transport glucose into the cell. The glucose can be used for glycolysis, or synthesis of glycogen, fatty acids and protein. The signal cascade also activates the expression of genes.
What is GLP-1
An incretin hormone secreted by the intestine in response to the presence of nutrients (like carbohydrate, protein and lipid) in the lumen of the small intestine.
Once in the circulation, GLP-1 has a half-life of less than 2 minutes, due to rapid degradation by the enzyme dipeptidyl peptidase-4.
GLP-1 is a potent antihyperglycaemic hormone, inducing glucose-dependent stimulation of insulin secretion while suppressing glucagon secretion.
Attractive as a drug target because, when the plasma glucose concentration is in the normal fasting range, GLP-1 no longer stimulates insulin to cause hypoglycaemia. By contrast, using insulin as a drug has a risk of hypoglycaemia.
What is GIP?
Gastric inhibitory peptide (glucose-dependent insulinotropic peptide)
The presence of glucose in the intestinal lumen also stimulates the release of this. As an incretin, stimulates insulin release from pancreatic β-cells.
Where is glucagon released from?
What does it do?
Maintains normoglycemia (normal blood glucose)
What is glucagon stimulated by?
What is glucagon inhibited by?
hyperglycaemia after a meal
What does glucagon stimulate?
blood glucose in increased (from liver)
gluconeogenesis - new glucose generated (from amino-acids)
What are the metabolic effects of glucocorticoids?
- Stimulation of gluconeogenesis (glucose from AAs and glycerol from triglyceride breakdown)
- Mobilization of amino acids from extrahepatic tissues (act as substrates for gluconeogenesis)
Inhibition of glucose uptake in muscle and adipose tissue (conserves glucose)
- Stimulation of fat breakdown in adipose tissue: The FAs released by lipolysis are used for production of energy in tissues like muscle, and the released glycerol provide another substrate for gluconeogenesis.
(Insulin opposes the action of glucocorticoids by inhibiting amino acid mobilization and lipolysis)
What are the metabolic effects of catecholamines? (adrenaline and noradrenaline)
α-adrenergic activity stimulates glycogenolysis in the liver and muscle.
β-adrenergic activity increases lipolysis by adipose tissue.
Together, these effects lead to increased blood glucose and fatty acids, providing substrates for energy production within cells throughout the body.
Insulin opposes catecholamine action by inhibiting glycogenolysis and lipolysis.
What are the metabolic effects of Growth Hormone?
Increases protein synthesis
Promotes lipolysis and fatty acid utilisation
Reduces tissue uptake of glucose
Promotes gluconeogenesis in the liver
often said to have anti-insulin activity, because it suppresses the ability of insulin to stimulate uptake of glucose in peripheral tissues and it enhances glucose synthesis in the liver.
Growth hormone counteracts in general the effects of insulin on glucose and lipid metabolism, but shares protein anabolic properties with insulin.
What level of fasting blood glucose is considered hyperglycaemic?
What is it?
Fasting blood glucose of >7mM
- Occurs in diabetes mellitus when glucose sinking fails
- Renal glucose reuptake exceeded if blood glucose >10 mM
- Glucose reacts with and alters properties of proteins
eg glycated haemoglobin (measure of long term hyperglycaemia)
- Excess glucose produces aberrant cell messengers, endothelial dysfunction, pancreatic beta-cell dysfunction, oxidative stress, chronic inflammation.
Thus glucose is toxic.
What is hypoglycaemia?
Blood glucose <4mM.
Dizziness and loss of consciousness (due to brain dysfunction)
medical emergency that involves abnormally low blood glucose
an inadequate supply of glucose to the brain, resulting in impairment of function - brain has an absolute requirement for glucose
most common forms of hypoglycemia occur as a complication of treatment of diabetes mellitus with insulin or oral medications
What are some complications of hyperglycaemia?
kidney damage, neurological damage, cardiovascular damage, damage to the retina or damage to feet and legs.
Diabetic neuropathy may be a result of long-term hyperglycaemia.
Cellular effects of chronic hyperglycaemia are numerous. They include glycation of proteins, dysfunction of endothelial cells, dysfunction of pancreatic beta-cells, oxidative stress and chronic inflammation.
What does the glucose tolerance test look like in diabetes?
Drinking a glucose solution causes blood glucose to rise dramatically.
If blood glucose exceeds ~10 mM, glucose appears in the urine because the capacity of the kidney to reabsorb glucose is exceeded.
What sorts of effects on body fluids does diabetes have?
- increased osmolarity of the blood (polydypsia)
- Osmotic pressure of blood
stimulates excessive drinking
- Osmotic pressure of urine
excessive water loss - dehydration
- Other effects
metabolic acidosis (keto-acids)
raised K (K loss from cells)
What is Diabetic Ketoacidosis?
A potentially life-threatening complication in patients with DM.
Predominantly in those with T1DM, but can occur in T2DM.
Acidic ketones are products of fatty acid metabolism which increase when cells cannot take up glucose.
Vomiting, dehydration, deep gasping breathing ("Kussmaul respiration"), confusion and occasionally coma are typical symptoms.
What does acidosis cause?
Hyperkalaemia (high blood potassium).
Protons move into cells and displace potassium ions which move out of cells into the bloodstream.
If renal function is normal, the excess potassium is excreted by the kidneys. However, subsequent insulin administration would cause potassium movement into cells and may cause hypokalaemia (low blood potassium).
Why is there hyperglycaemia in
T1 - destruction of pancreatic beta-cells.
T2 - there is resistance of adipose tissue, skeletal muscle and liver to the action of insulin
What is Type 1 Diabetes Mellitus?
Autoimmune destruction of pancreatic b-cells
(Insulin dependent; juvenile)
No other cells are affected
Low blood insulin - little secreted.
No glucose uptake into muscle & fat cells
High blood glucose - causing damage
Weight loss but hyperphagia
Tend to metabolise fats
Glucose lost through urine (hence mellitus)
Thirst, diuresis (hence diabetes) and dehydration
tiredness and irritability
Begins in childhood
What are the classical features of T1DM?
Autoimmune destruction of insulin-producing beta cells of the pancreas.
The subsequent lack of insulin leads to increased blood and urine glucose.
The classical symptoms are polyuria (frequent urination), polydipsia (increased thirst), polyphagia (increased hunger), and weight loss.
What is the treatment for T1DM?
long acting or
programmed infusion (mini pump)
over-use - insulin coma
Preventing high blood glucose concentrations - diet
use glucose meter to measure
What are the possible contradictory causes of coma?
smell of acetone in expired air
too much insulin
missed a meal
What is Type 2 Diabetes Mellitus?
Non-insulin dependent diabetes
Cells resistant to insulin action
cannot store glucose
cannot utilise glucose
blood insulin tends to be high
more complex and variable than type I.
Classically disease of >40 years
1.4 million in UK and increasing
But also in young now
What are the risk factors for T2DM?
obesity and over weight
lack of exercise
high sugar and high fat diet
What is Type 2 Diabetes Mellitus?
a metabolic disorder that is characterized by high blood glucose in the context of insulin resistance and relative insulin deficiency. The classic symptoms are excess thirst, frequent urination, and constant hunger
What percentage of diabetes is due to T2?
10% is T1DM and gestational diabetes
What are the treatments for T2DM?
Control blood glucose
- most important
Use meter to measure
low sugar, low fat (not saturated lipids)
Sulphonylureas - Stimulate insulin secretion
Thiazolidinediones - Insulin sensitisers
Gliptins (dipeptidyl peptidase-4 [DPP-4] inhibitors)
Complications of T2DM?
Having diabetes makes high blood pressure and other heart and circulation problems more likely because diabetes damages arteries and makes them targets for hardening (atherosclerosis). Atherosclerosis can cause high blood pressure, which if not treated, can lead to blood vessel damage, stroke, heart failure, heart attack, or kidney failure.
Studies show a link between insulin resistance, which is a precursor to type 2 diabetes, and diabetic dyslipidemia, atherosclerosis and blood vessel disease. These conditions can develop even before diabetes is diagnosed.
Patients with diabetes often have unhealthy cholesterol levels including high LDL ("bad") cholesterol, low HDL ("good") cholesterol, and high triglycerides. This triad of poor lipid counts often occurs in patients with premature coronary heart disease. It is also characteristic of a lipid disorder associated with insulin resistance called diabetic dyslipidemia in those patients with diabetes
What is first line treatment for T2DM?
How does it work?
It works by reducing the amount of glucose that the liver releases into the bloodstream. It also makes the body's cells more responsive to insulin.
How do Sulphonylureas work?
What are some examples of this type of drug?
increase the amount of insulin that is produced by the pancreas.
glibenclamide, gliclazide, glimepiride, glipizide, gliquidone.
How do Thiazolidinediones work?
(eg. pioglitazone) make the body’s cells more sensitive to insulin so that more glucose is taken from the blood.
How do gliptins work?
By preventing the breakdown of a naturally occurring hormone called glucagon-like peptide-1 (GLP-1).
GLP-1 helps the body produce insulin in response to high blood glucose levels, but is rapidly broken down by dipeptidyl peptidase 4 (DPP-4).
By inhibiting DPP-4, the gliptins (linagliptin, saxagliptin, sitagliptin and vildagliptin) act to prevent high blood glucose levels, but do not result in episodes of hypoglycaemia.
How does Exenatide work?
Exenatide is a GLP-1 agonist, an injectable treatment that acts in a similar way to the natural hormone GLP-1 (see the section on gliptins, above).
It boosts insulin production when there are high blood glucose levels, reducing blood glucose without the risk of episodes of hypoglycaemia ("hypos").
What is the basis for insulin supplementation in T2DM when insulin levels are already high?
It might seem counter-intuitive to use insulin supplementation to treat Type 2 diabetes in which insulin is already high, but the tissues may not be completely insulin resistant and increasing the insulin further may stimulate glucose uptake. High glucose is more of a problem than high insulin.
What are the complications of Diabetes Mellitus?
Renal failure - poor renal filtration
Diabetic retinopathy (retinal disease)
Large vessel disease
Major arteries - atherosclerosis
heart and brain important
erectile dysfunction (impotence)
Summarise the issues when
Glucose concentration is too low
Glucose concentration is too high
too low – metabolic insufficiency
too high – chemical pathogenesis