Introduction to diabtes mellitus Flashcards
Describe the basic effects of insulin on glucose
decrease HGO
increase muscle uptake
Describe the basic effects of insulin on protein
decrease proteolysis
Describe the basic effects of insulin on lipids
Decrease lipolysis
Decrease ketogenesis
Describe the mitogenic actions of insulin
Lipoproteins Smooth muscle hypertrophy- Important in high blood pressure Ovarian function Clotting Energy expenditure
Describe the structure of the GLUT 4 receptor
Outer core is hydrophobic- to keep it embedded in the hydrophobic core of the phospholipid bilayer
Inner region is hydrophilic- to allow glucose, which is also hydrophilic, to move through the transporter by facilitated diffusion
What is the action of insulin on the expression of GLUT 4 channels and what is the consequence of this
Vesicles containing GLUT 4 are insulin responsive. Insulin acts on these pre-made GLUT 4 receptors and recruits them into the plasma membrane of muscle cells and adipose tissue, driving glucose into these cells. This results in a 7-fold increased glucose uptake into the cell.
What is the main glucose sink in the body
Muscle
What happens to protein synthesis inside a muscle cell when insulin is released
When insulin is present, as well as IGF1, protein synthesis is driven.
Amino acids — Protein
What happens to proteins in muscle cells in the absence of insulin
Proteolysis is stimulated- cortisol stimulates this too.
Protein — Amino Acids
These amino acids can be respired in the Krebs cycle.
If they are gluconeogenic amino acids (alanine) they can enter the bloodstream and be taken to the Liver, where they can be used to make glucose
Describe the presence of glucose in the blood
Glucose present in blood all time, not only after meals
What is glycogen
Glycogen in liver is stored glucose
Describe the effect of insulin on protein synthesis in the Liver
In the presence of insulin, protein synthesis is stimulated.
Amino acids — Protein
Describe the effects of an absence of insulin on proteolysis in the liver.
A lack of insulin, protein deficiency and glucagon stimulates the proteolysis of protein into amino acids in the liver.
Protein — amino acid
What is the potential fate of these amino acids in the liver
In the absence of insulin, but in the presence of glucagon, cortisol, and catecholamines, these amino acids may be converted into glucose via gluconeogenesis.
This glucose is then released into the blood stream (increased hepatic glucose output).
What else can be used in gluconeogenesis
Pyruvate and lactate
Describe the characteristics of fat fuel stores in the body
Weight (9-10kg)
Energy (37kJ/G)
Time (30-40 days)
Describe the characteristics of protein fuel stores in the body
Weight (8-9kg)
Energy (17KJ/G)
Time (15 days)
Describe the characteristics of carbohydrate fuel stores in the body
Weight ( 0.5kg)
Energy (16KJ/g)
Time ( 16 hours)
What takes longer to breakdown, fat or protein
Fat
Describe the events that take place in lipoproteins in response to insulin
Lipoprotein lipase in lipoproteins is sensitive to insulin. Catalyses the breakdown of triglycerides into NEFA and Glycerol, NEFA enters
Why is it important that we breakdown Triglycerides
Triglycerides are too big to pass through plasma membranes on their own, hence they need to be broken down
What happens in adipocytes in response to insulin
Increased expression of GLUT 4 channel proteins on surface.
Glucose enters the adipocyte
Glucose – acetyl co-A — NEFA
Some glucose is also converted into glycerol-3-phosphate
Glycerol-3-phosphate + NEFA — Triglyceride.
What happens to the triglycerides in adipocytes in the absence of insulin
In the absence of insulin, but in the presence of catecholamines, cortisol, and growth hormone, triglycerides will be broken down into glycerol and NEFAs
Why is it important that we have separate circulation for the gut and liver
So that food can be processed before it enters the circulation
What is a consequence of this different circulation for the gut
Adipocytes in omental circulation are different to that of the systemic circulation, such as in the arms and legs. As a result of their different anatomical location, they are more metabolically active, and have a faster turnover rate. Omental adipocytes predict ischaemic heart disease
Can NEFAs be used in gluconeogenesis
No, they are used in the TCA cycle instead
Describe gluconeogenesis in the liver
In absence of insulin, presence of glucagon.
Glycerol enters the liver- converted into glycerol-3-phosphate.
Some triglycerides in the liver are also broken down into glycerol-3-phosphate.
This glycerol-3-phosphate is converted into glucose in gluconeogenesis.
What percentage of the HGO does gluconeogenesis account for after a 10 hour fast
25%
Describe the different fuels for the brain
Can use Glucose Ketone bodies Can not use Fatty acids
What does insulin prevent the formation of
Ketone bodies
What allows the brain to survive during a fast
Ketone bodies
What is a key sign of insulin deficiency
The presence of ketones in the blood when blood glucose levels are also high
Describe glycogen stores in the muscle
The glucose released can only be used by the muscle cells themselves.
Describe the formation of ketone bodies in the liver
NEFA taken into the liver
NEFA is converted into fatty acyl coA (shuttle on mitochondrial membrane)
In the presence of glucagon, absence of insulin:
Fatty acyl coA – Acetyl coA
Acetyl coA- – Acetoacetate
Acetoacetate — Acetone + 3-hydroxybutyrate
Describe the process of glycogenesis in the presence of insulin
Glucose is taken into the liver.
Glucose — Glucose-6-phosphate
G6P — Glycogen
Describe the process of glycogenolysis
In the absence of insulin, presence of glucagon
Glycogen— G6P
G6P — Glucose
This glucose is then released into the bloodstream to increase HGO
Describe the characteristics of the fasted state
low insulin to glucagon ratio [glucose] 3.0-5.5mmol/l [NEFA] low [amino acid] when prolonged Increased Proteolysis Increased Lipolysis Increased HGO from glycogen and gluconeogensis Muscle to use lipid Brain to use glucose, later ketones Ketogenesis when prolonged
Describe the characteristics of the fed state
Stored insulin released then 2nd phase High [insulin] to [glucagon] ratio Stop HGO, Glycogen gluconeogenesis protein synthesis proteolysis Lipogenesis
What do patients with ischaemic heart disease and obesity normally have
Insulin resistance- regardless of whether they are diabetic or not.
What is T1DM defined as
Absolute insulin deficiency (although not always the case)
Describe the presentation of T1DM
Absolute insulin deficiency Proteolysis with weight loss Hyperglycaemia- Increased HGO Glycosuria with osmotic symptoms Ketonuria Increased lipolysis
Explain why glycosuria occurs
As GLUT 4 is not activated, glucose is not transported into the relevant cells, so although there is a lot of glucose in the circulation, it is not available for cellular metabolism. The increase in plasma glucose overcomes the renal threshold for glucose reabsorption, and glycosuria results. The glucose draws water with it by osmosis, so the patients claim of passing large amount of urine night and day, making them very thirsty, so they complain of polydipsia and polyuria
What is a more serious aspect of type 1 diabetes
The enormous increase in ketogenesis. Although ketones are a useful fuel when needed, if produced in excess they cause a fall in pH, as they are weak ketoacids. The danger is that the pH can fall dangerously low, which in turn can have a negative impact on the activity of a number of brain and other enzymes. This is known as diabetic ketoacidosis.
What is cachexia
The extreme loss of weight
Describe insulin induced hypoglycaemia
Increased: insulin Glucagon Catecholamines Cortisol Growth hormone Glucose enters muscles Increased HGO later with glycogenolysis and gluconeogenesis (glucagon triumphs) Lipolysis increased Patients cannot switch off the insulin injected, prolonged effect. However, it will get better, glucagon produced
What is the role of subcutaneous insulin
To switch HGO off
What is the role of intramuscular glucagon
Administered when the patient is unconscious.
Reverse insulin induced hypoglycaemia.
Restores HGO.
Where does insulin resistance reside
All metabolic sites and all arms of intermediary metabolism
In T2DM, what is there enough insulin to suppress
Enough insulin to suppress
Ketogenesis
proteolysis
Describe the two different reaction pathways of insulin
Binding of insulin to the insulin receptor may cause tyrosine kinase to phosphorylate IRS (insulin receptor substrate). This passes down the PI3K-Akt pathway
and is responsible for the metabolic effects of insulin.
However, it may also phosphorylate different substrates in the MAPK pathway to simulate mitogenesis- also important in blood pressure and dyslipidaemia.
Which pathway is resistant to insulin
PI3K-Akt pathway
Describe what happens in insulin resistance when the patient can still make insulin
Beta cells try to overcome the resistance by making more insulin, so the patient becomes hyperinsulinemic and euglycemic. Increased mitogenic reactions.
Describe the metabolic actions of insulin in insulin resistance
GLUCOSE
PROTEIN
LIPID
All normal
Describe the mitogenic reactions of insulin in insulin resistance
Lipoproteins- low HDL
Smooth muscle hypertrophy- high blood pressure
Ovarian function- polycystic ovarian syndrome
Clotting- abnormal effects
Energy expenditure- abnormal effects
What can patients with DM have
Urinary tract infections- due to high presence of glucose.
Describe the presentation of T2DM
Insulin resistance 60-80% obese Dyslipidaemia Later insulin deficiency Hyperglycaemia Less osmotic symptoms With complications Adipocytokines Inflammatory state Energy expenditure High [TG] Low [HDL Hypertension BP>135/80 Waist circumference Men>102 Women>88 Fasting glucose >6.0mmol/l
What is meant by dyslipidaemia
Abnormal carriage of lipoproteins in the blood
Is insulin resistance a disease
No, it is a pathophysiological state
What does T2DM usually present with
Myocardial infarction
Describe a diet for T2DM
Total calories control reduce calories as fat reduce calories as refined carbohydrate increase calories as complex carbohydrate increase soluble fibre Decrease sodium
What is key for the diet in patients with T2DM
Control portion sizes
