Clinical diabetes Flashcards
Diagnosis
What is central to the diagnosis?
why can’t you do fingerprick test?
What sample do you need and above what value is diabetes?
What is another tyoe of test? above what value is diabetes?
3 symptoms of diabetes
what is you above normal but below diabetes threshold? (2 things)
what does this mean?
why are HbA1c effective? who is it not effective with?
Hyperglycemia is central to the diagnosis
Diagnosis of diabetes can be done by doing fasting blood sugar, you can’t do it by a fingerprick test -> as it gives capillary blood sugar
You need a venous blood sugar sample – it is normally around 5mmol/L, if 6.17 then above normal, if 7 or above diabetes.
Another type of test is oral glucose tolerance test, you give them 75g of glucose and test blood sugar at that time and 2 hours later. If above 11.1mmol/l = diabetes.
Diagnosis also depends on symptoms, if they have various symptoms:
• Polyuria
• Polydipsia
• Weight loss.
One of the tests being positive will allow a diagnosis to be made.
If you’re above normal but not above the diabetic threshold, then it is said you have impaired glucose tolerance or impaired fasting glycemia.
This means someone is predisposed to diabetes but by changing lifestyle it can be prevented.
You also cannot make a diagnosis based on glycosuria since various conditions can cause this, fingerpick test (need venous sample)
HbA1c measures blood sugar attached to RBCs, gives an average blood sugar level over 3 months, this is useful but can’t do it on its own. It is not possible to use it for children or patients with haemoglobinopathy.
Types of Diabetes
3
Type 1 – Beta cell destruction
Type 2 – Insulin resistance and/or insulin deficiency due to beta cell dysfunction
Gestational diabetes
Type 1
occurs mostly in?
geographically? meaning?
what is the most common cause?
what are the genetic factors? why doesnt everyone have this?
State a few of the environmental factors
what is the pre-diabetic state?
- Develops predominantly in children and young adults but can occur in all age groups.
- There is also marked geographical variation, more common as you go north from the equator.
- This means there must also be some environmental factors.
Commonest cause of Type-1 DM is autoimmune destruction of beta-cells leading to NO beta cell function.
Strongest linkage is with HLA genes within the MCH region on chrom. 6
There are genetic factors (such as having HLA haplotypes DR3 and 4). But not everyone who has these has type 1 DM, this means there is some role of environmental interaction.
Environmental – Viruses can directly destroy beta cells or by an autoimmune response. E.g. mumps, coxsackie B, rubella
- Dietary components
- Stress
- Drugs and toxins
But these need to attack someone who is vulnerable, we aren’t 100% sure what causes it though.
Pre-diabetic state = mild abnormalities of insulin secretion and glucose tolerance BUT can be detected.
Type 2 Diabetes
what is t2 closely linked to and associated with?
who are more likely to get it when theyre younger?
The incidence of type 2 DM is rapidly increasing, it is set to double by 2020. There is a large amount of un-diagnosed diabetes.
Type-2 DM is closely linked to insulin resistance.
There is also geographical variation and ethnic one, in the UK it is much more common in Indians and African-Caribbean’s.
Its prevalence is closely associated with BMI.
Compared to white patients, Indian patients have younger age of onset of type-2 diabetes and earlier proteinuria and renal disease.
• Type-2 accounts for most diabetes (85%). Patients do not require insulin to remain alive, although 20% are treated with insulin to control blood glucose. Incidence is getting younger.
The treatment for type 1 is evidently insulin. Now we have recombinant human insulin.
Viruses
Viruses can directly destroy B-cells or indirectly by an autoimmune response
-> Mumps Occasionally precedes IDDM autoimmune B-cell destruction islet cell antibodies develop can induce interleukin production and HLA hyperexpression in B-cells
Coxsackie B
- IgM anti-coxsackie B antibodies in newly diagnosed type-1 DM
- Antigen identified in islets post-mortem
- Direct cytotoxic action on B-cells
Retroviruses
Rubella
CMV
Epstein-Barr
Genetic factors of type 1 diabetes
may be too much info
HLA haplotypes DR3 and DR4 predispose to type-1 DM
linkage disequilibrium with true susceptibility loci
HLA class II antigens on the cell surface present foreign and self antigens to T-lymphocytes and initiate the auto- immune response
Strong linkage between HLA-DR and DQ regions
Polymorphisms of the DQB1 gene resulting in amino acid substitution in class II antigens may determine B-cell damage
Region of the insulin gene on chrom. 11 is linked to type-1 DM, insulin or pre-cursors can act as B-cell autoantigens
Insulin – Physiology
Where does insulin act?
What does a lack of insulin lead to?
what is a complication of this?
What are we trying to achieve when we give insulin?
Name one insulin analogue and its effect
Insulin acts on adipose tissue, muscle and liver. A lack of insulin results in raised blood sugar levels. There is breakdown of adipose tissue (FA mobilisation) leading to diabetic ketoacidosis.
When we give insulin to a patient we try imitating the normal background levels of insulin.
Pharmacologists have created various insulin analogues by adding residues e.g. lysine, which make the new insulin faster acting, you can add other things to manipulate the insulin molecule.
Insulin Therapy
What is the aim of this therapy?
What if you give too much?
what if stopped insulin?
Why is high glucose in blood very bad?
What would be the most ideal treatment?
So, the aim of insulin therapy is to normalise blood glucose levels, prevent diabetic complications and restore normal quality of life.
However intensive insulin treatment -> increased hypoglycemia = very bad!
As stated earlier, a lack of insulin causes mobilisation from adipocytes and breakdown of fatty acids by liver and muscle. This causes ketoacidosis. For this reason, it is important diabetics do not stop their insulin, or they would die. Glucose also has an osmotic effect, causing diuresis, dehydration and circulatory collapse.
Ideal treatment would be a pancreas transplant or beta cell transplant
Type-2 Diabetes
What is this a combination of?
What causes beta cells to release large amounts of insulin? What will be the consequence of this?
what are aims of treatment for type 2 diabetes?
What is the initial treatment? why? and what if this doesnt work?
What are insulin sentisisers?
What other medication can we give?
What are the drugs trying to achieve? (insulin sensitisers)
Type-2 DM is a combination of insulin resistance and beta cell dysfunction
Genetic or environmental factors lead to insulin resistance, causing beta cells to release very large amounts, causing hyperinsulinemia to maintain normal glucose levels.
But eventually the beta cells are working so hard they cannot cope and start to dysfunction. Leading to decreased insulin response -> hyperglycemia.
In type 2 diabetes, insulin deficiency is less severe than in type 1 DM and insulin levels remain high enough to prevent excess lipolysis and ketoacidosis.
Aims of treatment in type-2 DM are: • Abolish symptoms and acute complications of hyperglycemia • Reduce threat of chronic complications • Increase life expectancy • Restore quality of life
In initial stages we will encourage patient to lose weight and exercise to increase their sensitivity, but as progresses, beta cell failure becomes more prominent and type-2DM patients may require insulin.
We tend to use insulin sensitisers to decrease insulin resistance at target tissues.
We can also give medication to help pancreas produce more insulin. We often use these in combination. Through this we can:
o Decrease plasma glucose levels
o Decrease excessive lipolysis and reduce FFAs
o Decrease excessive hepatic gluconeogenesis
o Improve insulin-mediated glucose uptake
Treatment is stepwise:
diet exercise
oral monotherapy
oral combination
insulin + oral agents
Insulin resistance is defined as
The inability of insulin to produce its usual biological effects at circulating concentrations that are effective in normal subjects.
Metformin
what does it do?
How does it achieve this?
- It helps decrease hepatic glucose output
- Decrease FA oxidation
Work by increased kinase activity of insulin receptor as well as increased expression (translocation) of GLUT-4 transporter AND increased glycogen storage.
Thiazolidnediones (glitazones)
what type of drug is this?
What do they do?
who is it favourable to?
How is it similar in action to metformin?
Thiazolidnediones (glitazones) are unique oral insulin sensitising agents. They help lower blood glucose and insulin levels. This preserves endogenous insulin secretory reserve.
The mechanism of action is different working on PPAR-gamma.
Both metformin and glitazones increase sensitivity of body to insulin.
Favorable effect in non-diabetic patients with insulin resistance
PPAR-Y and Insulin Resistance
How does this act?
What are the general effects?
Long term effects?
Nuclear transcription
Genes affected
Increased GLUT-4 expression, hence increased Insulin sensitivity in fat, muscle and liver tissue
Pre-adipocyte differentiation
Lipoprotein lipase -> adipogenic (‘Fatty acid steal’ from circulation
improves insulin sensitivity
but long term effects unknown)
Sulphonylureas
How does this help beta cells produce more insulin?
Why is too much od this bad?
Sulphonylureas work by helping the beta cells produce insulin. They work by blocking K+ ATP channels -> depolarisation -> increased insulin release.
We do have to be careful as if we give too much we could cause hypoglycemia due to too much uptake of glucose from the blood.
