Flashcards in Diabetes-2 Deck (23):
Why do diabetes mellitus and diabetes insipidous share “diabetes” in their name?
They both have the symptom of excessive urination
What is diabetes?
This is a spectrum of disease which manifests themselves as an inability of insulin to properly regulate glucose metabolism either due to a lack of insulin production or an inability of produced insulin to function
What are the two major causes of death from diabetes?
The build up of ketones and wasting away due uncontrolled gluconeogenesis and glycogenolysis
What are the different forms of diabetes?
Type 1 (Juvenile Diabetes/Insulin dependent diabetes mellitus)
Type 2 (Adult onset/ Non-insulin dependent diabetes mellitus)
Maturity onset diabetes of the young
What is the major problem with diabetes (now that type 1 is treatable)?
There are inappropriately high circulating levels of glucose are dangerous and often result in non-enzymatic addition of sugar to proteins leading to pathological complications such as retinopathy, nephropathy, neuropathy, circulatory problems and atherosclerosis
Why is HbA1c a better measure of blood glucose?
This is a form of glycated haemoglobin and it will fluctuate less than blood glucose and provides a good measure of the long term exposure of the circulation to glucose
What is type-1 diabetes?
This is characterized by a lack of insulin and is more commonly seen in younger generations, it affects .3% of the population in western societies and fewer elsewhere
The absence of insulin means levels of glucose in the blood are very high but that it cannot be taken up into muscle and fat so there is a lack of fuel for these tissues with patients feeling tired and hungry
Above 20mM most of the glucose spills over into the urine
Urine becomes hyperosmolar due to high glucose so water moves to urine compensate so excessive urination results in high levels of thirst
fatty acids are not suppressed and therefore will remain high these are partially oxidised in the liver to ketone bodies which is used as an alternative energy source
ketones are acidic so high levels can induce ketoacidotic state in which blood pH becomes dangerously low
What are the causes of type-1 diabetes?
The most common cause is immune system attack on insulin producing beta cells of the pancreas this results in type-1 diabetes often clusters in families with a history of other autoimmune disorders
There is typically the presence of autoantibodies to islet cell antigens, the most common being autoantibodies is insulin, IAP2 (a protein phosphatase) and GAD65 (glutamic acid decarboxylase)
The speed of the onset of disease correlates well with the number of different islet cells
Beta cell mass slowly decreases and for long period there is still enough insulin and patients are asymptomatic
What is the evidence for a genetic link in type 1 diabetes?
There is evidence of a genetic link but no single gene has been identified that definitely causes diabetes however in identical twins if one twin gets type-1 diabetes there is 30% chance the other twin will get type 1 and a 70% lifetime expectancy of diabetes
MHC alleles may play a role with diabetes being more common in those with the DQA*301 allele and the DRB*401
What are the non-HLA genetic causes of type1 diabetes?
A polymorphism in the non-coding region of the IDDM2 locus which seems to regulate insulin gene expression in thymus and so modulate immune response against insulin
A mutation in lymphoid specific phosphatase which controls T cell function
Cytotoxic T-lymphocyte antigen-4 which has a disease associated allele in the non-coding region that results in much lower expression of this gene
How is type-1 diabetes treated?
Insulin replacement therapy is the only effective treatment
It was previously purified from animal pancreases however it is now produced from a recombinant yeast
What are the problems with insulin replacement therapy?
Injected insulin is not at entering the body via the normal route
Problems with tissue damage at the site of injection
Problems with insulin needing to dissociate from its crystalline form causing it to take time to work
Possibility of hypoglycaemia if too much insulin is given
Problem of maintaining insulin levels overnight
What changes were made to insulin to make it better to use for therapy?
There has been addition of a Lysine and Proline which allows it to mimic the sequence of IGF-1 which exists as a monomer therefore there is no need for the crystals to dissociate this has also been achieved through addition of an aspartate
Long acting insulin was made by deleting the last amino acid and adding a fatty acyl group allowing it to bind to albumin
What are the potential future prospects of treatment of type 1 diabetes?
Islet transplantation has been shown to have some success but is limit by the lack of availability
Artificial Islets may eventually be possible
What is Maturity onset diabetes of young?
This makes up around 2% of diabetes to 0.1% of population
Similarities to type-2 diabetes as there is no islet cell antibodies but there is beta cell destruction
It differs from type 2 diabetes due to the patients age, the fact it has an autosomal dominant inheritance and has no association with diabetes
What are the genes responsible for maturity onset diabetes of the young?
MODY1 is caused by mutations in hepatic nuclear factor with insulin secretion being normal at birth but decrease dramatically with age
MODY2 is caused by mutations in glucokinase affecting glucose sensing in pancreas Insulin secretion is impaired at birth but remains relatively stable
MODY3 which is cause by mutations in hepatocyte nuclear factor insulin secretion is normal at birth but decreases dramatically with age
MODY4 which is caused by ODX-1 transcription factor in beta cells involved in regulating insulin gene expression
MODY5 HNF transcription factor
What is mitochondrial diabetes/ maternally inherited diabetes and deafness?
Families with heritable form of the diabetes but where diabetes was exclusively inherited from the mother
These are caused by mutations in the mitochondria and is maternally inherited as the oocyte contributes all functional mitochondira to the child
This may cause 1-2% of all diabetes
When mutant mitochondria predominate the cells oxidative capacity is greatly reduced
The level of penetrance is variable as the number of defective mitochondira inherited can vary greatly between siblings and subsequent domination of wild type vs mutant mitochondria depends on a range of factor
In beta cells this results in a reduced capacity to secrete insulin in response to glucose as insulin secretion is linked to glycolysis
What is gestational diabetes?
Severe insulin resistance is brought on by hormonal changes and metabolic stress of pregnancy in women with low insulin secretory capacity this can result in a form of diabetes
This affects 2% of pregnancies of non-diabetic women
Symptoms normally disappear after birth but 60% of these women go on to develop diabetes in later life so they may have an underlying pre-disposition
What is type 2 diabetes?
This affects around 5-10% of the western population
It is very prevalent in westernised countries but not in third world countries implying that a role is played by lifestyle and food consumption
This is a progressive disease in which glucose tolerance slowly degenerates over a number of years and mainly affects older people
At diagnosis patients invariably have normal or excessive circulating levels of insulin implying that the pancreas has not been completely destroyed
As the disease progresses the beta cells lose their ability to secrete insulin and/or die In severe insulin resistance this is associated with an accumulation of amyloid plaques in the beta cells and in some patients this may contribute to the death of beta cells and thus the development of diabetes
Circulating levels of insulin distinguish type-2 and type-1 diabetes as well as the lack of antibodies to islets in type 2
What are the symptoms of type 2 diabetes?
The symptoms of insulin resistance and type-2 diabetes are not particularly obvious so most people don’t realise they have a problem until disease gets quite extreme
When type 2 diabetes is extreme then blood glucose levels can get above 20mM at which stage the kidneys cannot reabsorb all the glucose from the urine so glucose appears in the urine
As glucose levels increase in the urine its osmolarity increases so more water is drawn into urine causing polyuria and polydipsia
Insulin is unable to stimulate uptake of glucose by body tissues leading to signals of hunger
What is the result of insulin resistance in type 2 diabetes?
An increasing number of the general population have insulin resistance
Most obese subjects are also insulin resistant
This is mainly caused by a reduction in the ability of insulin to act on liver, muscle and fat
It appears to first occur in muscle then fat then the liver
It is linked to high levels of circulating glucose and fatty acids
About 25% of insulin resistant patients are eventually unable to secrete insulin causing glucose to reach diabetic levels
Glucose toxicity and ageing contribute to beta cell birth defects
What causes insulin resistance?
Cytokines from fat tissues like TNFalpha