diabetes Flashcards
what is the use of measuring C peptide when monitoring diabetes
it is a measure of at least some insulin being made - some functional beta cells left when C peptide is present
(C peptide:insulin is 1:1)
why is T1 diabetes not an acute illness
because you start to make autoantibodies many years prior to diagnosis (long preclinical period)
which type of antibodies for diabetes has autoantibodies but looks like T2DM
autoantibodies against GAD
is T1 diabetes B cell or T cell mediated
T cell - CD8
what are the mechanisms by which CD8 T cells destroy beta cells of the pancreas
via perforin and granzyme B
what is wrong with the current treatment for T1DM
- incapable of mimicking physiological glucose control and therefore cannot prevent complications such as hypoglycaemia very well
- have to inject multiple times per day
which group of diabetics are suitable for autologous haematopoietic stem cell transplantation
newly diagnosed diabetes with no ketoacidosis
who is suitable for islet transplantation
people with severe hypoglyacemia
problems with islet transplantation
- availability of organ donors (quantity and quality)
- viability and function of islets
- immunosuppression
- longevity of the graft
- cost
- allosensitization
explain the mechanism for the release of insulin
glucose enters beta cell via GLUT2 –> glucose undergoes glycolysis –> ATP –> increased ATP/ADP ratio leads to inhibition and closure of ATP-sensitive K+ channels –> depolarisation –> opening of voltage dependent Ca channels –> Ca influx –> fusion of insulin containing secretory granules with plasma membrane
action of the SNS on insulin release
NA inhibits insulin release
what are the effects of insulin of carbohydrate metabolism
- glucose transport into adipose and muscle (GLUT 4)
- increases rate of glycolysis in muscle and adipose tissue
- glycogen synthesis in adipose tissue, muscle and liver
what are the effects of insulin on lipid metabolism
- FA and TAG synthesis in adipose tissue
- uptake of TG from the blood into adipose tissue and muscle
- increase rate of cholesterol synthesis in the liver
- increases the production of malonylcoenzyme A - reduces the amount of FA entering hepatic mitochondria
explain the effects of insulin on protein metabolism
- amino acid transport into tissues
- protein synthesis in muscle
finish this sentence…
the excess carbohydrates that cannot be stored as glycogen are converted under the stimulus of insulin into
fats - stored in adipose tissue
where are GLUT 1, 2, 3 and 4 found
1 - all the cells of the body
2 - pancreatic beta cells, liver, intestine and kidney
3 - neurons
4 - striated muscle and adipose tissue
function of GLUT 2
ensures that glucose uptake by pancreatic beta cells and hepatocytes occurs only when circulating glucose is high
function of GLUT 3
crucial for allowing glucose to cross the BBB and enter neurons
insulin deficiency leads to what
hyperglycaemia, ketoacidosis, dehyradtion, polyuria, polydispsia, glucosuria, hypotension
what things push towards ketogenesis in diabetes
- increased oxaloacetate
- decreased malonylCoA –> increases carnitine action
- increased FFA (due to TAG hydrolysis)
what are the ketoacids
acetone
acetoacetate
beta-hydroxybutyrate
what are the drug names of the genetically modified long acting insulin?
glargine insulin (lantis) detemir insulin (levemir)
why is detemir insulin also linked to weight loss in diabetics
because the genetic modification of adding a FA to the end of the B chain means that it is able to pass the BBB and act on the brain to suppress appetitie
what are the drug names of the genetically modified short acting insulin?
insulin glulisine (apidra) insulin Lispro (humalog) insulin aspart (novorapid)
what is the typical insulin regime for a T1 diabetic
basal bolus
- one injection of long acting insulin at bed time
- one inject of short acting insulin immediately prior to each meal
what is the advantage of an artificial pancreas
has a continuous glucose sensor to determine the flow of insulin from the pump
what are the three main chronic complications of diabetes
- retinopathy
- nephropathy
- neuropathy
three ways you can measure the level of diabetes control
- measuring blood glucose
- HbA1C
- fructosamine
how is HbA1C formed
when glucose is high it non-enzymatically binds to proteins on Hb via an irreversible covalent bond
what is the advantage of measuring HbA1C over blood glucose
HbA1C gives you an indication of the average level of blood glucose for the preceding 3 months
what is the target HbA1C
7%
why is a target of less than 7% of HbA1C not a good thing
due to the risk of mortality due to increased incidence of hypoglycaemia
what does the fructosamine level indicate and when would you measure it
the level of red cell turnover
measure when a patient has high blood glucose but low HbA1C –> its low because of the high number of reticulocytes
how do you monitor the development of nephropathy in diabetics
measure the urinary microalbumin
what is the classification of hypoglycaemia
blood glucose <4mmol/L
how do you have 2 types of symptoms for hypoglycaemia in diabetics and what are the symptoms
acute fall - sympathetic nerve drive –> tachycardia, anxiety, dry mouth an tremor
chronic low levels - brain malfunction, paralysis, coma and death
treatment of hypoglyacemia
- if conscious - give glucose orally followed by a meal containing carbs
- if diminished consciouness - give bolus of glucagon
precipitating causes of ketoacidosis
- infection
- cessation of insulin
- new onset diabetes
- AMI or pancreatitis or other illness
- unknown
what is the treatment for ketoacidosis
- admission to hospital
- IV saline
- administration of insulin
- replacement of potassium
why do you replace potassium when treating for ketoacidosis
because insulin pushes K into cells and therefore you will have low potassium in the blood
- need to prevent this as this can cause arrhythmia and death
how many cells does an islet of Langerhans contain
50-300
4 types of cells in the islet of langerhans and what do they produce
alpha - glucagon
beta - insulin and amylin
gamma - pancreatic polypeptide
delta cells - somatostatin
what forms the majority of the islet of Langerhans
beta cells
what enzymes cleave preproinsulin
prohormone convertase 1 (pre) and 2 (pro)
explain phases of insulin secretion
- initial sharp rise in secretion that lasts for 2-5 minutes in response to increased blood glucose
- prolonged secretion phase if the glucose lasts for a long time
how do amino acids cause insulin release
transported into the beta cell via specific transporters, and is then used in the TCA cycle like glucose
how do FAs cause insulin release
increased FA causes an increased malonyl CoA which inhibits CPT-1 causing insulin secretion
why is more insulin secreted if glucose is given orally compared to intravenously
due to the incretin effect - the glucose in the gut triggers the release of incretin hormones which increases the release of insulin
two main incretin hormones
glucagon-like peptide-1 (GLP-1) - (more potent)
glucose-induced insulinotropic polypeptide (GIP)
which cells of the gut secrete GLP-1
L cells of small intestine
when is GLP-1 released
in response to glucose and FAs
action of GLP-1
- both stimulates secretion of insulin and the synthesis of insulin
- inhibits gastric emptying
- inhibits glucagon secretion
- promotes beta-cell proliferation, differentation and maturation
what are the 2 groups of drugs that are mimicing the effects of GLP-1
GLP-1 agonists
DPP-4 inhibitors
how do DPP-4 inhibitors work
they inhibit the enzyme that degrades GLP-1 –> enhances endogenous GLP-1 effects
which cells produce GIP
K cells of the duodenum
what stimulates GIP secretion
glucose and FAs
action of GIP
activates lipoprotein lipase to enhance fat clearance from the blood
explain the regulation of GIP
its effect is dependent on the plasma glucose concentration
action of amylin
- inhibits glucagon secretion
- delays gastric emptying
- inhibits food intake
what is the drug that is an analogue of amylin
pramlintide
action of pancreatic polypeptide
- inhibits food intake
- increases energy expenditure
- inhibits secretion of enzymes from the pancreas
- blocks the contraction of the gall bladder
what is the function of somatostatin on the pancreas
- inhibits insulin and glucoagon secretion
- inhibits pancreatic exocrine function
(appears to be to prevent exaggerated responses to a meal)
definition of diabetes
a disorder of the metabolism causing excessive thirst and the production of large amounts of urine
what is the difference between diabetes mellitus and diabetes insepidus
mellitus - polyuria is secondary to glycosuria, in turn due to hyperglycaemia
insipidus - pituitary problem causing increased ADP –> polyuria
what are the two intracellular pathways that insulin activates
MAP kinase
PI-3K pathway (this one causes GLUT4 expression on cell surface)
the consequences of diabetes relates to what 3 things
- macrovascular changes
- microvascular changes
- cellular changes
what are the macrovascular changes that occur with chronic poorly controlled diabetes
- accelerated and more severe atheroma
- this leads to sequelae such as MI, stroke, angina
what causes accelerated atheroma in diabetics
- increased hepatic production of atherogenic lipoproteins
- suppression of lipid uptake in peripheral tissues
- abnormal endothelial function with pro-coagulant results
(lead to hyperlipiaemia and hypertension)
what 3 organs/system are particularly affected by the macrovascular changes associated with diabetes
kidney
retina
would healing
The microvascular changes that occur with chronic poorly controlled diabetes relate to
glycosylation of proteins
what are advanced glycation end products
stable and irreverisble glycosylated proteins due to hyperglyceamia
why does diabetes predispose to nephropathy
- diabetic glomerulosclerosis/arteriolosclerosis
- impaired neutrophil function –> pyelonephritis
- papillary necrosis
- accelerated atherosclerosis in larger arteries
what are the two histological signs of diabetic nephropathy
- Kimmelsteil Wilson nodules in the mesangium of the glomerulus –> eventually become balls of collagen
- arteriolar wall thickening by acellular proteinaceous material (hyaline arteriolosclerosis)
(result in very thick BM and poor perfusion to the glomerulus)
what is the primary process underlying diabetic retinopathy
vascular proliferation in response to ischaemia due to microvascular injury (hyaline arteriolosclerosis) and reduced perfusion
why is there poor wound healing in diabetics
related to impaired perfusion due to microvascular injury
3 pathways for chronic hyperglycaemia that cause damage to tissues
- AGEs
- activation of protein kinase C
- intracellular hyperglycaemia and abnormal polyol pathways
how do AGEs elicit their effects
they bind to RAGE (specific receptor) on inflammatory cells (T cells and macrophages), endothelial cells and vascular smooth muscle
what are the receptor mediated effects of AGEs
- release of pro-inflammatory cytokines and GFs from macrophages causing growth and proliferation abnormalities
- generation of ROS in endothelial cells –> damage
- increased pro-coagulant activity by endothelial cells
- proliferation and matrix production by vascular smooth muscle –> hyaline arteriolosclerosis
what are the extracellular effects of AGEs
- cross linking of Type 1 collagen in vessel walls altering their dynamics (can lead to vessel injury)
- AGE-induced cross linking of collagen IV in BM –> alters attachment of endothelium, permeability and causes thickening
- can trap other proteins including LDL
how does hyperglycaemia cause activation of protein kinase C
intracellular hyperglycaemia stimulates DAG overproduction –> PKC activation
actions of PKC in diabetes
- pro-angiogenic GFs
- elevated endothelin-1 and reduced NO –> small vessel constriction
- pro-fibrogenic GFs like TGF-beta –> increases production of BM and matrix
- pro-inflammatory cytokines from endothelium
overall function of PKC in diabetes
causes structural and functional abnormalities in the capillary bed including wall thickening, constriction and abnormal responses to attempts to modulate calibre, abnormal endothelial function and pro-inflammatory cytokines
how are polyols made during diabetes
excessive IC glucose is metabolized through intermediates called polyols to fructose
how do polyols cause damage in diabetes
metabolism to fructose uses up glutathione (need this to protect the cell against oxidative stress)
what causes neuropathy in diabetics
- AGE-related damage leading to loss of axons
- possibly polyol-related damage
- microvascular injury leading to neuronal ischaemia
which liver problem is associated with diabetes
non-alcoholic steatohepatitis/non-alcoholic fatty liver disease
histology of NASH
- fat accumulation
- infiltrate of neutrophils and lymphocytes
- fibrosis
commonest cause of death in a diabetic is
MI/stroke/renal failure due to macrovascular changes
