Diabetes Mellitus Flashcards
What is diabetes mellitus?
a chronic syndrome of hyperglycaemia with anomalies in carbohydrate, fat and protein metabiolism due to lack of insulin production, decreased cellular insulin sensitivity or both
Genetic susceptibility plays a key role in what kind of diabetes?
Type II diabetes
(to a lesser extent in type I diabetes) following twin studies
What serotypes increase an individuals susceptibility to diabetes 14 fold?
- HLA-DR3
- HLA-DR4
What countries have the highest incidence of diabetes?
Nordic countries
What countries have the lowest incidence of diabetes?
Asian countries
Verge postulated that early exposure to __________ could increase diabetic risk in infants
dairy milk
What viral infections have been associated with increased diabetes risk?
- congenital rubella
- 20% of new cases were positve with coxsackie antibodies
Insulin resistance is observed in ________ stages of pregnancy
later stage
What is the effect of physical activity type II diabetes?
diminishes risk by:
* increasing sensitivity to insulin
* glucose metabolism
The basis for the autoimmune theory of diabetes stems from …
inflammation within the islets of langerhans
autoimmune destruction of B cells.
What happens to B cells as diabetes (type I) progresses ?
- decrease in number
- decrease in their ability to regenerate
More than __% of type I diabetics have autoantibodies against B cells
90%
In type I diabetes there is often a normal count of other langerhans cells (a-cells, PP cells). True or false
True
Give examples of autoantibodies that can be implicated in type I diabetes
- islet cell antibody
- glutamic acid decarboxylase antibody
- zinc transporter 8
What autoantigen is postulated to be implicated in the selective descruction of B cells?
pro-insulin
Present in b-cells and not in other langerhans cells
Genetic susceptibility to diabetes comes from what groups of genes?
Human leucocyte antigen (HLA) genes
What HLA genes have a strong association with diabetes ?
HLA-DR3
HLA- DR4
What type of white cell is the most abundant in islet lesions?
T-lymphocytes
followed by macrophages, lymphocytes and plasma cells
What type of immunity is involved in the pathogenesis
- humoral immunity (plasma cells)
- cellular immunity (white cells)
What is the role of insulin?
acts on insulin sensitive tissue such as adipose and muscle to encourage glucose uptake
What is the response of B cells to insulin resistance?
to increase insulin manufacture to preserve normal glucose tolerance
The reduction of B cells seen in diabetes is due to …
elevated glucose, fatty acids and amyloid deposition which causes B cell apoptosis
B cell loss in type II diabetes is amplified by …
the fact that the pancreas is incapable of regenerating B cells beyond the 3rd decade
so afer 30 years b cell regeneration is difficult /impossible
What is the function of GLP-1?
glucagon like peptide- 1 (produced in the gut)
acts on b cells to enhance insulin production
acts on a cells to suppress glucagon production
What is the effect of type II diabetes on GLP-1 ?
glucagon suppression by GLP-1 on a cells is insufficient
The levels of GLP-1 in diabetic patients are lower in comparison to non-diabetic patients. True or false
false
levels in diabetic and non-diabetic patients are similar
What part of the CNS regulates liver glucose?
hypothalamus
What is the role of bile acids in glucose homeostasis ?
they instigate fibroblast growth factor 19 (FGF-19) which induces glycogen and reduces glucose production
What is the consequence of hypothalamic inflammation that is caused by a fatty diet?
leads to reduced insulin sensitivity and dysregulation of body weight
What is the consequence of a high fat diet and physical inactivity?
- initial fill of adipose tissue under the skin
- fat accumulates and is then stored in muscle, liver, pancreas, blood vessels and pericardial tissue.
- adiposity in intra-abdominal cavity leads to impaired glucose uptake due to intracellular impairment of glucose signalling
Outline the ways in which you can test for diabetes
- random venous plasma glucose
- fasting plasma glucose
- oral glucose tolerance test
- glycated haemoglobin (HbA1c)
*
What is the cut-off point of FPG?
126mg/dl
What is the cut-off point of OGTT?
200mg/dl
What is the purpose of HbA1c test ?
useful for assessing the adequacy of glycaemic control, reflecting the mean plasma glucose over the previous 2 months
What instances is a HbA1c test unsuitable for diagnosis of diabetes?
- patients with haemoglobinopathies such as sickle cell anaemia or thalassaemia (RBCs affected)
- children
- acutely ill patients
- patients on steroids
What is pre-diabetes?
patients with impaired fasting glucose (IFG) or impaired glucose tolerance
glucose levels are not elevated enough to be diabetes but greater than normally considered
When should pregnant women receive an OGTT? (as per endorsement by American Diabetes Association)?
24-28 weeks of gestation
Systemic manifestations of diabetes can be divided into …
microvascular and macrovascular
What types of complications are first to occur in diabetes? Give some examples
microvascular complications often occur first
retinopathy, neuropathy and nephropathy
Macrovascular complications that can arise from diabetes include…
- cardiovascular disease
- cerebrovascular accidents
What diabetic complication results from hyperglycaemia?
- diabetic ketoacidosis
What diabetic complication results from hypoglycaemia?
diabetic coma
For a FPG test, what is classsified as fasting?
fasting is defined as no caloric intake for at least 8 hours
What type of glucose load is used to perform the OGTT test ?
one containing the equivalent of 75g anhydrous glucose dissolved in watter
When should an OGTT test for diagnosis of gestational DM not be performed?
they should not be performed in the morning after an overnight fast of at least 8 hours
List indications for type II diabetes testing
- > 45 years who are overweight (BMI >25kg/m2)
- <45 years who are overweight and have additional risk factors
- first degree relatives with DM
- sedentary lifestyle
- delivered baby >9lb or have been diagnosed with gestational dm
- hypertension
- HDL <35mg/dl or triglycerides >250mg/dl
- previous testing with impaired glucose tolerance or impaired fasting glucose
- history of vascular disease
What is the effect of hyperglycaemia on kidneys?
causes expansion and injury of mesangial cells (contractile glomeruli cells) due to increase in mesangial cell glucose concentration
Initial mesangium expansion is caused by ________ and subsequently ___________
cell proliferation
cell hypertrophy
What is the consequence of mesangial expansion?
increased rebasorption; hyperfiltration
increased glomerular permeability- leads to proteinurea
absorption of proteins by proximal tubules leading to interstitial scarring and fibrosis (foreign protein presence triggers an inflammatory reaction)
Name the preferred indicator of advanced stage diabetic nephropathy
tubular interstitial fibrosis
more accurate indicator of renal failure than glomerular sclerosis
What kidney functions are affected by nephropathy?
- EPO release
- activation of vitamin D
- salt and water homeostasis
How does diabetic retinopathy cause blindness?
through long-standing microvascular damage in the retina
What constitutes vascular damage?
- increased vessel permeability and degeneration
- micro aneurysms
- disproportionate angiogenesis
________ alters colour perception.
cellular
What are the stages of retinopathy?
- proliferative
- non-proliferative
Deterioration of diabetic retinopathy leads to …
retinal detachment
What are the oral manifestations of diabetes?
- burning mouth syndrome (or glossodynia)
- candidiasis
- dental caries
- gingivitis
- neurosensory dysethesias
- periodontitis
- salivary dysfunction
- taste dysfunction
- xerostomia
Diabetic neuropathy affects both the _____ and ___ systems
autonomic and somatic nervous systems
What are the pathological changes that occur in neuropathy?
- endothelial thickening
- subsequent hypoxia
(blood supply to neurons is compromised which causes them to suffer from hypoxia)
What is the consequence of disease progression on neuropathy?
- loss of sensation to thermal/physical stimuli
patients can experience allodynia (pain in response to traditionally non-painful stimuli) or hyperesthesia (heightened pain response)
Autonomic and sensory fibres are more affected in neuropathy when compared to motor neurones. True or false
True
Longer fibres are affected first in neuropathy (exhibit signs of degeneration). How is this clinically manifested?
parasthesia, anaesthesia and loss of reflexes in the feet
similar symptoms can follow in the hands
Neuropathy that affects both the hands and feet is termed as …
Glove and stocking distribution
What is the consequence of neuropathy induced anaesthesia in diabetics ?
they do not respond to lower limb injuries thus increasing the risk of ulcers and of greater consequence amputation.
State some ways in which neuropathy in the autonomic nervous manifests itself
- orthostatic hypotension
- diarrhoea
- urinary incontinence
The atherosclerotic process is ________ diabetics, particularly if poorly controlled
accelerated
What is diabetic cardiomyopathy?
It described injury to the cardiac muscle cells and their performance, non atrributable to hypertension of CAD disease in diabetics
What are the primary signs of cardiomyopathy?
- changes in myocardial structure
- changes to calcium signalling and calcium uptake
Cellular behaviour within vessels are affected by ________ and ________ which favour thrombosis in diabetics
oxidative stress and longstanding inflammation
Glycaemic control is proportional to the severity of periodontal disease; this relationship is also bidirectional. Briefly elucidate the meaning of this
this means that poor periodontal health worsens diabetes
poorly controlled diabetes will also worsen the periodontal condition
Outline probable theories for the negative bidirectional relationship observed with periodontitis and diabetes
- change in bacterial composition of subgingival plaque
- weakened immune defence which impair leucocyte action
- release of tumour necrosis factor
these increase collagen breakdown and decrease collagen synthesis; resulting in destruction of the periodontum
What is the cause of increased caries susceptibility in diabetes?
- reduced salivary production - reduced acid buffering capacity providing a good environment for S. mutans
- periodontal destruction
Salivary dysfunction in diabetics is especially seen in what kinds of patients?
those with neuropathy
What is the cause of xerostomia from diabetes?
- soft tissue irritation
- chronic inflammation
- discomfort
What are the potential causes of xerostomia in diabetic patients?
- reduced parotid salivary flow rate
- diabetic medications
Xerostomia resulting from diabetic medications often presents first as…
polydipsia
What is a potential cause for salivary hypofunction in diabetes ?
alteration of the basement membrane of the salivary glands
What is a contributing factor for altered taste sensation observed in diabetics?
reduced saliva
Immunosuppression of diabetics predisposes them to opportunistic infections like candidiasis. List risk factors for diabetics to develop fungal infections
poorly controlled diabetics that
* smoke
* wear dentures
* are long term steroid user
Diabetics with dental and facial abscesses should be treated with urgency to avoid…
spread to deep fascial spaces
Oral lichen planus is seen to be associated more often with what type of diabetes?
Type I diabetes
Oral lichen planus is also thought to have autoimmune aetiology (remember autoimmune diseases do not often occur independently)
What is the MOA of sulfonylureas?
bind to sulfonylurea receptors on beta cells and trigger release of insulin
Give examples of sulfonylureas
- glipizide, glimepiride (3rd gen)
What is the MOA of meglitinides ? Give some examples
bind to sulfonylurea receptors as well
nateglinide
What is the MOA of biguanides? Give an example
- decrease gluconeogenesis and increases peripheral glucose uptake
Metformin
What is the MOA of thiazolidinediones ? Give examples
activate peroxisome proliferator-activated receptor gamma (PPAR-y) to affect glucose and lipid metabolism
pioglitazone
What is the MOA of acarbose miglitol ?
inhibits alpha-glucosidase in the gut and this prevents break down of some complex carbohydrates into simple sugars that then cannot be absorbed
Give examples of diabetic agents that are insulin secretagogues
- sulfonylurea
- meglitinides
Give examples of drugs that are insulin sensitizers ?
- biguanides
- thiazolidinediones
What are the adverse effects of sulfonylureas?
- hypoglycaemia
- weight gain
What are the adverse effects of meglitinides?
generally none but hypoglycaemia is possible
What are the adverse effects of biguanides?
- diarrhoea
- abdominal pains
- risk of lactic acidosis
What diabetic agent is contraindicated in renal insufficiency and heart failure?
biguanides
What diabetic agent promotes weight loss and has a low risk of developing hypoglycaemia when used alone?
biguanides
What are the adverse effects of thiazolidinediones?
- weight gain
- water retention
- may precipitate congestive heart failure
- possible risk of experiencing bone loss
What are the adverse effects of acarbose miglitol ?
- bloating
- diarrhoea
- flatulence (action of colonic bacteria on undigested carbohydrates)
Why are neurosensory disorders such as burning mouth syndrome (glossodynia) seen in diabetes?
reduced density of epithelial nerve fibres with axonal degeneration
results in persistent painful condition
What diet and lifestyle changes should be recommended to diabetic patients?
- aim to intake approx. 1000 kilocalories under energy needs to improve insulin sensitivity
- limit carbohydrate intake- beneficial for patients that are on insulin medication
- high fibre diet for cardiovascular health and glycaemic control
- exercise - reduce abdominal fat, improve BP, improve circulation, improve insulin sensitivity
What type of insulin should be used during fasting?
long acting insulin
Rapid acting insulin is used to cover ___________.
meal times
Briefly outline how the circulation and vascularisation in diabetics impact wound healing
- decreased vascularity in diabetics potentially encourages hypoxia
- hypoxia increased inflammation and free radical release
- hyperglycaemia increases free radical production and AGE (advanced glycation end products)
- AGE inhibits vascular proliferation
- hyperglycaemia prevents gap junction (proteins) formation and encourages TNF-a production which synergistically inhibit angiogenesis
Innate immunity is suppressed in diabetics. What is the reason for this ?
- AGE products decrease neutrophil and monocyte count in circulation
- neutrophils and monocytes may also be inactivated
- decrease in antimicrobial proteins produced by oral epithelial cells (caused by high blood glucose)
- TNF-alpha presence which inhibits the inflammatory cascade- the first stage of healing. TNF-a is seen in obese and type II diabetics
Give examples of antimicrobial proteins produced by oral epithelial cells
- beta defensins
- cathelicidin
- psoraisin
Give examples of growth factors that are involved in wound healing
- EGF- epidermal
- IGF- insulin like
- NGF- nerve
There are lower levels of growth factors involed in healing seen in diabetics. True or false
True
NGF encourages proliferation of what kinds of cells?
- keratinocytes
- endothelial cells
What is the consequence of suppression of the HPA axis through stress?
predisposition of patients to infection and delayed healing
