Pathogenesis of type 1 diabetes mellitus Flashcards
What does diabetes mellitus mean?
Passing lots of sweet urine
What does diabetes insipidus mean?
Passing lots of insipid urine - ADH insufficiency
List the diagnostic criteria for DM (all types)
- Fasting blood glucose
- OGTT
>Need 2 abnormal tests or 1 plus symptoms - HbA1c
Fasting blood glucose results
<6: normal
6.1-6.9: impaired
>7 diabetes
OGTT results
Oral glucose tolerance test - 2 hour glucose <7.7: normal 7.8-11: impaired >11.1: diabetes
What are the symptoms of diabetes
- thirst
- tiredness
- passing lots of urine
- blurred vision
- thrush (oral/genital)
Define HbA1c and explain results
average glucose over a period of 6-7 weeks
42-47 : Pre-diabetes
>48: diabetes
This is not currently rolled out in Glasgow as it is a much more expensive test to perform
List the different types of diabetes
> Type 1 - > Type 2 > MODY - Maturity onset diabetes of the young > Gestational > Secondary
Define gestational diabetes
women become very resistent to their own insulin, mainly in the third trimester of pregnancy
If threshold for insulin is already very high, this pushes the woman over to hyperglycaemia
Evolutionary, this is not necessarily bad as it maintains glucose delivery to the baby even during low-fed states
High blood glucose passes to the baby - grows very large and causes obstetric problems
List the causes of secondary diabetes
Pancreatitis - pancreatic infection destroys beta cells
Cystic fibrosis
Haemochromatosis - iron causes toxicity to beta cells of pancreas
Steroid-induced - causes insulin resistance
Acromegaly - GH excess; GH normally works against insulin, causing diabetes
NB: excess of any counter-regulatory hormone (cortisol, etc.) can cause diabetes
Which types of diabetes are insulin deficient
Type 1 MODY Pancreatitis - can wane and wax, periodically requires insulin treatment. Difficult to treat because patients often have chaotic lifestyles Cystic fibrosis Haemochromatosis
NB: Insulin-deficient forms require insulin treatment
Which types of diabetes are insulin resistant?
Type 2
Gestational
Steroid-induced
Acromegaly
NB: patients often have very high levels of insulin in circulation
What auto-antibodies can be found in T1DM?
ICA (islet cell antibody) I-A2 (insulinoma-associated antigen-2) IAA (insulin auto-antibody) GAD65 (glutamic acid decarboxylase 65) ZnT8 (zinc transporter)
ICA, I-A2 and GAD65 most commonly used in clinical practice
more sensitive if all used in combination
What is the typical presenting history for T1DM
Child/adolescent history of weight loss, thirst, polyuria, nocturia and fatigue Viral illness recently Family history of T1DM and thryoid High blood glucose level High blood ketones
Why does weight loss occur in T1DM
Glucose is not absorbed into muscles/fat cells from the blood
Results in both fat and muscle bulk
How is ketoacidosis diagnosed?
Blood ketones > 3
Which other disorders are closely associated with T1DM?
History of other autoimmune disorders, especially thyroid disorders
Which genes are likely to increase susceptibility to T1DM?
HLA - e.g. DR3/4 - DR2/8 insulin (VNTR) PTPN22 IL2RA CTLA-4 IFIH1
What are precipitating events linked to T1DM?
> enteroviruses (especially coxackie)
rotavirus
bacteria (e.g. mycobacteria avium paraTB)
Environmental
- Cow’s milk (early introduction)
- Wheat proteins (trigger coeliac which is associated to T1DM)
Vit D deficiency may be linked due to same distribution of T1DM cases depending on latitude)
Insulin resistance (e.g. puberty)
? psychological stress
What effect does puberty have on insulin resistance?
- stresses out beta cells
- fast growth requires calories to be diverted away from fat cells to growing tissues
- this can be facilitated by insulin resistance -> stresses the beta cells as they must produce more insulin
How can we predict the onset of T1DM?
> HLA
Auto-antibodies
First-phase insulin response to glucose - inject glucose and determine if first phase insulin response is blunted - suggests early-stage impairment
T-cell function
Elevated lysophosphatidylcholine - sensitive marker for predicting T1DM, especially in siblings of patients
Reduced beta cell mass (by PET scanning) - mass can be seen shrinking before the onset of symptoms
Which other autoimmune diseases are associated with T1DM?
> Thyroid disease (hyper and hypo) V. strongly associated
Coeliac disease - strongly associated
Addison’s disease = primary adrenal insufficiency (hypocortisolism)
Pernicious anaemia
Inflammatory bowel disease (UC/Crohn’s)
Premature ovarian failure
How do insulin pumps work?
Deliver bolus amounts of insulin with food
Delivers different basal rates from hour-to-hour to mimic pancreas
Continuous glucose monitoring
How do beta cells know how much insulin to release?
Insulin is stored in secretory granules in beta cells
GLUT2 on beta cells senses blood glucose level; ultimately this determines how much insulin is released
How is insulin released?
Glucose is taken up and converted by glucokinase to G6P, which is converted to pyruvate, which generates ATP
K channel (SUR) is ATP sensitive and closes in response to increased ATP levels This depolarises beta cell and causes voltage-sensitive calcium channel to open NB: SUR = sulfonyl urea
Voltage-dependent calcium channel opens in response to membrane depolarisation
caclium influx into the cell by facillitated diffusion
amount of calcium entry determines how many secretory granules of insulin are exocytosed
Islet transcription factors - modulate each stage and refine the whole mechanism
Define MODY
Any of several hereditary forms of diabetes mellitus caused by mutations in an autosomal dominant gene disrupting insulin production
Often referred to as ‘monogenic diabetes’ to distinguish it from types of diabetes that involve more complex combinations of causes involving multiple genes and environmental factors
All different types occur at different stages of the insulin release pathway
What are the different types of MODY
> HNF-1alpha > Glucokinase > HNF-4alpha > HNF-1beta > Neonatal
Describe HNF-1alpha diabetes
Type of MODY
66% cases due to mutation of hepatic nuclear factor 1-alpha
- causes a deficiency
- wipes out one of the islet transcription factors
- this puts a braking mechanism on insulin release
Describe glucokinase diabetes
Type of MODY
30% cases
- next most prevalent type is mutation in glucokinase -> downregulation of enzyme
- glucose signal does not transfer through to insulin
Describe HNF-4 alpha diabetes
Type of MODY
Third most common type (5%) is HNF-4 alpha mutation
- absence causes pathway to breakdown
Describe HNF-1beta diabetes
Type of MODY
Has some distinct clinical features, including atrophy of the pancreas and several forms of renal disease
Describe neonatal diabetes
Monogenic form of diabetes that occurs in the first 6 months of life
neonatal DM (1%) = deficiency in the K+ channel
- no calcium depolarisation and subsequent insulin release
Type of MODY
How are MODY patients treated?
Can be given insulin
A lot of patients can be treated with glidazide, which has a better quality of life as tablet rather than injection
What is glidazide?
Sulphonurea
Binds to K+ channel, causing closure, which leads to depolarisation and calcium influx allowing insulin to be released
