Diabetes Flashcards
What are the four cell types found in the islets of langerhans in the pancreas?
Beta cells - make and secrete insulin
Alpha cells - secrete glucagon
Delta cells - secrete somatostatin
PP cells - secrete pancreatic polypeptide
Where is insulin synthesized? What is its precursor? What process converts this to insulin? What components does a molecule of insulin have? What is proinsulin? What is the role of preinsulin?
Insulin is synthesized in the rough endoplasmic reticulum of pancreatic beta cells as a larger single chain preprohormone – called preproinsulin.
It is then cleaved to form insulin.
Insulin contains two polypeptide chains linked by disulfide bonds.
Connecting (C) peptide, a byproduct of cleavage, has no known physiologic function.
Proinsulin – provides a tertiary structure which is recognised by insulin receptors.
Give the five types of insulin preparation and their relative length of time in the blood
Ultrafast/ultra short acting - lispro Short acting - regular Intermediate acting - NPH + lente Long-acting - ultralente Ultra long acting - glargine
Briefly decribe the stages of insulin, from glucose entering the cell to release of insulin
Glucose enters the beta cell through the GLUT2 glucose transporter
Glucose is phosphorylated by glucokinase, creating glucose phosphate
Glucose phosphate is metabolised, leading to the production of ATP
ATP blocks removal of K+ from the cell by inhibiting the ATP-sensitive K+ channel (called KATP)
This causes depolarization of the membrane
Voltage gated Ca2+ channels open
Influx of Ca2+
Causes fusion of secretory vesicles with the cell membrane
Insulin is released
What is the typical pattern of release of insulin?
Why is this?
Release of insulin is biphasic – 2nd phase if 1st phase hasn’t increased blood glucose levels.
There are two phases because:
- Only 5 % of insulin granules are immediately available for release i.e. the RRP – readily releasable pool
- Reserve pool must undergo preparatory reactions to become mobilised and available for release
Which two proteins make up KATP channels?
How can these be altered?
What can this cause?
Kir6
SUR1
Genetic mutations can alter these
Problems with insulin secretion
What is MODY?
The activity of what is impaired?
This is a type of monogenic diabetes with a genetic defect in beta cell function.
It is a familial form of early-onset type diabetes, with the primary defect being in insulin secretion.
Activity of glucokinase is impaired
What are the three basic steps in signalling cascades?
- Reception – signal molecule binds to the receptor
- Transduction – signal transduction pathway how the initial binding triggers a cellular response
- Response – activation of cellular responses
The insulin receptor is a member of which family?
Receptor tyrosine kinase family
What is the diagnostic criteria for diabetes?
Any of the following criteria:
- HbA1c >48 m/m
- Fasting glucose above 7 mmol/L
- 2-hr glucose in OGTT >11.1 mmol/L
- Random glucose >11.1 mmol/L
The WHO recommends normal BG as what?
What should this really be?
WHO - <6.1 mmol/L
Should be <5.6 mmol/L
Which antibodies are typically present at diagnosis of T1DM?
GAD
What are three useful discriminatory tests between T1DM and T2DM?
GAD/ Anti-Islet Cell antibodies
Ketones
C-peptide (plasma)
What is type III diabetes?
List some causes
This is when other diseases cause secondary diabetes
Pancreatic disease
- Chronic or recurrent pancreatitis Haemochromatosis
- Cystic Fibrosis
Endocrine disease - Cushing’s syndrome, Acromegaly, Phaechromocytoma, Glucagonoma
Drug induced
- Glucocorticoids
- Diuretics
- B-blockers
What five things should you look out for in monogenic diabetes?
Strong Family History Associated Features (renal cysts etc) Young Onset GAD-negative C-peptide positive
Define gestational diabetes
Any degree of glucose intolerance arising or diagnosed during pregnancy.
Basic criteria for diagnosing T1DM?
Fasting glucose ≥ 7.0mmol/l
Random ≥ 11.1mmol/l AND symptoms, OR repeat test
Why can’t you use HbA1c in T1DM?
Can’t HbA1c to test for type I diabetes due the rapid onset of the disease.
Is the risk of getting T1DM more, less or the same if your mother or father has diabetes?
8% if father
3% if mother
What % of familial risk of T1DM does HLA make up?
What are the two highest risk genotypes?
50%
DR3-DQ2
DR4-DQ8
How does seasonality affect the risk of T1DM?
Seasonality – it is less common in those born in the summer months, particularly July
What are some possible triggers for T1DM?
Viral infection
Maternal factors
Weight gain
Autoantibodies in T1DM
- Which two are commonly used?
- Which is used if all others are negative?
- Which is better in children?
- Which is better in the older?
GAD (female) and IA-2 (male) are commonly used
Zn transporter can be used if all others are negative
IAA (insulin autoantibody) is better in children
Zn transporter is better in the older
Which “risk factors” accelerate the progression of T1DM?
Infection Insulin resistance Puberty Diet/weight Stress
What are four biochemical markers of increased disease progression?
Raised glucose ketones
Decreased insulin
Decreased B-cell mass
Decreased C-peptide
What is the classic triad of presenting features in T1DM?
What other things should you look out for?
- Polyuria
- Polydipsia
- Weight loss
Other things
- Fatigue
- Blurred vision
- Thrush
- FHx of autoimmune conditions e.g. thyroid
How should you manage a newly diagnosed patient with T1DM?
- Blood glucose and ketone monitoring
- Insulin - usually basal bolus regimen
- CHO estimation
- Regular dietician contact
- Appropriate medical clinic review
- Regular check of prevailing glycaemic control - HbA1c (ideal range 48-58 mmol/L)
What five things should you do at an annual review assessment for T1DM?
Weight Blood pressure Bloods: HbA1c, Renal Function and Lipids Retinal screening Foot risk assessment
What is LADA?
What is the commonest age range for diagnosis?
Latent autoimmune diabetes – a form of type I with endogenous secretion for about first four years after diagnosis.
20-30
Definition - ‘A diagnosis of LADA is established by the presence of elevated levels of pancreatic auto-antibodies in patients with ‘recently diagnosed’ diabetes who do not initially require insulin’.
You have to have lost what % of beta cell mass before getting raised blood sugar?
What % do you need to lose to get insulin dependence?
Which type of diabetes is slower at losing beta cell mass?
50%
>90%
LADA is slower at losing B cell mass.
When should you suspect LADA?
Occurs in young adults 25 to 40 Male preponderance Usually non-obese Auto-antibody positive Associated auto-immune conditions Non-insulin requiring at diagnosis Sub-optimal control on oral agents
Name five clinical features of DIDMOAD aka Wolfram syndrome
Diabetes Insipidus Diabetes Mellitus Optic Atrophy Deafness Neurological anomalies
What are some autoimmune conditions commonly associated with T1DM?
Thyroid disease Coeliac disease - 5% in Type 1 DM; 1% in the population Pernicious Anaemia Addison’s disease IgA deficiency
What are the two important things that HbA1c correlates with?
As HbAc1 concentration increases, incidence of microvascular complication decreases
As HbAc1 concentration increases, incidence of hypos increases
Secretion of insulin at a basal rate accounts for what % of total insulin production?
50%
How many units of insulin, and at what times would you prescribe for a 60 kg male aged 16?
- e.g. start at 0.3 units/kg body weight
- Divide it around 50% prandial 50% Basal
- Total= 18 units
- Lantus (long acting) - 9 units pre-bed (2200hrs)
- Prandial – 3 /3 /3 units pre-meals
What is advanced CHO counting?
Who is it suitable for?
Synchronizing the amount of insulin taken to amount of carbohydrate consumed.
Who is it suitable for?
- For those on multiple daily injections (MDI)
- For people on continuous subcutaneous insulin infusion (SCII) pumps
What is the goal of pancreatic islet transplantation in T1DM?
To restore the symptoms of hypos again
What is the natural history of beta cell function in T2DM?
initially, the beta cells compensate for increasing insulin resistance.
The body tries to compensate for resistance by increasing insulin production, you ultimately get to a point where the pancreas burns out and insulin production starts to lower in the pancreas. At this point, blood glucose tends to rise.
What is is that we think anatomically decreases beta cell function?
Excess fat around the pancreas
What four things is central adiposity (apple shape) associated with?
High blood pressure
High Triglycerides
Low HDL
Insulin resistance
What is the most common external manifestation of insulin resistance?
Acanthosis nigricans = thickening and slight pigmentation of the skin, around folding areas e.g. around the neck
What is the natural history of T2DM?
B-cell decline precedes the development of Type 2 diabetes by up to 15 years.
Following the development of insulin resistance there is a compensatory increase in insulin secretion by the β-cells of the pancreas (hyperinsulinaemia) in order to achieve normal blood glucose levels.
Eventually, β-cell function starts to decline, leading to impaired glucose tolerance (IGT) and Type 2 diabetes.
What are the four main types of neuropathy found in T2DM?
Briefly describe each
- Peripheral – this is the classic case; glove and stocking type lesions; can either be symptomatic with lots of pain, or asymptomatic with loss of sensation e.g. pain/ loss of feeling in feet, hands
- Autonomic e.g. changes in bowel, bladder function, sexual response, sweating, heart rate, blood pressure, hypoglycaemic unawareness
- Proximal – most often seen when you lose the dermatomal distribution of a single neuron e.g. pain in the thighs, hips or buttocks leading to weakness in the legs (Amyotrophy)
- Focal Neuropathy e.g. sudden weakness in one nerve or a group of nerves causing muscle weakness or pain e.g. carpal tunnel, ulnar mono neuropathy, foot drop, bells palsy, cranial nerve palsy
What are the risk factors for neuropathy in diabetes?
Increased length of diabetes Poor glycaemic control Type 1 diabetes > Type 2 diabetes High Cholesterol/ Lipids Smoking Alcohol Inherited Traits (genes) Mechanical Injury
What are the two type of peripheral nerve damage in diabetes?
Peripheral nerve damage can be distal symmetric or sensorimotor neuropathy.
