Diabetes I Flashcards
Describe insulin synthesis?
- Insulin is synthesized as pre-pro-insulin and processed to pro-insulin.
- Pro-insulin is then converted to insulin and C-peptide and stored in secretary granules awaiting release on demand
How is insulin secreted?
- glucose from GI tract
- activates GLUT 2 receptors of beta cells
- increase in ATP closes ATP-gated K+ channels to stop it flowing out
- depolarization
- Ca2+ entry and insulin granule exocytosis
- once secreted acts to trigger glucose uptake from blood
Where is insulin produced?
beta cells of pancreatic islets
Describe the biphasic nature of insulin secretion?
- there is a readily releasable pool of insulin filled granules that can be released without nutrients
- there is a reserve pool of insulin filled granules that is strictly metabolic dependent - this acts as the reserve pool
Describe the tissue distribution and function of the GLUT 1 transporter?
- found in most cells
- helps in basal glucose uptake
GLUT 2?
Location and functions
- found in liver, beta cells, hypothalamus, basal lateral membrane small intestine
- carrier for glucose and fructoose in liver and intestine
GLUT 3?
Location and functions
- found in neurons, placenta, testes, brain
- used for basal glucose uptake
GLUT 4?
Tissue distribution and functions
- found in skeletal and cardiac muscle, fat
- activity increased by insulin
GLUT 5?
- found in the mucosal surface in small intestine, sperm, kidneys
- involved in fructose transport
Where does glucose in the blood come from?
- our diet - Sugary foods and drinks, starchy food and carbohydrate are digested and absorbed into the blood as glucose
- gluconeogenesis - glucose is made by the liver and exctreted into the blood
- glycogenolysis - glycogen is broken down releasing glucose into the blood
How is glucose stored?
stored in the muscle as glycogen
How is glucose normally regulated?
- blood glucose rises
- pancreas produces insulin
- tissues of the body remove glucose from the blood and use it or fuel it
- blood glucose falls
What is diabetes?
A disorder of metabolism where the body is no longer able to regulate the glucose (sugar) levels in the blood
- results from defects in insulin secretion, action or both
Consequences of diabetes?
This usually leads to high sugar levels in the blood which ultimately leads to damage of blood vessels and organs of the body.
Pathogenesis of diabetes?
pancreatic beta cell apoptosis
Type 1 diabetes pathogenesis?
Auto-immune reactions leading to islet cells destruction
Type 2 diabetes pathogenesis?
- Genetic predisposition coupled with excessive exposure to glucose and fatty acids (Gluco-lipotoxicity) → oxidative stress in the mitochondria and abnormal folding of protein in the ER
- Glucotoxicity also down-regulates GLUT4 levels in insulin-responsive cells
What goes wrong in diabetes?
- blood glucose rises
- pancreas can not produce insulin or tissues cannot respond to insulin
- tissues of the body have no glucose for fuel
Consequences of raised blood glucose?
- high glucose in the blood passes into the urine
- polyuria, dehydration , thirst - cellular metabolism stops
- weakness, weight loss, fatigue - cells of the body’s immune system cannot work properly
- increased risk of infections - glucose molecules in the blood bind on to proteins lining the blood vessels and damage the blood vessels
- stroke, retinopathy, nephropathy, neuropathy, heart disease
Types of diabetes?
- type 1
- type 2
- gestational diabetes
- other
Pathogenesis of type I DM?
- genetic HLA-DR3/DR4/environment/viral infection
- autoimmune insulitis
- antibodies against glutamic acid decarboxylase and insulin - beta cell destruction
- severe insulin deficiency
Clues to type 1 DM?
- thin
- short history
- ketones ++ in plasma and urine
Latent autoimmune diabetes of adults?
- Slow onset type I DM occurring in the middle aged (> 30 yrs)
- Initially controlled with nutrition and exercise
- Gradually dependent on insulin
Diagnosis of LADA?
- Positive auto-antibodies (Anti-GAD)
- Low C-peptide levels
- Usually no family history
Hypergluconaemia and how it causes DM2?
- insulin has a suppressive effect on Alpha cells and glucagon(binding of the insulin receptor on alpha cells)
- the most common cause of increased glucagon is an absence or deficiency of the restraining influence of insulin on glucagon production
Why DKA is not common in DM2?
DKA is not common in DM2 because the little insulin secretion in the circulation is not sufficient to suppress the hepatic glucose production effects of glucagon
Impaired incretin effect and how it causes DM2?
- The hormones glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are responsible for the incretin effect.
- Phenomenon whereby insulin secretion increases more in response to an oral compared with an intravenous glucose challenge.
- In DM2 there is loss of insulinotropic effects of GLP-1 & GIP
Peripheral tissue resistance to insulin and how it causes DM2?
- GLUT 4 primarily found in adipose, skeletal and cardiac muscles
- In DM2 there is decreased translocation of GLUT 4 to the membrane as a result the insulin in circulation can not be able to bind the IR
Maturity onset DM in the young (MODY)?
Single gene defects
- Autosomal dominant inheritance
- multiple generations affected
Features of MODY?
- Early onset <25 years
- Absence of obesity, no ketosis & no evidence of beta cell destruction
- Hyperglycaemia often corrected by diet
Drugs that cause secondary diabetes?
- corticosteroids (prednisolone)
- thiazide diuretics
- stavudine
Diseases that cause secondry diabetes?
- Pancreatic disease
eg CA pancreas, previous pancreatitis - Liver disease
- Endocrine disease
eg Cushing’s syndrome
Risk factors?
- overweight (BMI ≥ 25kg/m2)
- waist circumference ≥90 cm in women and ≥ 100 cm in men
- family history
- diabetes in previous pregnancy
- smokers: current and former
- heavy/at risk drinking
Diagnosing diabetes?
- Symptoms AND an abnormal blood sugar
- If the patient has NO symptoms they need TWO abnormal blood glucose measurements to make the diagnosis
- If they have one abnormal and one normal result check again after 3 months
Interpretation of blood glucose values?
Normal FBG is <126 mg/dl OR 7 mmol/L
Normal RBG is <200 mg/dL OR 11.1 mmol/L
Glycated hemoglobin A1c that indicates diabetes?
> 6.5%
Clinical presentations of diabetes?
- typical symptoms of high sugar
- subacute- weeks, months or years
- acute/severe (DKA)
- infections
- complications
eg visual loss, cataracts or foot numbness/sores - incidental finding screening
eg hypertensive patients
Typical symptoms of high sugar?
- Frequent urination (polyuria)
- Excessive thirst (polydipsia)
- Dizziness
- Weight loss
- Tiredness
- Blurred vision
- Numbness and/or burning pain in the legs
Infections associated with diabetes?
- Skin infections
- fungal (thrush oral or genital)bacterial (cellulitis, abscesses and boils)
- UTI
- Pneumonia
- TB
- Foot infection
