Diabetes and Hypoglycaemia Flashcards
How are blood glucose levels maintained?
- Dietary carbohydrate
- Glycogenolysis
- Gluconeogenesis
Role of the liver in glucose metabolism
After meals- stores glucose as glycogen
During fasting- makes glucose available through glycogenolysis and gluconeogenesis
Describe glucose homeostasis in a fed state
Describe glucose homeostasis in a fasting state
Decrease in:
- insulin
- peripheral uptake
Increase in (glucose production):
- lipolysis, proteolysis
- liver gluconeogenesis
Why is regulation of glucose essential?
· Brain and erythrocytes require continuous supply, therefore we need to avoid deficiency of glucose
· High glucose and metabolites cause pathological changes to tissues e.g. micro/macro vascular diseases, neuropathy: - therefore we need to avoid excess
Insulin
hormone which regulates blood glucose levels by storing glucose into tissues
Actions of insulin in the liver
- Stores glucose in the form of glycogen after eating (increases glycogen synthesis)
- Decreases gluconeogenesis (because we don’t want to increase blood glucose after eating)
- Increases lipogenesis
Actions of insulin in striated muscle
- Increases glucose uptake from plasma/blood
- Increases glycogen synthesis
- Increases protein synthesis
Actions of insulin in adipose tissue
- Increases glucose uptake
- Increases lipogenesis
- Decreases lipolysis (because when lipids are broken down they can be used to produce glucose via gluconeogenesis)
Describe the counter-regulatory hormones of insulin
What is diabetes mellitus?
a metabolic disorder characterised by:
- chronic hyperglycaemia
- glycosuria (glucose in your urine)
- abnormalities of lipid and protein metabolism
Why is there hyperglycaemia and glycosuria in diabetes mellitus?
The hyperglycaemia results from increased hepatic glucose production and decreased cellular glucose uptake
Blood glucose > ~10mmol/L exceeds renal threshold → glycosuria
Classification of diabetes
Type I Diabetes - INSULIN DEFICIENT
Type II Diabetes - INSULIN RESISTANT
Secondary Diabetes
Gestational Diabetes
Secondary Diabetes
brought on by other diseases, medical conditions, and medications
Chronic pancreatitis, pancreatic surgery, secretion of antagonists
Gestational Diabetes
a form of diabetes mellitus that occurs during some pregnancies
blood glucose levels will usually go back to normal after birth
Type I Diabetes
Insulin secretion is deficient due to autoimmune destruction of β-cells in pancreas by T-cells
· Predominantly in children and young adults; but other ages as well
· Sudden onset (days/weeks)
· Appearance of symptoms may be preceded by ‘pre-diabetic’ period of several months
strong link with HLA genes within the MHC region on chromosome 6
Pathogenesis of Type I Diabetes
HLA Class II on β-cell surface presents as foreign and self-antigens (autoantigens) to T-lymphocytes to initiate autoimmune response
Circulating autoantibodies against these antigens:
· Glutamic acid decarboxylase
· Tyrosine-phosphate-like molecule
· Islet auto-antigen
Destruction of β-cells with decreased insulin secretion (deficient) → Type I Diabetes
What does destruction of pancreatic β-cells in Type I diabetes lead to?
HYPERGLYCAEMIA
-due to absolute deficiency of insulin and amylin
What is amylin?
glucoregulatory peptide hormone co-secreted with insulin which lowers blood glucose by slowing gastric emptying & suppressing glucagon output from pancreatic cells
Metabolic complications of Type I Diabetes
During hyperglycaemia:
- Brain responds to hyperglycaemia with polyphagia (excessive eating) in an attempt to increase insulin levels and store glucose (however insulin is not being produced!)
- Kidneys are not able to reabsorb all of the blood glucose, and so glucose will pass into the urine→glycosuria.
- Increased levels of glucose in kidneys causes an osmotic effect, and so more water will be secreted into urine, causing polyuria (increased urination).
- As you urinate more, you can become dehydrated→volume depletion. Volume depletion will increase your thirst, causing polydipsia (excessive thirst) so you can replenish that volume. If the volume is not replenished, it can lead to a diabetic coma.
Furthermore, insulin deficiency causes:
- Increased lipolysis
- Causing increased fatty acids (FFA)
- Increased FFA undergo β-oxidation in the liver, producing ketone bodies
- Increased ketone bodies lead to ketoacidosis (DKA), which can also lead to a diabetic coma
Type II Diabetes
Insulin secretion is retained but there is target organ resistance to the actions of insulin
· Slow onset (months/years)
· Patients middle aged/elderly- prevalence increases with age
· Strong familiar incidence
· Pathogenesis uncertain- insulin resistance, β-cell dysfunction:
>may be due to lifestyle factors- obesity, lack of exercise
Describe the pathophysiology of type II DM
Metabolic complications of type II diabetes
Type 2 diabetes mellitus causes Hyper-osmolar non-ketotic coma (HONK)
[Hyperosmolar Hyperglycaemia State (HSS)]
- Development of severe hyperglycaemia
- Extreme dehydration
- Increased plasma osmolality
- Impaired consciousness
- No ketosis
- Death if untreated
Approaches to diagnosing diabetes
We test for diabetes depending on whether there are symptoms present or not
Diagnosis of diabetes in the presence of symptoms
In the presence of symptoms: polyuria, polydipsia & weight loss for Type I diabetes
Random plasma glucose ≥11.1mmol/L (200mg/dL)
OR
Fasting plasma glucose ≥7.0mmol/L (126mg/dL). Fasting is defined as no caloric intake for at least 8 hours
OR
Oral glucose tolerance test (OGTT)- plasma glucose ≥11.1mmol/L
Diagnosis of diabetes in the absence of symptoms
Test blood samples on 2 separate days
Impaired glucose tolerance (IGT)
A disorder in which blood glucose levels become elevated which may signal borderline diabetes mellitus (pre-diabetes)
Fasting plasma glucose <7mmol/L
AND
OGTT value of 7.8-11.1mmol
Impaired fasting glycaemia (IFG)
A disorder in which blood glucose levels become elevated during period of fasting, but not enough to prompt a diagnosis of diabetes mellitus (pre-diabetes)
Fasting plasma glucose 6.1 to 6.9mmol/L
AND
OGTT value of <7.8mmol/L
Why is an oral glucose tolerance test (OGTT) performed?
performed to confirm a diagnosis of:
- diabetes mellitus
- acromegaly (too much GH)
How is an OGTT performed?
· 75g oral glucose administered
· blood samples collected at 0 and 120 mins after glucose
· subjects tested fasting after 3 days or normal diet containing at least 250g carbohydrate
If the blood glucose levels become ≥11.1 mmol/L, then you may have diabetes.
Treatment of Type I diabetes
insulin therapy
Treatment of Type II diabetes
Healthier diet and regular exercise are recommended as treatment at first.
Oral Medications:
- metoformin
- sulphonylureas
- Thiazolidinediones
- SGLT2 inhibitors
- dipeptidyl peptidase inhibitor (DDP-4; Gliptins)
Metformin (type II diabetes)
- decreases gluconeogenesis and increases peripheral utilisation of glucose
- acts only in the presence of endogenous insulin meaning it is effective only if there are some residual functioning pancreatic islet cells
- the drug helps type 2 diabetics respond better to their own insulin, lower the amount of sugar created by the liver, and decreasing the amount of sugar absorbed by the intestines
Sulphonylureas (type II diabetes)
work mainly by stimulating the cells in the pancreas to make more insulin
also help insulin to work more effectively in the body
Dipeptidyl Peptidase Inhibitor (DPP-4; Gliptins) -type II diabetes
block the action of DPP-4, an enzyme which destroys the hormone incretin
incretin helps the body produce more insulin only when it is needed and reduces the amount of glucose being produced by the liver when it is not needed
Why is glycaemic control important?
To prevent complications or avoid hypoglycaemia
Monitoring Glycaemic Control
Self-monitoring to be encouraged:
· capillary blood measurement
· urine analysis: glucose in urine gives indication of blood glucose concentration above renal threshold
3-4 months: blood HbA1c (glycated Hb; covalent linkage of glucose to residue in Hb).
Others: urinary albumin (index of risk of progression to nephropathy)
Long term complications of diabetes (both type I and II)
· Microvascular disease: retinopathy, nephropathy, neuropathy
· Macrovascular disease: related to atherosclerosis heart attack/stroke
Hypoglycaemia
low blood glucose concentration
Defined as plasma glucose <2.5mmol/L
What is the most common cause of hypoglycaemia?
Drugs
- common in type I
- insulin & insulin secretagogues in type II patients (less common)
- uncommon in patients who do not have drug treated diabetes mellitus. In these patients hypoglycaemia may be caused by alcohol, critical illnesses such as hepatic, renal or cardiac failure, sepsis, hormone deficiency, inherited metabolic dx.
Hypoglycaemia in diabetes is caused by
Sulfonylureas: exogenous insulin & insulin secretagogues such as:
- glyburide
- glipizide
- glimepiride
these stimulate endogenous insulin, suppressing hepatic and renal glucose production and increase glucose utilisation
Hypoglycaemia in patients without diabetes is caused by:
· Drugs such as alcohol (ethanol)
-ethanol inhibits gluconeogenesis, but not glycogenolysis, resulting in hepatic depletion of glycogen
· Other drugs most commonly found to cause hypoglycaemia are quinolone, quinine, beta blockers, ACE inhibitors and IGF-1.
· Endocrines disease; e.g. cortisol disorder
· Inherited metabolic disorders e.g. hereditary fructose intolerance
· Insulinoma (tumour of the pancreas which produces more insulin)
· Others: severe liver disease, non-pancreatic tumours (beta cell hyperplasia), renal disease (metabolic acidosis, reduced insulin elimination)
Sepsis
-cytokines are produced in sepsis which accelerate glucose utilisation and induce inhibition of gluconeogenesis during glycogen depletion
CKD
-mechanism not clear, but likely to involve impaired gluconeogenesis, reduced renal clearance of insulin and reduced renal glucose production
What is reactive hypoglycaemia?
Post-prandial hypoglycaemia
-drop in blood glucose levels within four hours after eating
Can occur in people with and without diabetes
What is reactive hypoglycaemia?
Post-prandial hypoglycaemia
-drop in blood glucose levels within four hours after eating
Can occur in people with and without diabetes
Cause of reactive hypoglycaemia
Cause is unclear:
- Possibly a benign (non-cancerous) tumour in the pancreas causing an overproduction of insulin
- Too much glucose may be used up by the tumour itself
- Deficiencies in counter-regulatory hormones e.g. glucagon
Response to hypoglycaemia in normal patients
1st line of defence: Pancreatic β-cell secretion of insulin decreases
> hepatic glycogenolysis and gluconeogenesis is increased
> reduced glucose utilisation of peripheral tissue, including lipolysis and proteolysis
2nd line of defence: Counter Regulatory Hormones Release e.g. glucagon, epinephrine, cortisol and GH
> glucagon stimulates hepatic glycogenolysis
> epinephrine from adrenal gland stimulates hepatic glycogenolysis and gluconeogenesis (renal gluconeogenesis too)
> if hypoglycaemia is prolonged beyond 4 hours, cortisol and GH will support glucose production and limit utilisation
What signals for the 2nd line of defence (release of counter regulatory hormones) in response to hypoglycaemia?
autonomic nervous system sends signals to the adrenal gland and pancreas to release counter-regulatory hormones in the defence against hypoglycaemia.
Signs and symptoms of hypoglycaemia
Divided into two categories:
1) Neurogenic (autoimmune)
2) Neuroglycopaenia
Neurogenic symptoms of hypoglycaemia
- symptoms triggered by falling glucose levels
- activated by ANS & mediated by sympathoadrenal release of catecholamines and Ach
Neuroglycopaenic symptoms of hypoglycaemia
-symptoms occur as a result of neuronal glucose deprivation
Include:
- confusion
- difficulty speaking
- ataxia
- parathesia
- seizures
- coma
- death
