Diabetes and hypoglycaemia Flashcards
What is glucose?
Glucose is a major energy substrate
What is blood glucose levels maintained through?
○ Maintenance of blood glucose levels through (4-6mmol):
○ Dietary carbs eaten and then absorbed
○ Glycogenolysis in liver
○ Gluconeogenesis
What is the role of the liver after a meal?
stores glucose as glycogen
What is the role of the liver during a fast?
makes glucose available through glycogenolysis and gluconeogenesis
Why is it important to regulate glucose?
○ Brain and erythrocytes require continuous supply: – therefore avoid deficiency
○ Brain and RBCs cannot metabolise glucose themselves
○ High glucose and metabolites cause pathological changes to tissues;
What is diabetes mellitus?
Metabolic disorder characterised by chronic hyperglycaemia, glycosuria and associated abnormalities of lipid and protein metabolism
What is hyperglycemia a result of?
Hyperglycaemia result of increased hepatic glucose production and decreased cellular glucose uptake
What is glycosuria and at what level does it occur?
Glucose in urine
Blood glucose > ~ 10mmol/L
What is involved in the diagnosis of diabetes mellitus?
○ In the presence of symptoms: (polyuria, polydipsia & weight loss for Type I)
○ Random plasma glucose ≥ 11.1mmol/l (200 mg/dl)
▪ Random is defined as any time of day without regard to time since last meal OR
• Fasting plasma glucose ≥ 7.0 mmol/l (126 mg/dl) Fasting is defined as no caloric intake for at least 8h
OR
• Oral glucose tolerance test (OGTT): plasma glu ≥ 11.1 mmol/l
○ In the absence of symptoms:
-test blood samples on 2 separate days
What are the value range of patients with impaired glucose tolerance(IGT) of:
- Fasting plasma glucose
- OGTT value
○ Fasting plasma glucose 6.1-6.9mmol/L
○ OGTT value of 7.8 – 11.1 mmol
What are the value range of patients with impaired fasting glycaemia(IFG) of:
- Fasting plasma glucose
- OGTT value
○ Fasting plasma glucose ‹ 7.0 mmol/L and
○ OGTT value of < 7.8
What individuals is OGTT used . in and to determine what?
OGTT used in individuals with fasting plasma glucose of ‹ 7.0 mmol/L to determine glucose tolerance status.
In what patients should oral glucose tolerance test(OGTT) be carried out in?
○ In patients with IFG
○ In unexplained glycosuria
○ In clinical features of diabetes with normal plasma glucose values
○ For the diagnosis of acromegaly (excess GH results in excess glucose)
Steps involved in OGTT
- Check blood glucose first
- 75g oral glucose and test after 2 hour
- Blood samples collected at 0 and 120 mins after glucose
- Subjects tested fasting after 3 days of normal diet containing at least 250g carbohydrate
- If blood glucose >8.1 = diabetes
What is type 1 diabetes?
Insulin secretion is deficient due to autoimmune destruction of b-cells in pancreas by T-cells
What is type 2 diabetes?
- Insulin secretion is retained but there is target organ resistance to its actions
- Insensitivity of receptors
What is secondary diabetes caused by?
• Chronic pancreatitis, pancreatic surgery, secretion of antagonists
What does gestational diabetes occur due to and when?
- Occurs for first time in pregnancy due to placental hormones i.e. HPL
- Happens between 18-24 weeks
What are all the classifications of diabetes?
- Type 1
- Type 2
- Secondary
- Gestational
Who is type 1 DM predominantly in?
○ Predominantly in children and young adults; but other ages as well
What is the onset of type 1 DM?
Sudden onset
What is the most common cause of type 1 DM?
Most common cause is autoimmune destruction of B-cells
What strong genetic link is there for type 1 DM?
○ Strong link with HLA genes within the MHC region on chromosome 6
Pathogenesis of type 1 DM?
○ HLA class II cell surface presents as foreign and self-antigens to T-lymphocytes to initiate autoimmune response
○ Circulating autoantibodies to various cell antigens against:
○ Glutamic acid decarboxylase
○ Tyrosine-phosphatase-like molecule
○ Islet auto-antigen
○ The most commonly detected antibody associated with type 1 DM is the islet cell antibody
What does destruction of pancreatic beta cells cause?
Destruction of pancreatic ß-cell causes hyperglycaemia due to absolute deficiency of both insulin & amylin
What is amylin?
A glucoregulatory peptide hormone co-secreted with insulin
How does amylin lower blood glucose?
Lowers blood glucose by slowing gastric emptying, & suppressing glucagon output from pancreatic cells
What does amylin reduce in the intestines?
○ Reduces amount of glucose that can be absorbed from the intestine
What happens to amylin when islet cells are destroyed?
○ When islet cells are destroyed: amylin is deficient (which usually inhibits glucagon)
What is the presentation of type 2 DM?
○ 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
What are the metabolic complications of type 2 DM?
- Hyper-osmolar non-ketotic coma
2. Hyperosmolar hyperglycaemic state
Why are there no ketone bodies in hyper osmolar non-ketotic coma?
○ No ketone bodies
-Because lipolysis is not occurring so no production of ketone bodies
What happens in hyperosmolar hyperglycaemic state?
○ Development of severe hyperglycaemia ○ Extreme dehydration ○ Increased plasma osmolality ○ Impaired consciousness ○ No ketosis ○ Death if untreated
What is the treatment of type 2 DM, stepwise?
- Diet and exercise
- Oral monotherapy
- Metformin
- Oral combination
- Insulin +/- oral agents
- Sulphonylureas
- Gliptins
- GLP-1 analogues
What do sulfonylureas do?
○ Bind and close KATP channels, depolarize B cell releasing insulin
What do metformin do?
○ Decreases gluconeogenesis
○ Increases uptake of glucose from blood
What do thiazolidinediones do?
○ Activate PPARγ receptor (controller of lipid metabolism), which (somehow) reduces insulin resistance
What do SGLT2 inhibitors do?
Promote glucose excretion via kidney
What do incretin targeting drugs do?
○ Potentiate insulin release in response to rising plasma glucose
What are DPP-4 inhibitors also known as?
Also known as gliptins
What do DPP-4 inhibitors do ?
○ DPP4 usually destroys incretin so DPP4 inhibitors prevent this destruction and incretin stimulate insulin secretion
What are the aims of monitoring glycaemic control?
Prevent complications or avoid hypoglycaemia
What are long term complications that occur in both type 1 and type 2 DM?
- Micro-vascular disease
- Macro-vascular disease
What is hypoglycemia defined as?
Defined as plasma glucose < 2.5 mmol/L
What are the causes of hypoglycemia?
- Drugs
- Endocrine diseases
- Inherited metabolic disorders
- Insulinoma
- Severe liver disease
What are examples of inherited metabolic diseases?
- Glycogen storage disease type l (von Gierke’s disease)
- Galactosaemia
- Hereditary fructose intolerance
What is Glycogen storage disease type I a deficiency of?
○ Deficiency of G-6-Phosphatase: impaired glucose release from glycogen
What is galactosaemia a deficiency of?
○ Deficiency of galactose-1-phosphate uridyl transferase: liver damage
What is hereditary fructose tolerance a deficiency of?
Deficiency of fructose-1-phosphate adolase B: accumulation of fructose-1-phosphate in liver
What type of disorder is glycogen storage disease type 1A?
Autosomal recessive disorder
What synthesis is blocked and from what in glycogem storage disease type 1A?
Glucose synthesis from glycogen or by gluconeogenesis is blocked
What does accumulation of glycogen cause?
Accumulation of glycogen causes hepatomegaly
What deficiency is in galactosaemia?
○ Galactose-1-phosphate uridyl transferase deficiency
What disorder is galactosaemia?
○ Autosomal recessive disorder
What does the deficiency of G-1-PUT impar in galactosaemia?
Deficiency of G-1-PUT impairs conversion of galactose-1-phosphate to glucose-1-P
Where does Galactose 1 phosphate accumulate and why’s it bad in galactosaemia?
Gal-1-phosphate accumulates in liver - toxicity
What is galactose excreted in in galactosaemia?
Galactose excreted in urine
What disorder is hereditary fructose intolerance?
○ Autosomal recessive disorder
What deficiency is hereditary fructose intolerance of?
Deficiency of fructose 1-phosphate aldolase B
What happens to ingested fructose in hereditary fructose intolerance and what does it inhibit?
○ Ingested fructose accumulates – inhibits glycogenolysis at phosphorylase step.
What is fructose detected in hereditary fructose intolerance?
Fructose detected in urine
What is benign fructose intolerance due to?
Due to absence of fructokinase
What is the physiological counter-regulatory response to falling glucose levels in fasting?
○ Suppression of insulin release, limiting glucose entry into non-cerebral tissues
○ Secretion of glucagon, adrenaline, noradrenaline, cortisol and growth hormone to raise glucose level
What is the glucose counterregulatory hormone response to falling glucose levels in fasting?
○ Glucagon
▪ Secreted by a-cells of pancreas in response to hypoglycaemia
▪ Stimulates glycogenolysis and gluconeogenesis
○ Cortisol
▪ Increased gluconeogenesis
What are the neurogenic signs and symptoms of hypoglycaemia triggered and activated by?
○ Triggered by falling glucose levels
○ Activated by ANS & mediated by sympathoadrenal release of catecholamines and Ach
What is neuroglycopaenia due to in hypoglycemia?
○ Due to neuronal glucose deprivation
What are the signs and symptoms of neuroglycopaenia?
▪ confusion ▪ difficulty speaking ▪ ataxia ▪ paresthesia ▪ seizures ▪ coma ▪ death
