Diabetes and Hypoglycaemia Flashcards
How are blood glucose levels maintained
dietary carbohydrate
glycogenolysis
gluconeogenesis
Liver’s role in regulating glucose
after meals - stores glucose as glycogen
during fasting - makes glucose available through glycogenolysis and gluconeogenesis
Insulin function in adipose tissue
↑Glucose uptake
↑Lipogenesis
↓Lipolysis
Insulin function in liver
↓Gluconeogenesis
↑Glycogen synthesis
↑Lipogenesis
Insulin function in striated muscle
↑Glycogen synthesis
↑Glucose uptake
↑Protein synthesis
Diabetes Mellitus - define
…..a metabolic disorder characterised by chronic hyperglycaemia, glycosuria and associated abnormalities of lipid and protein metabolism:
the hyperglycaemia results from increased hepatic glucose production and decreased cellular glucose uptake
blood glucose > ~ 10mmol/L exceeds renal threshold – glycosuria
Diabetes Mellitus - type I vs type II
Type 1:
Insulin secretion is deficient due to autoimmune destruction of β-cells in pancreas by T-cells
Type 2:
Insulin secretion is retained but there is target organ resistance to its actions
Diabetes Mellitus - secondary vs gestational
Secondary:
chronic pancreatitis, pancreatic surgery, secretion of antagonists
Gestational:
Occurs for first time in pregnancy
Type 1 DM - cause
Commonest cause is autoimmune destruction of B-cells
interaction between genetic and environment factors
strong link with HLA genes within the MHC region on chromosome 6
Type 1 DM - onset
Sudden onset (days/weeks)
Appearance of symptoms may be preceded by
‘prediabetic’ period of several months
In type I DM circulating autoantibodies to various -cell antigens against:
glutamic acid decarboxylase
tyrosine-phosphatase-like molecule
Islet auto-antigen
HLA class II in type I DM
HLA class II cell surface present as foreign and self antigens to T-lymphocytes to initiate autoimmune response
Most common antibody in type I DM
The most commonly detected antibody associated with type 1 DM is the islet cell antibody
Destruction of pancreatic ß-cell causes
Destruction of pancreatic ß-cell causes hyperglycaemia due to absolute deficiency of both insulin & amylin.
Amylin - function
Amylin, a glucoregulatory peptide hormone co-secreted with insulin.
lowers blood glucose by slowing gastric emptying, & suppressing glucagon output from pancreatic cells.
Effect of insulin deficiency in type I DM
INSULIN
DEFICIENCY → Hyperglycemia (leads to glycosuria) → Glycosuria → Polyuria → Volume depletion (polydipsia) = diabetic coma
INSULIN DEFICIENCY → Increased
lipolysis → Increased free fatty acids (FFA) → Increased FFA oxidation (liver) → Ketoacidosis
(DKA) = diabetic coma
Type 2 DM- Presentation:
Slow onset (months/years)
Patients middle aged/elderly – prevalence increases with age
Strong familiar incidence
Type 2 DM - pathogenesis
Pathogenesis uncertain – insulin resistance; β-cell dysfunction:
may be due to lifestyle factors - obesity, lack of exercise
Metabolic complications of Type 2 DM
Hyper-osmolar non-ketotic coma (HONK)
[Hyperosmolar Hyperglycaemic State (HHS)]
Development of severe hyperglycaemia
Extreme dehydration
Increased plasma osmolality
Impaired consciousness
No ketosis
Death if untreated
Diagnosis, Type 2 DM, in presence of symptoms
In the presence of symptoms: (polyuria, polydipsia & weight loss for Type I)
Random plasma glucose ≥ 11.1mmol/l (200 mg/dl ).
OR
Fasting plasma glucose ≥ 7.0 mmol/l (126 mg/dl) Fasting is defined as no caloric intake for at least 8 h
OR
Oral glucose tolerance test (OGTT) - plasma glu ≥ 11.1 mmol/l
Diagnosis, Type 2 DM, in absence of symptoms
In the absence of symptoms:
test blood samples on 2 separate days
Compare IGT vs IFG classification
IGT – impaired glucose tolerance
IFG – impaired fasting glycaemia
If impaired fasting glycaemia = increased risk of developing diabetes + developing cardiovascular disease is also increased
but this seems to be lower than if you have pre-diabetes (impaired glucose tolerance)
OGTT should be carried out when
OGTT should be carried out:
in patients with IFG
in unexplained glycosuria
in clinical features of diabetes with normal plasma glucose values
OGTT - process
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
Metformin - type II DM treatment
↑
↓
↓ gluconeogenesis and ↑ peripheral utilisation of glucose;
effective if residual functioning beta cells as acts only in presence of insulin
Helps respond better to own insulin, lower the amount of sugar created by the liver, and decreasing the amount of sugar absorbed by the intestines.
Sulphonylureas - type II DM treatment
Stim the cells in the pancreas to make more insulin
They also help insulin to work more effectively in the body.
Dipeptidyl peptidase inhibitor (DPP-4; Gliptins): inhibitors work by blocking the action of DPP-4, an enzyme which destroys the hormone incretin.
Incretins - type II DM treatment
Help the body produce more insulin only when it is needed
and reduce the amount of glucose being produced by the liver when it is not needed
Monitoring glycaemic control - aim
Aim: to prevent complications or avoid hypoglycaemia
Self-monitoring - describe types
Capillary blood measurement
Urine analysis: glucose in urine gives indication of blood glucose concentration above renal threshold
Long term complications in DM
Occur in both type 1 and type 2 DM
Micro-vascular disease:
retinopathy, nephropathy, neuropathy
Macro-vascular disease:
related to atherosclerosis heart attack/stroke
Exact mechanisms of complications are unclear
Hypoglycaemia - define
Defined as plasma glucose < 2.5 mmol/L
Causes of hypoglycaemia + prevalence in types of DM
Drugs are the most common cause;
common in type 1 diabetes
Less common in type 2 diabetes taking insulin & insulin secretagogues
uncommon in patients who do not have drug treated DM:
Why hypoglycaemia uncommon in pt w/DM that is not drug treated
In these patients hypoglycaemia may be caused by alcohol, critical illnesses such as hepatic, renal or cardiac failure, sepsis, hormone deficiency, inherited metabolic dx.
Sulfonylureas - examples
Exogeneous insulin & insulin secretagogues such as glyburide, glipizide and glimepiride are examples of some of the more commonly used sulfonylureas.
Stimulation of endogenous insulin - effect
Stimulation of endogenous insulin suppresses hepatic and renal glucose production and increase glucose utilisation
List type II DM drugs that should not cause hypoglycaemia
Among drugs used to treat type 2 diabetes earlier in the disease, insulin sensitizers (metformin, Glitazones); glucosidase inhibitors; glucagon-like pepdide-1 (GLP-1) receptor antagonist and DDP-4 inhibitors should not cause hypoglycaemia.
Drugs that cause hypoglycaemia
Drugs such as alcohol may cause hypoglycaemia;
Other drugs most commonly found to cause hypoglycaemia are quinolone, quinine, beta blockers, ACE inhibitors and IGF-1
Hypoglycaemia in patients without diabetes - list
Endocrines disease; e.g. cortisol disorder
Inherited metabolic disorders, e.g. hereditary fructose intolerance.
Insulinoma
Others: severe liver disease, non-pancreatic tumours (beta cell hyperplasia), renal disease (metab. acidosis, reduced insulin elimination).
Ethanol effect on glucose regulation
Ethanol: inhibit gluconeogenesis, but not glycogenolysis.
The hypoglycaemia will typically follow several days alcohol binge with limited food intake; resulting in hepatic depletion of glycogen.
Sepsis effect on glucose regulation
Sepsis: relatively common cause of hypoglycaemia.
Cytokine accelerated glucose utilization and induced inhibition of gluconeogenesis in the setting of glycogen depletion
CKD effect on glucose regulation
CKD: mechanism not clear, but likely to involve impaired gluconeogenesis, reduced renal clearance of insulin and reduce renal glucose production.
Reactive hypoglycaemia - define
Also known as postprandial hypoglycaemia, drops in blood sugar are usually recurrent and occur within four hours after eating..
Reactive hypoglycaemia - can occur in who
can occur in both people with and without diabetes,
thought to be more common in overweight individuals or those who have had gastric bypass surgery.
Reactive hypoglycaemia - cause
Cause is unclear:
possibly a benign (non-cancerous) tumour in the pancreas may cause an overproduction of insulin,
too much glucose may be used up by the tumour itself.
deficiencies in counter-regulatory hormones: e.g. glucagon.
Explain effect of plasma glucose level decline in fast state
When plasma glucose level decline in fast state pancreatic beta-cells secretion of insulin is decreased (1st defence);
hepatic glycogenolysis and gluconeogenesis is increased
there is reduced glucose utilisation of peripheral tissue, inducing lipolysis and proteolysis
Counter-regulatory hormones function in response to hypoglycaemia
Counter-regulatory hormones are released:
Pancreatic alpha cells secrete glucagon to stimulate hepatic glycogenolysis (2nd defence)
Epinephrine release from adrenomedullary to stimulate hepatic glycogenolysis and gluconeogenesis; renal gluconeogenesis
If hypo is prolonged beyond 4 hours; cortisol and GH will support glucose production and limit utilisation.
Epinephrine effect
Epinephrine has similar hepatic effect as glucagon; inhibits insulin secretion..
Signs & Symptoms of hypoglycaemia - categories
Neurogenic (autonomic)
Neuroglycopaenia
Neurogenic (autonomic) symptoms - describe characteristics
Neurogenic (autonomic):
triggered by falling glucose levels
activated by ANS & mediated by sympathoadrenal release of catecholamines and Ach
Neuroglycopaenia symptoms - describe characteristics
Neuroglycopaenia:
Due to neuronal glucose deprivation.
Sign & symptoms include: confusion, difficulty speaking, ataxia, paresthesia, seizures, coma, death
