Diabetes and Hypoglycaemia Flashcards
What is the significance of glucose in the body?
Glucose is a major energy substrate maintained at 4 - 6 mmol/L
How are blood glucose levels maintained?
Blood glucose levels are maintained via:
- dietary carbohydrate
- glycogenolysis
- gluconeogenesis
Describe the role of the liver after meals
After meals the liver stores glucose as glycogen
What is the role of the liver during fasting?
During fasting the liver makes glucose available through glycogenolysis and gluconeogenesis
What is glycogenolysis?
Glycogenolysis: - breakdown of glycogen store to glucose
What is gluconeogenesis?
Gluconeogenesis:- making glucose from non-glucose sources,
e.g. lactate, alanine, fatty acids
Why is it important to maintain a sufficient blood glucose supply?
Brain and erythrocytes require continuous supply - Avoid deficiency
What is the consequence of excess blood glucose?
High glucose and metabolites cause pathological changes to tissues e.g.: micro/macro vascular diseases, neuropathy
What is insulin?
Insulin is the regulatory hormone of circulating glucose levels - reuptake of blood glucose into tissues
What is the role of insulin in the liver?
Stores glucose in liver in the form of glycogen
- Increases glycogen synthesis
- Increases lipid synthesis
- Decreases gluconeogenesis
What is the effect of insulin on muscles?
In muscles, glucose uptake is increased and converted into glycogen and proteins
How does insulin effect adipose tissues?
In adipose tissue, glucose uptake is increased and so is lipogenesis; lipolysis is decreased
Which metabolic processes does insulin inhibit?
- Gluconeogenesis
- Glycogenolysis
- Lipolysis
- Ketogenesis
- Proteolysis
List the metabolic processes activated by insulin
- Glucose uptake in muscle and adipose tissue
- Glycolysis
- Glycogen synthesis
- Protein synthesis
- Uptake of ions (Esp. K and PO₄⁻³
What is diabetes Mellitus?
DM is a metabolic disorder characterised by chronic hyperglycemia, glycosuria and associated abnormalities of lipid and protein metabolism
What causes hyperglycaemia in DM patients?
Hyperglycaemia results from
- increased hepatic glucose production
- decreased cellular glucose uptake
Why does glycosuria occur in DM patients?
blood glucose > ~ 10mmol/L exceeds renal threshold – glycosuria
What are the 4 ways diabetes is classified
- Type 1
- Type 2
- Secondary
- Gestational
What is type 1 diabetes?
Deficient insulin secretion due to autoimmune destruction of pancreatic B-cells by T-cells
Outline Type 2 Diabetes
Insulin secretion retained but target organs are resistant to its actions
Body can’t re-uptake glucose - plasma glucose levels increased
What is secondary diabetes?
Chronic pancreatitis, pancreatic surgery, secretion of antagonists cause diabetes
What is gestational diabetes?
Gestational diabetes occurs during pregnancy but mostly returns to normal.
Why are some patients unable to recover from gestational diabetes?
Patients unable to return glucose levels to normal after giving birth is usually because of lack of exercise or poor diet
Which population is mainly affected by Type 1 DM?
Predominantly in children and young adults; but other ages as well
Describe the onset of symptoms in type 1 DM patients
Sudden onset (days/weeks) Appearance of symptoms may be preceded by ‘prediabetic’ period of several months
What causes Type 1 DM?
Commonest cause is autoimmune destruction of B-cells
- interaction between genetic and environment factors
- strong link with HLA genes within MHC region on chromosome 6
What initiates the autoimmune response against B-cells in Type 1 DM?
HLA class II cell surface present as foreign and self antigens to T-lymphocytes to initiate autoimmune response
Describe the autoimmune response in Type 1 DM
Circulating autoantibodies to various cell antigens against:
- glutamic acid decarboxylase (pancreas)
- tyrosine-phosphatase-like molecule
- Islet auto-antigen
If autoantibodies to these cell antigens are found, we can assume B-cells are being destroyed in the pancreas
What is the most common autoantibody found in Type 1 DM patients?
The most commonly detected antibody associated with type 1 DM is the islet cell antibody
Outline the process of Type 1 DM Autoimmune response
- Genetics / environmental factors cause B-cell
autoantigens to form and circulate in blood + lymphatics - APCs present autoantigens to activate Th1 or Th2
- Th cells secrete cytokines, especially: INF-ɣ, IL-2
- These 2 cytokines activate macrophages to release IL-1
and TNF-𝛼 - TNF-𝛼 and Il-1 induce destruction of pancreatic B-cells
How do activated Th1 cells destroy pancreatic B-cells?
Activated Th1 secretes IL-2 which activates a specific autoantigen for T-cytotoxic CD8 cells which induce destruction of B-cells
How do Th2 induce pacreatic B-cell destruction?
Activated Th2 secretes IL-4 to stimulate B-lymphocytes production of islet cell autoantibodies (& antiGADes antibodies) - these destroy pancreatic B-cells
What is the consequence of B-cell destruction in Type 1 DM?
Destruction of pancreatic ß-cell causes hyperglycemia due to absolute deficiency of both insulin & amylin
What is amylin?
Amylin, a glucoregulatory peptide hormone co-secreted with insulin
What are the functions of amylin?
Lowers blood glucose by slowing gastric emptying, & suppressing glucagon output from pancreatic cells
Why does Type 1 DM cause metabolic complications?
Insulin deficiency leads to
increased hepatic output and impaired glucose uptake – hyperglycaemia
How does Type 1 DM cause dehydration?
Increased glucose osmotic effect causes diuresis, dehydration and circulatory collapse
How does Type 1 DM cause metabolic acidosis?
Increased lipolysis, blood level of ketone bodies formation (DKA) and metabolic acidosis.
Describe the presentation of Type 2 DM
Slow onset (months/years)
Patients middle aged/elderly – prevalence increases with age
Strong familial incidence
Describe the pathogenesis of type 2 DM
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 nonketotic coma (HONK)
- [Hyperosmolar Hyperglycaemic State (HHS)]
Outline the consequences of type 2 DM metabolic complications
- Development of severe hyperglycaemia
- Extreme dehydration
- Increased plasma osmolality
- Impaired consciousness
- No ketosis
- Death if untreated
What symptoms enable a type 1 DM diagnosis?
In the presence of symptoms: (polyuria, polydipsia & weight loss for Type I)
Describe the glucose levels required for a DM diagnosis
Random plasma glucose
- ≥ 11.1mmol/l (200 mg/dl ).
Fasting plasma glucose
- ≥ 7.0 mmol/l (126 mg/dl)
Oral glucose tolerance test (OGTT)
- plasma glu ≥ 11.1 mmol/l
How is diabetes diagnosed in absence of symptoms?
test blood samples on 2 separate days
What is defined as impaired glucose tolerance?
Impaired Glucose Tolerance (IGT)
Fasting plasma glucose >7mmol/L**
OGTT value of 7.8 – 11.1 mmol
What is impaired fasting glycaemia?
Impaired Fasting Glycaemia (IFG)
Fasting plasma glucose 6.1 to 6.9 mmol/L, and
OGTT value of < 7.8mmol/L
When is OGTT used?
OGTT used in individuals with fasting plasma glucose of ‹ 7.0 mmol/L to determine glucose tolerance status.
What is the significance of IFG?
If you have impaired fasting glycaemia, you are also thought to have an increased risk of developing diabetes
When should an OGTT be carried out?
- in patients with IFG
- in unexplained glycosuria
- in clinical features of diabetes with normal plasma glucose values
Outline how an OGTT is carried out?
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
What drug is used to treat T2DM?
Metformin
How does metmorfin reduce effects of T2 DM?
Metformin decreases gluconeogenesis and increases peripheral utilisation of glucose
Why is metmorfin not able to treat all T2 DM patients?
Only acts in presence of endogenous insulin
So only effective if residual functioning pancreatic islet cells are present
How do sulphonylureas work to reduce DM symptoms?
Work by stimulating pancreatic cells to make more insulin and help insulin work more effectively in the body.
What are DPP-4 gliptins?
Dipeptidyl peptidase inhibitor (DPP-4; Gliptins):
inhibitors work by blocking the action of DPP-4, an enzyme which destroys the hormone incretin.
What is the role of incretin?
Incretins 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
What is the aim of controlling glycaemic control?
Aim: to prevent complications or avoid hypoglycaemia
How can patients self monitor glycaemic control?
Self-monitoring to be encouraged: - Capillary blood measurement - urine analysis: glucose in urine gives indication of blood glucose above renal threshold
How are blood HbA1c used to monitor glycaemic control?
Every 3-4 months
blood HbA1c tested for glycated Hb; covalent linkage of glucose to residue in Hb
How is renal glycaemic control measured?
urinary albumin (index of risk of progression to nephropathy)
Why are DM patients more susceptible to stroke?
Abnormalities in serum lipids common in T1DM & T2DM increase risk of MI and stroke
HbA1c – aim at <7%
What are the long term complications of T1 and T2 DM?
Microvascular disease:
- retinopathy, nephropathy, neuropathy
Macro-vascular disease:
- related to atherosclerosis heart attack / stroke
Exact mechanisms of complications are unclear
What is hypoglycaemia?
Defined as plasma glucose < 2.5 mmol/L
What are the common causes of hypoglycaemia?
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 may patients who’re untreated for DM develop hypoglycemia?
May be caused by alcohol, critical illnesses such as hepatic, renal or cardiac failure, sepsis, hormone deficiency, inherited metabolic dx
Name some commonly used sulfonylureas to treat DM
Exogenous insulin & insulin secretagogues
e.g.
glyburide, glipizide and glimepiride
How do sulfonylureas use lead to hypoglycemia?
Stimulation of endogenous insulin suppresses hepatic and renal glucose production and increase glucose utilisation
What is a safer alternative to sulfonylureas to treat DM?
Insulin sensitizers
- metformin, Glitazones
Glucosidase inhibitors
- GLP-1 receptor antagonist
- DDP-4 inhibitors
These should not cause hypoglycaemia
What other non-diabetic drugs are commonly known to cause hypoglycemia?
Other drugs most commonly found to cause hypoglycaemia are quinolone, quinine, beta blockers, ACE inhibitors and IGF-1
What disorders may lead to hypoglycemia?
Endocrines disease;
- e.g. cortisol disorder
Inherited metabolic disorders
- e.g. hereditary fructose intolerance.
Insulinoma
Severe liver disease, non-pancreatic tumours (beta cell hyperplasia), renal disease (metab. acidosis, reduced insulin elimination).
How does alcohol lead to hypoglycaemia?
Ethanol inhibits gluconeogenesis, but not glycogenolysis.
Hypoglycaemia typically follows several days after alcohol binge with limited food intake
> results in hepatic depletion of glycogen
How does sepsis cause hypoglycemia?
Relatively common cause of hypoglycaemia
Cytokine accelerated glucose utilization
Induced inhibition of gluconeogenesis in setting of glycogen depletion
Explain how CKD may lead to hypoglycemia
Involves impaired gluconeogenesis, reduced renal clearance of insulin and reduce renal glucose production.
What is reactive hypoglycemia?
Hypos After Eating
AKA postprandial hypoglycaemia
Drops in blood sugar recurrent and occur within four hours after eating
Who is affected by postprandial hypoglycemia?
Can occur in both people with and without diabetes,
More common in overweight individuals / those with gastric bypass surgery
What are the potential causes of reactive hypoglycemia?
Benign (non-cancerous) tumour in pancreas may cause Insulin overproduction
Excess glucose may be used up by tumour itself.
Deficiencies in counter-regulatory hormones: e.g. glucagon
What is the first natural defence against hypoglycemia?
Pancreatic beta-cells secretion of insulin is decreased
- hepatic glycogenolysis and gluconeogenesis is increased
- Reduced glucose utilisation of peripheral tissue, inducing lipolysis and proteolysis
What is the 2nd Defence against hypoglycemia?
Counter-regulatory hormones are released:
Pancreatic alpha cells secrete glucagon to stimulate hepatic glycogenolysis
Adrenaline release from adrenomedullary to stimulate hepatic glycogenolysis and gluconeogenesis; renal gluconeogenesis
Describe what happens when hypoglycaemia occurs for > 4hrs
If hypo is prolonged beyond 4 hours; cortisol and GH will support glucose production and limit utilisation
Describe the effects of adrenaline in glucose metabolism
Epinephrine has a similar hepatic effect as glucagon; inhibits insulin secretion
Define hypoglycaemia clinically
Hypoglycaemia defined as plasma glucose level < 70 mg/dL (3.9 mmol/L)
Outline the counter-regulatory hormone response to hypoglycemia
Inhibition of endogenous insulin secretion
Stimulation of glucagon, catecholamines; (nor)adrenaline, cortisol and growth hormone secretion
What is the effect of the counter-regulatory hormone release against hypoglycemia?
Stimulate hepatic glucose production and cut down glucose utilization in peripheral tissues, increasing plasma glucose levels.
Outline the neurogenic signs & symptoms of hypoglycemia
Neurogenic (autonomic):
- Triggered by falling glucose levels
- Activated by ANS & mediated by sympathoadrenal
release of catecholamines and Ach
What is neuroglycopenia?
Shortage of glucose (glycopenia) in the brain, usually due to hypoglycemia.
What are the signs and symptoms of neuroglycopenia?
- confusion
- difficulty speaking
- ataxia
- paresthesia
- seizures
- coma
- death
