Diabetes and Hypoglycaemia Flashcards
What is Glucose and how is the blood glucose level maintained ?
Glucose is a major energy substrate
Blood glucose levels are maintained through :
- Dietary Carbohydrate
- Glycogenolysis - liver breaks down glycogen -> glucose
- Gluconeogenesis - non-carbohydrate sources produce glucose
What is the role of the liver ?
Following Meals - Stores glucose as glycogen
During Fasting -Makes Glucose available through glycogenolysis (break down of glycogen ) and gluconeogenesis (production of glucose from non-glucose sources )
Why is it important to regulate blood glucose level ?
Brain and erythrocytes require continuous glucose supply therefore must avoid glucose deficiency
High glucose can cause pathological changes to tissues:
e.g. micro/macro vascular diseases, neuropathy
At high blood glucose, blood passes pancreas. pancreatic beta cells release insulin, which stimulates glucose uptake from blood into liver, muscles, adipose tissue = reduces blood glucose. Insulin: glucose ➔ glycogen for storage.
At low blood glucose, blood passes pancreas. pancreatic alpha cells secrete glucagon, which stimulates breakdown of glycogen to glucose to increase blood glucose
What is the function of insulin in the liver, striated muscle and adipose tissue?
Insulin release is induced by high blood glucose to reduce blood glucose level
Liver :
Decreases gluconeogenesis
Increases glycogen synthesis
Increases lipogenesis (lipid synthesis)
Striated Muscle:
Increases glucose uptake into muscle
Increases glycogen synthesis
Increases protein synthesis
Adipose tissue :
Increases glucose uptake into adipose tissue
Increases lipogenesis
Decreases lipolysis
What are the counter-regulatory hormones to insulin and what are their functions ?
- Glucagon -Mobilises fuels, maintains blood glucose in fasting
- Activates gluconeogenesis /glycogenolysis and activates fatty acid release - Epiniphrine -Mobilises fuels in acute stress
- Stimulate glycogenolysis and stimulate fatty acid release - Cortisol -Changing long term
- Amino acid mobilisation and gluconeogenesis
4.Growth Hormone
see slide 7
Define Diabetes Mellitus
This is a metabolic disorder characterised by chronic hyperglycaemia, glycosuria and associated abnormalities of lipid and protein metabolism
Hyperglycaemia due to ⬆ hepatic glucose production + ⬇ cellular glucose uptake
Glycosuria (glucose in urine) as blood glucose exceeds renal threshold
What is classified as glycosuria?
Glycosuria = excess sugar in the urine
Blood glucose>10mmol/L = exceeds renal threshold
What are the different classifications of Diabetes ?
Type 1: Deficiency in Insulin secretion due to autoimmune destruction of beta-cells of the pancreas by T-cells
Type 2: Insulin secretion is retained but target organ resists its actions
Secondary: Due to Chronic pancreatitis, pancreatic surgery, secretion of insulin antagonists.
pancreas removed = lack of insulin production
Gestational - Pregnancy
Describe Type 1 DM
Predominantly in children + young adults
Sudden onset (days/weeks)
Appearance of symptoms may be preceded by prediabetic period of several months.
Cause - Autoimmune destruction of B-cells of pancreas by T-cells:
- Due to Interaction b/w genetic/environmental factors
- Strong link with HLA genes within the MHC region on chromosome 6, ⬆susceptibility/protect against disease
In susceptible individuals, environmental factors may trigger immune-mediated destruction of pancreatic B-cells
Pathogenesis of Type 1 DM
1.Destruction of B-cells starts with autoantigen formation
2.Autoantigens are presented to T-lymphocytes to initiate autoimmune response (secrete toxins to destroy pancreatic B-cells)
(Autoantigens are ingested by APCs which activate T-helper1+2 lymphocytes. Activated T-helper1 lymphocyte secretes IL2 + interferon. But IL2 then activates autoantigen which is specific to T-cytotoxic lymphocytes which then secrete toxins to destroy islet cells. + Activated TH2 lymphocyte produces IL4 = stimulates B-lymphocytes to proliferate + produce islet cell autoantibodies)
- = Circulating autoantibodies to various cell antigens against:
- Glutamic acid decarboxylase
- Tyrosine-phosphatase like molecule
- Islet auto-antigen
Most commonly detected antibody of T1DM = islet cell antibody
see notebook for clear process
How do both genetic predisposition and environmental factors link when it comes to pathogenesis of Type 1 DM ?
In a susceptible individual a environmental factor such as an infection by Epstein-Barr virus / CMV this will cause autoantigens to form on insulin-producing beta cells and circulate in the blood stream and lymphatics.
This will then be processed and presented as autoantigen by antigen presenting cells.
Activation of T helper 1 lymphocytes which will secrete interferon gamma and interleukin 2.
Interferon gamma will activate macrophages by releasing interleukin 1 and tumour necrosis factor alpha.
Interleukin 2 will activate autoantigen specific T cytotoxic cells.
Activation of T helper cell 2 will secrete IL-4 which will lead to activation of B lymphocytes which produces islet cell autoantibodies and antiGAD antibodies.
This will destroy beta cells with decreased insulin secretion
What is the most common antibodies found in Type 1 DM ?
Islet cell auto antibody
anti-glutamic acid dicarboxylic antibody.
Type 1 diabetes causes ……….glycaemia - How?
T1DM causes hyperglycaemia (⬇ insulin, ⬇ amylin)
Amylin = glucoregulatory peptide hormone, cosecreted w insulin. ⬇ blood glucose by slowing gastric emptying = suppresses glucagon secretion by pancreatic a-cells
What is amylin?
This is a glucoregulatory peptide hormone which is co-secreted with insulin.
It lowers blood glucose by slowing gastric emptying and supressing glucagon output from pancreatic cells
What are the metabolic complications of Type 1 DM?
Slide 14 + notebook
polyuria (osmotic diuresis)
What is the presentation of Type 2 DM ?
- Slow onset (months/yrs)
- Patients middle aged/elderly. Prevalence ⬆ with age
- Strong familiar incidence
- Pathogenesis is uncertain - insulin resistance, pancreatic Beta-cell dysfunction (insufficient insulin secretion)
Due to lifestyle factors, obesity ,lack of exercise
Pathophysiology of Type 2 DM ?
Insulin resistance
Genetic predisposition (family member has T2DM) + lifestyle factors = target organs insulin resistance. = Compensatory Beta-cell hyperplasia as they try to produce sufficient insulin to ⬇ blood glucose. Eventually , there is beta-cell failure (early) and impaired glucose tolerance. Further beta-cell failure (late) which leads to diabetes.
In cases where there is primary beta-cell failure, there will be diabetes straight away
What are the metabolic complications of Type 2 -DM
Pathogenesis of HONK state
Hyperglycaemic, Hyper-osmolar Non-Ketotic (HONK)
Insulin resistance of target cells = body thinks there is low blood glucose level bc low glucose uptake into cells
= ⬆ gluconeogenesis, ⬆ glycogenolysis
= develop Severe hyperglycaemia
= glycosuria
= osmotic diuresis = water moves from EC space into blood vessels = loss of water + electrolytes
= Extreme dehydration (= cardiovascular collapse)
loss of water + electrolytes = Increase plasma osmolality (blood becomes viscous) = thrombosis
hyperglycaemia = ⬆ plasma osmolarity = cerebral dehydration = Impaired consciousness
No ketosis
Death if untreated
Describe the pathogenesis of the HONK state
Low insulin will lead to increased gluconeogenesis and glycogenolysis which both lead to hyperglycaemia .
This leads to glycosuria (sugar in urine ), this leads to osmotic diuresis which is the loss of water thus dehydration through loss of water and electrolytes.
The loss of water and electrolytes can also lead to thrombosis.
Hyperglycaemia also increases plasma osmolarity which can cause increased blood viscosity and thrombosis as well as cerebral dehydration
How can HONK be diagnosed ?
⬆ glucose
⬆ osmolarity
⬆ pH (no ketones = alkaline. ketones are acidic)
How is Diabetes diagnosed? what are the symptoms
Type 1 :
presence of symptoms - polyuria, polydipsia, weight loss(forT1)
and weight loss
-Random plasma glucose>11.1mmol/l
Fasting plasma glucose >7.0mmol/l.
(FASTING = No calorific intake for more than 8h)
HbA1c (haemoglobin ) test > 48mmol/l - two tests
Oral glucose tolerance test
(plasma glucose >11.1 mmol/l
Where there are no symptoms :
Test blood samples on 2 separate days
What is the IGT and IFG (Pre-diabetes - at risk of developing diabetes + CVS disease) ?
Impaired glucose tolerance (IGT)
- Fasting plasma glucose >7mmol/l, then
- do OGTT to check if b/w 7.8-11.1mmol = IGT = pre diabetic
Impaired Fasting glycaemia (IFG)
- Fasting plasma glucose 6.1-6.9 mmol/L +
- OGTT value <7.8mmol/L
** OGTT used in individuals with fasting plasma glucose‹7.0 mmol/L to determine glucose tolerance status.
When should the oral glucose tolerance test be carried out ?
OGTT should be carried out to check body’s ability to metabolise glucose - clear glucose from blood
- In patients with IGT,IFG
- In unexplained glycosuria
- In clinical features of diabetes with normal plasma glucose values
- For the diagnosis of acromegaly (excess growth hormone )
75g oral glucose and test after 2 hours
Blood samples collected at time0 before giving glucose + 120 mins after administering glucose to check body’s ability to metabolise glucose
Subjects tested fasting after 3 hours of normal diet containing at least 250 g carbohydrate.
Treatment of T1DM
Treatment of T1DM = Insulin therapy
Outline the treatment of T2DM
- Lifestyle changes - Diet and exercise
- Oral monotherapy - Metformin
- Oral combination of drugs - Sulphonylureas,Gliptins,GLP-1 analogues
- Insulin + oral agents
Describe the drug treatment of Type 2 diabetes mellitus
- *Metformin:** Decreases gluconeogenesis + increases peripheral use of glucose
- *Sulfonylureas:** bind and close KATP channels, depolarize B cell releasing insulin
- *Thiazolidinediones:** reduces insulin resistance
- *Glitazones:** activate PPARγ receptor (controller of lipid metabolism), which (somehow) reduces insulin resistance
- *SGLT2 inhibitors:** promote glucose excretion via kidney. prevents glucose reabsorption in kidney
- *Incretin-targeting drugs:** potentiate insulin release in response to rising plasma glucose
- DPP-4 inhibitors - prevent breakdown of natural incretins
- Synthetic GLP-1 analogues - prevent breakdown of natural incretins
Incretin aids insulin production + reduces liver glucose production
How does Sulphonylurea work ?
It works by stimulating pancreatic beta cells to secrete insulin = ⬇ blood glucose
causes hypoglycaemia if patient hasn’t eaten
Outline the mechanism of Gliptins ?
This is a peptidyl-peptidase inhibitor which works by blocking peptidyl-peptidase 4 which is an enzyme which destroys the hormone incretin. Incretin helps the body produce more insulin and reduces the amount of glucose being produced by the liver when not needed.
Gliptins will block the enzyme which destroys incretin.
What are GLP-1 analogues ?
Anatagonist which mimics the actions of nitra-incretin hormones to help lower the blood glucose levels after a meal.
How are glycaemic levels monitored?
monitor glycaemic levels to prevent complications + avoid hypoglycaemia
Self-monitoring is encouraged:
- Capillary blood measurement (home)
- Urine analysis: glucose in urine indicates that blood glucose concentration is above renal threshold
3-4 months: Blood HbA1c (glycated Hb; covalent linkage of glucose to residue in Hb)
Urinary albumin = kidney damage (index of risk of progression to nephropathy)
What are the long term complications of Type 1/2 diabetes?
Microvascular disease:
Retinopathy, Nephropathy (kidney damage), Neuropathy (diabetic foot ulcer which cannot heal = amputate leg). hyperglycaemia = protein glycation = increase sorbitol = thickens basement membrane + loss of pericytes
Macrovascular disease:
Related to atherosclerosis, heart attack/stroke. hyperglycaemia = endothelial damage, platelet adhesion, plaque formation
Exact mechanisms of complications are unclear
Define Hypoglycaemia and causes
Hypoglycaemia: plasma glucose <2.5 mmol/L
- Hypoglycaemia in diabetes
- Hypoglycaemia in non-diabetic patients
Causes:
Drugs
-Common in type 1 diabetes
-Less common in type 2 diabetes taking insulin +insulin secretagogues (substance which promotes secretion)
Uncommon in patients who do not have drug-treated DM
In these patients hypoglycaemia may be caused by :
- Alcohol
- Critical illness (hepatic disease, renal disease ,cardiac failure,sepsis, insulinoma, hormone deficiency, inherited metabolic dx)
What are some commonly used sulfonylureas?
- Exogenous insulin
- Insulin secretagogues - glyburide, glipizide, glimepiride
cause hypoglycaemia
Stimulation of endogenous insulin suppresses hepatic and renal glucose production and increases glucose utilisation
What drugs are used to treat type 2 diabetes earlier in the disease ?
- Insulin sensitisers (Metamorfin, Glitazones)
- Glucosidase inhibitors
- glucagon-like peptide-1 (GLP-1) receptor antagonist
- DPP-4 inhibitors
These drugs should not cause hypoglycaemia
T2DM drugs increase risk of hypoglycaemia if used together with insulin secretagogues
What can cause hypoglycaemia in non-diabetic patients?
-Alcohol causes hypoglycaemia
-Drugs causing hypoglycaemia:
Quinolone
Quinine
Beta blockers
ACE inhibitors
IGF-1 - Insulin Growth Factor 1
Endocrine disease - cortisol disorder = hypoglycaemia
Inherited metabolic disorders - hereditary fructose intolerance = hypoglycaemia
Insulinoma (tumour) - beta cells of pancreas = excess insulin = hypoglycaemia
severe liver disease, non-pancreatic tumours (beta cell hyperplasia), renal disease (metabolic acidosis, reduced insulin elimination) = hypoglycaemia
How does ethanol lead to hypoglycaemia ?
Alcohol inhibits gluconeogenesis but not glycogenolysis
The hypoglycaemia will follow several days alcohol binge with limited food intake
This results in hepatic depletion of glycogen
How does Sepsis cause hypoglycaemia ?
Common cause
Releases cytokines
= Cytokine-accelerated glucose utilisation + induced inhibition of gluconeogenesis in the setting of glycogen depletion
How does CKD cause hypoglycaemia ?
Unclear mechanism
Impairs gluconeogenesis + reduced renal clearance of insulin + reduced glucose production
Outline reactive hypoglycaemia and the cause
Reactive hypoglycaemia aka postprandial hypoglycaemia
-Drops in blood sugar are usually recurrent and occur within four hours after eating
Reactive hypoglycaemia due to excessive pancreatic insulin production following carb-rich meal. excess insulin production continues after glucose from meal is digested = blood glucose level drops
Can occur in both diabetic +non diabetic patients
More common in overweight individuals/ gastric bypass surgery
The actual cause of reactive hypoglycaemia is unclear:
- benign tumour in the pancreas causing overproduction of insulin
- Too much glucose may be used up by the tumour itself after eating
- Deficiencies in counter-regulatory hormones e.g. glucagon
What is the normal counter-regulatory response to hypoglycaemia ?
brain requires glucose = strong counter-regulatory mechanisms to swiftly increase blood glucose.
- When plasma glucose level declines in fast state , pancreatic beta cells secretion of insulin will decrease
+ stimulate glucagon secretion by pancreatic alpha cells = + hepatic glycogenolysis and gluconeogenesis are increased
+ reduced glucose utilisation of peripheral tissue , inducing lipolysis and proteolysis
2.Counter regulatory hormones are released.
= stimulates adrenal gland to release cortisol + adrenaline. adrenaline stimulates hepatic glycogenolysis + gluconeogenesis.
- 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 + limit peripheral utilisation.
Outline the counter-regulatory respone to hypoglycaemia
Look at slide
cortisol, adrenaline and glucagon reduce peripheral glucose utilisation + increase glucose production (gluconeogenesis,glycogenolysis) to meet body demands
What are the signs and symptoms of hypoglycaemia ?
- Neurogeneic (Autonomic)
- Triggered by falling glucose levels
- Activated by ANS + mediated by sympathoadrenal release of catecholamine (adrenaline, noradrenaline) + ACh from postsyn sym. nerve endings
⬆ adrenaline - trembling, pale, sweating, mood changes, blurred vision (pupil dilate), headache, hunger, dry mouth, palpitation
2.Neuroglycopaenic
-Due to neuronal glucose deprivation
-Sign and symptoms:
Confusion
Difficulty speaking
Ataxia-degenerative disease of the nervous system
Paraesthesia-abnormal sensation of the skin
Seizures
Coma
Death
Fed state
plasma glucose ⬆ = insulin release = ⬇ liver glucose production = inhibition of glycogenolysis + inhibition of gluconeogenesis + ⬆ glucose uptake into liver to convert it to glycogen for storage
⬆ peripheral uptake of glucose into muscle + adipose tissue
⬇ peripheral catabolism (⬇ lipolysis + proteolysis) to reduce glucose in bloodstream
Fasting state
⬇ blood glucose level
⬇ insulin production by pancreas
⬆ gluconeogenesis - liver produces glucose from non-carb sources (lactate, aa’s) to ⬆ plasma glucose
⬇ peripheral uptake of glucose into muscles + adipose tissue
⬆ catabolism - breakdown of lipids (lipolysis) + proteins (proteolysis) to release glucose into bloodstream
