Diabetes and Hypoglycaemia Flashcards
- In what three ways can you plasma glucose levels be increased?
- Intake of dietary carbohydrates
- Glycogenolysis (Glycogen breakdown)
- Gluconeogenesis ( Glucose production from non-glucose stores eg lactate and fatty acids)
- How is glucose stored?
When will the stores of glucose be used?
•The liver stores glucose as glycogen after meals and makes glucose available through glycogenolysis and gluconeogenesis during fasting.
- Why should glucose levels be regulated?
- Need to avoid deficiency because the brain and erythrocytes require a continuous glucose supply.
- Need to avoid excess because high glucose and metabolites can cause pathological changes to tissues e.g. macro/microvascular diseases and neuropathy.
- What is the difference between :
- Glycogenolysis
- Glucogenesis
- Glycolysis
- Glycogenolysis : Glycogen —> Glycose
- Gluconeogenesis : non-carbohydrate substances —-> Glucose
- Glycolysis : Breakdown of glucose—> ATP
- What effect does insulin have on Adipose?
increased glucose uptake and lipogenesis (fat formation) , reduced lipolysis (to reduce glucose synthesis).
- What effect does insulin have on the Liver?
increased glycogen synthesis and lipogenesis,
reduced gluconeogenesis.
- What effect does insulin have on striated muscle?
increased glucose uptake, glycogen synthesis and protein synthesis.
- What is diabetes Mellitus?
•A metabolic disorder characterised by chronic hyperglycaemia (high blood glucose) , glycosuria (excess sugar in urine) and associated abnormalities of lipid and protein metabolism:
- What causes the body to be in a state of “hyperglycaemic “
increased hepatic glucose production
decreased cellular glucose uptake
(making glucose but the cells not taking it up)
- When do you get glycosuria?
when blood glucose > ~ 10mmol/L and exceeds renal threshold (filtration and reabsorption rates are not equal)
- What is the prevalence of diabetes Mellitus?
o Globally 422 million people currently have diabetes; estimated to increase by 2035 (WHO, 2014)
o In the UK 2018 ~ 3.8 million diagnosed with DM.
- What is type 1 diabetes?
Insulin secretion is deficient due to autoimmune destruction of beta -cells in pancreas by T-cells.
- What is Type 2 Diabetes?
Insulin secretion is retained but there is target organ resistance to its actions (receptor problems etc).
- What is secondary diabetes?
chronic pancreatitis, pancreatic surgery, secretion of antagonists
- What is gestational diabetes?
Occurs for first time in pregnancy.
- (Referring to type 1 diabetes)
What age is it most likely to present in?
How long is the onset?
Present predominantly in children and young adults (but other ages as well)
Onset is sudden (days/weeks).
- At first what might the symptoms of Type 1 diabetes be perceived as?
•Appearance of symptoms may be preceded by ‘prediabetic’ period of several months.
- What is the most common cause of Type 1 diabetes?
autoimmune destruction of B-cells but there are interactions between genetic and environment factors.
o strong link with HLA (human leukocyte antigen) genes within the MHC (major histocompatibility complex) region on chromosome 6.
- What is the pathogenesis of type 1 diabetes ?
o HLA class II cell surface present as foreign and self-antigens to T-lymphocytes initiate autoimmune response. o Circulating autoantibodies against various -cell antigens are present: - Glutamic acid decarboxylase (GABA production in pancreas), tyrosine-phosphatase-like molecule, Islet auto-antigen (most commonly associated with Type 1 Diabetes). • More than 90% of newly diagnosed persons with type 1 DM have one or another of these antibodies. • Destruction of pancreatic ß-cell causes hyperglycaemia due to absolute deficiency of both insulin & amylin.
- What is Amylin?
(glucoregulatory peptide hormone co-secreted with insulin) lowers blood glucose by slowing gastric emptying & suppressing glucagon output from pancreatic cells.
- What is the pathophysiology of diabetes mellitus Type 1?
o Genetic predisposition and environmental factors mean autoantigens form on beta cells which circulate around the body stream/lymphatics.
o Autoantigens are processed and presented by antigen presenting cells which then come into contact with T cells.
1. T helper 1 cells cause the activation of macrophages (release IL-1 and TNF-a) and autoantigen-specific T cytotoxic (CD8) cells.
2. T helper 2 cells activate B lymphocytes to produce autoantibodies.
The macrophages, cytotoxic cells and autoantibodies all cause beta cell destruction leading to decreased insulin
secretion
- What is the metabolic complication that follows from insulin deficiency causing increased lipolysis?
• Insulin deficiency causes increased lipolysis which produces free fatty acids for the formation of ketone bodies (metabolic acidosis can cause diabetic coma).
- What is the metabolic complication that follows from insulin deficiency causing hyperglycaemia?
•Insulin deficiency causes hyperglycaemia which causes glycosuria (filtration and reabsorption not equal) and polyuria. This leads to volume depletion which causes diabetic coma.
- What is the age range and onset of type 2 diabetes?
oSlow onset (months/years) and patients usually middle aged/elderly – prevalence increases with age
- Is there a strong familial incidence for type 2 diabetes?
yes
- What is the pathogenesis of type 2 diabetes?
•Pathogenesis uncertain but involved insulin resistance or β-cell dysfunction: may be due to lifestyle factors e.g. obesity, lack of exercise.
- What are some metabolic complications of type 2 diabetes ?
Hyper-osmolar non-ketotic coma (HONK), [Hyperosmolar Hyperglycaemic State (HHS)]
o Development of severe hyperglycaemia.
o Extreme dehydration – increased plasma osmolality.
o Impaired consciousness and death if left untreated.
o No ketosis (insulin is present so no lipolysis so no ketoacidosis).
- What are some common symptoms of type II diabetes ?
polyuria
polydipsia
weight loss for Type I
- How would you do tests to diagnose Type II diabetes when the patient IS showing symptoms?
- Random plasma glucose (any time of day) ≥ 11.1mmol/l (200 mg/dl ).
- Fasting (no caloric intake for at least 8h) plasma glucose ≥ 7.0 mmol/l (126 mg/dl).
- Oral glucose tolerance test (OGTT) for impaired fasting glycaemia - plasma glu ≥ 11.1 mmol/l
- How would you do tests to diagnose Type II diabetes when the patient ISN’T showing symptoms?
test blood samples on 2 separate days.
- What does :
-OGTT
-IGT
-IFG
mean?
OGTT = Oral glucose tolerance test
IGT = Impaired glucose tolerance (pre-diabetes )
IFG = Impaired fasting Glycaemia
- When would you do an impaired glucose test (IGT) ?
When Fasting plasma glucose >7mmol/L** and
OGTT value of 7.8 – 11.1 mmol
- When would you do an Impaired fasting glycaemia (IFG) test?
Fasting plasma glucose 6.1 to 6.9 mmol/L, and
OGTT value of < 7.8mmol/L
- What nmol/L of plasma glucose would you do an OGTT?
<7 nmol/L
-to determine glucose tolerance status
- When would you do an OGTT?
in patients with IFG
in unexplained glycosuria
in clinical features of diabetes with normal plasma glucose values
- How do you carry out an OGTT?
- Given 75g oral glucose and test blood glucose levels after 2 hour (samples taken at 0 and 120mins after glucose).
- Subjects tested fasting after 3 days of normal diet containing at least 250g carbohydrate.
- What is the Stepwise Treatment of Type II Diabetes:
- Exercise and Diet.
- Metformin monotherapy for type 2 diabetes: helps insulin to re-uptake glucose from plasma (increased peripheral utilisation) and reduce production by gluconeogenesis.
• Only works with insulin presence so some residual functioning pancreatic islet cells are required. - Combined therapy e.g. sulphonylureas (increases insulin production) or gliptins (inhibit incretin degrading enzymes DPP-4; incretin normally helps in glucose reuptake) etc.
- Why should one monitor their glucose ?
to prevent complications or avoid hypoglycaemia.
- You should encourage patients to self-monitor their glucose levels, how can this be achieved?
o Capillary blood measurement – prick fingers to check blood glucose levels.
o Urine analysis: glucose in urine gives indication of blood glucose concentration is above renal threshold.
- Whats a test you can use to monitor your blood glucose levels for the past 3-4 months?
Hint - people with diabetes have to have this test regularly
blood HbA1c test (glycated Hb; covalent linkage of glucose to residue in Hb).
- Whats something we can test for the presence in urine to monitor glucose levels?
urinary albumin (index of risk of progression to nephropathy).
- What is the difference between microvascular and macrovascular complications
Diabetes complications are divided into microvascular (due to damage to small blood vessels) and macrovascular (due to damage to larger blood vessels)
• Exact mechanisms of complications are unclear
- What are some examples of micro vascular disease complications?
retinopathy,
nephropathy
neuropathy
- What are some examples of macro vascular disease complications?
related to atherosclerosis heart attack/stroke
- What value of plasma glucose is defined as hypoglycaemic?
•Defined as plasma glucose < 2.5 mmol/L
- Is hypoglycaemia seen in diabetes patients or non-diabetic patients ?
present in patients with diabetes and without diabetes
- What is the most common cause of hypoglycaemia?
Drugs are the most common cause
- Out of type 1 and type 2 diabetes , which one is it more common to see hypoglycaemia?
o common in type 1 diabetes and less common in type 2 diabetes (taking insulin & insulin secretagogues).
- Hypoglycaemia is uncommon in patients who dont have drug treated diabetes , in these patients what might the cause of hypoglycaemia be?
alcohol critical illnesses such as hepatic, renal or cardiac failure sepsis hormone deficiency inherited metabolic dx.(diagnosis)
- What may cause hypoglycaemia is diabetic patients?
• Exogeneous insulin & insulin secretagogues e.g. glyburide, glipizide and glimepiride (common sulfonylureas).
o Endogenous insulin suppresses hepatic and renal glucose production and increase glucose utilisation.
- What are some drugs that are used to treat early type 2 diabetes that SHOULD NOT cause hypoglycaemia?
insulin sensitizers (metformin, Glitazones), glucosidase inhibitors, glucagon-like pepdide-1 (GLP-1) receptor antagonist and DDP-4 inhibitors.
- What are some drugs that would cause hypoglycaemia in patients WITHOUT diabetes?
quinolone quinine beta blockers ACE inhibitors IGF-1
- What are two endocrine diseases that might cause hypoglycaemia in patients WITHOUT diabetes?
cortisol disorder or Insulinoma (insulin secreting tumour)
- What is a hereditary metabolic disorder that might cause hypoglycaemia in patients WITHOUT diabetes?
hereditary fructose intolerance
55 What are some other diseases that might cause hypoglycaemia in patients WITHOUT diabetes?
: severe liver disease, non-pancreatic tumours (beta cell hyperplasia), renal disease (metabolic. acidosis, reduced insulin elimination).
- How does ethanol cause hypoglycaemia?
inhibit gluconeogenesis, but not glycogenolysis: hypoglycaemia follows several days when the alcohol binge with limited food take causes hepatic depletion of glycogen.
- How does sepsis cause hypoglycaemia?
* Relatively common cause*
glycogen depletion by cytokine accelerated glucose utilisation and induced inhibition of gluconeogenesis.
- How does chronic kidney disease cause hypoglycaemia?
unclear mechanism that may involve impaired gluconeogenesis, reduced renal clearance of insulin and reduce renal glucose production.
- What is reactive hypoglycaemia (AKA postprandial hypoglycaemia)
??
(Hypo’s after eating)
•Recurrent blood sugar drops (within four hours after eating) in both patients with and without diabetes.
- Who is most likely to have reactive hypoglycaemia?
•More common in overweight individuals or those who have had gastric bypass surgery.
- What causes reactive hypoglycaemia?
o a benign (non-cancerous) tumour in the pancreas that overproduces insulin
o too much glucose may be used up by the tumour itself
o deficiencies in counter-regulatory hormones: e.g. glucagon, epinephrine etc.
- What is the response to hypoglycaemia in a normal patient?
• Reduced plasma glucose levels in fast state cause pancreatic beta-cells secretion of insulin to be decreased (1st defence):
o Increased hepatic glycogenolysis and gluconeogenesis and reduced glucose utilisation of peripheral tissue which induces lipolysis and proteolysis.
- One of our bodies response to hypoglycaemia is to release regulatory hormones, what are these ?
Pancreatic alpha cells secrete glucagon to stimulate hepatic glycogenolysis (2nd defence).
o Epinephrine release from adrenomedullary stimulates hepatic glycogenolysis and gluconeogenesis + renal gluconeogenesis
o Prolonged hypoglycaemia (beyond 4 hours): cortisol and GH support glucose production and limit utilisation.
- What is the counter-regulatory response to hypoglycaemia?
• Inhibition of the endogenous insulin secretion and stimulation of glucagon, catecholamines (norepinephrine, epinephrine), cortisol and growth hormone secretion - stimulate hepatic glucose production and cut down glucose utilization in peripheral tissues - increasing in this way plasma glucose levels.
- What are the signs and symptoms of neurogenic (nervous system ) hypoglycaemia and what causes them?
mood changes, sweating and trembling, headaches, dizziness, extreme tiredness, pale, hunger and blurred vision.
o triggered by falling glucose levels
o activated by ANS & mediated by sympathoadrenal release of catecholamines and Ach
- What causes neuroglycopenia (shortage of glucose in the brain) and what are the symptoms?
o Due to neuronal glucose deprivation.
o Sign & symptoms include confusion, difficulty speaking, ataxia (lack of co-ordination, balance and speech), paraesthesia (tingling/prickling caused by peripheral nerve damage), seizures, coma, death.
