intro to diabetes Flashcards
where does glucose come from in the fasting state
all glucose comes from the liver (and a bit from kidney)
how do you get glucose in the fasting state
breakdown of glycogen
gluconeogenesis - uses 3 carbon precursors - lactate, alanine and glycerol
which cells is glucose delivered to in the fasting state
insulin indepdent tissues
brain
red blood cells
are insulin levels low or high in the fasting state
low
what does muscle use for fuel in the fasting state
FFA
in the fasting state are processes sensitive to insulin?
some processes are very sensitive to insulin, even low insulin levels prevent unrestrained breakdown of fat
what happens after feeding
postprandial state
there is a physiological need to dispose of a nutrient load
when does glucose rise
5-10 mins after eating
what does rising glucose stimulate
stimulates insulin secretion
where does ingested glucose
40% goes to the liver
60% goes to the periphery - mostly muscle
what do high insulin and glucose levels cause
they suppress lipolysis and levels of non-esterified fatty acids fall
what is the site of insulin and glucagon secretion the endocrine pancreas
islets of langerhans
what do beta cells do
secrete insulin
what do alpha cells do
secrete glucagon
what do delta cells do
paracrine ‘crosstalk’ between alpha and beta cells is physiological
ie local insulin release inhibits glucagon
an effect lost in diabetes
insulin action in muscle and fat cells
- insulin receptor
- intracellular signalling cascades
- glut 4 vesicle mobilisation to plasma membrane
- glucose entry into cell via GLUT 4
what are hormonal regulators of carbohydrate metabolism
insulin
counterregulatory hormones
give examples of counterregulatory hormones
glucagon, adrenaline, cortisol, growth hormone
how does insulin regulate carbohydrate metabolism
suppresses hepatic glucose output
- decrease glycogenolysis
- decrease gluconeogenesis
increases glucose uptake into insulin-sensitive tissues (muscle fat)
suppresses
- lipolysis
- breakdown of muscle
how does glucagon regulate carbohydrate metabolism
increases hepatic glucose output
- increase glycogenolysis
- increase gluconeogenesis
reduce peripheral glucose uptake
stimulate peripheral release of gluconeogenic precursors (glycerol, AAs)
- lipolysis
- muscle glycogenolysis and breakdown
define diabetes mellitus
a disorder of carbohydrate metabolism characterised by hyperglycaemia
how does diabetes mellitus cause morbidity and mortality
- acute hyperglycaemia - untreated can lead to acute metabolic emergencies diabetic ketoacidosis (DKA) and hyperosmolar coma
- chronic hyperglycaemia - leading to tissue complications
- side effects of treatment - hypoglycaemia
what serious complications is diabetes associated wirh
- diabetic retinopathy
- stroke
- diabetic nephropathy
- cardiovascular disease
6 types of diabetes
- type 1
- type 2
- maturity onset diabetes of youth (MODY)
- pancreatic diabetes
- endocrine diabetes
- malnutrition related diabetes
pathogenesis of type 1 diabetes
- an insulin deficiency disease characterised by loss of beta cells due to autoimmune destruction
- beta cells express antigens of HLA histocompatibility system perhaps in response to an environmental event
- activates a chronic cell mediated immune process leading to chronic insulitis
what does failure of insulin secretion lead to
- continued breakdown of liver glycogen
- unrestrained lipolysis and skeletal muscle breakdown providing gluconeogenic precursors
- inappropriate increase in hepatic glucose output suppression of peripheral glucose uptake
what does rising glucose concentration result in
increased urinary glucose losses as renal threshold (10mM) is exceeded
what does failiure to treat type 1 diabetes with insulin lead to
- increase in circulating glucagon (loss of local increases in insulin within the islets leads to removal of inhibition of glucagon release), further increasing glucose
- perceived stress leads to increased cortisol and adrenaline
- progressive catabolic state and increasing levels of ketones
aetiology of type 2 diabetes
impaired insulin secretions and insulin resistance
leads to impaired glucose tolerance
what does impaired insulin action in type 2 diabetes lead to
- reduced muscle and fat uptake after eating
- failure to suppress lipolysis and high circulating FFAs
- abnormally high glucose output after a meal
describe ketone production in type 2 diabetes
even low levels of insulin prevent muscle catabolism and ketogenesis so profound muscle breakdown and gluconeogenesis are restrained and ketone production is rarely excessive
effects of absent insulin secretion in type 1 diabetes
no hepatic insulin effect
no muscle/fat insulin effect
leads to unrestrained glucose and ketone production
hyperglycemia + raised plasma ketone
leads to impaired glucose clearance + muscle/fat breakdown
leads to glycosuria/ketonuria
pathophysiology of type 1 diaberes
severe insulin deficnecy due to autoimmune destruction of beta cell
pathophysiology of tyoe 2 diabetes
insulin resistance and impaired insulin secretion due to a combination of genetic predisposition and environmental factors
principles of treatment for diabetes
- control of symptoms
- prevention of acute emergencies, ketoacidosis, hyperglycaemia hyperosmolar states
- identification and prevention of long term microvascular complications
-HbA1c 50mmol/mol
real life treatment of type 2 diabetes
weight loss and excercise
if substantial will reverse hyperglycaemia
also management usually consists of medication to control BP, blood glucose and lipids
what does sulphonylureas do
stimulate insulin release by binding to B cell receptors
improves glycaemic control at the expense of weight gain
but can cause hypoglycaemia
what does thiazolidinediones do
bind to the nuclear receoptor PPAARy
activate genes concerned with glucose uptake and utilisation and lipid metabolism
improves insulin sensitivity
need insulin for a therapeutic effect
what would an ideal drug in type 2 diabetes do
- reduce appetite and induce weight loss
- preserve b cells and insulin secretion
- increase insulin secretion at meal time
- inhibit counterregulatory hormones which increase blood glucose such as glucagon
- not increase the risk of hypoglycaemia during treatment
when and where is GLP-1 secreted
upon ingestion of food
From L cells in the intestine
modes of action of GLP-1
- stimulates insulin secretion
- suppresses glucagon secretion
- slows gastric emptying
- reduces food intake
- increases B cell mass and maintains B cell function
- improves insulin sensitivity
- enhances glucose disposal
what do SGLT2 inhibitors do
block the reabsoptriyon of glucose in the kidneys
increase glucose exctreion
lower blood glucose levels
first line of oral agents
metformin
why doesnt DKA occur in type 2 diabetes
its rare becausr the low insulin leveks are sufficein to suppress the catabolism and prevent ketogeneiss
why does obesity cause type 2 diabetes
obiesty imparies insulin action
why does insulin secretion becoe impared in type 2 diabetes
possibly related to
- genetic predeposition
- glucotoxicity hyperglycaemia inhibits insulin secretion
main factor is lipid deposition in the pancreatic islets which prevent normal secretion of insulin
