Introduction To Diabetes 07.12.23 Flashcards
In the fasting state, what happens in regulation of CHO metabolism in non diabetic humans
In the fasting state
all glucose comes from liver (and a bit from kidney)
Breakdown of glycogen
Gluconeogenesis (utilises 3 carbon precursors to synthesise glucose including lactate, alanine and glycerol)
Glucose is delivered to insulin independent tissues, brain and red blood cells
Insulin levels are low
Muscle uses FFA for fuel
Some processes are very sensitive to insulin, even low insulin levels prevent unrestrained breakdown of fat
After feeding, what happens in regulation of CHO metabolism in non diabetic humans
After feeding (post prandial) - physiological need to dispose of a nutrient load
Rising glucose (5-10 min after eating) stimulates insulin secretion and suppresses glucagon
40% of ingested glucose goes to liver and 60% to periphery, mostly muscle
Ingested glucose helps to replenish glycogen stores both in liver and muscle
High insulin and glucose levels suppress lipolysis and levels of non-esterified fatty acids (NEFA or FFA) fall
Microstructure of islets of langerhans
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How does insulin secretion occur in the beta cells?
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How does insulin act in muscle and fat cells
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What are the key hormonal regulators of carbohydrate metabolism
Insulin
Glucagon
Adrenaline
Cortisol
Growth hormone
What does insulin do?
Supresses hepatic glucose output
Glycogenolysis
Gluconeogenesis
Increases glucose uptake into insulin sensitive tissues (muscle, fat)
Suppresses
Lipolysis
Breakdown of muscle
What does glucagon do?
Increases hepatic glucose output
Glycogenolysis
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 mortality and morbidity
Acute hyperglycaemia which if untreated leads to acute metabolic emergencies diabetic ketoacidosis (DKA) and hyperosmolar coma (Hyperosmolar Hyperglycaemic State )
Chronic hyperglycaemia leading to tissue complications (macrovascular and microvascular)
Side effects of treatment- hypoglycaemia
What complications are diabetes associated with?
Diabetic retinopathy
Diabetic nephropathy
Stroke
Cardiovascular disease
Diabetic neuropathy
What are the types of diabetes?
Type 1
Type 2 (inc. gestational and medication induced diabetes)
MODY (Maturity onset diabetes of youth)/monogenic diabetes
Pancreatic diabetes
Endocrine diabetes (acromegaly/cushings)
Malnutrition related diabetes
Define diabetes
Symptoms and random plasma glucose > 11 mmol/l
Fasting plasma glucose > 7 mmol/l
No symptoms - GTT (75g glucose) fasting > 7 or 2h value > 11 mmol/l (repeated on 2 occasions)
HbA1c of > 48mmol/mol (6.5%)
Define type 1 diabetes
An insulin deficiency disease characterised by loss of beta cells due to autoimmune destruction
How does type 1 diabetes occur?
Beta cells express antigens of HLA histocompatability system perhaps in response to an environmental event (?virus)
Activates a chronic cell mediated immune process leading to chronic ‘insulitis’
What does failure of insulin secretion leads to??
Continued breakdown of liver glycogen
Unrestrained lipolysis and skeletal muscle breakdown providing gluconeogenic precursors
Inappropriate increase in hepatic glucose output and suppression of peripheral glucose uptake
Why does urinary glucose increase in type 1 diabetes?
Rising glucose concentration results in increased urinary glucose losses as renal threshold (10mM) is exceeded
What does failure to treat type 1 diabetes with insulin leads to what?
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
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Impaired insulin action leads to
Reduced muscle and fat uptake after eating
Failure to suppress lipolysis and high circulating FFAs
Abnormally high glucose output after a meal
Even low levels of insulin prevent muscle catabolism and ketogenesis so profound muscle breakdown and gluconeogenesis are restrained and ketone production is rarely excessive
What are the principle treatment of diabetes
Control of symptoms
Prevention of acute emergencies, ketoacidosis, hyperglycaemic hyperosmolar states
Identification and prevention of long-term microvascular complications
Limited evidence yet that glucose control per se reduces cardiovascular events (confirmed by recent clinical trials, ACCORD, ADVANCE) in the short-term
But long-term follow-up indicates a modest reduction in IHD from tight glucose control if started at diagnosis
HbA1c 50mmol/mol (6.5%) (as low as possible in those not on insulin or sulphonylureas)
Treatment on type 2 diabetes in real life
Ideally consists of weight loss and exercise which if substantial will reverse hyperglycaemia
Lifestyle changes are important if they can be achieved
but most with Type 2 diabetes have been making the ‘wrong’ lifestyle choices all their lives and rarely respond to these approaches
At present, management usually consists of medication to control BP, blood glucose and lipids
What are thiazolidinediones (pioglitazone - ACTOS)
Bind to the nuclear receptor PPAR (peroxisome proliferator-activated receptor)
Activate genes concerned with glucose uptake and utilisation and lipid metabolism
Improve insulin sensitivity
Need insulin for a therapeutic effect
Glitazones relatively rarely used but may be useful in some sub-groups
Increase weight
Increase the risk of heart failure
Increase the risk of fractures
What would the ideal drug in type 2 diabetes consist of?
Reduce appetite and induce weight loss
Preserve -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
What is GLP-1 and where and when is it produced?
Upon ingestion of food GLP-1 is secreted from L cells in the intestine
What are GLP-1 modes of action
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What is the first line treatment for type 2 diabetes
Metformin
