Diabetes Mellitus Flashcards
What is the role of GLUT-4?
Recruited and enhanced by insulin
Transports glucose into cells
Highly- insulin responsive
7 fold increase in glucose uptake
Where is GLUT-4 found?
On muscle cells and adipose tissues
How is GLUT-4 structured?
Has inner hydrophilic chain and outer hydrophobic chain
What is the action of insulin on muscle cells?
Increased muscle glucose uptakes
Increased glycogenesis
Increased protein synthesis, decreased proteolysis
What is the action of insulin of fat cells?
Decreased lipolysis
Decreased ketogenesis
Increased lipogenesis
How is proteolysis inhibited?
Insulin inhibits proteolysis
What stimulates proteolysis?
Cortisol and glucagon
What is gluconeogenesis?
Glucose is formed from amino acids, lactate and glycerol
Mainly occurs in liver and cortex of kidney
Triglycerides can be used in gluconeogenesis
What stimulates gluconeogenesis?
Glucagon stimulates amino acid, pyruvate and lactate uptake by hepatocytes
Glucagon and cortisol stimulate hepatic gluconeogenesis when glucose levels are low
What happens to glycerol in gluconeogenesis?
Glycerol can be taken up by transporters in liver
It becomes glycerol-3P and can be converted to triglycerides
Triglycerides can be used in gluconeogenesis
How are NEFAs formed?
Lipoprotein lipase (LPL) breaks down triglycerides to glycerol and non- esterified fatty acids (NEFAs)- stimulated by insulin
Glycerol and non-esterified fatty acids (NEFA) are taken up by adipose cell and converted to triglycerides and are stored there - stimulated by insulin
Glucose undergoes de novo lipogenesis which also produces NEFAs in adipose tissues- stimulated by insulin
What happens in the breakdown of triglycerides in adipose tissues?
GH and cortisol stimualate the hydrolysis of triglycerides into NEFAs and glycerol
How are ketone bodies formed?
Fatty acetyl CoA undergoes B-oxidation to form acetyl-CoA which is then converted to ketone bodies (acetoacetone and acetone)
Stimulated by glucagon
What inhibits formation of ketone bodies?
Insulin
Through what circulation is insulin released?
Released via hepatic portal vein
What is glycogenolysis and how does it occur?
Glycogenolysis is the breakdown of glycogen into glucose
Glucose enters hepatocytes via GLUT-2
It becomes glucose-6-phosphate which is converted to glucose or glycogen
Glucagon stimulates breakdown of glycogen to G6P to glucose
What happens in the fasted state?
Low insulin to glucagon ration
Increased NEFA conc.
Decreased amino acid conc. when prolonged
Increased proteolysis Increased lipolysis Increased HGO from glycogenolysis and gluconeogensis Muscle uses lipids Brain uses glucose and later ketones Ketogenesis when prolonged
What happens in the fed state?
High insulin to glucagon ration Stoped HGO Increased glycogen Decreased gluconeogeneis Increased protein synthesis Decreased proteolysis Increased lipogenesis
How do we diagnose diabetes mellitus?
- Fasting glucose: test to determine glucose levels after fasting
- Random glucose: blood glucose taken when not fasting
- Oral glucose tolerence test: fasting glucose measured as base line then 75g oral glucose given.
Glucose conc. monitored- should rise then fall in a healthy person - HbA1C: formation of sugar Hb linkage indicates presence of excessive sugar. Determines 3 month average blood sugar levels
What is the diagnostic criteria for diabetes mellitus?
Fasting glucose: >7.0mmol/L
Random glucose: >11.1mmol/L
HbA1C: >48mmol/L
Diagnosis requires 2 positive results or 1 positive result and symptoms
What is the pathophysiology of Type 1 diabetes mellitus?
Dysfunctional insulin secreting beta cells of islets of langerhans
Diabetic ketoacidosis: formation of ketone bodies is elevated in T1DM. Metabolic acidosis is caused by high levels of ketogenesis- lowers blood pH
What are symptoms of T1DM?
Weight loss: proteolysis of muscles and lipolysis of adipose tissues
Hyperglycaemia
Glucosuria with osmotic symptoms: polyuria, polydipsia, nocturia
Ketones in blood and urine
What is hypoglycaemia?
T1DM treated with insulin injections however excess insulin administration results in reduced HGO and increases muscle and adipose tissue uptake of glucose (increased GLUT-4 translocation)
How is hypoglycaemia countered by the body?
Glucagon, cortisol, GH and catecholamine secretion increases glucose release
HGO is stimulated along with lipolysis
What is a problem with counter-regulatory responses to hypoglycaemia?
Can lead to impaired awareness of the patient to recognise hypoglycaemia- this can lead to recurrent episodes of hypoglycaemia which normalises the condition and leads to low counter- regulatory responses
What are symptoms of hypoglycaemia?
Autonomic symptoms:
- sweating
- pallor
- palpitations
- shaking
Neuroglycopenic symptoms:
- slurred speech
- poor vision
- confusion
- seizures
- loss of consciousness
How is T1DM managed?
Exogenous insulin (basal- bolus regime)
Self- monitoring of glucose
Structured education
Technology
What is the pathophysiology of T2DM?
Insulin resistance in liver, muscles and adipose tissues
Insulin still secreted
Leads to enhanced hepatic sensitivity to glucagon and increased glucagon levels contribute to excessive HGO
Leads to increased lipolysis and NEFA levels
What are useful diagnostic tests fro T1DM?
Antibodies: GAD and IA2
C- peptide
Presence of ketones
What causes insulin resistance?
Insulin produced by beta cells keeps increasing. Eventually demand for insulin by body exceeds amount of insulin pancreas can make- pancreas gets worn out
Pancreas can no longer make enough insulin to control blood glucose levels
What are 2 pathways affected in T2DM?
Normally insulin binds to insulin receptor and activates:
PI3K-Akt pathway- causes metabolic action. Understimulation of this pathway increases release of insulin by B cells
MAPK pathway is activated and causes growth and stimulation- no insulin resistance in this pathways so this pathway is overstimulated (increases Bp)
What are symptoms of insulin resistance?
High triglyceride conc. Low HDL conc. Hypertension: BP >135/80 mmHg Increased waist circumference Fasting glucose >6.0 mmol/L
What are risk factors for diabetes?
Dietary Lifestyle Ethnicity Age Increased BMI PCOS
What are symptoms of T2DM?
Hyperglycaemia Overweight Dsylipidaemia Less osmotic symptoms (hyperglycaemia increases osmolarity of circulation so stimulates osmotic flow into vasculature- increased BP) Insulin resistance Later insulin deficiency
What are long term symptoms of diabetes?
Retinopathy Neuropathy Nephropathy Cardiovascular Diabetic foot disease
What is a drug used for diabetes?
Metformin
Reduces gluconeogenesis and increases glucose uptake by myocytes
Enchances insulin sensitivity and glucose uptake in skeletal muscle - enhances GLUT-4 translocation
Doesn’t cause weight gain
What are treatments for T2DM?
Diet
Oral medication
Structured education
May need insulin later
