Diabetes Mellitus Flashcards
What is diabetes mellitus?
- chronic non-communicable disease characterised by hyperglycaemia
- caused by relative insulin deficiency/resistance/both
- irreversible
- reduced life expectancy and major health costs
How is Type 1 diabetes an autoimmune disease?
Immune mediated (T cell) disruption of pancreatic B cells within the islets of Langerhans => insulin deficiency
- autoantibodies against islet constituents
- insulitis
What is type 2 diabetes?
most common
chronic, progressive
characterised by abnormal insulin action and secretion
- often overweight and obese
- genetic component
- number of islets decreases so reduction in number of beta cells per islet = reduction in insulin
Who is at risk of type 2 diabetes?
- overweight and obese (BMI greater than 31)
- higher in identical twins than non-identical
- older - increased mitochondrial dysfunction and inflammation
- family history (first generation - healthy relatives can develop muscle insulin resistance)
- ethnicity
What are the causes of insulin resistance?
OBESITY:
- intrinsic: mitochondrial dysfunction, oxidative stress, ER stress
- extrinsic: lipid accumulation, increased circulating free fatty acids, chronic inflammation, altered adipokine levels
HYPERINSULINEMIA
increased lipid synthesis and exacerbated insulin resistance
What is insulinitis?
- infiltration of mononuclear cells
What does the pancreas do when a tissue is insulin resistant?
- tries to create more insulin but cell does not respond
- increases synthesis of lipids
How does insulin resistance occur in a healthy individual? How does the pancreas respond?
- associated with physiological conditions -> pregnancy or body weight gain
- beta cells in the islets increase in size and number in response = elevating their function = glucose tolerance maintained with increased insulin secretion
What is the significance of hyperglucagonaemia?
Occurs in all diabetes
- even when glucose is high
- alpha cells resistant to high levels of glucose/insulin (glucolipotoxicity)
- nothing to tell the cells to stop secreting glucagon
- no increase in alpha cell mass
How is diabetes diagnosed?
- Symptoms + 1 abnormal plasma glucose (thirst, increased urination, recurrent infection, weight loss)
- Asymptomatic + 2 abnormal plasma glucose when fasting
- Oral glucose tolerance (starve patient for a few hours, measure glucose levels before and after consuming sugary drink)
- HbA1C -> modified Hb when glucose gets attached to it (glycated) and measures percentage of glycated Hb
What are the main methods of treating diabetes? Which drugs do this?
Aim to lower blood glucose levels:
- decrease glucose and gluconeogenesis (TZD and biguanides (metformin)
- stimulate insulin secretion (sulfonylureas and meglitidines)
- stimulate glucagon peptide 1 (metformin and sitagliptin)
What does TZD do?
Thiazolidinedione
Increases level of transcription genes to decrease glucose and gluconeogenesis
What do meglitidines/sulfonylureas/gliclazides do?
stimulate closure of K+ channels in beta cells -> increase in calcium -> secretion of insulin
What does metformin do?
- inhibits gluconeogenesis by inhibiting complex 1 in mitochondria and activating AMPK
- Increases glucose uptake in muscle via GLUT4
- first line
- low risk of becoming hypoglycaemic
What does sitagliptin do?
- inhibits DPP-4 which inhibits GL1P
What are some acute complications of diabetes?
- ketoacidosis (only for type 1, lack of insulin means body switches to prolonged fasting = ketogenesis)
- hypoglycaemia (only type 1, low blood glucose)
What are the consequences of ketoacidosis?
Blood urine acid levels rise, dehydration, coma, death, life threatening
What are the causes type 2 of diabetes?
- alcohol excess = inhibited gluconeogenesis
- insulinoma = tumour of pancreatic beta cells
- excessive exercise = increased glucose usage
- reactive hypoglycaemia = in response to high carb meal and excessive insulin secretion
- type 1 diabetes = high insulin injections without meal
What are the signs and symptoms of type 2 diabetes?
Mild -> autonomic (trembling, sweating, anxiety, hunger)
Moderate - neuroglycopenic (confusion, disorientation, weakness, tiredness)
Severe - confusion, fitting, seizures, coma
What is prolonged hypoglycaemia?
Growth hormone and cortisol secreted -> decreased glucose use, and fat conversion and use
- neuroglycopenic symptoms
How is the protein kinase C pathway stimulated? How can hyperactivation of PKCs cause damage?
Excess glucose = increase protein kinase C
Damages blood vessels:
- increased permeability, occlusion, reactive oxygen species, inflammation
- mitochondrial dysfunction
What is dyslipidaemia?
fat deposition in skeletal muscle
worsens insulin resistance
What other forms of diabetes are there?
- maturity onset diabetes of the young = pancreatic beta cell dysfunction (inherited autosomal dominant)
- gestational diabetes = in pregnancy, increase complications during 2nd half of pregnancy, increased risk of developing T2D
- latent autoimmune diabetes of adults = antibodies to beta cells, become insulin dependent
- type 3c diabetes = disease of exocrine pancreas
How is insulin resistance in a healthy individual different to a diabetic?
Healthy individuals compensate by making bigger beta cells and more of them in the pancreas and increase their function so glucose tolerance still maintained with increased insulin secretion however in diabetics beta cells are failing
What is one mechanism of insulin resistance?
Proinflammatory cytokines/saturated FFAs/A.A can activate serine/threonine kinases => phosphorylates IRS => reduced Tyr phosphorylation => increased degradation
This means reduced insulin signalling and so no insulin response
What are the advantages and limitations of the HbA1c diagnosis?
advantages: reliable measure, HbA1c levels relatively stable vs glucose, easy to collect sample from patient, convenient for patient and fast
Limitations: costly ins some parts of the world, influence of Hb traits (HbS, HbF), affected by RBC turnover
What is the role of GLP-1?
Inhibits glucagon secretion and hepatic glucose production
promotes satiety
slows gastric emptying
stimulates insulin release
What are some macrovascular complications of diabetes?
atherosclerosis
- increased uptake of LDLs as LDLD receptor modification
- pro inflammatory cytokine production
What are the microvascular complications of diabetes?
- kidney disease (damage to blood vessels in glomerulus = proteinuria, glomerular hypertrophy, decreased filtration)
- nerve disease/neuropathy (peripheral, autonomic, proximal, focal_
- blindness (retinopathy
- non-proliferative and proliferative)
What are the differences in types of retinopathy?
non proliferative: dilation of veins and micro aneurysms
proliferative: fragile new blood vessels near optic disk (tend to bleed)
