30. Diabetes Mellitus Flashcards
What is diabetes?
What is type 1?
What is type 2?
Chronic non-communicable disease characterised by hyperglycaemia. Caused by relative insulin deficiency and/or resistance. Usually irreversible. Increasing prevalence.
Chronic autoimmune disease of generally young pts, genetic and env components, T cell-mediated disruption of the pancreatic beta cells within islets of langerhans (infiltrate = insulitis and destroy). Insulin deficiency - constant need for insulin injections. Association with HLA. Immunosuppression after diagnosis delats beta cell disruption.
Most common (85-90%), chronic, progressive, characterised by abnormal insulin action (cells don’t respond properly to it) and secretion. Usually older pts but increasing in younger. Often overweight. Genetic component (most genes still unknown, GKRP, PPARG)
What are some risk factors for T2 diabetes?
Describe one example of reduced response to insulin in target tissues due to obesity.
Obesity, family history, age (increased mit dysfunction, inflammation), ethnicity, incidence increase follows trend of urbanisation and lifestyle changes suggesting env influence
Insulin binds to muscle cell receptor -> IRS phosphorylated by receptor at tyrosine residue = cascade that activate cell to induce glucose transport into cell. BUT in presence of cytokines/chemokines in obesity, IRS is phosphorylated at threonine serine, so no tyrosine phosphorylation, so no cascade. Thus insulin circulating but no response from muscle cell
Describe 2 causes of insulin resistance.
Does insulin resistance = diabetes?
1) Obesity: accumulation of lipids and their metabolites or increased concentrations of circulating free FAs, chronic inflammation, aletered adipokine levels
2) Hyperinsulinaemia: increases lipid synthesis and exacerbates insulin release.
No - in healthy ppl it’s associated with physiological conditions such as pregnancy or weight gain. New beta cells can be generated in response. (Need second factor (deficiency in synthesis of insuin) for diabetes).
How do normal islets of langerhans compare to those in someone with insulin resistance? (NB: insulin resistance on its own is NOT diabetes)
What are the islets of langerhans like in someone with T2 diabetes?
Do most variants for T2 diabetes act by impairing insulin secretion or insulin action?
What are many of the susceptibility genes associated with T2 diabetes regulators of?
Increase in beta cell size and number, and in function. Glucose tolerance can be maintained by increased insulin secretion. (PIC)
Number of islets decreases and there is significant reduction in the number of beta cells per islet. Can have reduction before resistance develops. Diabetes = combo of insulin resistance + beta cell dysfunction
Secretion
Beta cell turnover or regeneration
List 3 other forms of diabetes mellitus aside from T1 and T2.
Describe the 3 ways diabetes can be diagnosed.
Maturity onset diabetes of the young (MODY) dominantly inherited form of DM, beta cell dysfunction, gestational diabetes (insulin resistance not compensated, increased risk of subsequent T2 diabetes), latent autoimmune disease of adults (LADA or type “1.5”)
1 abnormal plasma glucose (random ≥11.1mmol/L or fasting ≥7mmol/L) in the presence of symptoms (thirst, increased urination, recurrent infections, weight loss, drowsiness, coma)
OR
2 fasting venous plasma glucose samples in abnormal range (≥7mmol/L) recommended in asymptomatic people
OR
HbA1c (glycated Hb) measurement: reliable, relatively stable compared to glucose, easy to collect, convenient (no prior fast), average over 120 days. Cut point for diabetes diagnosis: 48mmol/mol (6.5%)
What is the main aim of diabetes treatment?
List the general classes of treatments used.
Briefly describe how insulin is secreted.
To lower BG.
Meglitinides, DPP-4 inhibitors, SGLT2 inhibitors, bile acid sequestrants, glitazones
Glucose enters beta cells via glucose transporter -> rise in ATP:ADP ratio -> KATP channels close -> membrane depolarisation -> opening of VGCa2+ channels -> insulin secretion. (Need to compensate for closing K channel - some drugs do this: sulfonyureas, meglitinides)
How do some of the TZD (glitazone) drugs and metformin work?
What effect does metformin have on GNG?
TZD: increase insulin sensitivity by binding PPAR gamma transcription factor and inducing genes involved in improved sensitivity to insulin (e.g. more GLUT4 produced)
Metformin: increased production of AMP kinase activation - improves glucose transport and improved insulin receptor function by increasing GLP-1
Metformin BLOCKS GNG (b/c insulin stops GNG but if no insulin then GNG keeps producing glucose into theblood, but metformin stops this)
How does GLP-1 work?
How is GLP-1 degraded? How can this be inhibited?
Inhibits glucagon secretion and hepatic glucose production, slows gastric emptying, promotes satiety, restores beta cell function and promotes differentiation, increases insulin sythesis
By DPP-4. Can use things to block this e.g. sitagliptin inhibits DPP-4 so GLP-1 more sttable and acts for a longer time. Metformin increases GLP-1.
What are 2 acute complications of diabetes?
What is the Whipple triad?
Ketoacidosis (continual use of FA for energy leads to production of ketone bodies - acetoacetate and beta-hydroxybutyrate. Blood and urine acid levels rise -> dehydration -> coma -> death. More common in T1. Emg treatment: fluids, electrolytes, insulin)
Hypoglycaemia (abnormally low, harmful plasma glucose conc, <70mg/dl (<3.9mmol/L)).
Defines hypoglycaemia: low BG, symptoms/signs associated with low BG, reduction of these S/S by carbohydrate ingestion
What are some causes of hypoglycaemia?
What symptoms of hypoglycaemia would you see when:
a) mild hypo (70mg/dl)
b) moderate hypo (55mg/dl)
c) severe hypo (40mg/dl)
Basically stimulation of glucose utilisation and inhibition of glucose release: Alcohol excess (GNG inhibited at level of LD), insulinoma (beta cell tumour activates glucokinase), excessive exercise (increses glucose utilisation), reactive hypoglycaemia (in response to high carb meal due to excessive insulin secretion), T1 diabetes (high insulin doses e.g. inject but miss meal)
a) autonomic symptoms: trembling, palpitations, sweating, anxiety, hunger, tingling
b) autonomic and neuroglycopaenic symptoms: difficulty concentrating, confusion, weakness, drowsiness, dizziness, vision changes, difficulty speaking, tired
c) confusion, disorientation, convulsion, seizures, loss of consciousness, death
What ‘stress hormones’ are secreted during prolonged hypoglycaemia, and what do they do?
What are the serious consqeuences of prolonged hypoglycaemia?
Growth hormone, cortisol - decrease rate of glucose utilisation by most cells converting to fat utilisation
Related to neuroglycopaenia (shortage of glucose for brain), may produce permanent brain damage, loss of congnitive function, seizures, coma. REQUIRES ASSISTANCE AND IS DIABETIC EMG!
What are 2 chronic complications of diabetes?
Excess glucose divered to other pathways. Give 2 examples.
Hyperglycaemia: macrovascular (atherosclerosis due to glycated protein modification of oxidised LDL receptor = high uptake of LDL into vessel -> plaque formation - CDV events), microvascular (kidney disease, nerve disease, blindness (retinopathy), amputation.
Dyslipidaemia: ectopic fat deposition in skeletal muscle and liver and exacerbation of insulin resistance, macrovascular complications
1) Hyperactivation of PKCs can damage blood vessels: increased permeability, occlusion, ROS levels, inflammation, and mitochondrial dysfunction.
2) Proteins can also undergo advanced glycation -> mediates cellular damage e.g. reduce attachement of beta cells to matrix
What is diabetes retinopathy?
What are the 2 types?
Microcomplication of diabetes, occurs after 20yrs of poorly controlled, Disease of retina involving damage to blood vessels in back of eye.
Non-proliferative: dilation of retina veins, microaneurysms -> internal hemorrhaging and odema in retina (mian cause of vision loss)
Proliferative: fragile new BVs near optic disc, grow on vitreous chamber and elsewhere in retina, can bleed, reduce vision and cause seperation and detachment of retina areas
Microvascular Complications
What is diabetes nephropathy?
What is diabetes neuropathy? What are the 4 different forms?
Glucose accumulation -> damage to glomerulus BV. Get proteinuria, glomerular hypertrophy, decreased GFR and renal fibrosis. Leading cause of end-stage renal disease.
Damage to nerve fibres and BVs supplying nerves. Peripheral (pain/feeling loss in hands, feet etc.), Proximal (pain in thighs and hips, legs weak), Autonomic (digestion changes, bowel/bladder problems, ED, heart nerves), Focal (affect any nerve in body -> pain and weakness)
List some macrovascular complications.
Nutrient supply to tissues and O2 supply to heart, brain and extremities compromised. Stroke. Heart disease. Peripheral vascular disease (ulceration, gangrene, amputation)
