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DIABETES (Diabetes mellitus = a condition associated with an elevated…

- - - - alpha cell secretes glucagon
      - beta cell secretes insulin
      - delta cell secretes somatostain
        
        suppresses secretion of other hormones and can be used therapeutically
      - F cell secretes pancreatic polypeptide
    - - glut2 glucose transporter allows glucose to enter the cell where it is metabolised by glycolysis and the TCA cycle to produce ATP. the ATP produced closes an ATP-sensitive K channel sitting on the surface of the beta cell. This causes membrane depolarisation so a voltage gated calcium channel opens - calcium influx causes exocytoosis of insulin-containing vesicles - INSULIN IS SECRETED
      - in response to ingestion of food, stored insulin is released first, followed by newly synthesised insulin - this gives a biphasic response of insulin secretion
        
        second release occurs in the case of a prolonged glucose stimulus
      - C-peptide can be used as a measure of endogenous insulin secretion in people with diabetes (synthetic insulin doesn't contain any C peptide)
      - INSULIN IS THE HORMONE OF STORAGE I.E. ANABOLIC -
        increases glucose uptake in fat and muscle
        increases glycoge storage in liver and muscle
        increases amino acid uptake in muscle
        increases protein synthesis
        increases lipogenesis in adipose tissue
        increases cell proliferation
        decreases gluconeogenesis from 3 carbon prescursors
        decreases keotgenesis in the liver
        
        mytogenic hormone i.e. high insulin is linked to increased levels of cancer
        
        insulin causes the translocation of GLUT4 glucose tansporters - they are insulin-dependent i.e. only bring in glucose in the presence of insulin from the cytoplasm to the cell-surface membrane
        
        the liver makes glucose via gluconeogenesis and contains a lot of stored glycogen, glucose comes in via diet, kidneys make a tiny contribution to gluconeogensis, tissues use glucose as predominant energy source, brain uses a substantial amount
        
        there is a constant flux of glucose coming in/being stored/used
        
        3-carbon precursors = alanine, pyruvate, lactate, glycerol
        
        cortisol, GH, adrenaline etc all antagonise insulin so that the breakdown of glycogen in muscle is optomised during exercise - COUNTEREGULATORY HORMONES
        
        blood glucose is maintained within a narrow range by homeostatic mechanisms for optimal functioning of the brain, maintenance of energy source for most tissues, integrity and health of blood vessels
        
        insulin resistance is a poorly understood mechanism - the problem is somewhere in the cascading second messenger system so failed translocation of GLUT4 to the cell surface - may be inherited - usualy due to single gene mutations
        
        very very rare but severe insulin resistance syndromes - leprechaunism, rabson-mendenhall syndrome, type a insulin resistance
        
        biggest worldwide cause is obesity - particularly central as central adipose is much more metabolically active
  - - - cpmmonest cause = autoimmunity to insulin, targetted T and B lymphocytes towards the beta cells in the pancreas leading to autoimmune destruction
      - no insulin at all is produced in true type 1 diabetes
  - - - 2hr plasma glucose in OGTT or random plasma gluocse >11,1mmol/L
        
        currently the gold standard test for diabetes - sued to assess the state of glucose tolerance - 75g oral gluocse load with no restriction or modification of carb intake for 3 days, fast overnight, test in morning while seated no smoking, blood samples taken at 0 and 2 hours
      - HBA1c >48mmol/mol
        
        glycosylated haemoglobin - glucose binds to haemoglobin in proportion to the levels of glucose in your blood - a marker of the quality of glycaemic control over 120 days (lifetime of RBC)
        
        rate of formation of glycated haemoglobin is directly proportional to ambient blood glucose concentration
        
        blood sample can be taken at any time of day, irrespective of food consumption
        
        normal <41
        
        pre-diabetes 42-47
        
        should not be used as a diagnostic test in some situations -
        
        rapid onset of diabetes, suspected type 1 diabetes/children/drugs, pregnancy as glucose levels can rise rapidly and H1AC is lower, condtions where red cell surivavl may be reduced or increased, renal dialysis - redcued Hba1c especially fi treated with erythropoetin, iron and vitamin b12 deificiency
    - - type 2
        
        most common form of diabetes
        
        risk factors = genetics, race, increasing age, central obesity, low birth weight
        
        most genes involved relate to beta cell function or mass rather than obesity/insulin resistance
        
        type 2 diabetes is more common with age as we generally put more weight on, pancreatic function declines with age as amyloid and other proteins are gradually deposited in beta cells so they can't function as well
        
        classical presentations of type 2 diabetes
        
        asymptomatic - found on rotuine screening
        
        osmotic symptoms - thirst, polyuria
        
        malaise, chronic fatigue
        
        infections e.g. thrush, boils
        
        blurred vision
        
        complication as the presenting problem e.g. retinopathy, neuropathy
        
        metabolic syndrome
        
        central obesity, high blood pressure, high triglycerides, low HDL-cholesterol, insulin resistance
        
        other medical disorders associated with type 2 diabetes -
        
        obstructive sleep apnoea, polycystic ovarian disease, hypogonadotrophic hypogonadism, NAFLD
      - the pancreas can initially compensate for slight insulin resiatnce - blood glucose levels may rise but still be within normal limits
      - type 1 diabetes -
        
        typical presentations -
        
        polyuria, thirst, fatigue, malaise, weight loss, blurred vision, nausea, vomiting
        
        usually acute presentations - not asymptomatic
        
        usually commences at young age - usual presentation is in childhood, adolesence or young adulthood, can present any age, short histroy of florid osmotic symptoms and rapid weight loss, ketonuria/ketonaemia usually present, high risk of metabolic decompensation - ketoacidosis
        
        pathogenesis -
        
        genetic predisposition - HLA haplotypes (HLA-DR, HLA-DQ) as risk alleles
        
        environmental trigger
        
        autoimmune mechanism activated - destruction of pancreatic beta cells
        
        associated autoimmune disorders -
        
        thyroid disease, pernicious anaemia, coeliac disease, addison's disease, vitligo
      - secondary diabetes
        
        exocrine pancreas disorders
        
        pancreatectomy
        
        trauma
        
        tumours
        
        endocrinopathies - GH/adrenaline/cortisol excess tumours
        
        drugs e.g. glucocorticoids
        
        monogenic diabetes
        
        MODY
        
        maturity-onset diabetes of the young
        
        early-onset diabetes
        
        not insulin dependent
        
        autosomal dominant inheritance
        
        obesity unusual
        
        caused by a single gene defec altering beta cell function
        
        not ketoacidotic
        
        1-2% of type 2 diabetes
- - - - lifestyle changes with dietary modificatyion and exercise delays proression of glucoe intolerenance to type 2 diabetes
    - - glycaemic index is a measure of change in blod=od glucose following ingestion of a particular food - different carbohydrate-containing foods can be ranked by their effect on post-prandial glycaemia
      - low GI foods produce a slow, gradual rise in blood glucose after ingestion
        
        e.g. starchy foods, pulses
        
        aim for low glycaemic index foods
    - - 45-60% unrefined, complex carbohydrate, <35% monounsatured fat, 10-15% protein, high intake fo dietary fibre, low intake of salt
    - - insulin dosage adjustment is based on carbohydrate content of meals
  - - - stimulate secretion of endogenous insulin
      - used in non-obese pateints (may be insulin-deficient)
      - used as a monotherapy, or in combination with metformin, glitazone, insulin
      - choice is based on duration of action and method of elimination
      - promote weight gain
      - main adverse effect is hypoglycaemia
    - - decreases hepatic glucose production
      - encourages weight loss
      - increases insulin sensitivity in muscle
      - effective as monotherapy or in combination with sulfonylurea, glitazone, insulin
      - side-effects include nausea and diarrhoea
      - side effects tend to occur at the beginning of treatment
      - contraindicated in renal impairment due to the risk of lactic acidosis
    - - insulin secretagogues - direct effect on beta cells
      - stimulate rapid endogenous insulin release when given with meals
        
        convert high glycaemic index foods into lower glycaemic index foods
      - side effects include weight gain and hypoglycaemia, but lower risk than sulfonylureas
    - - delay digestion of carbohydrate and slow down post-prandial absorption of glcuose
      - do not cause weight gain
      - limited efficacy, can be used in combination
      - GI side effects are common - bloating, flatulence
      - SGLT2 inhibitors - sodium-glucose cotransporter inhibitors- act as a glucuretic to remove glucose that would otherwise be reabsorbed
        
        canagliglozin, dapaglifoxin, empaglifoxin
    - - PPAR-gamma activation in fat reduces insulin resistance in liver and muscle
        
        small insulin-sensitive adipocytes - lipolysis reduced,adiponectin production raised, lowers plasma FFA, increases plasma adiponectin - so reduce TG redcues glucose output by the liver and increases glucose uptake by muscle
        
        slow onsetof action - take 2-3months to achive maximal effects becasue act on nuclear receptors for gene expression/protein synthesis
        
        promote peripheral weight gain, but redistribute body fat to reduce visceral depot
        
        contraindicated in congestive heart failure and hepatic ipairment - may cause fractures
    - - GLP1 glucagon-like peptide 1 GLP1
        
        potent insulinotropic hormone is released in response to meals
        
        rapidly degraded in plasma by enzyme DPP4 dipeptidyl peptidase 4
        
        plasma GLP1 is lower in people with impaired glucose tolerance and in type 2 diabeets compared to healthy non-diabetic subjects
        
        product of proglucagon gene of the intestinal L cells
        
        stimulates glucose-dependent insulin secretion, suppresses glucagoen secretion, slows gastric emptying, redcues food intake - positive effects on weight, improves insulin sensitivity
        
        exenatide - incretin mimetic, synthetic exedine
        
        act like a GLP1 peptide, have to be given by injection, promote weight loss, given in combination with either metformin or sulfonylurea, main side effect is nausea
        
        GLP-1 analogue = liraglutide
        
        gliptins = DPP4 inhibitors - increase natural endogenous GLP1 levels circulating in the blood (not generally as effective as GLP1 analogues)
        
        oral route of admin, taken in combination with metformin, weight netural, few side effects
  - - - types and formulations of insulin
        
        short-acting - soluble, actrapid
        
        intermediate-acting - isophane
        
        insulin analogues are based on human insulin but with substitution of a single amino acid in the insulin chain
        
        which amino acid alters the time-action profile
        
        peak effect mimics gastric emptying time
        
        basal bolus (multiple injection) - short/fast acting insulin before meals, intermeditae/long acting once daily
        
        lipohypertrophy at insulin injection sites - slows down insulin absorption, resolves if the site is avoided
        
        side-effects -
        
        hypoglycamiea
        
        sweating, palpitations, trembling, hunger, dizziness
        
        mismatch occurs between plasma iinsulin and glucose concentrations
        
        admin of too much insulin, inadequate consumption of food, increased phsyical exercise, alcohol without food
        
        treatment of hypoglycaemia
        
        mild=self-treated - oral fast-acting carbohydrate, supplementary snack
        
        severe=external help required, parenteral therpay, oral therapy
        
        morbidities -
        
        weight gain
        
        lipodystrophy at injection sites
        
        peripheral oedema (salt and water retention)
- - - - excessive loss of body water is usually just a nuisance if thirst is intact, but is dangerous when it is not
    - - problems can arise from -
        
        Inadequate ADH action = Diabetes inspidus
        
        inappropriately dilute urine and high urine volume = hypotonic polyuria
        
        this excessive water loss results in hypernatraemia
        
        may be due to -
        
        cranial DI = inadequate ADH release (can rarely be congential, but is usually from pituitary/hypothalamic disease and can follow surgical treatment for disease, head injury, or intracranial infection
        
        nephrogenic DI = renal insensivity tyo ADH (rarely this is congenital, usually acquired from hypercalcaemia, hypokalaemia, or accompanying obstructive uropathy, chronic renal failure, or treatment with lithium or demeclocycline)
        
        Treatment -
        
        cranial DI = give DDAVP (nasal, rhynyl, tablets)
        
        nephrogenic DI = thiazide and/or amiloride diuretics paradoxically reduces urine output
        
        add indomethacin to lower intrarenal prostaglandins those oppose ADH - this can limit urine volume
        
        advise limit high salt diet to lower urinary osmoles and thus urine volume
        
        partial DI - occasionally medications which can promote SIADH e.g. chlorproamide which may upregulate renal ADH receptors and sensitivity
        
        can get gestational DI in preganncy
        
        ADH action in excess of needs of water balance
        
        this results in excessively concentrated urine and moderate body water excess with hyponatraemia caused by -
        
        non-osmotic i.e. appropriate release - to severe hypotension or hypovolaemia e.g. haemorrhage (this is the vasopressin side of ADH action)
        
        physiologically inappropriate excessive ADH release/responsiveness = SIADH
        
        causes can be intracrnaial, intrathoracic, drugs e.g. chlorproamide, bendroflumethiazide, some sedatives, nicotene, severe ACTH or thyroid hormone deficiency, pain
        
        causes of hyponatraemia =
        
        is the patient dehydrated? if yes, body Na+ depletion is likely
        
        check urinary Na osmolatrity - may indicate inappropriately high sodium loss in urine (adrenal insuffiency, salt wasting renal disease, diuretic excess, hypomagnesiaemia etc)
        
        if the patient is oedematous then treat this condition e.g. cardiac/liver failure
        
        if none of these are the case = SIADH - this is shown by demonstarting inappropriately concentrated urine with coexisting hyponatraemia and/or low plasma osmolarirt
        
        TREATMENT -
        
        restrict fluid intake
        
        occasionally demeclocycline is required (induces partial nephrogenic DI)
        
        AVP receptor blockers e.g. tolvaptan
        
        care must be taken to avoid rapid correction of hyponatraemia and it is best if plasma Na+ rises toward the normal range at <10mmol/L/day
  - - - DI (cranial or nephrogenic)
        
        We must check to see if the criteria for DI are met i.e. that the polyuria is inappropriately hypotonic even when the plasma is hypertonic - thus DI may be excluded by finding a urine osmolartiy of >600, but to confirm DI a water deprivation test is often needed. Cranial DI will respond to administration of an ADH-like drug e.g. DDAVP, but nephrogenic DI will not
      - habitual/psycogenic
      - osmotic diuresis e.g from glucose, mannitol, hypercalcaemia
      - renal impairment
  - - - maintain blood volume and circulation - role at a high concentration
        
        on vascular smooth muscle and heart - vasocontriction and hypertrophic changes
    - - role in ACTH release and stress responses
        
        expressed on anterior pituiatry
    - - appropriate retention of water to maintain osmolarity
        
        distal neprhon
- - - - generally occuring 10 y after onset, morbidity is falling due to the UK retinal screening programme, meas diabetes is no longer a common cause of blindness, thickening of the basement membrane and loss of embedded pericytes, increased capillary permeability, diabetic macular oedema, also cataracts accelerate and premature
        
        backrgound = microaneurysms, hard exudates, haermorrhages(dot, blot fame)
        
        pre-proliferative - cotton wool spots, venous abnormalities, dilation, bleeding
        
        prolfierative = neovascularsation, and if advanced vitreous haemorrhage, tractional retinal detchment andrebeotic glaucoma
        
        managemnet
        
        panretina photocoagulation
        
        tiny laser is used to make bruns that stop retinal vessels from leaking
        
        optimal coherence tomograhy
        
        anti-VEGF e.g. ranibizumabn
        
        cataract operations
    - - hyperglycaemia, hypertension, smoking, age/duration of diabetes, genetic/familial factors/ethnicity