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Diabetes Mellitus (T1DM (Diagnosis (History, Physical, Investigations,…

- - - - 1) Exercise
        Type: combined resistance & aerobic exercise;
        
        Aerobic: 5d/wk, 150min/wk, mod-vigorous intensity 10min intervals
        
        Resistance: ≥2d/wk
        
        No more than 2 consecutive days without activity
        MOA: blocks insulin action; insulin independent ￪GLUT4 translocation, ￪supply/perfusion to muscle, ￪glucose demand=use BG & glycolysis, ￪insulin sensitivity; epinephrine/catecholamines release during exercise have inhibitory effect on pancreatic insulin secretion; overall mobilization of fuel
        NB: even if cannot lose weight, exercise still has independent risk reduction for T2DM
      - 2) Diet modification
        
        Reduce sugary beverages
        
        DASH/Mediterranean
    - - 1) α-glucosidase inhibitor
        Prototype: acarbose
        MOA: Glucosidases cleave oligo/disaccharides into monosaccharides to be absorbed in small intestine; AGI (saccharide analogue, with greater affinity than glucose) reversibly inhibits glucosidase ∴ delay absorption, reduces post-prandial BG spike; Acarbose inhibits α-amylase
        PK: Acts locally in GI tract, minimal systemic bioavailability (2%)
        Indications: T2DM ⟶ post-prandial hyperglycaemia; new onset/mild hyperglycaemia
        Contraindications: IBS, IBD ⟶ AGI has GI Sfx, may exacerbate
        Sfx: GI⟶flatulence, bloating, abdo discomfort, diarrhea (due to bacterial action on undigested CHO ⟶ generate gas
        NB: AGI considered addition to other anti-diabetic Rx (not first line)
      - 2) Biguanides
        Prototype: metformin
        MOA: (proposed) actions on: ①Liver: ￬gluconeogenesis (via ￪AMPK), inhibition of mitochondrial respiratory chain at complex 1; ②Muscles/Fat: ￪action of insulin (via ￪AMPK); ③GI: ￬glucose absoprtion; ④Pancreas ￬ glucagon; ⑤￪ glycolysis in tissues in general
        PK: not metabolized, excreted in urine unchanged (renal clearance via tubular secretion)
        Contraindications: Metabolic acidosis, renal impairment (￬resulting in lactic acidosis)
        Sfx: Abdo pain, nausea, diarrhea (?mechanism); ￬absorption of B12 & folate (?mechanism) ￪effect with ￪ dose/duration; hypoglycaemia rare (does not stimulate insulin)
        NB: can be used to tx PCOS/hyperinsulinaemia, independent CV benefit beyond glucose lowering, ￬microvascular complications
      - 3) Incretins
        Prototypes: ①GLP-1 analogues/incretin mimetics tide: liraglutide, executide; ②DPP-4 inhibitors gliptin: sitagliptin, saxagliptin, alogliptin, linagliptin
        MOA: ①GLP-1 & GIP both lower BG and stim insulin release, GLP-1 also ￬glucagon release, delays gastric emptying and regulates β-cell growth; ②DPP-4 inactivates GLP-1 & GIP ∴ DPP-4i prolongs activity of incretins
        Contraindications: none of major sig; but safety of sitagliptin in pregnancy not established
        Sfx: generally well tolerated, can be immunogenic - hypersensitivity response; GLP-1 analogues can have weight loss, nausea/vomiting
        NB: Insulin secretion gluose po>glucose iv and the effect of po glucose on insulin secretion is called incretin effect
      - 4) Insulins
        Prototypes: ① short acting - insulin R (regular), insulin aspart insulin lispro, insulin glulisine; ② intermediate acting - neutral protamine Hagedorn (NPH) insulin, insulin lente; ③ long acting - insulin ultra-lente, insulin glargine (AKA brand Lantus), insulin protamine zinc, insulin detemir
        MOA: ①￪ glucose uptake by cells via GLUT4 (muscle and adipose) ②￪glycogen synthesis, ￬glycogenolysis (muscle and liver) ③￬gluconeogenesis (liver) ④￪amino acid uptake, ￪protein synthesis (muscle) ⑤￪TG synthesis ￬lipolysis (adipose); ⑥binds IGF-1 receptor for growth promoting effect
        PK: Insulin is a peptide∴cannot take po, usually sc
        ① short acting: 10-15min onset, 1-2hr peak, 3-6.5hr duration
        ② intermediate acting: 1-3hr onset, 5-8hr peak, ≤18hr duration
        ③ long acting: 1.5-6hr onset, 16-20hr peak, 24-30hr duration
        but considerable inter-individual variability and unpredictability in the time to peak hypoglycaemic effect. slower onset=slower absoprtion=larger crystal size
        Indication: T1DM, T2DM
        Contraindications: None of major sig
        Sfx: Hypoglycaemia; lipidystrophy (localized atrophy of sc fat or enlargement (lipoatrophy or lipohypertrophy); edema (Na retention)
        NB: 1 unit of insulin = amount required to lower blood glucose to 2.5mM in a fasting rabbit (from historical); most preparations 25-30units/mg, supplied in concentrations of 100units/mL=3.6mg/mL
      - 5) Insulin secretagogues
        
        5a) Meglitinide
        Prototype glinide: Repaglinide, nateglinide
        MOA: stimulate insulin secretion via sulfonylurea receptor SUR1 (causes depolarization by stopping K+ efflucx, causing Ca2+ influx via VGCC thus causing insulin release); relys on functioning β cells (∴ not useful for T1DM)
        PK: Rapid, complete absorption, peak plasma concentration <1hr post po admin, metabolized in liver (need dose adjustment if impaired liver function), short elimination half-life (1-2hrs); Nateglinide acts more quickly than rapaglinide and has a shorter duration of action, food will ￪absorption of nateglinide (min. impact on repaglinide); administer just before meals (rapid onset&offset)⟶post-prandial hyperglycaemia indications
        Contraindication: Concomitant gemfibrozil (fibrate, can be used to manage cholesterol ∴ risk of co-admin) and repaglinide (gemfibrozil sig reduces repaglinide leads to up to ￪8x repaglinide levels ⟶ hypoglycaemia
        Sfx: hypoglycaemia - less common than with sulfonylureas, ~1%; weight gain (greather than metformin)
        NB: useful for post-prandial hyperglycaemia management, allows for flexible in choosing meal times (can be taken just before eating) adv over sulfonylurea as less flexibility; Repaglinide more effective at lowering HbA1c levels than nateglinide
        
        5b) Sulfonylurea
        Prototype 1st gen amide: tolbutamide, chlorpropamide, tolazamide, acetohexamide
        Prototype 2nd gen ide: glyburide, glipizide, glimepiride
        MOA: stimulate insulin secretion via SUR-1 on β cells; reduce glucagon levels (?mech by increasing insulin and somatostatin)
        PK 2nd gen: short half life (3-5hr); all sulfonylureas metabolized by liver, excreted in urine (small proportion excreted unchanged)∴dose adjustment if hepatic impairment, caution with renal impairment
        Contraindications: None of major sig; ?pregnancy (GDM should not be treated with sulfonylurea, use insulin)
        Sfx: Hypoglycaemia-caused by oversecretion of insulin, more frequent with glyburide; Flushing-when taken with EtOH, more common with 1st gen; Weight gain- ￪insulin action on adipose(less frequent with 2nd gen); Haemotologic toxicities-rare, anaemia, thrombocytopaenia (esp w chlorpropamide)
        NB: Due to concerns of hypoglycaemia, esp w glyburide, sulfonylureas should be initiated at low dose, carefully observed for changes in BG over first few weeks of therapy; Irregular diets, EtOH excess increase risk of hypoglycaemia; Hypoglycaemic effects diminish with time, likely due to progressive loss of β-cells ∴ ￬ response
      - 6) Thiazolidinediones TZD
        Prototype glitazone: Rosiglitazone, proglitazone
        MOA: PPAR-𝛄 agonists; PPAR-𝛄 receptors in nucleus of muscle, fat, liver⟶has role in regulation of genes for lipid and protein metabolism, insulin signal transduction and adipocyte/tissue differentiation⟶①Adipose: ￪uptake and storage of FFA, (￬FFA release) ②Muscle&Adipose: ￪expression & translocation of GLUT4 ③Liver: ?mech ￬gluconeogenesis; PPAR agonism also ￬inflammatory cytokines, ￪adiponectin (stimualte glucose uptake in muscle, protect against atherosclerosis by stabilizing plaques, ￬endothelial apoptosis)
        PK: rosiglitazone-peak plasma 1hr after administration, absorption not affected by food; pioglitazone-peak plasma 2hr; TZD metabolized by CYP450: rosiglitazone-CYP2C8(major)/CYP2C9(minor); pioglitazone-CYP2C8(major)/CYP3A4(minor) [beware of drug interactions with CYP450)
        Contraindications: Heart failure; not for GDM/breastfeeding(secreted into breast milk)
        Sfx: weight gain (redistribution of adipocytes from visceral to subcutaneous; edema (TZD promote retention of Na, water by upregulating tubular transporters for Na and ￬GFR); CVD (heart failure likely due to edema, CHF, myocardial ischaemia both reported with rosiglitazone); fractures (TZD impair osteoblasts, ￪fracture rate observed in F pt)
        NB: pioglitazone ￪HDL (variable effects on LDL, TG; less benefit with rosiglitazone)
      - 7) SGLT2 Inhibitors
        Prototype gliflozin: Empagliflozin, canagliflozin, dapagliflozin
        MOA: sodium-dependent glucose transporter SGLT2 reabsorbs glucose in proximal tubule, SGLT2 inhibitors prevent reabsorption ∴￪urinary glucose excretion (~60-100g/day)
        PK: rapid oral absorption, long elimination half life (od administration), hepatic metabolization
        Contraindications: CKD eGFR<45 empagliflozin, canagliflozin; eGFR<60 dapagliflozin
        Sfx: polyuria, volume depletion, hyperkalemia, euglycaemia DKA(rare)
        NB: easy to administer, promotes weight loss, diuretic (￬BP), low risk of hypoglycaemia
    - - Complications
        
        Chronic
        
        Microvascular
        
        Renal:
        
        Diabetic nephropathy
        
        Infection
        ↳Pyelonephritis
        ↳Perinephric abscess
        ↳Renal papillary necrosis
        
        Renal tubular necrosis (post contrast dye)
        
        Diabetic nephropathy most common, but clues suggesting non-diabetic renal disease:
        
        onset of proteinuria <5yrs from Dx; acute onset; urine RBC casts/cellular casts/acanthocytes; ssx of systemic disease; significant ￬GFR (>30%) within 2-3mo initiation ACEi or ARB
        
        Tx: ensure adequate glycaemic control; good BP control (<130/80mmHg) with ACEi or ARB; manage hyperlipidaemia; RRT/transplant if progress; screen BP each visit, UACR/serum Cr q yearly
        
        NB causes of transient proteinuria
        
        febrile illness; UTI; recent major exercise; decompensated CHF; menstruation; acute severe ￪BP or ￪glucose
        
        Nervous system:
        
        Diabetic neuropathy
        
        Stocking-glove distribution/length dependent sensory polyneuropathy (bilateral, distal foot, moving proximal. Starts in hands usually when ascended from foot to knee)
        
        Can progress to motor neuropathy (foot/wrist drop, CN neuropathy, mononeuropathy multiplex)
        
        Autonomic neuropathy (postural hypotension, resting tachycardia, loss of sweating, GI neuropathy, gastroparesis, urinary bladder atony, impotence
        
        Most common is symmetric sensory polyneuropathy
        
        can lead to complications (ulcers, charcot arthropathy dislocation, stress fracture, amputation
        
        Tx: ensure adequate glycaemic control, pain control (TCA amitriptyline, topical capsaicin cream, gabapentin/pregabalin), and foot care
        
        Eye:
        
        Diabetic retinopathy ± macular oedema
        ↳Non-proliferative: microaneurysms, dot haemorrhages, exudates, retinal oedema
        ↳Proliferative: fibrous tissue, capillary/angiogenesis in retina and into vitreous chamber
        ↳Tx: pan-retinal photocoagulation (severe non-prolif; prolif); vitrectomy (severe prolif w/ vitreous haemorrhage ± macular traction); intravitreal anti-VEGF (if clinically sig macular oedema)
        
        Cataracts
        ↳subcapsular
        ↳nuclear
        
        Glaucoma
        
        Macrovascular
        
        Cerebrovascular
        
        ￪risk ischaemic stroke with DM
        
        stroke outcomes worse in DM pt
        
        ￪hospital and long term stroke mortality; ￪residual neurological/functional disability; ￪LOS
        
        Peripheral Vascular
        
        ischaemia of lower extremities; impotence; intestinal angina
        
        Prevalence amputation in DM ~3%; incidence of gangrene of foot ￪30x compared to age matched controls
        
        Assess peripheral pulses, cap refill, temperature, atrophy
        
        ABI:Ⓝ>0.9-1.2, Claudication=0.5-0.9, Ischaemia=<0.5
        
        Compare R ankle:R brachial, L ankle:L brachial, lowest = ABI
        
        Statin therapy recommended to ￬CV risk in T1/2DM if clinical macrovascular disease; age≥40yo; if age<40yo and one of : DM Hx> 15yr and age≥30yo; microvascular complications; other reasons for tx
        -Tx target LDL≤2.0mM
        
        Cardivascular
        
        Ischaemic heart disease or cardiomyopathy
        
        ￪Risk of MI in DM
        
        ￪mortality risk in DM with or without prior MI
        
        T2DM Hx>15yr has same CV mortality risk as non-DM with prior MI
        
        Diabetic Foot
        
        Both neuropathy and angiopathy lead to foot ulcer/infection, risk for amputation
        
        Hx prior foot ulcer is strongest RF/predictor for future DFU
        
        Foot assessment:
        
        appearance (colour, nails, symmetry, swelling, deformities)
        
        skin (absence of hair, colour, thickness, dryness, cracking, calluses, blistering, infection, ulceration)
        
        assess circulation
        
        assess sensation (10g monofilament + either vibration, proprioception
        
        Footcare advice:
        
        see MD if neuroapthy/any foot problems occur
        
        check feet for cuts, blisters, redness, swelling od
        
        wash feet & dry esp b/w toes od
        
        use lotion to prevent drying/cracking od
        
        cut toenails straight to prevent ingrown nails
        
        always wear socks (white) & well-fitting shoes
        
        never walk barefoot
        
        smoking cessation
        
        Acute
        DKA↲
        HHS↲
        Hypoglycaemia↲
        
        Hyperosmolar Hyperglycaemia Syndrome
        AKA Non-ketotic hyperosmolar hyperglycaemia
        Typically T2DM
        Manifestation: characterized by profound dehydration, ￪osmolar state, ￪￪￪BG along with hypernatraemia, ￪/N ketones, often ￬LOC or coma
        O/E: Hypotension, tachycardia, altered mental status, ⊖Nausea/Vomiting/Abdo pain,⊖Kussmaul, ⊖ acidosis, small anion gap
        
        DKA
        Typically T1DM
        Definition:
        relative/absolute insulin deficiency + counterregulatory hormone excess (￬ insulin:glucagon = ￪hepatic gluconeogenesis, ￪glycogenolysis, ￪ketogenesis
        Pathophysiology:
        
        Insulin deficiency⟶hyperglycaemia; ￪lipolysis; hyperglucagonaemia; ￪cortisol ⟶ ￪ketogenesis; ￪glycogenolysis ⟶ ketones = high anion gap metabolic acidosis HAGMA
        
        ⟶H + HCO3 = CO2 + H2O ⟶ ￪CO2 = hyperventilate/tachypnea + ￪depth of breathing (Kussmaul breaths)
        
        ⟶H exchanged for K ⟶ intracellular K depletion plus aldosterone effect ⟶ total body K+ depletion
        
        glucose, H2O, K+, Pi, Mg are lost through kidneys
        
        dehydration secondary to osmotic diuresis due to electolyte imbalances ⟶ ileus ⟶ vomiting ⟶ +++dehydration
        
        free water loss > Na loss ⟶ hyperosmolar state ⟶ neurons generate intracellular neurogenic osmoles to prevent neuronal degeneration
        
        Sx: Nausea, vomiting, abdo pain, polydipsia, polyuria, SOB/Kussmaul breathing
        O/E: Tachycardia, dehydration, hypotensive, tachypnea/Kussmaul/resp distress, abdo tenderness, lethargy/obtundation/coma
        Precipitating factors: Insulin (inadequate or omission), Infection (pneumonia, sepsis, UTI), Infarction (cerebral, coronary, mesenteric, peripheral), Others (Rx, pregnancy, new-onset T1DM)