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Clinicians should consider and investigate: Vitamin B12 deficiency (particularly in metformin userscheck serum B12) Hypothyroidism (check thyroid function) Chronic kidney disease (check renal function and eGFR) Alcohol excess Medication-related neuropathy Urgent referral criteria per NICE NG19: Same-day referral to the multidisciplinary foot care service for new ulceration, signs of infection, or suspected active Charcot arthropathy Emergency hospital admission for suspected sepsis, acute limb-threatening ischaemia, or deep-seated soft tissue or bone infection Treatment and Management Options in the UK Management of diabetic neuropathy encompasses both disease-modifying strategies targeting the underlying metabolic dysfunction and symptomatic treatments addressing neuropathic pain and functional impairment

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Lifestyle factors amplify adaptation effects: consuming calorie-dense foods despite reduced hunger, relying on liquid calories that bypass satiety signals, or eating too quickly can override medication benefits

Furthermore, the inherent limitations of transgenic animal models must be acknowledged