Hungry Bone Syndrome

Chronic metabolic disorder characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both, leading to disturbances in carbohydrate, fat, and protein metabolism.

Classified by:

• Type 1: autoimmune destruction of pancreatic β-cells → absolute insulin deficiency; typically younger onset but can present at any age (LADA; latent autoimmune diabetes in adults)

• Type 2: progressive insulin resistance with relative insulin deficiency; strongly associated with obesity, sedentary lifestyle, genetic predisposition; majority of cases (~90%)

• Gestational diabetes: glucose intolerance first recognized in pregnancy

• Other specific types: monogenic diabetes (MODY), pancreatic disease (pancreatitis, cystic fibrosis, pancreatectomy), endocrinopathies (Cushing's, acromegaly, pheochromocytoma), drug-induced (glucocorticoids, antipsychotics, thiazides), post-transplant diabetes

• Classic osmotic symptoms: polyuria, polydipsia, polyphagia, unexplained weight loss (more prominent in T1DM)

• Fatigue, blurred vision (osmotic lens changes)

• Recurrent infections: candidiasis (genital, oral), UTIs, skin infections, slow wound healing

• T1DM: often abrupt onset, may present with DKA as first presentation (especially children/adolescents), lean body habitus

• T2DM: often insidious/asymptomatic, detected incidentally or via screening; acanthosis nigricans (insulin resistance marker), central obesity

• Chronic complications (screen at diagnosis for T2DM, 5 years post-diagnosis for T1DM, then annually):

• Microvascular: retinopathy (leading cause of adult blindness), nephropathy (leading cause of ESRD), peripheral neuropathy (glove-and-stocking distribution, risk of foot ulceration/Charcot joint), autonomic neuropathy (gastroparesis, orthostatic hypotension, erectile dysfunction)

• Macrovascular: coronary artery disease, stroke, peripheral arterial disease

• Red flags for acute decompensation: altered consciousness, Kussmaul breathing, fruity breath odor (DKA), profound dehydration with normal/mild acidosis (HHS)

Any ONE of the following (WHO/ADA criteria), confirmed on a second occasion unless unequivocal hyperglycemia with symptoms:

• Fasting plasma glucose ≥7.0mmol/L (126mg/dL)

• 2-hour plasma glucose ≥11.1mmol/L (200mg/dL) during 75g OGTT

• HbA1c ≥6.5% (48mmol/mol)

• Random plasma glucose ≥11.1mmol/L (200mg/dL) with classic symptoms

Prediabetes: fasting glucose 6.1–6.9mmol/L (impaired fasting glucose), 2-hr OGTT 7.8–11.0mmol/L (impaired glucose tolerance), or HbA1c 5.7–6.4%

Type differentiation:

• C-peptide (low/absent in T1DM, preserved/elevated in T2DM)

• Autoantibodies for T1DM: anti-GAD65, islet cell antibodies (ICA), anti-IA2, anti-insulin antibodies

• Consider MODY genetic testing if strong family history, young onset, atypical features (non-obese, negative autoantibodies)

Ongoing monitoring: HbA1c every 3–6 months (target individualized, generally <7% for most adults, less stringent in elderly/comorbid), lipid profile annually, renal function (eGFR, urine albumin:creatinine ratio) annually, dilated eye exam annually, foot exam annually (monofilament, pulses).

Differentials for new hyperglycemia: stress hyperglycemia (acute illness), steroid-induced, pancreatic pathology, endocrinopathies as above.

Type 1 DM:

• Insulin therapy is mandatory, lifelong; basal-bolus regimen preferred:

• Basal: long-acting insulin (glargine, detemir, degludec) once/twice daily

• Bolus: rapid-acting insulin (lispro, aspart, glulisine) with meals, dose adjusted by carbohydrate counting

• Total daily dose typically 0.4–1.0 units/kg/day (higher during puberty/illness)

• Insulin pump/CGM (continuous glucose monitoring) increasingly standard of care where available

• Structured education: carbohydrate counting, hypoglycemia recognition/management (15g fast-acting carbs, recheck in 15 min), sick-day rules

Type 2 DM (stepwise, per ADA/EASD):

• Foundation: lifestyle modification (diet, weight loss, exercise ≥150 min/week) at all stages

• First-line pharmacotherapy: metformin 500mg od-bd, titrate to 1000mg bd (max 2550mg/day) : unless contraindicated (eGFR <30, avoid/reduce dose if 30–45)

• Second-line/add-on (guided by comorbidities):

• Established ASCVD or high CV risk: GLP-1 receptor agonist (semaglutide, liraglutide, dulaglutide) or SGLT2 inhibitor (empagliflozin, dapagliflozin) ; proven CV benefit

• Heart failure or CKD: SGLT2 inhibitor preferred ; renal and cardiac protective

• Weight management priority: GLP-1 RA (also dual GIP/GLP-1;tirzepatide) ;substantial weight loss effect

• Cost-sensitive/no compelling comorbidity: sulfonylurea (glimepiride, gliclazide; hypoglycemia risk) or DPP-4 inhibitor (sitagliptin ; weight neutral, low hypoglycemia risk)

• Insulin initiation in T2DM: when HbA1c remains above target despite 2–3 oral agents, or symptomatic hyperglycemia; typically basal insulin added first (e.g., glargine, starting 10 units or 0.1–0.2 units/kg od, titrate by fasting glucose)

Complication-specific management:

• Nephropathy: ACE inhibitor/ARB (renoprotective, first-line if albuminuria present regardless of BP), SGLT2 inhibitor add-on for renal protection

• Retinopathy: laser photocoagulation, anti-VEGF intravitreal injections for proliferative/macular edema

• Neuropathy: pain management (duloxetine, pregabalin, gabapentin, amitriptyline); foot care education, regular podiatry

• CVD risk reduction: statin therapy (most diabetics qualify for at least moderate-intensity statin), BP control (target <130/80 in most), aspirin for secondary prevention

Monitoring targets: HbA1c individualized (<7% most adults, <8% frail elderly/limited life expectancy, tighter in pregnancy planning), BP <130/80, LDL per risk category.