New Onset Hyperglycemia

Definition and Diagnostic Criteria

Step 1: Rule Out Transient/Secondary Causes

• Acute stress (severe infections, burns, trauma, surgery) - catecholamines and cortisol oppose insulin action; diabetes diagnosis requires persistence of hyperglycemia after resolution of the acute illness
• Medications: glucocorticoids (most common), antipsychotics (especially atypical), tacrolimus/cyclosporine, thiazide diuretics, beta-blockers, statins at high dose
• Endocrinopathies: Cushing syndrome, acromegaly, pheochromocytoma, glucagonoma, primary hyperaldosteronism
• Pancreatic disease: pancreatitis (acute or chronic), hemochromatosis, cystic fibrosis, pancreatic cancer
• Gestational hyperglycemia (separate criteria apply)
• Robbins Pathologic Basis of Disease, p. 1015

Step 2: Classify the Type

Type 1 Diabetes (T1D) - ~5-10% of cases

• Autoimmune destruction of pancreatic β cells → absolute insulin deficiency
• Often younger patients (peaks at puberty), but can occur at any age
• Typically lean or normal weight, with acute symptomatic presentation
• Autoantibodies present in >90%: anti-GAD65, anti-IA-2, anti-ZnT8, anti-insulin
• HLA class II gene linkage (MHC)
• Risk of diabetic ketoacidosis (DKA) without insulin
• C-peptide: low or undetectable
• Idiopathic T1D exists (no autoimmunity detected) in a minority

Type 2 Diabetes (T2D) - ~90-95% of cases

• Insulin resistance + inadequate β-cell secretory response ("relative insulin deficiency")
• Usually adult onset, but rapidly increasing in adolescents due to obesity epidemic
• ~80% are overweight or obese; acanthosis nigricans may be present
• Insidious onset - often asymptomatic for years; many present with microvascular complications already established
• No islet autoantibodies; amyloid deposits in islets on pathology
• C-peptide: normal to elevated (early), may decline late
• No HLA linkage; TCF7L2 and other polygenic risk loci

• Age ≥45, BMI ≥25 (≥23 in Asians), family history (40% lifetime risk with one parent affected, 70% with both)
• Prediabetes, gestational diabetes history, PCOS
• Dyslipidemia (HDL <35, TG >250), hypertension
• Racial/ethnic risk: Asian, African American, Hispanic, Native American
• Long-term glucocorticoid use, antipsychotic therapy
• Sleep apnea, chronic sleep deprivation, smoking

LADA (Latent Autoimmune Diabetes in Adults)

• Autoimmune T1D presenting in adults (age >35), often misclassified as T2D
• Antibody positive (especially anti-GAD65), relatively lean, responds initially to oral agents but progresses to insulin dependence within months-years
• Check anti-GAD antibody when the presentation is atypical for T2D

Monogenic Diabetes (MODY)

• Accounts for 1-3% of diabetes diagnosed under age 30
• Autosomal dominant single-gene mutations impairing insulin secretion
• MODY2: glucokinase mutation (elevated "glucose threshold" for insulin release)
• MODY3: HNF-1α mutation (most common; sulfonylurea-responsive)
• Often misdiagnosed as T1D or T2D; suspect when: strong family history of diabetes across generations, negative autoantibodies, no obesity, no insulin resistance features

Step 3: Initial Workup

Step 4: Clinical Presentation Clues

• Polyuria - osmotic diuresis from glycosuria
• Polydipsia - compensatory response to hypovolemia
• Weight loss - breakdown of muscle/adipose; glucose lost in urine
• Fatigue, blurred vision, genital mycotic infections

Step 5: Immediate Management Based on Type

Symptomatic / Markedly Elevated Glucose (>300-400 mg/dL or ketonuria)

• Check for DKA or hyperosmolar hyperglycemic state (HHS)
• DKA: predominantly T1D; ketones ++, anion-gap acidosis, pH <7.3
• HHS: predominantly T2D; profound hyperglycemia (>600), no significant ketosis, osmolality >320
• Both require hospitalization and IV fluid resuscitation

T1D

• Insulin is mandatory - basal-bolus regimen (long-acting + rapid-acting)
• Typical starting total daily dose ~0.4-0.5 units/kg/day, divided 50% basal / 50% prandial
• Continuous subcutaneous insulin infusion (pump) is an option
• Glucose monitoring (SMBG or continuous glucose monitor)
• Check ketones when glucose persistently elevated (≥2+ indicates risk of DKA)

T2D

• Lifestyle modification first (diet, exercise, weight loss)
• Metformin is first-line pharmacotherapy (unless eGFR <30, liver disease, contrast procedure)
• Target HbA1c <7% for most patients (less strict in elderly/comorbid patients)
• Add second agent if HbA1c not at goal after 3 months:
  • Cardiovascular disease or high CV risk → GLP-1 receptor agonist or SGLT-2 inhibitor preferred
  • Heart failure or CKD → SGLT-2 inhibitor preferred
  • Weight management priority → GLP-1 RA or SGLT-2 inhibitor
• Insulin if markedly symptomatic, very high HbA1c (>10%), or failure of oral agents

Insulin Preparations (Quick Reference)

• Goldman-Cecil Medicine, Table 210-7

HbA1c Caveats