Monogenic diabetes: An evidence-based clinical approach

Table 3 Conditions that can be mistaken for monogenic diabetes, the impact of misdiagnosis, and the clinical clues for suspecting appropriate diagnosis

	Stage of life	Misdiagnosis	Clinical clues	Impact of accurate diagnosis on the management plans
HNF1A and HNF4A related diabetes	Neonate and infancy	Congenital hyperinsulinism	Transient neonatal hypoglycaemia (diazoxide discontinued in the first decade in the majority). Progresses to hyperglycemia (usually < 25 years); Association with Fanconi syndrome; Family history of diabetes; Macrosomia independent of glycaemic control (HNF4A-MODY is a more likely cause than HNF1A-MODY)	Treatment with diazoxide; Natural history differs from other causes of congenital hyperinsulinism
	Childhood and adolescence	T1DM	Islet antibodies absent within 3-5 years of diagnosis	Stop insulin; Treat with low-dose sulfonylurea (respond initially); use other antidiabetics as necessary; avoid SGLT2i in HNF1A-MODY
			Diabetic ketoacidosis is usually absent even when omitting insulin; serum C-peptide > 0.6 ng/mL (> 0.2 nmol/L) after 3-5 years of onset; low insulin requirement (< 0.5 U/kg/day)
	Adults	T2DM	Absence of features of insulin resistance; BMI in the normal range	Treat with low dose SU (respond initially); use other antidiabetics as necessary; avoid SGLT2i in HNF1A-MODY; Aim to reduce CVD risk despite normal lipids in HNF1A-MODY
	Pregnancy	GDM	Insulin is recommended therapy, consider additional glyburide if control inadequate, especially in 1st trimester	Treat with insulin, fetal growth surveillance from 26 weeks
GCK related diabetes	Childhood and adolescence	T1DM	Stable nonprogressive mild fasting hyperglycemia; islet antibodies absent within 3-5 years of diagnosis; diabetic ketoacidosis absent on omitting insulin; strong family history	Stop insulin; pharmacological intervention is not needed
	Adults	T2DM	Stable nonprogressive mild fasting hyperglycemia; no features of insulin resistance or obesity; strong family history	Pharmacological intervention is not needed; screening for microvascular and macrovascular complications is not indicated
	Pregnancy	GDM	Stable nonprogressive mild fasting hyperglycemia; Minimal rise in plasma glucose levels after oral glucose or food	Insulin if the fetus does not have the mutation; no treatment if the fetus carries the mutation
Neonatal diabetes mellitus	Neonate and infancy	T1DM	Negative autoantibody testing; Extra-pancreatic features (gastrointestinal anomalies, congenital defects, and neurological disorders); unusual family history; small for gestational age	Should be transitioned to high-dose sulfonylurea from insulin
Mitochondrial diabetes	Adults	T2DM	Maternal inheritance; associated sensorineural hearing loss or progressive external ophthalmoplegia at an early age	Oral antidiabetics; may require insulin later; avoid metformin

MODY: Maturity-onset diabetes of the young; SU: Sulfonylurea; T1DM: Type 1 diabetes mellitus; T2DM: Type 2 diabetes mellitus; BMI: Body mass index; SGLT2i: Sodium-glucose co-transporter-2 inhibitor; GDM: Gestational diabetes mellitus; CVD: Cardiovascular disease.