Differentiating Diabetes mellitus type 2 from other diseases

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Seyedmahdi Pahlavani, M.D. [2]Basir Gill, M.B.B.S, M.D.[3]

Overview

Type 2 diabetes mellitus must be differentiated from other disorders that may present with polyuria, polydipsia, weight loss or weight gain. Such disorders may include other forms of diabetes mellitus (e.g. type 1 DM, MODY), other endocrine disorders (e.g. hypothyroidism, cushing's syndrome, wolfram syndrome, alstrom syndrome) or drug-related disorders.

Differentiating Diabetes Mellitus Type 2 from other Diseases

• Type 2 DM must be differentiated from other forms of diabetes mellitus as well as other endocrine disorders based on the symptoms and laboratory findings. The following table shows the appropriate history and symptoms, and laboratory findings that may distinguish type 2 DM from other diseases:

Disease	History and symptoms					Laboratory findings								Additional findings
	Polyuria	Polydipsia	Polyphagia	Weight loss	Weight gain	Serum glucose	Urinary Glucose	Urine PH	Serum Sodium	Urinary Glucose	24 hrs cortisol level	C-peptide level	Serum glucagon
Type 1 Diabetes mellitus	+	+	+	+	-	↑	↑	Normal	Normal	N/↑	Normal	↓	Normal	Auto-antibodies present (Anti GAD-65 and anti insulin antibodies)
Type 2 Diabetes mellitus	+	+	+	+	-	↑	↑	Normal	Normal	↑	Normal	Normal	↑	Acanthosis nigricans
MODY	+	+	+	-	+	↑	↑	Normal	Normal	↑	Normal	Normal	N	-
Psychogenic polydipsia	+	+	-	-	-	Normal	Normal	Normal	↓	Normal	Normal	Normal	Normal	-
Diabetes insipidus	+	+	-	-	-	Normal	Normal	Normal	↑	Normal	Normal	Normal	Normal	-
Transient hyperglycemia	-	-	-	-	-	↑	↑	Normal	Normal	↑	Normal	Normal	N/↑	In hospitalized patients especially in ICU and CCU
Steroid therapy	+	-	-	-	+	↑	↑	Normal	Normal	↑	↑	N/↑	N/↑	Acanthosis nigricans,
RTA 1	-	-	-	+	-	Normal	Normal	↑	Normal	↑	Normal	Normal	Normal	Hypokalemia, nephrolithiasis
Glucagonoma	-	-	-	-	-	↑	Normal	Normal	Normal	-	Normal	Normal	↑	Necrolytic migratory erythema
Cushing syndrome	-	-	-	-	+	↑	-	Normal	↓	N/↑	↑	Normal	Normal	Moon face, obesity, buffalo hump, easy bruisibility

Differentiating Diabetes Mellitus Type 2 from other Types of Diabetes in Nonpregnant Adults

Category	Type 2 diabetes	Type 1 diabetes	Monogenic diabetes syndromes (ie, MODY)	Types of diabetes secondary to other medical conditions
Epidemiologya	90%-95%	5%-10%	<5%	<5%
Pathophysiology	Nonautoimmune progressive loss of insulin secretion from β cells, usually in the setting of insulin resistance	Autoimmune β-cell destruction, usually leading to absolute or near-absolute insulin deficiency	Rare form of diabetes caused by a variant in a single gene disrupting β-cell glucose sensing or insulin production, inherited in an autosomal dominant manner; the most common forms are GCK-MODY (MODY2; glucose-sensing defect), HNF1A-MODY (MODY3), and HNF4A-MODY (MODY1)	Many different secondary forms of diabetes exist; examples include diseases of the exocrine pancreas (such as cystic fibrosis and pancreatitis), diabetes due to endocrinopathies such as Cushing syndrome or acromegaly, or diabetes secondary to SARS-CoV-2 infection
Age at diagnosis	Usually ≥35 y but increasingly seen in youth and younger adults, especially in the setting of obesity and/or family history	Can occur in adults at any age, often with more indolent onset compared with children (termed latent autoimmune diabetes in adults)	Usually <25 y	Any age
Degree of hyperglycemia on presentation	Usually mild (blood glucose <250 mg/dL) if detected early; however, can be moderate or severe in long-standing undiagnosed diabetes	Usually moderate (blood glucose of 250-600 mg/dL); can be severe (blood glucose >600 mg/dL) in some cases	Mild; usually HbA1c <7.5% at diagnosis	Mild, moderate, or severe
Symptoms	Can be asymptomatic or with symptoms	Usually with catabolic symptoms (polyuria, polydipsia, weight loss); can be asymptomatic in adults	Usually asymptomatic	Can be asymptomatic or with symptoms
BMI	Usually BMI ≥25	Usually BMI <25, but can be diagnosed in those with overweight or obesity	Variable, but obesity usually not present	Any
Family history	Often a first-degree relative with type 2 diabetes, but not always	Sometimes a first-degree relative with type 1 diabetes or other autoimmune disease; 85% have no family history	Autosomal dominant family history, confirmed to be MODY diabetes	Not usually
Diabetic ketoacidosis	Can be seen on presentation in those with severe insulin deficiency or glucotoxicity (termed ketosis-prone type 2 diabetes); euglycemic diabetic ketoacidosis has been described in individuals taking SGLT2i	Ketoacidosis common on presentation in children; variable on presentation in adults	Unlikely	Rare; has been reported with SARS-CoV-2 infection and can occur with severe pancreatitis
Autoantibodies present	Not usually seen, but can be present in up to 10% of individuals, depending on the population	Common, but 5%-10% will not have antibodies present on diagnosis, and levels can wane over time; the following antibodies are often tested: glutamic acid decarboxylase (GAD), islet tyrosine phosphatase–related islet antigen 2 (IA-2), zinc transporter 8 (ZnT8) and/or insulin autoantibodies (IAA)	Unlikely	Unlikely
Race and ethnicity	Any; more common in Asian American and Pacific Islander, Black, Latino, and Native American individuals than White individuals	Any; more common with European ancestry	Any; most described in populations of European ancestry	Any
Genetic testing	Not commercially available	Not commercially available; currently only in research studies	Yes; required for definitive diagnosis	Not commercially available
Duration prior to diagnosis	Long (years)	Short (months)	Long (years; potentially lifelong undiagnosed in mild cases)	Variable
Stimulated C-peptideb	Detectable	Low or undetectable (<200 pmol/L); may be detectable soon after diagnosis or for prolonged duration in adult-onset	Detectable	Variable
Drugs that may exacerbate or contribute to development of diabetes	Long-term glucocorticoids, use of immunosuppressant drugs after organ transplantation (e.g., new-onset diabetes after transplant),c and second-generation antipsychotics such as olanzapine and clozapined	Immune checkpoint inhibitors such as nivolumab and pembrolizumab (for cancer)	None	Antiretroviral therapies (ie, certain protease inhibitors and nucleoside reverse transcriptase inhibitors) in people with HIV; glucocorticoid treatment with active COVID-19
Related comorbidities	See Figure 1 in the Supplement	Other autoimmune conditions	Associated features of a specific MODY type (eg, renal cysts, partial lipodystrophy, maternally inherited deafness, severe insulin resistance in the absence of obesity)	Depends on secondary medical condition
Treatment	Lifestyle change, oral agents, noninsulin injectables, insulin	Insulin	Depends on type; no treatment (GCK-MODY), sulfonylureas (HNF1A-MODY or HNF4A-MODY), sometimes insulin is needed	Variable; depends on secondary medical condition; DPP4i or GLP-1 less preferred in patients with pancreatitis

Abbreviations: BMI, body mass index (calculated as weight in kilograms divided by height in meters squared); DPP4i, DPP-4 inhibitor; GLP-1RA, glucagon-like peptide-1 receptor agonist; MODY, maturity-onset diabetes of the young; SGLT2i, sodium-glucose cotransporter 2 inhibitor.

a The exact prevalence of different types of diabetes may depend on the population; thus, ranges are provided for each type.

b Refer to endocrinologist for testing; usually performed after stimulation with glucagon injection or mixed meal test. A C-peptide measurement (with simultaneous glucose) obtained within 5 hours of eating can replace a formal C-peptide stimulation test for classification.

c Screen with oral glucose tolerance test after immunosuppressive regimen is stable.

d Screen for prediabetes or diabetes at baseline when prescribed these drugs; repeat at 3 months, if clinically indicated, and annually.