Metabolically healthy obesity: Is it really healthy for type 2 diabetes mellitus?

Table 1 Definitions of metabolic health in previous publications

Ref.	BP, kPa (mmHg)	Plasma glucose, mmol/L	TG, mmol/L	HDL-C, mmol/L	LDL-C, mmol/L	TC, mmol/L	WC, cm	Insulin sensitivity	CRP, mg/L		Intrahepatic lipid content	Others	Metabolic health
NECP ATP III[9]	SBP ≥ 17.3 (130) and/or DBP ≥ 11.3 (85) and/or treatment	FPG ≥ 5.60	≥ 1.70	< 1.29 in women, < 1.03 in men	-	-	> 88 in women, >102 in men	-	-		-	-	< 3 of above
Karelis et al[17]	-	-	≤ 1.70	≥ 1.30 and no treatment	≤ 2.60 and no treatment	≤ 5.20	-	HOMA-IR ≤ 1.95	-		-	-	> 3 of above
Meigs et al[4]	SBP ≥ 17.3 (130) or DBP ≥ 11.3(85) or treatment	5.6 < FPG ≤ 6.9	≥ 1.70	< 1.30 in women, < 1.00 in men	-	-	> 88 in women, > 102 in men	-	-		-	-	< 2 of above
Meigs et al[4]	-	-	-	-	-	-	-	HOMA-IR ≥ 75th percentile	-		-	-	None of above
Aguilar-Salinas et al[89]	SBP > 18.6 (140) and/or DBP > 12.0 (90) and/or treatment	FPG ≥ 7.0, or 2-h OGTT ≥ 11.1, or RBG ≥ 11.11 or treatment	-	< 1.04	-	-	-	-	-		-	-	None of above
Wildman et al[18]	SBP ≥ 17.3 (130) or DBP ≥ 11.3 (85) or treatment	FPG ≥ 5.56 or treatment	≥ 1.70	< 1.30 in women, < 1.04 in men or treatment	-	-	-	HOMA-IR > 90th percentile	> 90th percentile		-	-	< 2 of above
van Vliet-Ostaptchouk et al[90]	SBP ≥ 17.3 (130) or DBP ≥ 11.3 (85) or treatment	FPG ≥ 6.10 or treatment or history/diagnosis of type 2 diabetes	≥ 1.70 or treatment	< 1.03 in men or < 1.30 in women or treatment	-	-	-	-	-		-	-	<2 of above
Jana V van Vliet-Ostaptchouk et al[90]	SBP ≥ 18.6 (140) or DBP ≥ 12.0(90) or treatment	FPG ≥ 7.0 or treatment or history/diagnosis of type 2 diabetes	≥ 1.70 or treatment	< 1.03 in men or < 1.30 in women or treatment	-	-	-	-	-		-	-	< 2 of above
Smith et al[20]	SBP < 17.3 (130) and/or DBP < 11.3 (85)	FPG < 5.60, or 2-h OGTT glucose < 7.80	< 1.07	≥ 1.29 in women, ≥ 1.04 in men	-	-	-	GIR > 8 mg/kg FFM/min during an HECP (insulin infusion rate: 40 mU/m2/min)		-	< 5% of liver volume by imaging or < 5% of hepatocytes with intracellular TG by histology	Basic criteria: Absence of diagnosis or therapy of cardiometabolic diseases	all of above

BP: Blood pressure; SBP: Systolic blood pressure; DBP: Diastolic blood pressure; FPG: Fasting plasma glucose; OGTT: Oral glucose tolerance test; RBG: Random blood glucose; HbA1c: Glycosylated hemoglobin A1c; TG: Triglyceride; HDL-C: High-density lipoprotein cholesterol; LDL-C: Low-density lipoprotein cholesterol; TC: Total cholesterol; WC: Waist circumference; HOMA-IR: Homeostasis model assessment of insulin resistance; GIR: Glucose infusion rate; HECP: Hyperinsulinemic-euglycemic clamp procedure; hs-CRP: High-sensitivity C-reactive protein.

Table 2 Cohort studies of the association of metabolically healthy obesity and type 2 diabetes in the last 5 years

Ref.	Definition of “metabolic health”	MHO, n	Main findings
Wei et al[30], 2020	Having < 2 of the following criteria: (1) TG ≥ 1.7 mmol/L or lipid-lowering drugs; (2) SBP ≥ 17.3 kPa (130 mmHg) or DBP ≥ 11.3 kPa (85 mmHg) or anti-hypertensive drugs; (3) FPG ≥ 5.6 mmol/L; and (4) HDL-C < 1.04 mmol/L for men and < 1.29 mmol/L for women.	693	MHO was associated with an increased incidence of diabetes, and the association did not differ by the presence or absence of NAFLD.
Feng et al[7], 2020	Having < 2 of the following criteria: (1) Hyperglycemia, defined as FPG ≥ 5.6 mmol/L (100 mg/dL); (2) Elevated blood pressure, defined as SBP ≥ 17.3 kPa (130 mmHg) and/or DBP ≥11.3 kPa (85 mmHg) or antihypertensive drug treatment; (3) Hypertriglyceridemia, defined as TG ≥ 1.7 mmol/L (150 mg/dL); and (4) Reduced HDL-C levels, defined as drug treatment to increase HDL-C levels.	3728	The MHO phenotype was associated with an increased incidence of diabetes in older adults. The presence of metabolic disorders in the group with MHO was associated with increased diabetes risk and was predicted by the waist circumference at baseline.
Kim et al[32], 2019	Having two or fewer metabolic abnormalities as follows: (1) WC ≥ 90 cm in men and ≥ 85 cm in women; (2) SBP ≥ 17.3 kPa (130 mmHg) or DBP ≥ 11.3 kPa (85 mmHg) or medication use; (3) FPG ≥ 5.6 mmol/L (100 mg/dL) or claim for T2DM or on anti-diabetic medications; (4) Hypertriglyceridemia ≥ 1.7 mmol/L (150 mg/dL) or on lipid medications; and (5) HDL-C < 1.04 mmol/L (40 mg/dL) in men and < 1.29 mmol/L (50 mg/dL) in women, or medication use.	796371	MHO and MHNW phenotypes were transient phenotypes, and their change into metabolic unhealthy status was an important risk factor for the development of T2DM both in obese and normal-weight subjects. Transition into a metabolically unhealthy phenotype was a more significant risk factor of developing T2DM than obesity itself.
Wang et al[33], 2018	Having < 2 of the following criteria: (1) SBP ≥ 17.3 kPa (130 mmHg) or DBP ≥ 11.3 kPa (85 mmHg) or current treatment for hypertension; (2) Fasting TG level ≥ 1.7 mmol/L; (3) HDL-C level < 1.03 mmol/l for males or < 1.29 mmol/L for females; and (4) FPG ≥ 5.60 mmol/L.	2153	Stable metabolically healthy overweight/obesity Individuals and those who transitioned to the metabolically healthy status from MUNW did not have an increased risk of incident T2DM. Participants who transitioned from the metabolically healthy overweight/obesity to metabolically unhealthy overweight/obesity phenotype and stable MUNW phenotype showed an increased risk of incident T2DM.
Fingeret et al[31], 2018	Having two or fewer metabolic abnormalities as follows: (1) FPG ≥ 5.6 mmol/L or drug treatment; (2) Fasting TG ≥ 1.7 mmol/L or drug treatment; (3) Fasting HDL-C < 1.30 mmol/L in women and < 1.00 mmol/L in men or drug treatment; (4) SBP ≥ 17.3 kPa (130 mmHg), DBP ≥ 11.3 kPa (85 mmHg), or drug treatment; and (5) WC ≥ 102 cm for men and ≥ 88 cm for women.	170	MHO leads to a higher risk of developing cardiovascular risk factors such as hypertension, diabetes, dyslipidemia as compared with MHNW. MHO is transient and should be regarded by clinicians as a warning sign.
Liu et al[91], 2018	Having < 2 of metabolic abnormalities as follows: (1) TG ≥ 1.7 mmol/L; (2) HDL-C < 1.0 mmol/L; (3) SBP ≥ 17.3 kPa (130 mmHg) and/or DBP ≥ 11.3 kPa (85 mmHg); and (4) FPG ≥ 5.6 mmol/ L (≥ 100 mg/dL).	1184	MHO and MUNW phenotypes had an increased risk for diabetes. Both baseline metabolic status and follow-up changes played more important roles than obesity for diabetes incidence after adjusted for potential confounding factors. MHO is a transient condition.
Janghorbani et al[29], 2017	Having none of metabolic abnormalities as follows: (1) TG ≥ 1.7 mmol/L (150 mg/dL); (2) HDL < 1.04 mmol/L(40 mg/dL) in men and < 1.29 mmol/L(50 mg/dL) in women; (3)BP ≥ 17.3/11.3 kPa (130/85 mmHg) or on antihypertensive medication; and (4) FPG ≥ 5.6 mmol/L (100 mg/dL).	75	Metabolic abnormalities increased risk for incident T2D at any BMI status. Also, obesity is a risk factor for the incidence of T2DM, even in the absence of any metabolic abnormalities.
Latifi et al[25], 2017	Having none of metabolic abnormalities as follows: (1) WC ≥ 102 cm in men and ≥ 88 cm in women; (2) TG ≥ 1.7 mmol/L (150 mg/dL) or drug use; (3) HDL < 1.04 mmol/L (40 mg/dL) in men and 1.29 mmol/L (50 mg/dL) in women or drug consumption for hyperlipidemia; (4) BP ≥ 17.3/10.6 kPa (130/80 mmHg) or a history of anti-hypertensive drug consumption; and (5) FPG ≥ 5.6 mmol/L (100 mg/dL), or a history of diabetes mellitus or consumption of anti-diabetes drugs.	NA	There was a specific higher risk of developing metabolic syndrome and diabetes in MHO.
Navarro-Gonzalez et al[14], 2016	Having < 3 of the following criteria: (1) TG ≥ 1.7 mmol/L (150 mg/dL); (2) HDL-C > 1.04 mmol/L (40 mg/dL) for men and > 1.29 mmol/L (50 mg/dL) for women; (3) BP ≥ 17.3/11.3 kPa (130/85 mmHg); or (4) FPG ≥ 5.6 mmol/L (100 mg/dL). All individuals currently taking a pharmacological treatment for hypertension were assumed to have raised BP.	389	MHO individuals had an increased risk of incident type 2 diabetes but mainly among those who progressed MUO. MHO individuals who remained with one or no metabolic health risk factors or lost weight overtime did not have a significant risk of diabetes. Metabolically unhealthy individuals had a greater risk of diabetes compared with subjects with MHO.
Guo et al[3], 2016	Having all three components as follows: (1) Untreated SBP < 17.3 kPa (130 mmHg) and DBP < 11.3 kPa (85 mmHg); (2) Untreated FPG < 5.6 mmol/L (100 mg/dl) or HbA1c < 5.7%; and (3) Untreated TC < 6.2 mmol/L (240 mg/dL) and HDL ≥ 1.04 mmol/L (40 mg/dL) in men and ≥ 1.29 mmol/L (50 mg/dL) in women.	260	People with healthy obesity have lower risks for diabetes, coronary heart disease, stroke, and mortality compared with unhealthy subjects regardless of their BMI status. Obesity did not affect the risks of coronary heart disease, stroke, and mortality, but did increase diabetes risk.
Jung et al[40], 2016	Having < 2 of the following criteria: (1) SBP ≥ 17.3 kPa (130 mmHg) and/or a DBP ≥ 11.3 kPa (85 mmHg), or on antihypertensive treatment; (2) TG ≥ 1.7 mmol/L; (3) FPG ≥ 5.6 mmol/L (impaired fasting glucose, IFG); (4) HDL-C < 1.0 mmol/L in men and < 1.3 mmol/L in women; (5) HOMA-IR ≥ 90th percentile (≥ 2.91); and (6) Hs-CRP ≥ 90th percentile (≥ 2.0 mg/L).	4635	MHO subjects have a substantially increased risk of incident type 2 diabetes compared with MHNO subjects in an Asian population. The presence of FLD assessed by FLI partially explains this increased risk.
Chang et al[16], 2016	Having none of the following criteria: (1) BP ≥ 17.3/11.3 kPa (130/85 mmHg) or current use of blood pressure-lowering agents; (2) FPG ≥ 5.6 mmol/L (100 mg/dL) or current use of blood glucose-lowering agents; (3) TG ≥ 1.7 mmol/L (150 mg/dL) or current use of lipid-lowering agents (15); (4) HDL-C < 1.04 mmol/L (40 mg/dL) in men or < 1.29 mmol/L (50 mg/dL) in women; or (5) Insulin resistance, defined as HOMA-IR score ≥ 2.5.	8140	Metabolically healthy overweight and obese individuals were both associated with an increased incidence of diabetes, even in the absence of NAFLD. Obese phenotype itself can drive the development of diabetes, even in the absence of metabolic abnormalities and NAFLD.
Ryoo et al[34], 2015	Having < 2 of the following criteria: (1) SBP ≥ 17.3 kPa (130 mmHg) and/or DBP ≥ 11.3 kPa (85 mmHg); (2) TG ≥ 1.7 mmol/L; (3) FPG ≥ 5.6 mmol/L; (4) HDL-C < 1.0 mmol/L; and (5) HOMA-IR ≥ 90th percentile.	240	The risk for diabetes was in proportion to both metabolic health status and degree of obesity in Korean men. Additionally, metabolically healthy status was a more significant determinant for the development of diabetes than obesity itself.

TG: Triglycerides; BP: Blood pressure; SBP: Systolic blood pressure; DBP: Diastolic blood pressure; FPG: Fasting plasma glucose; HOMA-IR: Homeostatic model assessment of insulin resistance; TC: Total cholesterol; HDL-C: High-density lipoprotein cholesterol; hs-CRP: High sensitivity C reactive protein; WC: Waist circumference; T2DM: Type 2 diabetes mellitus; MHO: Metabolically healthy obesity; MUO: Metabolically unhealthy obesity; MHNW: Metabolically healthy normal weight; MUNW: Metabolically unhealthy normal weight; NAFLD: Non-alcoholic fatty liver disease; FLI: Fatty liver index.