Fasting plasma mannose levels are associated with insulin sensitivity independent of BMI in Japanese individuals with diabetes

Abstract

BackgroundRecently, an integrated network analysis has revealed dysregulation in the metabolism of mannose, a glucose epimer, in severely obese individuals without diabetes. In addition, fasting plasma mannose levels (M0) are associated with insulin resistance independent of BMI. Since the association between mannose and insulin sensitivity (IS) in those with impaired glucose tolerance remains unknown, we aimed to investigate this association in individuals without severe obesity but with varying degrees of glucose tolerance.MethodsBased on 75 g OGTT data in Japanese individuals without diabetic medication, individuals were classified as having normal glucose tolerance (NGT), impaired glucose metabolism (IGM), or diabetes (DM). In each group, 25 individuals were consecutively recruited [total 75 individuals, age: 65 ± 11 (mean ± SD); BMI: 24.9 ± 3.8 kg/m2]. QUICKI and Matsuda index (MI) were calculated as IS indices. M0 was assayed using HPLC. Normally-distributed loge-transformed (ln-) values were used for MI and leptin.ResultsIn the simple regression analysis, ln-MI was negatively correlated with BMI (NGT: r = − 0.639, IGM: r = − 0.466, DM: r = − 0.613) and ln-leptin (NGT: r = − 0.480, IGT: r = − 0.447, DM: r = − 0.593) in all 3 groups. Ln-MI was not significantly correlated with M0 in NGT (r = 0.241, P = 0.245) and IGT (r = − 0.296, P = 0.152) groups, it was moderately and negatively correlated in the DM group (r = − 0.626, P < 0.001). Similar results were obtained, when QUICKI was used instead of MI as an index of IS. In multiple regression analysis in the DM group, QUICKI (Q) and ln-MI (M) were independently predicted by BMI (Q: β = − 0.413; M: β = − 0.400) and M0 (Q: β = − 0.413, M: β = − 0.426), accounting for 51.2% (P = 0.0004) and 51.2% (P = 0.0004) of the variability, respectively, which was larger than the prediction for BMI alone (Q: 38.4%, M: 37.6%).ConclusionFasting plasma mannose was associated with IS independent of BMI in Japanese individuals with DM.

The metabolic footprint of compromised insulin sensitivity under fasting and hyperinsulinemic-euglycemic clamp conditions in an Arab population

“…In contrast, we monitored apparently healthy subjects of Arab descent at the fasting state and under HIEC conditions. We found that metabolic signatures, including BCAA, AAA, as well as mannose, reported previously as predictors of T2D or IR in longitudinal studies 10 , 12 , 13 , 17 , appeared as significantly associated with the levels of IS under HIEC, but not at fasting state. At fasting state metabolism related to insulin signaling is suppressed and catabolic processes are activated to fulfill the energy needs of the body 21 .…”

“…The metabolic composition of the body is defined as metabolic phenotype or metabotype. We and others have previously reported metabolic signatures of diabetes [9][10][11][12][13][14][15][16] . For example, alterations in the levels of certain circulating metabolites, including branched chain amino acids (BCAA), aromatic amino acids (AAA), as well as a number of lipids, were recognized as predictive markers of T2D in longitudinal studies 12,13 .…”

“…Elevated levels of mannose have been identified as a marker of IR and T2D in multiple studies 9,10,17,35 . In the previous study, it was suggested that plasma mannose is a product of glycogen breakdown catalyzed by liver hexose 6-phosphate, which enables conversion of mannose-6-phosphate into mannose, and its accumulation 36 .…”

“…Metabolic signatures of insulin resistance in plasma and muscle samples were also previously reported 11,14,16 . Elevated levels of BCAA, AAA, and alanine as well as phospholipids were identified as associated with insulin resistance determined by HOMA-IR 14 Fasting plasma mannose concentrations also correlate with compromised IS in individuals with T2D 10 and associate with insulin resistance 17 . In subjects divided into resistant and sensitive to insulin based on HIEC, alpha-hydroxybutyrate, 1-linoleoylglycrophosphatidylcholine and glycine were found to serve as metabolic markers of IR, based on their associations with M-values 18 .…”

Genetically Higher Level of Mannose Has No Impact on Cardiometabolic Risk Factors: Insight from Mendelian Randomization

“…It has also been reported that the plasma concentration of mannose was higher in participants with normal glucose tolerance than impaired glucose tolerance; a strong correlation between the mannose level and fasting blood glucose (FBG) was additionally reported [ 10 ]. In the same line, a positive correlation between the plasma mannose level and BMI and FBG was observed [ 11 , 12 ]. In a rodent model fed with a high-fat diet, mannose supplementation prevented weight gain and improved glucose hemostatis, while those animals had a significantly higher level of total cholesterol and high-density lipoprotein (HDL) [ 13 ].…”