Novel biomarkers for prediabetes, diabetes, and associated complications

Figures & data

Table 1 Characteristics of biomarkers for prediabetes, diabetes, and associated complications

Traditional biomarkers
Biomarker	Mechanism of action	Sensitivity and specificity	Advantages	Disadvantages	Association with dysglycemia
1. HbA1c	HbA1c forms when glucose attaches to the amino-terminal group of the β subunit of hemoglobin^Citation17	Diabetes ^Citation28 When HbA1c≥6.5% compared to FPG FPG≥126 mg/dL (7.0 mmol/L) and 2-hour plasma glucose ≥200 mg/dL (11.1 mmol/L) Sensitivity: 0.589 Specificity: 0.960 Prediabetes^Citation28 HbA1c ≥5.7, <6.5 for prediabetes Sensitivity: 0.354 Specificity: 0.834	Increased HbA1c levels are associated with increased morbidity and mortality^Citation18 More reliable biomarker of chronic glycemia HbA1c correlates with greater convenience, greater pre-analytical stability, and less day-to-day perturbation during periods of stress and illness^Citation23	HbA1c has moderate sensitivity in diagnosing diabetes when compared to OGTT and FPG^Citation24^–^Citation26 No consensus which cut-off points for HbA1c would be most sensitive^Citation26^–^Citation29 HbA1c threshold for prediabetes does not consider ethnicity, BMI, and age, all of which may significantly alter HbA1c levels^Citation30,Citation31 HbA1c is not always a reliable measure of average circulating glucose levels^Citation40 Changes in the production rate or circulating life span of red blood cells affect HbA1c levels, as well as hemoglobin variants such as HbS, HbC, HbD, and HbE^Citation36,Citation39	HbA1c is a reflection of chronic glycemia^Citation17
2. FA	FA is a ketoamine created by glycosylation of total serum proteins, primarily albumin^Citation41	Diabetes ^Citation38 2.5 mmol/L for diabetes (FPG >7 mmol/L or HbA1c≥6.5%) Sensitivity: 0.82 Specificity: 0.94 Prediabetes ^Citation38 Limited data	FA reflects average blood glucose concentration over the previous 1–4 weeks^Citation38 FA is especially beneficial in conditions that affect hemoglobin status or rate of erythrocyte turnover^Citation52 FA is cost-effective, simple, and convenient, as it does not require fasting^Citation42,Citation43	FA has higher within-subject variation and falsely low levels in conditions leading to rapid albumin turnover^Citation44 Not all studies have found that mean serum FA levels are useful for prediabetes screening^Citation37,Citation38,Citation41,Citation47	FA increases in states of high glucose concentrations^Citation41
3. GA	Glycosylation of albumin and measured by the ratio of GA to total albumin	Diabetes ^Citation50 When GA is ≥15.5% Sensitivity: 0.83 Specificity: 0.83 Prediabetes ^Citation49 When GA >13.35% for prediabetes Sensitivity: 0.41 Specificity: 0.71 The combination of GA with HbA1c can predict prediabetes with greater sensitivity than HbA1c alone^Citation49	GA is a superior index of glycemic control than HbA1c in patients with renal failure, hemolytic anemia, and those receiving blood transfusions^Citation41 GA is preferred over FA in clinical conditions that result in protein loss such as nephrotic syndrome, liver disease, and thyroid disease^Citation41 GA may be artificially low in individuals with increased BMI, body fat mass, and visceral adiposity^Citation53	Inaccurate when there are changes in albumin turnover Falsely lower levels in obesity^Citation52	Serum GA is associated with prediabetes and diabetes^Citation49
4. OGTT	Measures fasting and 2-hour plasma glucose levels	Diabetes Sensitivity: 0.93^Citation155 Prediabetes Sensitivity: 0.811^Citation155	OGTT is more strongly correlated with IR and secretion than HbA1c^Citation25 OGTT provides important information with regard to risk that HbA1c or FPG cannot^Citation4	OGTT is variable, invasive, and time consuming It is inconvenient because it requires fasting and shows day-to-day perturbation during periods of stress and illness	Elevated FPG and 2-hour levels are associated with prediabetes and diabetes
5. 1, 5 AG	1,5 AG is a dietary monosaccharide. Plasma concentrations are inversely correlated with plasma glucose 60	Diabetes ^Citation47 When 1,5 AG <17 mcg/mL for diabetes defined by optimal HbA1c >6% cutoff Sensitivity: 0.96 Specificity: 0.88 Prediabetes ^Citation62 Data not available	1,5 AG is a useful biomarker as it reflects glucose levels within the past 10–14 days It is stable, replicable, and less costly compared to other glycemic diagnostic tests^Citation61	Plasma 1,5 AG levels can change based on dietary habits, sex, and race^Citation64,Citation65 Levels are also affected by renal hemodynamics or treatment with SGLT2 inhibitors^Citation66,Citation67	Plasma 1,5 AG levels are lowered in subjects with prediabetes and diabetes compared with subjects with normoglycemia
Novel biomarkers
Biomarker	Mechanism of action	Association with dysglycemia and complications
6. Adiponectin	Adiponectin is derived from adipose tissues and exhibits insulin-sensitizing, anti-inflammatory, and anti-atherogenic properties. It is an independent predictor of diabetes^Citation68	Lower levels of adiponectin are associated with increased IR and obesity, while higher levels have been related to lifestyle intervention groups in diabetes prevention trials^Citation68 Adiponectin levels are inversely related to the risk of incident prediabetes, independent of ethnic or sex differences^Citation69 Adiponectin levels were directly correlated with insulin sensitivity and indirectly correlated with insulin secretion^Citation69
7. FetA	FetA is a hepatic secretory glycoprotein that has been proposed to promote lipid-induced IR through the TLR4-inflammatory signaling pathway, resulting in production of inflammatory cytokines^Citation71	FetA correlates with increased risk of developing T2DM and associated complications^Citation70
8. α-HB	α-HB is an organic acid byproduct produced during the synthesis of α-KB, a product of amino acid catabolism (threonine and methionine) and glutathione anabolism (cysteine formation pathway) in hepatic tissue^Citation156	IR, increased oxidative stress, and lipid oxidation may cause chronic shifts in glutathione synthesis leading to elevated α-HB levels^Citation88 α-HB was found to be significantly associated with IR independent of sex, age, BMI, and collection site^Citation76 IR was associated with reductions in glycine and serine, which are upstream of α-KB
9. L-GPC	L-GPC is a metabolite formed by the enzyme phospholipase A2 in the liver and by lecithin-cholesterol acyltransferase in the circulation. Phospholipase A2 activity is increased during inflammation^Citation76,Citation92,Citation93	L-GPC is a negative predictor of T2DM progression^Citation76,Citation93
10. Lp(a)	Lp(a) is a lipoprotein subclass that contributes to atherogenesis^Citation94	Lp(a) has an inverse relationship with prevalence of prediabetes and T2DM^Citation95
11. Triglycerides	Esters derived from glycerol and three fatty acids	Associated with β-cell dysfunction and reduced insulin secretion in subjects with prediabetes^Citation94,Citation96
12. HDL	A major lipoprotein	HDL-C promotes insulin secretion • Low HDL-C concentration may lead to progression from prediabetes to diabetes • Increased proportion of small HDL3 over HDL-C in subjects with prediabetes • Decreased proportion of HDL-LpPLA2 in prediabetes^Citation97
13. Ceramide	Lipid molecules	Positively associated with prediabetes and T2DM^Citation85,Citation98
14. Ferritin and transferrin	Ferritin is an intracellular protein that stores and releases iron	Elevated serum ferritin and transferrin saturation have been strongly associated with increased risk of prediabetes and diabetes. Iron has properties that contribute to IR such as production of highly active radical formation, damage to DNA and cell membrane integrity, β-cell oxidative stress leading to decreased insulin secretory capacity, and interference with glucose uptake in skeletal muscles and adipocytes. Moreover, catalytic iron stimulates the formation of reactive oxidative species, hepatic dysfunction, and β-cell apoptosis, all of which contribute to IR^Citation103^–^Citation106
15. MBL-associated serine proteases	MBL-associated serine proteases are important enzymes for innate immune responses and activation of the lectin pathway of the complement system^Citation108	MASP1 has been shown to positively correlate with prediabetes, diabetes, and CVD^Citation109
16. THBS1	THBS1 directs formation of multiprotein complexes that modulate cellular phenotype (e.g., stimulates/inhibits migration of vascular smooth muscle cells or endothelial cells, respectively)^Citation110	THBS1 positively associated with:^Citation109 • Higher prediabetes prevalence • Increased IR • Increased 2-hour glucose • Adipose inflammation and metabolic dysregulation in obesity and type 2 diabetes
17. GPLD1	GPLD1 has a postulated role in the insulin-mimetic signaling pathway of glycosylphosphatidylinositol compounds, though the exact mechanism is not known GPLD1 cleavage generates second messengers that can act as inulin-mimetic molecules^Citation109	GPLD1 positively associated with:^Citation109 • Type 2 diabetes and prediabetes (less strongly) • MASP1, another novel prediabetes biomarker • HDLs in serum
18. Acyl-carnitine	Acyl-carnitines interact with NF-Kβ, which promotes inflammation and IR The precise role acyl-carnitines play has not yet been elucidated^Citation118	Elevated levels of acyl-carnitine found in individuals with prediabetes Associated with inflammation and IR^Citation116,Citation117
19. miRNA	miRNAs are involved in cell growth, differentiation, proliferation, and death Specific miRNAs ^Citation124,Citation126 miR-192 regulates the tumor protein p53 miR-193b involved in brown adipocyte differentiation and inflammation reduction miR-15a thought to directly inhibit uncoupling protein-2 gene expression, leading to increased oxygen consumption and reduced ATP generation, thus promoting insulin synthesis Others thought to play a role in β-cell function^Citation100	Many miRNAs have been found to be elevated in individuals with prediabetes^Citation122 miR-192 and 193b associated with subjects with IFG and IGT; associated with high triglyceride levels and fatty liver index^Citation120 Other miRNAs play a role in insulin production, secretion, and regulation^Citation126
Inflammatory biomarkers
Biomarker	Mechanism of action	Association with dysglycemia and complications
20. CRP	Derived from IL-6-dependent hepatic biosynthesis Primary marker of acute phase response^Citation131	Associated with type 2 diabetes and IR Found to be associated with prediabetes CRP found more elevated in subjects who had prediabetes and IR than those with prediabetes but insulin sensitive^Citation108
21. IL-6	IL-6 cytokines exhibit immunoregulatory actions and are involved in glucose homeostasis and metabolism through action on pancreatic β cells,^Citation157 adipocytes, hepatocytes, and skeletal muscles^Citation158	Associated with type 2 diabetes and IR^Citation131
22. WBCs	WBC count is a marker of immunity and inflammation^Citation140 NLR is an indicators of subclinical inflammation and microvascular and macrovascular complications in diabetes^Citation142,Citation143	WBC count has been predictive of: • Worsening insulin action • Secretory function and T2DM • Coronary heart disease • Higher 1-hour post-load glucose level^Citation140
23. Fibrinogen	Fibrinogen actions affect blood viscosity, platelet aggregation, and fibrin formation	Fibrinogen associated with: • Prediabetes and weakly associated with diabetes • Higher 1-hour post-load glucose level atherosclerosis^Citation134
24. PAI-1	Marker of reduced fibrinolysis Decreased activity leads to defective coagulation^Citation147,Citation148	Independent predictor of diabetes^Citation147
25. IL-18	IL-18 increases during hyperglycemia^Citation149	Associated with increased risk of T2DM Increased IL-18 correlated with progression from prediabetes to diabetes^Citation149
26. IL-1RA	IL-1RA is an anti-inflammatory marker elevated when IL-1 pathway induced by glucose and free fatty acids during overfeeding^Citation150	Associated with: • Decreasing insulin sensitivity • Temporary increasing β-cell function • Elevated in prediabetes and diabetes^Citation151

Abbreviations: HbA1c, hemoglobin A1c; FPG, fasting plasma glucose; BMI, body mass index; FA, fructosamine; GA, glycated albumin; OGTT, oral glucose tolerance test; IR, insulin resistance; 1, 5 AG, 1, 5 anhydroglucitol; FetA, fetuin-A; TLR4, toll-like receptor 4; T2DM, type 2 diabetes mellitus; α-HB, alpha-hydroxybutyrate; α-KB, α-ketobutyrate; L-GPC, L-alpha glycerylphosphorylcholine; Lp(a), lipoprotein(a); HDL-C, high-density lipoprotein cholesterol; HDL-LpPLA₂, HDL-associated lipoprotein-associated phospholipase A2; MBL, mannose binding lectin; CVD, cardiovascular disease; THBS1, thrombospondin 1; GPLD1, glycosylphosphatidylinositol-specific phospholipase D1; NF-Kβ, nuclear factor-κB; miRNA, microRNA; IFG, impaired fasting glucose; IGT, impaired glucose tolerance; CRP, C-reactive protein; IL, interleukin; WBC, white blood cell; NLR, neutrophil-lymphocyte ratio; PAI-1, plasminogen activator inhibitor-1; IL-1RA, IL-1 receptor antagonist; SGLT₂, sodium-glucose co-transporter 2.

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