Biomarkers of Blood Glucose Regulation: Fasting Blood Glucose

Elevated blood glucose is a classic sign of metabolic dysfunction. It is associated not only with diabetes mellitus but with cardiometabolic risk factors such as visceral obesity, high blood pressure, dyslipidemia, and cardiovascular disease itself.

Several biomarkers reflect the body’s ability to regulate blood glucose. Optimal glucose levels in the blood must be sustained within the narrow range needed to maintain the delivery of glucose to tissues and to the brain without allowing a surplus to build up. These markers can be assessed over time to provide early detection of abnormalities in blood glucose regulation.

Optimal Takeaways

Glucose is a simple sugar with a complex job. It provides our cells, especially brain and muscle cells, with fuel that they can convert into energy. Glucose can be used immediately or stored as glycogen to be utilized later. If glucose remains too high in the blood, it can become damaging and alter proteins, cells, tissues, and blood vessels, leading to chronic diseases such as diabetes mellitus, cardiovascular disease, and kidney failure. Addressing high blood glucose early on with lifestyle and nutrition changes is very important.

Standard Range: 65 - 99 mg/dL (3.6 - 5.5 mmol/L)

The ODX Range: 75 - 86 mg/dL (4.2 - 4.8 mmol/L)  

Low fasting glucose is associated with hypoglycemia, insulinoma, and stroke (Pagana 2022, Park 2013).

High fasting glucose is associated with diabetes (type 1, type 2, gestational), insulin resistance, cardiovascular risk (Pagana 2022), and cancer (Lu 2019).

Above optimal levels are also associated with metabolic syndrome (Hsiao 2013), undiagnosed diabetes and prediabetes (Bowen 2015), atherosclerosis (Fernandez-Friera 2017), ischemic heart disease, myocardial infarction, and thrombotic stroke (Park 2013).

Overview

Measuring blood glucose in the fasting state helps identify abnormalities in glucose regulation, including hyperglycemia and hypoglycemia. Excess glucose damages cells and tissues and can lead to organ dysfunction and cardiometabolic disease.

Elevated levels may indicate insulin resistance, pre-diabetes, diabetes, or increased cardiovascular risk. Fasting glucose should be repeated to confirm trends and accuracy. 

Traditional criteria for diagnosing diabetes don’t identify prediabetes until fasting glucose has reached 100-125 mg/dL (5.6-6.9 mmol/L), and they don’t identify diabetes until fasting glucose is above 126 mg/dL (7.0 mmol/L) (ADA 2021). However, early research revealed that levels above 85 mg/dL (4.7 mmol/L) were adversely associated with cardiovascular disease and myocardial infarction, indicating advanced cardiometabolic dysfunction (Bjornholt 1999).

Fasting glucose above 89 mg/dL (4.9 mmol/L) increases the risk of progressing to diabetes by 6% for every 1 mg/dL rise (0.56 mmol/L) (Nichols 2008). Conversion of prediabetes to diabetes, in turn, increases CVD risk by 1.3-3.6 (Bancks 2019). Fortunately, the conversion rate can be reduced significantly through lifestyle modifications, including a healthy diet, healthy approaches to weight loss, and regular exercise (Mayans 2015).

Data from 4,184 healthy individuals enrolled in the Progression of Early Subclinical Atherosclerosis (PESA) study found subclinical atherosclerosis (coronary artery calcification or plaque) in 50% of the study population despite them not being identified as high risk using conventional lab ranges. Fasting glucose was significantly higher at 89 mg/dL (4.94 mmol/l) in the group diagnosed with atherosclerosis versus 86 mg/dL (4.77 mmol/L) in those without atherosclerosis. Hemoglobin A1C was also significantly higher in those with atherosclerosis (Fernandez-Friera 2017).

A large study of 10,913 non-diabetic men and women confirmed an increased risk of CVD when fasting glucose was within the traditionally “normal” (but not optimal) range. The Cardiovascular Risk and Metabolic Assessment (CARMA) study investigated cardiometabolic risk in seemingly healthy individuals. Results found that those with fasting plasma glucose of 85-89 mg/dL (4.72-4.94 mmol/L), 90-94 mg/dL (5.00-5.22 mmol/L), and 95-99 mg/dL (5.27-5.49 mmol/L) had a significantly greater risk of adverse CVD outcomes than those with fasting glucose below 85 mg/dL (4.72 mmol/L). Hazard ratios for the three at-risk groups were 1.34, 1.47, and 1.53, respectively, with risk increasing as fasting glucose increased (Shaye 2012).

Individuals experiencing their first MI were more likely to have impaired glucose tolerance and diabetes in a case-control study of 600 subjects. The risk of MI in those without diagnosed dysglycemia increased by 2.7 when fasting glucose was above 94 mg/dL (5.2 mmol/L) compared to 81 mg/dL (4.5 mmol/L) or less. Researchers suggested a cut-off for fasting glucose of 88 mg/dL (4.9 mmol/L) to distinguish MI cases from controls (Gerstein 1999).

It has become more widely understood that higher fasting glucose, especially above 100 mg/dL (5.55 mmol/L), is associated with ischemic heart disease, myocardial infarction, and thrombotic stroke. However, low fasting glucose, below 70 mg/dL (3.89 mmol/L), was associated with an increased risk of all categories of stroke in a prospective cohort study of 1,197,384 Korean subjects (Park 2013).

It should be noted that non-fasting blood glucose can also help identify early glucose dysregulation. Research suggests that random blood glucose above 99 mg/dL (5.49 mmol/L) is more strongly associated with undiagnosed diabetes and should be incorporated into public health screenings. Mean random blood glucose of 89.9 mg/dL (4.99 mmol/L) was maintained by healthy individuals, versus 99.1 mg/dL (5.50 mmol/L) in those with undiagnosed prediabetes and 156 mg/dL (8.66 mmol/L) in undiagnosed diabetes (Bowen 2015). An earlier study noted an increase in post-prandial glucose of 21 mg/dL (1.2 mmol/L) independently and significantly increased the risk of myocardial infarction in subjects without established glucose intolerance (Gerstein 1999).

Maintaining blood glucose and other biomarkers of cardiometabolic health within the optimal range will help prevent or reduce the risk of associated chronic disease and should be the objective of healthcare practitioners. Testing should be repeated and accompanied by additional biomarkers of glucose regulation, including fasting insulin, C-peptide, hemoglobin A1C, 1,5 Anhydroglucitol, triglycerides, and HOMA2 calculations as part of a comprehensive cardiometabolic assessment.

References

American Diabetes Association. “2. Classification and Diagnosis of Diabetes: Standards of Medical Care in Diabetes-2020.” Diabetes care vol. 43,Suppl 1 (2020): S14-S31. doi:10.2337/dc20-S002 

American Diabetes Association. “2. Classification and Diagnosis of Diabetes: Standards of Medical Care in Diabetes-2021.” Diabetes care vol. 44,Suppl 1 (2021): S15-S33. doi:10.2337/dc21-S002 

Bancks, Michael P et al. “Long-term Absolute Risk for Cardiovascular Disease Stratified by Fasting Glucose Level.” Diabetes care vol. 42,3 (2019): 457-465. doi:10.2337/dc18-1773 

Bjornholt, J V et al. “Fasting blood glucose: an underestimated risk factor for cardiovascular death. Results from a 22-year follow-up of healthy nondiabetic men.” Diabetes care vol. 22,1 (1999): 45-9. doi:10.2337/diacare.22.1.45 

Bowen, Michael E et al. “Random blood glucose: a robust risk factor for type 2 diabetes.” The Journal of clinical endocrinology and metabolism vol. 100,4 (2015): 1503-10. doi:10.1210/jc.2014-4116 

Fernandez-Friera, Leticia et al. “Normal LDL-Cholesterol Levels Are Associated With Subclinical Atherosclerosis in the Absence of Risk Factors.” Journal of the American College of Cardiology vol. 70,24 (2017): 2979-2991. doi:10.1016/j.jacc.2017.10.024

Gerstein, H C et al. “Relationship of glucose and insulin levels to the risk of myocardial infarction: a case-control study.” Journal of the American College of Cardiology vol. 33,3 (1999): 612-9. doi:10.1016/s0735-1097(98)00637-8

Hsiao, Fone-Ching et al. “Elevated fasting glucose levels within normal range are associated with an increased risk of metabolic syndrome in older women.” European journal of internal medicine vol. 24,5 (2013): 425-9. doi:10.1016/j.ejim.2013.03.013

Lu, Jieli et al. “Predictive Value of Fasting Glucose, Postload Glucose, and Hemoglobin A1c on Risk of Diabetes and Complications in Chinese Adults.” Diabetes care vol. 42,8 (2019): 1539-1548. doi:10.2337/dc18-1390

Mayans, Laura. “Metabolic Syndrome: Insulin Resistance and Prediabetes.” FP essentials vol. 435 (2015): 11-6. 

Nichols, Gregory A et al. “Normal fasting plasma glucose and risk of type 2 diabetes diagnosis.” The American journal of medicine vol. 121,6 (2008): 519-24. doi:10.1016/j.amjmed.2008.02.026 

Pagana, Kathleen Deska, et al. Mosby's Diagnostic and Laboratory Test Reference. 16th ed., Mosby, 2022.

Park, Chanshin et al. “Fasting glucose level and the risk of incident atherosclerotic cardiovascular diseases.” Diabetes care vol. 36,7 (2013): 1988-93. doi:10.2337/dc12-1577

Shaye, Kivity et al. “Fasting glucose levels within the high normal range predict cardiovascular outcome.” American heart journal vol. 164,1 (2012): 111-6. doi:10.1016/j.ahj.2012.03.023