What does an elevated Fasting Blood Sugar (FBS) hexokinase level indicate?

From the Guidelines

Elevated hexokinase levels in fasting blood sugar (FBS) testing may indicate increased glucose metabolism, often seen in conditions like diabetes, hyperthyroidism, or certain cancers, and thus, it is crucial to consult with a healthcare provider for proper evaluation and interpretation of this finding in the context of other clinical parameters. The diagnosis of diabetes, which could be one of the underlying causes of elevated hexokinase levels, is established by identifying the presence of hyperglycemia, with a fasting plasma glucose (FPG) ≥7.0 mmol/L (126 mg/dL) being diagnostic of diabetes, as recommended by the American Diabetes Association (ADA) and endorsed by the World Health Organization (WHO) 1.

Key Points to Consider

• Elevated hexokinase levels suggest increased cellular glucose uptake and metabolism, which can occur in various conditions, including diabetes, and thus, require further investigation to determine the underlying cause.
• The diagnosis of diabetes is primarily based on the measurement of fasting glucose levels, with a value of ≥7.0 mmol/L (≥126 mg/dL) being diagnostic, as per the guidelines and recommendations for laboratory analysis in the diagnosis and management of diabetes mellitus 1.
• Other diagnostic criteria for diabetes include a 2-h postload glucose >11.1 mmol/L (200 mg/dL) during an oral glucose tolerance test (OGTT), or symptoms of diabetes and a casual plasma glucose ≥11.1 mmol/L (200 mg/dL) 1.
• The use of hemoglobin A1c (HbA1c) for the diagnosis of diabetes, with a threshold of ≥6.5%, is also recommended, although it may not be suitable for all individuals, such as those with certain forms of anemia or hemoglobinopathies 1.

Recommendations for Next Steps

• Consult with a healthcare provider for proper evaluation and interpretation of elevated hexokinase levels in the context of other clinical parameters.
• Additional tests, such as a complete metabolic panel, HbA1c, and possibly imaging studies, may be ordered to determine the underlying cause of elevated hexokinase levels.
• Maintaining a balanced diet, staying hydrated, and continuing any prescribed medications are recommended while awaiting further evaluation and diagnosis.
• Recording any symptoms experienced will help the healthcare provider make an accurate diagnosis and develop an appropriate treatment plan.

From the Research

Elevated Fasting Blood Sugar (FBS) Hexokinase Level

• An elevated Fasting Blood Sugar (FBS) hexokinase level is associated with hyperglycemia, which is a risk factor for the development of insulin resistance, beta-cell glucotoxicity, and vascular complications of diabetes 2.
• Hexokinases (HKs) catalyze the first step of glucose metabolism, and increased flux of glucose metabolism through glycolysis gated by HKs can produce increased levels of glycolytic intermediates with overspill into effector pathways of cell dysfunction and pathogenesis 2.
• HK2 has similar saturation characteristics to HK1, except that in persistent hyperglycemia, it is stabilized to proteolysis by high intracellular glucose concentration, increasing HK activity and initiating glycolytic overload and unscheduled glycolysis 2.
• HK2-linked unscheduled glycolysis in skeletal muscle and adipose tissue in impaired fasting glucose drives the development of peripheral insulin resistance 2.
• Glucokinase (GCK or HK4)-linked glycolytic overload and unscheduled glycolysis occurs in persistent hyperglycemia in hepatocytes and beta-cells, contributing to hepatic insulin resistance and beta-cell glucotoxicity, leading to the development of type 2 diabetes 2.

Hexokinase Activity and Glucose Metabolism

• Hexokinases play a critical role in the cellular uptake and utilization of glucose, and their activity can be determined by measuring adenosine diphosphate (ADP) levels 3.
• HK2/hexokinase-II integrates glycolysis and autophagy to confer cellular protection, and its activity is important for cell survival 4.
• Akt inhibition promotes hexokinase 2 redistribution and glucose uptake in cancer cells, suggesting that HK2 activity is important for glucose metabolism in cancer cells 5.

Diagnostic Criteria for Diabetes

• The current diagnostic criterion of HbA1c ≥ 6.5% is less likely to detect diabetes than those defined by FPG and 2hPG, and may not be effective in diagnosing diabetes in all patients 6.
• Fasting plasma glucose (FPG) ≥ 126 mg/dL and 2-hour plasma glucose (2hPG) ≥ 200 mg/dL are alternative diagnostic criteria for diabetes that may be more effective in detecting diabetes than HbA1c ≥ 6.5% 6.