Glucose is a monosaccharide sugar that our bodies obtain from food and use as our principal energy source. The basic molecular form of glucose is C6H12O6. Glucose enters our body in several different forms such as fructose and galactose, which are monosaccharides and isomers of glucose. These monosaccharides can combine to form disaccharides such as lactose and sucrose. Larger polymers of glucose are the polysaccharide forms of glucose which, include starch, glycogen, and cellulose. Our bodies must break down complex sugars into glucose, fructose, and galactose for absorption and metabolism. In addition to obtaining glucose from the diet, our liver and kidneys are capable of producing glucose through a process called gluconeogenesis, and particularly, our liver and muscles can liberate glucose from glycogen stores through glycogenolysis. Within our bodies, glucose is the starting substrate for many vital processes such as glycolysis, citric acid cycle, Cori cycle, glycogenesis, hexose-monophosphate (HMP) shunt, and fatty acid synthesis.
Etiology and Epidemiology
Plasma glucose is measurable in several different ways, and its measurement is most important for the screening, diagnosis, and monitoring of diabetes and metabolic dysregulation presents in conditions such as metabolic syndrome. These conditions result in pathological hyperglycemia or high glucose levels. More than 20 million people in the U.S. have diabetes, with 90-95% of these patients having type 2 diabetes. Type 2 diabetes is estimated to be undiagnosed in at least 30% of the U.S population. Hence, adequate monitoring of plasma glucose in high-risk or pre-diabetic individuals can help guide lifestyle interventions that effectively reduce the risk of becoming diabetic.
Absorption of glucose into cells depends on specific transporters. Some require sodium (Na+) as a co-transporter while others do not. The Na+ dependent transport of glucose uses the Na+/K+ ATPase pump to generate a negative potential gradient that drives passive transport of Na+ into the cell. This gradient also allows other molecules, such as glucose, to be transported into the cell against their concentration gradients. In particular, glucose in the lumen of the gut and renal tubules get absorbed via sodium-glucose cotransporters (SGLTs). The expression of these transporters can change depending on the body’s glucose needs. Once glucose enters these cells, Na+ independent glucose transporters bring glucose into the blood. Na+ independent transport of glucose refers to specialized transporters that vary in type depending on specific tissues. The glucose transporter type 1 (GLUT1) is found in red blood cells and brain and is not subject to regulation by insulin. GLUT2 is in the intestinal epithelium, liver, kidney and notably, the pancreas. These transporters are regulated by different hormones to control the level of plasma glucose as needed.
Glucose homeostasis in the plasma depends on the balance of the hormones glucagon and insulin. Both hormones get released from the pancreas (insulin from beta-cells found in the Islet of Langerhans and glucagon from alpha-cells) in response to plasma glucose levels. In response to high glucose levels, insulin promotes the uptake of glucose into cells that have glucose transporter type 4 (GLUT4), found in adipose tissue and skeletal and cardiac muscles. Insulin exerts its effects through binding to insulin receptors, which possesses tyrosine kinase activity and by activation of a series of downstream events beginning with insulin substrate-1 (IRS-1) culminates in the increased expression of GLUT4. Additionally, insulin can down-regulate its own receptors, which may contribute to the pathophysiology of insulin resistance (receptor and post-receptor defects) in metabolic dysregulation of obesity and diabetes. In particular, insulin receptors are found to be decreased in obesity and increased in starvation. Other actions of insulin to modulate blood glucose concentrations include stimulating glycogenesis in liver and muscle tissues and fat deposition and inhibiting glycogenolysis and gluconeogenesis. Glucagon promotes the release of glucose into the blood through gluconeogenesis, which occurs primarily in the liver, and glycogenolysis, which occurs in the liver and muscle. It also increases fatty acid and ketoacid concentrations in blood.
Importantly, plasma glucose levels undergo regulation through a few key pathways: glycolysis, gluconeogenesis and glycogenesis/glycogenolysis. Insulin can affect glycolysis and gluconeogenesis through dephosphorylation of the phosphofructokinase-2 enzyme (PFK-2), which increases levels of fructose 2,6-bisphosphate (F-2,6-BP). This molecule directly increases the activity of the enzyme PFK-1, which converts fructose-6-phosphate to fructose 1, 6-bisphosphate and commits glucose to the glycolysis pathway and directs it away from gluconeogenesis. In contrast, glucagon similarly influences glycolysis and gluconeogenesis through phosphorylation of fructose 2,6-bisphosphatase, which decreases levels of F-2,6-BP and subsequently, the activity of PFK-1. This activity shunts glucose away from glycolysis and towards gluconeogenesis and glycogenolysis.
Other hormones that influence glucose homeostasis include incretins such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP). Incretins potentiate the release of insulin in response to oral glucose. Other hormones that influence glucose metabolism include pancreatic amylin, glucocorticoids (increase insulin resistance and gluconeogenesis), thyroid hormones (promotes glucose absorption, glycogenolysis, gluconeogenesis), growth hormones (inhibits glucose uptake into cells) and epinephrine.
Diabetes mellitus refers to a disorder in regulating blood glucose levels and is associated with genetic and lifestyle factors, such as family history, race, obesity, and diet. Diabetes resulting from other causes include monogenic diabetes (such as neonatal diabetes), maturity onset of diabetes in the young (MODY), gestational diabetes, pancreatic insufficiency or drug-induced. High blood glucose levels characterize the disorder due to insulin resistance and ultimate insulin deficiency. Diabetes occurs most commonly as two main types: type 1 or type 2. Type 1 occurs in younger patients and due to an autoimmune pathology in which the immune system attacks beta-cells of the pancreas, resulting in a loss of insulin. Without insulin, the body loses the primary stimulus to transport blood glucose into cells. These patients require lifelong injections of insulin to replace their deficiency. Type 2 diabetes occurs in the majority of patients with weight gain. This type is more strongly associated with obesity, progressive metabolic dysregulation, and insulin resistance. The body produces insulin in type 2 diabetes, but the cells are less sensitive to insulin; hence, a higher level of insulin is needed to stimulate cells to take up glucose. In diabetes, glucose stays elevated outside of the cells resulting in starved cells despite high glucose levels in plasma. Cells switch to protein and fatty acid catabolism, which can result in increased urea and ketones. When glucose levels stay high in the plasma, it can cause osmotic damage to nerves resulting in peripheral neuropathies, reduce wound healing, increase inflammation through reactions that create oxidative stress and inflammation and modified to become advanced glycation products (AGEs) which promote both microvascular and macrovascular complications. Notably, glucose can react with the amino group of a protein non-enzymatically, forming compounds such as fructosamine, that reflect the level of glucose control over 2 weeks. Clinical presentation includes polydipsia, polyuria, weight loss with polyphagia. Hence, the widespread elevation of glucose in plasma can lead to irreversible organ damage over time and control of glucose levels is crucial to preventing these long-term outcomes.
Plasma glucose levels can be measured using blood glucose meters or analysis of glycated hemoglobin (HbA1c). Plasma glucose can be measured with high precision and accuracy using enzymatic methods such as glucose oxidase and hexokinase, etc. HbA1c is specific for diabetes but not very sensitive and has greater utility to monitor diabetes control over 2 to 3 months. Also, it is falsely elevated with iron deficiency and, hence, not appropriate or cost-effective for the developing world.
Use of glucose meters is common in physician offices or by patients to monitor blood glucose levels and establish patterns of glucose fluctuations over time with regular use and recording. Meters require a drop of blood applied to a test strip that inserts into a meter to estimate the plasma glucose level. The simple use of the meter can also help screen for acute hypoglycemic or hyperglycemic episodes and help patients plan meals, activities and insulin treatment.
Current laboratory recommendations for plasma glucose measurement are to draw fasting blood samples in the morning rather than later in the day, as glucose levels tend to be higher in the morning than the afternoon. These samples should be placed on ice to minimize glycolysis and quickly processed (via plasma separation within 60 minutes) as glucose concentrations decrease at a rate of 5 to 7% per hour. If plasma separation cannot occur within 60 minutes, the lab tech can add a glycolytic inhibitor such as fluoride.
Oral Glucose Tolerance Test (OGTT)
The OGTT requires a fasting blood glucose measurement in the morning. After the measurement, the patient receives oral glucose (usually a glucose load of 75g anhydrous glucose dissolved in water) that the patient consumes. The plasma glucose levels are measured again at 1-hour and 2-hours to analyze the glucose level changes. This test is no longer routinely used for diagnosis of diabetes since it is cumbersome but is still sometimes used for gestational diabetes.
Essential factors to consider when checking plasma glucose levels is the time at which the patient last consumed anything caloric. Plasma glucose levels tend to be lowest before meals or when fasting. In addition, evidence suggests that fluctuations of glucose levels throughout the day may contribute to a missed diagnosis of diabetes. Hence, recommendations are to check fasting plasma glucose in the mornings when endogenous levels of glucose predominate compared to later in the day. When processing a sample of plasma glucose, it is crucial to limit the amount of glycolysis that occurs after drawing a sample. To limit glycolysis in a sample, process the sample within the hour or use a glycolytic inhibitor to stabilize the sample.
Additionally, some glucose measurement differences have been found depending on the method of blood processing. For instance, plasma glucose levels are about 11% higher than in whole blood with normal hematocrit while postprandial capillary blood glucose levels are 20% higher than in venous blood.
Results, Reporting, Critical Findings
Normal plasma glucose levels are defined as under 100 mg/dL during fasting and less than 140 mg/dL 2-hours postprandial. Additionally, glucose levels in healthy individuals can vary with age. Fasting plasma glucose in adults tend to increase with age starting in the third decade of life but does not increase significantly beyond 60 years of age. Normal HbA1c is lower than 5.7%.
Diagnosis of diabetes depends on plasma glucose, which is measurable during fasting, the oral glucose tolerance test (OGTT) or using the A1c criteria. Fasting plasma glucose measurements show glucose levels at the point in time whereas HbA1c measures the average amount of glycation to hemoglobin, usually accumulating over 2 to 3 months. According to the American Diabetes Association (ADA), fasting (defined as at least 8 hours of no caloric intake) plasma glucose greater than or equal to 126 mg/dL is diagnostic. Confirmation of the diagnosis requires two abnormal test results conducted from the same sample or two separate samples. Other equivalent diagnostic criteria include 2-hour plasma glucose of greater than or equal to 200 mg/dL during OGTT or A1c of greater than or equal to 6.5% (performed in an accredited laboratory). Clinically, a patient with symptoms of hyperglycemic crisis and random glucose of greater than or equal to 200 mg/dL also meet the diagnostic criteria.
Patients who are at the borderline of these criteria for diabetes are considered prediabetic. The ADA criteria define prediabetes as impaired fasting glucose (IFG) defined as fasting plasma glucose of 100 mg/dL to 125 mg/dL or impaired glucose tolerance (IGT) 2-hour plasma glucose (in OGTT) of 140 mg/dL to 199 mg/dL or A1c of 5.7 to 6.4%. Patients with prediabetes are at high risk of progressing to diabetes. In particular, a systematic review found that increased A1c from 6 to 6.5% correlated with an increased 5-year incidence of diabetes.
The definition of hypoglycemia is generally plasma glucose under 70 mg/dL, but symptoms may not occur until plasma glucose is less than 55 mg/dL. Such low levels of plasma glucose indicate a dangerous, potentially life-threatening situation characterized by seizures and coma. Importantly, plasma glucose reference values for hypoglycemia currently vary widely and diagnosis still largely relies on clinical presentation.
Measurements of plasma glucose levels are important for the screening of metabolic dysregulation, pre-diabetes, and diabetes. Evidence finds that the onset of diabetes type 2 can occur as early as 4 to 7 years before clinical diagnosis. Additionally, plasma glucose levels can be used as a tool to monitor diabetes, screen for hypoglycemic episodes, guide treatment or lifestyle interventions and predict risk for comorbidities, such as cardiovascular or eye and kidney disease. In particular, evidence reports that plasma glucose level monitoring in patients with type 2 diabetes can predict complications and mortality. Higher glucose correlates with more significant co-morbidities and risk for mortality. In a 15-year study of 1939 patients with type 2 diabetes, patients with fasting plasma glucose equal to or greater than 140 mg/dL showed a significantly increased risk of death. Similarly, type 2 diabetic patients with fasting plasma glucose equal to or greater than 140 mg/dL were found to have increased cardiovascular mortality. Other studies also report the risk of a first myocardial infarction increases with higher fasting plasma glucose levels.
Enhancing Healthcare Team Outcomes
Routine screening of plasma glucose levels in at-risk patients would aid early diagnosis and intervention to limit the complications and mortality risks of diabetes. In particular, continuous monitoring of glucose in intensive care patients has been suggested to help prevent severe hyperglycemia and hypoglycemia and associated mortality risks. With continuous glucose monitoring (CGM), hypoglycemia or hyperglycemic episodes can be detected early and provide guidelines for rapid insulin/interventional adjustments. Hence, access to accurate measurements of glucose in real-time alerts health professionals to the efficacy of treatment and helps decrease the risk of missed episodes of hypoglycemia/hyperglycemia. [Level III]
Serum glucose monitoring can inform and direct care for several potentially deleterious sequelae if elevated. As a result, it is the responsibility of everyone on the health care team to be involved in the testing, patient education, monitoring, and therapy when appropriate. This includes physicians, specialists, nurses (including specialty-trained nurses), and pharmacists, such that everyone is on the same page and directing their efforts to optimize patient care and outcomes. [Level V]