Glucose: Diagnostic Significance and Clinical Insights
Authors: Dr. Payal Bhandari, M.D., Hailey Chin
Contributors: Vivi Chador, Nigella Umali Ruguian, Amer Džanković, Tejal
Key Insights
Glucose tests are important for managing conditions like diabetes. HbA1c shows the average blood sugar level over the past 8 to 12 weeks. These tests help diagnose and monitor metabolic issues like insulin resistance and diabetes. They also allow for early intervention, lifestyle changes, and tracking treatment success for those with high blood sugar. Normalizing blood glucose is key to preventing conditions like heart disease, obesity, and autoimmune or neurodegenerative disorders.
Figure 1: Symptoms and Signs Associated with an Abnormal Blood Glucose Test
What Is Glucose?
Glucose is a type of sugar that acts as the main energy source for the body. The body uses a process called cellular respiration to turn glucose into energy (ATP). Figure 2 demonstrates this three step process:
Glycolysis: One glucose molecule is broken into two pyruvate molecules in the cell’s cytoplasm, creating 2 ATP and 2 NADH (energy carriers).
Krebs Cycle: Pyruvate moves into the mitochondria and is further broken down, producing 2 ATP and more energy carriers (NADH and FADH).
Electron Transport Chain: Electrons from NADH and FADH move through a series of proteins, generating 34 ATP. Oxygen is needed to complete this step.
If oxygen isn’t available, the process stops, energy runs out, and cells die.
Figure 2: Cellular respiration is a process that converts energy from plants into high-energy molecules like ATP, NADH, and FADH, releasing carbon dioxide (CO2) when we breathe out. This 3-step process produces the most energy in the electron transport chain in the mitochondria, creating 34 ATP, plus 2 ATP each from glycolysis and the Krebs cycle.
Role of Glucose
Glucose helps cells produce energy (ATP) through a process called glycolysis. ATP powers many essential body functions.
Foods like fruits, vegetables, grains, and dairy break down into glucose during digestion. Once in the bloodstream, glucose may appear as forms like fructose or sucrose. Cells use glucose for energy immediately or store it as glycogen for later use. During low-energy states, stored glycogen can be converted to energy through a process called ketogenesis.
Regulation of Blood Glucose Levels
The body usually gets energy (ATP) from glucose through a process called glycolysis, which breaks down food. However, during fasting, intense exercise, insulin deficiency (like in diabetes), or when the brain needs more energy than the body, fats and proteins are used instead.
This process, called ketogenesis, breaks fats and proteins into amino acids, lactic acid, and glycerol for energy. Since the brain can’t directly use fats for energy, glycerol from fats is converted into glucose through gluconeogenesis to produce ATP.
Harvesting Energy After A Meal
After eating, food is broken down in the small intestine into glucose, fatty acids (FAs), and amino acids (AAs), which enter the bloodstream. Insulin, a hormone from the pancreas, moves glucose into tissues for energy (ATP). Excess nutrients are sent to the liver, where:
Glucose is stored as glycogen or turned into FAs or AAs.
FAs are converted into triacylglycerol (TAG) and stored in liver cells or released into the blood as VLDL particles.
AAs provide energy for muscles and fat tissue or are used to make proteins, glucose, or other molecules.
The liver detoxifies harmful byproducts (like ROS), which are excreted through stool, urine, or sweat.
Harvesting Energy During Short-Term Fasting and Intense Emotions
During short-term fasting or intense emotions, the body adjusts how it produces energy. The liver’s energy process slows, and hormones like glucagon (from the pancreas) and catecholamines (from the adrenal glands) reduce insulin levels. This triggers an enzyme, lipoprotein lipase (LPL), to break down stored glycogen and fat into acetyl-CoA.
Acetyl-CoA is converted into ketone bodies like acetoacetate, primarily in the liver. Acetoacetate enters the energy cycle (Krebs cycle) to produce ATP. Some acetoacetate is turned into beta-hydroxybutyrate, while a small amount becomes acetone, a toxin exhaled through the lungs.
Harvesting Energy During Low Energy States, such as Starvation and Intense Exercise
When glycogen stores run out during starvation or intense exercise, the body uses other sources for energy:
The liver releases stored fat (VLDL cholesterol) into the bloodstream.
Fat tissue breaks down fatty acids and glycerol, which are sent to the liver to create ketones (ketogenesis).
Muscles break down proteins, releasing lactate, alanine, and glycerol into the blood. These are transported to the liver to make glucose (gluconeogenesis).
Figure 3: Circadian rhythm genes control glucose and ketone production in the liver to manage energy. Fat, muscle, and liver cells use nutrients to make ATP. Ketones help provide energy during fasting or exercise, balance blood sugar, and improve insulin sensitivity, reducing hunger, anxiety, and stress.
Pathophysiology of Abnormally High Blood Glucose Levels
Figure 4: The clinical manifestations of extremely high or low blood glucose levels include, but are not limited to, multi-organ damage, hormonal imbalances, infections, cancers, brittle bones (osteoporosis), osteoarthritis, diabetes, vascular diseases, and many other health conditions.
Hyperglycemia means high blood sugar, often linked to diabetes. While it can be inherited, it’s usually caused by an unhealthy lifestyle. High blood sugar is often seen with high cholesterol, triglycerides, VLDL, and LDL, and low HDL. Low blood sugar isn’t a concern if it comes with low cholesterol, triglycerides, VLDL, and LDL, and normal or high HDL. It also supports healthy hormone production in the ovaries, testes, thyroid, and adrenal glands.
Abnormal blood sugar is linked to poor gut health and low blood flow to the digestive system. Healthy gut bacteria digest food, absorb nutrients, and remove waste. Slow stomach emptying can lower good bacteria and cause nutrient problems .
Figure 5: Healthy gut bacteria aid digestion, nutrient absorption, and waste removal. Dysbiosis occurs when there are fewer healthy bacteria, disrupting metabolism and boosting harmful pathogens that affect immunity.
Dysbiosis disrupts the body’s ability to process proteins, fats, and carbs, leading to undigested food and toxins in the bloodstream. This thickens blood and reduces oxygen delivery to tissues. The kidneys produce more red blood cells, and the liver stores fat and makes glucose.
Chronic dysbiosis lowers energy production and harms cells. The immune system focuses on tissue repair instead of fighting infections or cancer. White blood cells can attack the body, causing autoimmune problems and increasing the risk of diseases like atherosclerosis, infections, and cancer . Abnormal blood glucose levels raise the risk of metabolic disorders and organ damage.
The consequence of severely high or low blood glucose levels include, but are not limited to the following diseases:
Atherosclerosis-Induced Vascular Inflammation
Figure 6: Atherosclerosis causes artery thickening (tunica intima hyperplasia) and clot formation by platelets. Macrophages ingest oxidized LDL cholesterol, becoming foam cells that release inflammatory proteins and ROS. Chronic inflammation increases white blood cells and platelets, damaging cells and microbiota, reducing organ function, and raising the risk of health issues.
Atherosclerosis causes inflammation in blood vessels, leading to fat and iron buildup in the pancreas. This reduces insulin and glucagon production, making it harder for cells to take in glucose and produce energy. The liver then makes more glucose, blocks fat breakdown, and raises levels of harmful proteins, fats, cholesterol, and sugars in the blood. This thickens the blood, reducing oxygen flow to tissues and energy production.
Hormonal and Energy Imbalances
High blood glucose is linked to stress, which activates the “fight-or-flight” response. Stress hormones raise thyroid hormone levels, speeding up metabolism and fat breakdown. However, long-term imbalances can disrupt hormone control.
This leads to more fat storage, higher blood glucose and insulin, and lower cholesterol removal by the liver. Over time, it can cause fat buildup in arteries, leading to heart disease and thyroid disorders like Hashimoto’s or Graves’ disease. Symptoms include irregular periods, infertility, fatigue, weak bones, and skin problems.
Figure 7: The pituitary gland makes several important hormones, including thyroid-stimulating hormone (TSH), corticotropin, and growth hormone. These hormones help control other glands and maintain energy balance in the body. Patients with pituitary disorders often need lifelong treatment, education, and support to manage related issues like abnormal blood glucose levels.
Autoimmune Disorders
Conditions like rheumatoid arthritis (RA), lupus, inflammatory bowel disease (IBD), and multiple sclerosis are linked to high blood glucose and inflammation in the body. A study of 111,758 patients found that RA patients had a 50% higher risk of death, similar to people with diabetes. RA patients also have a similar risk of heart problems as diabetic patients.
Chronic Liver Dysfunction and Damage
Figure 8: The liver plays a key role in fat metabolism, making glucose, proteins, and detoxifying waste. When the liver is damaged, it reduces energy production and creates harmful molecules that damage cells, leading to conditions like fatty liver disease, fibrosis, and cirrhosis.
Chronic Kidney Dysfunction and Damage
A high-fat diet can disrupt energy processes, raising blood glucose and causing fat buildup in the kidneys, damaging them. A 2020 study linked high blood glucose to worsening kidney function and a higher risk of chronic kidney disease (CKD). People with CKD are more prone to further kidney damage from medications. A plant-based, nut- and oil-free diet can help reduce kidney problems and high blood glucose effects.
Brain and Nervous System Damage
The brain has more cholesterol than other tissues. Since lipoproteins can’t cross the blood-brain barrier, brain cells make their own cholesterol for energy. When the liver doesn’t process fat well, it increases glucose and creates harmful ROS, which damage the blood-brain barrier. This allows toxins to affect brain cells.
White blood cells then attack brain cells, making it harder to clear harmful proteins like beta-amyloid, leading to more cholesterol production. This can cause brain issues like:
Learning disabilities
Poor blood flow to the brain
Cognitive problems (e.g., dementia)42
Pathophysiology of Abnormally Low Blood Glucose Levels
Very low blood glucose levels are often linked to low hemoglobin A1c (HbA1c) and can suggest problems like anemia, shortened red blood cell (RBC) lifespan, and reduced energy production. These issues can increase the risk of illness and death. Low HbA1c levels can sometimes look like high HbA1c levels.
Several factors can cause low blood glucose, including:
Overuse of blood sugar-lowering medications in people with diabetes can lead to hypoglycemia, causing the body to release growth hormones like insulin and thyroid hormones. This alters metabolism and reduces oxygen supply to tissues.
Certain drugs can interfere with vitamin absorption and liver function, lowering nutrient levels and affecting energy production.
Dehydration can cause RBCs to shrink or swell, damaging them and reducing oxygen delivery to tissues. This can disrupt liver metabolism and lower blood glucose by increasing reactive oxygen species (ROS), which harm cell energy production.
Figure 9: Effects of water osmosis on the integrity and functioning of blood cells. Water osmosis is the transportation of water throughout a cell that is determined by the cell’s solute concentration. Hypotonic cells have a higher solute concentration inside the cell than outside of the cell causing more water to be transported inside of the cell. Isotonic cells have the same solute concentration inside the cell and outside the cell causing water to be transported into and out from the cell equally. Hypertonic cells have less solute concentration inside the cell causing the cell to transport water out of the cell.
Fluid loss that can lower blood glucose includes:
Slow blood loss (e.g., heavy periods, hemolytic anemia)
Excess blood loss (e.g., surgery, trauma)
Frequent blood donation
Chronic dehydration can disrupt gut bacteria, increasing undigested proteins, fats, and sugars in the blood. This causes more inflammation and damage to red blood cells. It also raises iron levels, which affects heme production and lowers HbA1c levels.
Conclusion
Interpreting glucose tests requires considering factors like age, medications, and other health conditions that affect glucose, red blood cells, and organ function. Other tests may help guide treatment.
Treating abnormal glucose levels involves medications and lifestyle changes to address underlying causes and prevent complications. Poor diet, lack of sleep, and high stress can lower glucose levels. A healthy diet, 7-9 hours of sleep, and stress management are key to maintaining proper glucose levels.
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