Reversing Prediabetes

Understanding the Source of Blood Glucose Elevation

Insulin resistance is far more than just a blood sugar problem. It's a complex physiological state involving multiple organ systems, what researchers call the "Ominous Octet" - eight interconnected mechanisms that contribute to hyperglycemia. By understanding how these systems work together, we can develop root cause prevention and treatment strategies.

BRAIN INSULIN RESISTANCE
Many experts now believe insulin resistance begins in the brain. Toxins, processed foods, and chronic stress disrupt normal hunger and satiety signals, setting the stage for metabolic dysfunction throughout the body (Sears & Perry, 2015). Environmental endocrine-disrupting chemicals can alter insulin signaling not just in peripheral tissues but through central mechanisms that affect global glucose regulation (Schulz & Sargis, 2021).
How to test: Unfortunately, brain insulin resistance is difficult to measure directly outside research settings, but symptoms like constant hunger, food cravings (especially for carbohydrates), and difficulty feeling satisfied after eating may indicate central regulation issues.
How to address: Reducing exposure to environmental toxins, minimizing ultra-processed foods, managing stress, and ensuring adequate sleep can all help restore normal brain signaling patterns. Practicing mindful eating can reconnect you with natural hunger and fullness cues.


FAT CELL DYSFUNCTION
Adipose tissue isn't just for energy storage - it's an active endocrine organ affecting whole-body insulin sensitivity. Initially, fat cells help manage glucose loads, but as they become insulin resistant, they not only fail to take up glucose but actively release free fatty acids that cause further problems throughout the body. These elevated free fatty acids impair insulin secretion and disrupt insulin signaling pathways, creating a vicious cycle (Sears & Perry, 2015).
Interestingly, even lean individuals with prediabetes often show elevated fasting free fatty acids (Pfeiffer & Kabisch, 2021).
How to test: Serum free fatty acids can be measured in both fasting state and after dextrose consumption during an oral glucose tolerance test (OGTT). Elevated levels, especially when they don't drop appropriately after dextrose consumption, suggest adipose tissue insulin resistance.
How to address: Omega-3 fatty acids help adipose tissue by promoting the formation of smaller, more insulin-sensitive fat cells capable of storing more fat without becoming dysfunctional. Regular physical activity, especially strength training and high-intensity interval training, can improve adipose tissue function and insulin sensitivity. Fat tissue is also disrupted by a variety of environmental toxins.


LIVER INSULIN RESISTANCE
The liver plays a crucial role in glucose regulation through storage of glucose as glycogen, glucose production, and adjusting insulin levels. When adipose tissue becomes insulin resistant, the free fatty acids released travel directly to the liver, promoting fatty liver development and liver insulin resistance (Sears & Perry, 2015).
How to test: Indexes derived from fasting glucose and insulin measurements, such as HOMA-IR, primarily reflect liver insulin resistance rather than whole-body insulin sensitivity (Abdul-Ghani et al., 2007). Elevated liver enzymes (ALT, AST) and imaging studies showing fatty infiltration also suggest hepatic insulin resistance.
How to address: Omega-3 fatty acids (again) improve liver function and protect against non-alcoholic fatty liver disease (Aziz et al., 2024). Reducing refined carbohydrates and added sugars, and especially alcohol intake, helps decrease the liver's fat production, while intermittent fasting (eating earlier in the day is preferable) may improve hepatic insulin sensitivity.


MUSCLE INSULIN RESISTANCE
Skeletal muscle is the primary site of glucose disposal, accounting for approximately 70-80% of whole-body glucose uptake after a meal. Muscle becomes insulin resistant largely due to fatty acids from fat cells, and due to inflammatory cytokines released from several organs (Sears & Perry, 2015).
How to test: During an oral glucose tolerance test, the decline in plasma glucose between the 1 hour and the 2 hour marks primarily reflects muscle glucose uptake (Abdul-Ghani et al., 2007). This can provide insight into muscle insulin sensitivity.
How to address: Regular exercise is the most powerful intervention for muscle insulin resistance. Both aerobic exercise and resistance training improve muscle glucose uptake through both insulin-dependent and insulin-independent pathways. Omega-3 fatty acids have demonstrated protective effects against muscle insulin resistance as well (Sinha et al., 2023). Adequate vitamin D and magnesium are also important for optimal muscle insulin sensitivity. Air pollution from PM2.5 particles impact muscle insulin resistance, and can be mitigated at home using an air purifier.


GASTROINTESTINAL/INCRETIN EFFECT ABNORMALITIES
The gut plays a crucial role in glucose metabolism through the secretion of incretin hormones that stimulate insulin release. Approximately 65-70% of insulin response following oral glucose comes from incretin effects that don't occur when glucose is administered intravenously.
The key incretins are GIP from K-cells (in the duodenum and small intestine) and GLP-1 from L-cells, with GLP-1 being one of the most potent insulin-releasing substances known (Holst & Orskov, 2004). In type 2 diabetes, incretins are released but the pancreas fails to respond.
How to test: Incretin effects are difficult to measure outside research settings, which typically compare insulin responses to oral versus intravenous glucose administration.
How to address: Plant polyphenols show glucose lowering effects, sometimes stimulating GLP-1 secretion by modulating gut microbiota and inhibiting DPP-IV activity so incretin levels can rise (Wang et al., 2021). Dietary approaches that support a healthy gut microbiome may improve incretin function.


PANCREATIC BETA CELL DYSFUNCTION
Pancreatic beta cells make insulin. These cells may fail to respond adequately to the signals causing insulin release. These insulin-producing cells require proper redox signaling balance - neither too little nor too much oxidative capacity is optimal for insulin secretion (Ježek et al., 2021). Beta cells are particularly vulnerable to inflammatory mediators, which can impair function long before cell death occurs (Sears & Perry, 2015).
How to test: The C-peptide is the best way to measure beta cell function. The C-peptide to glucose ratio at 1 hour during an OGTT (called C-peptide index or CPI) serves as a predictive marker. Patients who later develop diabetes show average CPI values of 2.5, compared to 6.56 in those who don't develop diabetes (Zhang et al., 2017).
How to address: Reducing overall inflammation and oxidative stress helps protect beta cell function. Dietary approaches rich in antioxidants, omega-3 fatty acids, and polyphenols provide beta-cell protection. Managing blood glucose levels within normal ranges prevents glucotoxicity that damages beta cells over time.



ALPHA CELL DYSFUNCTION
Alpha cells in the pancreatic islets contribute to hyperglycemia through dysregulated glucagon secretion. Glucagon, a type of stress hormone, normally raises blood glucose, but in diabetes, its secretion becomes excessive and poorly regulated.
GLP-1 normally inhibits glucagon release from alpha cells, a function that may be impaired as glucose regulation becomes impaired (Wang et al., 2021).
How to test: Glucagon can be measured as part of an oral glucose tolerance test. In healthy individuals, glucagon levels decline after glucose consumption, but this suppression may be impaired in prediabetes.
How to address: GLP-1 receptor agonist medications help normalize glucagon secretion. Dietary approaches that minimize blood sugar spikes and reduce overall inflammation may help restore normal alpha cell function. Stress reduction techniques are important since glucagon is a type of stress hormone.


KIDNEY GLUCOSE REABSORPTION
The kidneys play an underappreciated role in glucose balance. Normally, they reduce blood glucose by allowing excess to spill into the urine when levels get too high. But in diabetes, they paradoxically increase glucose reabsorption, worsening hyperglycemia.
How to test: Glucose in the urine can be easily tested, but more sophisticated measurements of kidney function and glucose handling require specialized tests not routinely available.
How to address: There are many interventions to optimize kidney health if this is starting to become a problem. They may involve avoiding foods with added phosphates, measuring and addressing blood CO2 levels, and other approaches.


ENVIRONMENTAL FACTORS & THERAPEUTIC INTERVENTIONS
Environmental factors significantly impact insulin sensitivity across all organ systems. Air pollution exposure, particularly to fine particulate matter (PM2.5), worsens insulin resistance (Hectors et al., 2013). A quality air purifier can reduce PM2.5 in your home, providing hours of cleaner air daily.
Heavy metal exposure causes persistent disruptions in gut microbiota that don't self-correct after exposure ends (Jin et al., 2023). These metals cause shifts in microbiome composition that affect metabolism and insulin sensitivity. Intriguingly, animal studies suggest fecal microbiome transplantation may help treat heavy metal-induced dysbiosis (Jin et al., 2023). Approaches involving probiotics and prebiotics, and the fasting-mimicking diet improve metabolism.
Plant compounds offer some of the most promising natural interventions. Epicatechin (found in cocoa), epicatechin-containing foods, and anthocyanins show particular promise for improving insulin resistance (Williamson & Sheedy, 2020). Cocoa flavanols improve insulin sensitivity in both healthy and hypertensive populations and enhance blood vessel function in people with type 2 diabetes (Bapir et al., 2022).
A systematic review of 19 randomized controlled trials found anthocyanin supplementation improved HOMA-IR (Daneshzad et al., 2019). These colored compounds found in berries and other vibrant foods work through multiple mechanisms.
Polyphenols (plant substances present in many plant-based foods, including olive oil) undergo processing by intestinal enzymes and gut microbiota, with high concentrations remaining in the digestive tract. Several polyphenols stimulate GLP-1 secretion by acting on specific receptors, activating taste receptors, and regulating cellular signaling. They also indirectly boost GLP-1 by altering gut microbiota composition, particularly increasing bacteria that produce short-chain fatty acids that stimulate GLP-1 release (Wang et al., 2021).


CONCLUSION
Insulin resistance is a whole-body condition involving an intricate dance between the brain, fat tissue, liver, muscle, gut, pancreatic beta and alpha cells, and kidneys. By understanding each component of this interconnected system, we can develop personalized approaches that target each individual's unique pattern of dysfunction.
Future research and clinical practice should focus on identifying which components of the "ominous octet" predominate in individual patients, allowing for more precisely tailored intervention strategies. Addressing as many aspects as possible offers the best chance for meaningful improvement.