Due to numerous factors, humans today may have lost certain metabolic efficiencies that safeguarded early existence. Depending upon a hunter-gatherer’s foraging success, daily survival for homo sapiens was most often shaped by the biodiversity of available food sources, foraging behaviors that provided an abundance of daily exercise, and distinct periods of intermittent fasting. This was due to living in a world filled with unpredictable food supply.
Paleontologists suggest our evolutionary path morphed to human-like bodies with elongated legs and shorter arms over a million years ago. So, the earliest adaptation was learning how to live life on the ground. Although they lost tree-climbing skills, their new bodies needed to absorb nutrients on a faster, more regular basis just to meet the physiological demands of burning food to fuel a taller body with a larger brain. Evidence also exists of campfire hearths used for heat where food was likely shared.
“As a medical student in 2025, many of the important medical decisions you will make as a practicing physician are going to be linked to this evolution of metabolic derangements at a cellular level,” says Dr. Hans Wolf, founder of WOLFPACC Physician’s Achievement Concept Course. “For starters, the human body still needs a variety of nutrients, daily exercise, and distinct periods between food intake. But practicing medicine isn’t about finding a magic solution; it’s about applying the basic sciences to your diagnoses.”
At a cellular level, disorders occur when an abnormal chemical reaction disrupts the body’s natural metabolism. However, the list of contributing factors is long and includes genetics, aging, ethnicity, daily exercise, dietary habits, and both physical and mental forms of trauma. Not surprisingly, these same causes have been directly linked to human health from wayback then until now. But today, people have better food availability, which in turn may have led to a more sedentary lifestyle with added culprits like smoking and excessive alcohol consumption.
The Loss of Metabolic Flexibility
For about 99.5% of human history (or roughly 84,000 generations), survival depended on metabolic flexibility and people’s ability to adapt. Daily life was shaped by varying diets and frequent physical activities, often under fasting conditions. This trait allowed early humans to survive despite fluctuations in food supply, relying on stored fat reserves during periods of scarcity and utilizing alternative energy sources like ketone bodies and muscle-derived lactate. Such adaptability over millions of years, stabilized energy balance to ensure survival.
However, with the Agricultural Revolution around 12,000 BC, humans began storing food in large quantities, which reduced their reliance on metabolic flexibility. Although we don’t know everything about our ancestors, it is likely this move from nomadic (hunter-gatherers) to sedentism (cultivation of land and animal domestication) changed human health after becoming exposed to the consequences of metabolic deficiencies. Plus, the search for answers likely began with plant-based solutions, some of which are still being discussed intensely today.
It was the somewhat sudden organization of tribal societies that continued to impose demands that eventually pushed aboriginal populations to adopt a lifestyle with a fixed habitat. But the same mechanisms of preserving glycogen and optimizing fat as fuel that once ensured survival, now contributed to a less useful accumulation of body fat. A combination of the slowing of metabolism over time and nutrient-poor diets loaded with energy-dense foods did negatively impact flexibility and contributed to a rise in metabolic disorders. These changes illustrate both the adaptability and challenges created by our human evolution.
Centuries of Forced Sedentism
A key example of changes due to sedentism include metabolic syndrome. This condition is associated with being overweight or obese, particularly when excess fat accumulates in the abdominal region. It is often closely tied to a sedentary lifestyle and typically leads to insulin resistance, where the body struggles to process sugar from food efficiently at the cellular level. This increases the risk of cardiovascular disease with factors such as high blood pressure, elevated blood sugar, high triglycerides, and low HDL cholesterol. Additionally, as people age, they tend to lose fat-burning muscle mass due to reduced physical activity.
Evolution had definitely shaped the human metabolic system for times of energy deficiency rather than the presence of opulence. Around 1500 BCE, the ancient Egyptians recognized a rare disease that caused excessive urination, but did not understand the cause of this metabolic derangement. In India, physicians had identified two types of disorders after noticing how ants were attracted to patients’ urine, which they called “honey urine.” The first accurate description, experimentations, and the name “diabetes” didn’t occur until the second century AD under Greek physician Aretaeus of Cappadocia.
Nowadays, type 2 diabetes has become one of the most common public health issues due to increased prevalence, morbidity and mortality caused by its complications. In addition to diabetes, atherosclerosis is a plaque buildup in the arteries that is associated with metabolic syndrome and can take away years of healthy living. Due to poor fat oxidation, about half of us have cholesterol deposits in our arteries by age 40. When the inner artery walls are damaged, inflammatory cells send chemical signals that cause cholesterol and cell waste to accumulate, attracting white blood cells that contribute to the formation of plaque.
Metformin versus Berberine
The primary goal of ancient medicine was to restore balance. Chinese, Indian and Greco-Arab physicians used herbal formulas and medicinal plants to treat metabolic disorders like obesity and diabetes. Berberine is a compound found in various plants like European barberry, Oregon grape and goldenseal. It has been used medicinally for over 3,000 years to improve gut health, dysentery, uterine and vaginal disorders as well as reduce fever due to infections or wounds. Metformin is a derivative of European Galega plants that has been used since the Middle Ages to relieve symptoms of diabetes by decreasing blood sugar.
- Metformin – Metformin has been a key player in managing type 2 diabetes for decades and remains a first-line treatment due to its efficacy and FDA-approval. It reduces glucose production in the liver, decreases glucose absorption in the intestines, and enhances insulin sensitivity, enabling cells to absorb and utilize glucose more effectively. Metformin is not only effective in reducing hemoglobin A1c but also offers additional benefits, such as potential cancer prevention.
- Metformin works relatively quickly, typically taking about 4-5 days to achieve full effects, compared to berberine, which may take up to three months to show results. As a first-line anti-diabetic drug, it does have a boxed warning for a rare, yet life-threatening condition called lactic acidosis. Phenformin is a biguanide medication that came before metformin, and although it is still studied in clinical trials for its efficacy against cancer cells, it was taken off the market due to its high risk of lactic acidosis.
- Physicians should also be aware of other common side effects, which include gastrointestinal discomfort like nausea, diarrhea, bloating, and gas, as well as the risk of vitamin B12 deficiency (feeling very tired, breathless or faint). While some early studies suggest potential anti-aging and heart-protective benefits, these findings are not yet conclusive. Like any medication, it requires careful consideration of risks, benefits, and individual patient suitability.
- Berberine – Berberine is a natural compound derived from plants and used in Chinese medicine for centuries to manage diabetes. Today, research highlights berberine’s potential as a powerful tool in addressing metabolic conditions like prediabetes, T2DM and metabolic syndrome. Recent studies suggest it is a potent hypoglycemic that works as effectively as metformin, and in some cases, may be better at lowering A1c levels while reducing cholesterol and improving insulin sensitivity and lipid metabolism.
- Berberine has also been shown to improve gut microbiota balance, which may further enhance its metabolic benefits. Recent clinical studies have also highlighted its antioxidant, anti-inflammatory, and immune-modulating properties, making it a promising option for managing metabolic dysfunction. For instance, a 2023 clinical study found that participants with obesity taking 1.5 grams of berberine daily for 24 weeks achieved significant reductions in BMI and waist circumference.
- Despite its promising natural options for managing metabolic derangements, berberine does come with some limitations. It may cause mild gastrointestinal side effects such as diarrhea or constipation. It can also interact with certain medications, posing risks for individuals taking drugs metabolized by the liver, such as those for blood pressure or autoimmune disorders. Berberine may inhibit the absorption of vitamin B12 and iron and is not recommended for pregnant or breastfeeding women.
Human flexibility allowed us to become the planet’s dominant living species, but the current rise in metabolic syndrome may be due to the changes in early metabolic processes. To evolve, a human’s body had to be flexible as they were forced to adapt to the climate and vegetation available during different seasons. It was this unique level of metabolic flexibility that safeguarded survival, and somewhat independent of daily food sources. Since muscle mass is essential for processing glucose and fatty acids, a decline in lean tissue further impacts metabolic health as adults age.
Neither… Either… or Both?
“As a medical student, you learn the basics of doctoring during the pre-clinical phase and have likely practiced taking medical histories and performing physical exams,” explains Dr. Wolf. “Along with a ton of basic sciences, this prepares you to interpret lab results and imaging to make correct diagnoses. Some patients may have no problem taking either metformin or berberine, while others may not be able to tolerate either. More recent clinical studies have highlighted how taking both may produce the best benefits for those who meet certain criteria.”
Metformin is a widely used first-line medication for managing diabetes, known for its proven effectiveness. However, as a prescription drug, it comes with potential risks and side effects. One serious concern is its boxed warning for lactic acidosis, a rare but life-threatening condition. Long-term use of metformin can also lead to vitamin B12 deficiency and anemia, and it may interact with other medications such as thyroid treatments or certain diuretics. For the most common type of diabetes that accounts for about 90% of all cases, berberine combined with metformin has good efficacy and safety in the treatment of T2DM for patients who qualify.
Despite the differences in structure, both metformin and berberine exert hypoglycemic actions with lipid lowering effects that could be excellent in treating insulin resistance for metabolic deficiencies related to type 2 diabetes, obesity and cardiovascular disease. At a cellular level, both work by reducing glucose production in the liver and increasing glucose uptake in muscle cells. Current research suggests metformin may be more potent in regulating blood sugar levels while berberine may be more effective for treating hyperlipidemia and obesity, with antioxidant properties that suggest even broader therapeutic potential.
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Since obesity and metabolic syndrome are highly impactful on increasing the risk of developing chronic conditions, pharmaceutical companies are hurrying to find replacements for the chemical balance of human metabolic flexibility. As doctors, we might consider the generations that enjoyed food diversity, daily physical activity, and natural periods of fasting between food intake. After all, there will always be the medical threats posed by injuries, illnesses and genetic effects. Dr. Hans Wolf devoted decades to developing WOLFPACC’s “The Power 5” Methodology for helping medical students understand how to apply the basic sciences that they learned in medical school to the practice of medicine. If you’re ready to be the best physician you can be, contact us today to schedule a USMLE or COMLEX review program.
