Diabetes is a leading cause of blindness, non-traumatic lower limb amputations, peripheral neuropathy, and end-stage renal disease, and a significant risk factor for atherosclerotic cardiovascular disease. Mortality from diabetic complications accounts for 43% of all deaths among people under 70.

Insulin resistance (IR) is a decrease in insulin sensitivity in muscles, adipose tissue, liver, and other insulin-dependent tissues, accompanied by impaired glucose homeostasis. Insulin resistance is the leading cause of type 2 diabetes and the best predictor of this disease.

The risk of developing insulin resistance is increased by a lack of exercise and a diet high in fat and carbohydrates. IR is associated with metabolic inflexibility – the inability of the body to switch between glucose oxidation and fatty acid oxidation, depending on the availability of these energy sources. In obesity, IR occurs not only due to an excess of fatty acids but also to metabolic inflexibility – the ability to oxidize fats is impaired, which leads to the accumulation of triglycerides in skeletal muscles. Studies have confirmed that, compared with people with average body weight, obese patients have a lower ability to oxidize fat and the rate of fat oxidation during exercise.

Treatment of Insulin Resistance: Exercise and Medication

Exercise and certain medications improve glucose and fatty acid metabolism in skeletal muscle, reducing insulin resistance and improving insulin sensitivity, as well as reducing complications of diabetes such as inflammation and oxidative stress.

1. Metformin

Metformin is a drug for the treatment of IR. Like exercise, it improves insulin sensitivity. Metformin reduces glucose production in the liver and increases the oxidation of fats in the liver and throughout the body. In overweight or obese patients with insulin resistance, metformin improves glucose uptake and fatty acid oxidation in skeletal muscle, increasing insulin sensitivity.

Another benefit of metformin is that in patients with prediabetes or polycystic ovary syndrome (PCOS), metformin reduces the incidence of severe COVID-19. In these patients, elevated blood glucose increases the risk of severe COVID-19, as high glucose causes endothelial dysfunction and reduces the body’s ability to regulate immune and inflammatory responses.

American scientists have shown that patients with prediabetes or PCOS who took metformin before contracting coronavirus were less likely to suffer from mild, moderate, and severe COVID-19 than those who took medications not associated with prediabetes or PCOS.

The protective effect of metformin can be explained by the fact that metformin attenuates endothelial dysfunction, prevents the penetration of the virus into the cell, and attenuates inflammatory responses during COVID-19, which can lead to dysfunction of internal organs.

The article “Metformin Reduces COVID-19 Severity in Prediabetic Patients” contains details of the study. The study was published in Diabetes Research and Clinical Practice.

Metformin may slow aging

In nematodes, metformin prolongs lifespan by 36%. This effect can be explained by:

• Metformin activates AMPK, an enzyme that regulates the cell’s uptake and oxidation of glucose and fatty acids. Activated AMPK reduces hepatic glucose production, increases glucose uptake by skeletal muscle, stimulates oxidation, and inhibits fatty acid synthesis. By activating AMPK, metformin prolongs the life of the musculoskeletal system.
• Activation of AMPK increases mitochondrial production of reactive oxygen species, which triggers stress defense mechanisms and increases life expectancy. The mechanism of lifespan extension based on mitochondrial oxidative stress is called mitohormesis.
• Metformin inhibits the mTORC1 target of rapamycin, a protein complex that regulates cell growth and nutrition, oxidative stress, autophagy, protein, lipid, and glucose synthesis and metabolism. Suppression of mTORC1 prolongs lifespan. [see “Rapamycin”]
• Metformin alters the microbiome with anti-inflammatory effects. Metformin suppresses the expression of genes encoding inflammatory cytokines that are observed during cellular aging. This property may underlie the ability of metformin to downregulate SASP in aging cells.

In studies in Drosophila and mice, metformin has shown conflicting results. Metformin did not affect lifespan in Drosophila, although it activated AMPK and reduced lipid stores. In cancer-prone mice, metformin increased lifespan and inhibited carcinogenesis. In long-lived and outbred mice, metformin alone did not significantly prolong lifespan, but metformin in combination with rapamycin did significantly prolong life. Although metformin did not increase lifespan in long-lived mice, it may be effective in stressful situations that shorten lifespan.

Human studies have shown that metformin is associated with reduced morbidity and mortality from cardiovascular disease, reduced incidence of cancer, overall mortality, depression, and frailty-related illnesses. Metformin also protects against neurodegeneration and chronic kidney and liver diseases. However, all of these studies compared type 2 diabetic patients treated with metformin with the general population. Therefore, it is unclear whether metformin will benefit people who do not have diabetes.

A study in healthy 70-year-olds showed that metformin taken for six weeks affected not only metabolic genes and pathways but also collagen and mitochondrial genes in adipose tissue and DNA repair genes in muscle, highlighting its targeting for multiple signs of aging.

Metformin is well tolerated. However, in some elderly patients, adding metformin to exercise attenuated its principal effect, increasing insulin sensitivity. Metformin also prevented the increase in mitochondrial respiration of skeletal muscles, which usually occurs during exercise.

Details of the study are in the article “Anti-Aging Drugs“. The study was published in the Nature journal.

Metformin Reduces Dementia Risk in Diabetes Patients

Insulin resistance contributes to the development of cognitive impairments. In individuals with type 2 diabetes, the risk of dementia is 1.5 to 2 times higher than in those without diabetes. Both diabetes and prediabetes accelerate the progression from mild cognitive impairments to dementia.

Restoring insulin signaling in the brain can enhance cognitive functions:

• In diabetes patients, metformin, when administered to patients with diabetes, can reduce the risk of developing dementia. Therefore, metformin should be considered as a first-line therapy for diabetes in patients at risk of dementia or Alzheimer’s disease. In adults without diabetes, metformin is not adequate for dementia prevention.
• In patients with mild cognitive impairments, metformin improves verbal memory in patients with moderate cognitive impairments, as confirmed by a randomized controlled trial involving 80 participants. Metformin was prescribed at a dosage of 1000 mg twice a day, while the control group received a placebo. The study lasted for 12 months. Metformin was well-tolerated in 92.5% of cases and did not induce severe adverse effects. In 7.5% of cases, participants reported gastrointestinal symptoms. Due to these symptoms, some participants took metformin at a lower dosage – 500-1500 mg daily. Verbal memory improvement was more pronounced with a metformin dosage of 2000 mg daily in younger participants, those with lower glycated hemoglobin levels, and those with higher baseline fasting insulin levels.
• In patients with moderate cognitive impairments or mild dementia, taking metformin for 8 weeks enhances planning and decision-making abilities. Metformin also improves learning new information, attention, and memory.

Metformin in Gestational Diabetes

Gestational diabetes, characterized by elevated blood glucose levels during pregnancy, increases the risk of excessive weight gain, cesarean sections, and preeclampsia. Additionally, gestational diabetes heightens the likelihood of adverse outcomes for the fetus and contributes to the long-term development of type 2 diabetes in both mothers and their offspring.

In 2023, Irish researchers investigated whether early metformin administration, initiated immediately after diagnosing “gestational diabetes,” could enhance glycemic control, reduce the need for insulin therapy, and mitigate gestational weight gain.

Early metformin did not outperform a placebo concerning the combination of commencing insulin therapy and fasting blood glucose levels ≥5.1 mmol/L at the 32nd or 38th week of pregnancy. However, pregnant women taking metformin commenced insulin therapy at a later stage, exhibited improved glycemic control, and gained less weight.

Metformin influenced not only mothers but also newborns. Among the metformin group, newborns had lower weight and height. Metformin increased the proportion of infants with a gestational age less than 2.5 kg, as it suppresses a protein complex regulating amino acid transport across the placenta, potentially contributing to reduced muscle mass and an increased risk of obesity in the long run.

Metformin did not impact the risk of hypertension during pregnancy, preeclampsia, antepartum, postpartum hemorrhage, labor induction, cesarean section, or the need for neonatal intensive care.

For further details on this study, please refer to the article “Metformin in Gestational Diabetes,” published in The Journal of the American Medical Association.

Metformin has side effects such as lactic acidosis, dizziness, muscle pain, fatigue, and gastrointestinal intolerance. In addition, metformin increases the risk of diabetic neuropathy, which is the leading cause of diabetic foot, lower limb amputations, and disabling neuralgia. Metformin significantly lowers the level of vitamin B12, which is necessary for DNA synthesis and neuroprotection. B12 deficiency can lead to irreversible damage to the nervous system.

In a study by Chinese scientists, metformin use increased the risk of diabetic peripheral neuropathy (DPN) by 84%. The higher the daily dose of metformin, the higher the risk. Average doses increased the risk of DPN by 1.53 times, and high doses increased it by 4.31. Patients under 60 who visited the doctor less frequently, had fewer comorbidities and did not take antihypertensive and hypolipidemic drugs had a higher risk of DPN.

In the same study, vitamin B12 supplementation prevented increased DPN risk in patients taking metformin.

Details of the study are in the article “Metformin increases the risk of diabetic neuropathy“. The study was published in the Frontiers in Endocrinology journal.

2. Physical Activity

Dutch scientists showed that exercise could increase insulin sensitivity for at least 16 hours in healthy people and patients with type 2 diabetes. Physical activity increases the concentration of the GLUT4 protein in skeletal muscles, which is necessary for transporting glucose into the cell. In addition, physical activity reduces the level of intracellular glucose. Since the transport of glucose into the cell occurs along a concentration gradient, physical activity promotes glucose uptake by the cell from the bloodstream.

Three types of training are prescribed for the treatment of insulin resistance:

• Aerobic – walking, running, cycling;
• Strength – training on simulators or lifting free weights;
• Combined workout.

Concurrent Training

Competitive Training (CT) – the performance of physical exercises aimed at developing aerobic capacity and muscle strength during the same or different sessions, carried out sequentially in one training day or one training week.

Compared to strength or aerobic training alone, CT has a more significant effect on glucose (glycated hemoglobin) homeostasis, cardiorespiratory endurance, muscle strength, and reduction of abdominal fat in people with or at risk of developing type 2 diabetes. Concurrent training improves oxygen uptake, transport and utilization, and fat oxidation during aerobic exercise. Adding strength training to aerobic training improves insulin sensitivity by increasing muscle hypertrophy, increasing muscle glucose storage, and reducing the dose of insulin needed to maintain normal blood glucose levels.

What is More Effective in Treating Insulin Resistance: Drugs or Exercise?

A team of scientists from Chile, Spain, and Portugal investigated the effect of a 12-week concurrent training program on the maximum rate of fat oxidation, glucose metabolism, and insulin resistance in overweight or obese adults compared to pharmaceutical treatment with metformin.

The study involved 14 patients:

• overweight (body mass index ≥ 25.0-29.9 kg/m2) or obese (body mass index ≥ 30.0 kg/m2) with insulin resistance (HOMA-IR insulin resistance index ≥ 2.5-5.0 );
• lowered in physical activity – less than 150-300 minutes per week of aerobic exercise or less than 75-150 minutes per week of intense aerobic workout.

The participants were not taking any medication other than metformin.

The participants were divided into two groups:

• 7 people in the metformin group had two doses of 850 mg daily for 12 weeks.
• 7 people in the concurrent training group, without metformin, had 3 workouts per week for 12 weeks.

Participants had their fasting glucose and insulin levels measured one week before and one week after the intervention to calculate HOMA-IR, body composition, maximum fat oxidation rate, and maximum oxygen consumption (VOC).

HOMA-IR is the standard for assessing insulin resistance.

HOMA-IR = fasting insulin × fasting glucose / 405

Concurrent Training

The first and third weekly workouts are aerobic exercises on a bicycle ergometer at 65-85% of the IPC, and the second is strength exercises. Each workout lasted 60-75 minutes, and all workouts began with a 15-minute warm-up that included a 5-minute exercise on a bicycle ergometer at <65% BMD, joint mobility exercises, and dynamic stretching. Participants performed strength exercises for the upper body (chest press, deadlift, biceps workout) and lower body (leg press, lying hip flexion, leg extension). During strength training, six exercises were performed in a circle: one for the upper body, 30-60 seconds of rest, then one for the lower body - and so on for all six strength exercises. The cycle was performed three times per workout. To control the intensity of strength training during the first three weeks, the level of perceived load (from 0 to 10) was used, and the target zone was 7-8. After weeks 3, 6, and 9, a one-rep max (1RM) was assessed for load adjustments, with a 50-60% target zone of 1RM.

Results

Compared to metformin, concurrent training:

• Increased the maximum rate of fat oxidation. Before the intervention, the top rate of fat oxidation was 4 and 2.5 g/h for the metformin and CT groups, respectively. After the intervention, 7 and 11.5 g/h for the metformin and CT groups, respectively. Percentage difference: −30.3% for the metformin group and 308.1% for the CT group.
• Significantly reduced HOMA-IR, fasting insulin levels, and body fat mass.
• Reduced body weight and body mass index (BMI).

The results are presented in the table:

Conclusion

Concurrent training for 12 weeks is more effective than metformin in improving the maximum rate of fat oxidation and reducing insulin resistance in overweight or obese patients.

Although metformin increases liver and body fat oxidation, combined with exercise decreases cardiorespiratory endurance and fat oxidation.

Conversely, concurrent training can eliminate metabolic inflexibility by increasing the ability to oxidize fatty acids that accumulate in skeletal muscle cells and reducing insulin resistance. In the present study, the improvement in insulin sensitivity was manifested as a decrease in fasting insulin levels, while fasting glucose levels remained the same.

Two aerobic workouts per week, alternating with one strength workout, improve cardiorespiratory endurance and fat oxidation, lowers fasting insulin levels, and increase insulin sensitivity in obese or overweight people.

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Sources

• Overweight and Obese Adult Patients Show Larger Benefits from Concurrent Training Compared with Pharmacological Metformin Treatment on Insulin Resistance and Fat Oxidation
• Metformin treatment and risk of diabetic peripheral neuropathy in patients with type 2 diabetes mellitus in Beijing, China
• Metformin is associated with reduced COVID-19 severity in patients with prediabetes
• Early Metformin in Gestational Diabetes

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