Insulin or Metformin: What Is the Difference

Insulin and metformin are two cornerstones of diabetes treatment, but they work in opposite ways. Insulin is a hormone that itself «drives» glucose into cells, while metformin is a tablet that reduces glucose production by the liver and increases tissue sensitivity to one's own insulin. In the sporting environment both substances are also discussed, and it is here that the difference between them becomes a matter of life and death.

Hormone and Tablet: The Basic Difference

Insulin is a protein hormone produced by the beta cells of the islets of Langerhans in the pancreas. Medicinal insulins are identical to human insulin or are its modified analogs with different rates of action: ultra-short, short, intermediate and long-acting. Since insulin is a protein, it is destroyed in the stomach, so it is administered subcutaneously, and in hospital — intravenously.

Metformin is a synthetic molecule of the biguanide class, historically associated with the plant goat's rue (Galega officinalis). It is taken orally, in tablets of ordinary or extended release. It is not a hormone and does not replace insulin, but changes how the body uses and produces glucose.

Its role in clinical practice differs too. Metformin, in most guidelines, in particular in the ADA/EASD consensus, is traditionally regarded as one of the first-line drugs for type 2 diabetes. Insulin is vital in type 1 diabetes, and in type 2 diabetes it is prescribed when other agents are insufficient, during pregnancy and in acute conditions.

So the first answer to the question «what is the difference» is simple: insulin adds the hormone itself to the body, while metformin helps the body work better with the insulin it already has.

How Insulin Works

Insulin binds to the insulin receptor on the surface of cells and triggers a cascade of intracellular signals. In skeletal muscle and fat tissue this leads to the translocation of GLUT4 glucose transporters to the cell membrane, and glucose from the blood rapidly enters the cells. In the liver insulin suppresses the formation of new glucose and stimulates glycogen storage.

In addition, insulin is one of the main anabolic hormones. It inhibits protein breakdown in muscle, promotes fat synthesis and suppresses lipolysis. It is precisely this anabolic and anticatabolic action that made insulin an object of abuse in bodybuilding.

The effect of insulin is direct and powerful: by injecting the hormone, a person effectively bypasses their own regulation of glucose levels. If the dose exceeds the requirement or the person has not eaten, blood glucose levels fall and hypoglycemia develops.

In medical practice insulin doses are selected individually, taking into account glucose levels, nutrition and physical activity, and patients are taught self-monitoring, recognition of the signs of hypoglycemia and what to do if it occurs.

How Metformin Works

Metformin's main effect is a reduction in glucose production by the liver. The exact molecular mechanism is still debated: classically it is associated with the inhibition of complex I of the mitochondrial respiratory chain and the activation of AMP-activated protein kinase (AMPK), but other pathways have also been described, in particular effects on glucagon signals and the intestine (Rena et al., 2017).

Metformin also moderately improves the sensitivity of peripheral tissues to insulin and changes glucose processing in the intestine. At the same time it does not stimulate insulin secretion, so by itself it rarely causes hypoglycemia.

Metformin's effectiveness is confirmed in classic studies. In the UKPDS 34 study (1998), in patients with type 2 diabetes and overweight, metformin therapy was associated with a reduction in the risk of diabetes-related complications and mortality. In the Diabetes Prevention Program (Knowler et al., 2002), metformin reduced the incidence of diabetes in people with prediabetes, although intensive lifestyle change was more effective.

Metformin's effect on body weight is usually neutral or a slight decrease, which favorably distinguishes it from insulin, on which weight often increases.

Risks: Hypoglycemia vs. Gastrointestinal Effects

Insulin's most dangerous risk is hypoglycemia. A mild form manifests as trembling, sweating, palpitations, hunger and anxiety. Severe hypoglycemia leads to confusion, seizures, coma and can end in death or irreversible brain damage. That is why even in medicine insulin therapy requires training and constant self-monitoring.

Other side effects of insulin are weight gain, hypokalemia (especially with intravenous administration), lipodystrophy at injection sites, and allergic reactions.

Metformin more often causes gastrointestinal disturbances: nausea, diarrhea, bloating, a metallic taste. They usually diminish with gradual dose escalation, taking it with food, or switching to an extended-release form. With long-term use a decrease in vitamin B12 levels is possible, so it is recommended to monitor it periodically.

A rare but serious complication of metformin is lactic acidosis. The risk increases with severe renal failure, hypoxia, decompensated heart failure and alcohol abuse. Therefore the drug is not prescribed with a significant reduction in kidney function, and before procedures with iodine-containing contrast it is sometimes temporarily discontinued.

• Insulin:risk of hypoglycemia, weight gain, the need for injections and self-monitoring.
• Metformin:digestive disturbances, B12 deficiency, rarely — lactic acidosis.

Sport, Muscles and Doping

In bodybuilding insulin is used outside medical indications because of its anabolic and anticatabolic properties. Publications, in particular Evans and Lynch (2003) in the British Journal of Sports Medicine, describe severe cases of hypoglycemia in bodybuilders. The editors emphasize: non-medical use of insulin can lead to death, and no amount of «experience» guarantees against a fatal error.

Insulins and insulin mimetics are included in section S4 «Hormone and metabolic modulators» of the WADA Prohibited List and are prohibited both in and out of competition. Athletes with type 1 diabetes may use insulin only with a granted Therapeutic Use Exemption (TUE).

Metformin is not among the prohibited substances. However, for physically active people there are interesting data: in the MASTERS study (Walton et al., 2019) in elderly people metformin blunted the gain of muscle mass in response to strength training, and in the work of Konopka et al. (2019) it reduced mitochondrial adaptations to aerobic training. Whether these results transfer to young athletes is not yet known.

These data are important for people who take metformin without diabetes for reasons of «longevity» or «cutting»: the potential benefit is uncertain, while the effect on training adaptations may be negative.

Editorial Conclusions

Insulin is a replacement hormone with a powerful and rapid action, which is necessary in type 1 diabetes and often in progressive type 2 diabetes. Metformin is a tablet drug that reduces glucose production by the liver and rarely causes hypoglycemia.

In medicine these agents often complement rather than compete with each other. In sport, however, the difference is fundamental: insulin is prohibited and deadly dangerous with non-medical use, while metformin is not prohibited but may blunt training adaptations.

Discuss any changes in diabetes treatment with an endocrinologist and do not experiment with doses on your own.

We also recommend reading our materials on the signs of hypoglycemia, on the glycated hemoglobin test, and on the effect of metformin on training results.

References

1. UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet. 1998;352(9131):854–865.
2. Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346(6):393–403.
3. Rena G, Hardie DG, Pearson ER. The mechanisms of action of metformin. Diabetologia. 2017;60(9):1577–1585.
4. Davies MJ, Aroda VR, Collins BS, et al. Management of hyperglycemia in type 2 diabetes, 2022. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2022;45(11):2753–2786.
5. Walton RG, Dungan CM, Long DE, et al. Metformin blunts muscle hypertrophy in response to progressive resistance exercise training in older adults: a randomized, double-blind, placebo-controlled, multicenter trial: the MASTERS trial. Aging Cell. 2019;18(6):e13039.
6. Konopka AR, Laurin JL, Schoenberg HM, et al. Metformin inhibits mitochondrial adaptations to aerobic exercise training in older adults. Aging Cell. 2019;18(1):e12880.
7. Evans PJ, Lynch RM. Insulin as a drug of abuse in body building. Br J Sports Med. 2003;37(4):356–357.
8. World Anti-Doping Agency. Prohibited List. Montreal: WADA; актуальна редакція.