What causes type 2 diabetes?

Take-home points

• If T2DM boils down to one primary cause, it is body fatness. Gaining body fat increases the risk of T2DM, and losing body fat increases the chance of remission.  
• Diet and exercise control body fatness. Alongside sleep and stress, these lifestyle factors may also help to manage T2DM independent of body fatness.
• Effective medical and surgical options are available to treat the underlying cause of T2DM and manage its associated symptoms.

‍What is type 2 diabetes?  

Type 2 diabetes mellitus (T2DM) is a metabolic disorder which considerably impacts human life. Characterised by high levels of sugar in the blood, T2DM damages small blood vessels and associates with heart disease, chronic kidney disease, and certain cancers and diseases of the brain. For these reasons, T2DM is the ninth leading cause of death and is responsible for over 1 million deaths per year.^1,2 Approximately 1 in 11 adults have diabetes, 90% of which are T2DM, and the global prevalence of the disease is increasing by roughly 2.5 % each year.^3,4

Causes of type 2 diabetes?

The leading theory of T2DM is known as the personal fat threshold.⁵ Expanding on the twin-cycle hypothesis which highlighted that too much fat in the liver and pancreas is central to T2DM, the personal fat threshold more generally posits that body fatness is the primary cause of T2DM.⁶ It states that everyone has a limit to how much body fat they can store without developing T2DM. By consuming too much energy (calories) relative to one’s activity levels, fat cells store the excess energy safely under the skin until they can no longer expand in size or number; at this point, energy starts accumulating in the blood and is stored in and around vital organs.⁷ As more fat is stored around the body, the pancreas eventually becomes dysfunctional and can no longer produce enough insulin to keep pulling sugar out of the bloodstream. Thus, T2DM ensues and blood sugar levels rise.

The personal fat threshold is strongly supported by many lines of evidence. First is that a progressive increase in body weight associates with a greater risk of developing T2DM.⁸ In addition, a series of prospective human studies indicate that weight loss alone can normalise blood sugar levels and insulin function.⁹ The more bodyweight lost, the greater the chance of T2DM remission. One of these trials, in particular, known as the DiRECT trial, offered a groundbreaking insight - demonstrating that 86.1% of type 2 diabetics who lost 15kg or more achieved T2DM remission within 12 months. Weight loss was also the only strong predictor of T2DM remission in this clinical trial.¹⁰

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Lifestyle changes such as diet and exercise are usually the means to achieve weight loss in these types of studies, but long-term outcomes of weight loss surgery report similar benefits.¹¹ In fact, within only a week of bariatric surgery in type 2 diabetics, it is common for high blood sugar levels to return to the normal range. Such dramatic results are explained by a vast drop in energy intake and rapid loss of fat from the liver and pancreas.¹²

Determinants of the personal fat threshold?

As previously explained, the more body weight that is lost or gained, the more likely it is that an individual will cross their personal fat threshold and either develop T2DM or put it into remission. For example, a person with a personal fat threshold of 100 kg will increase their risk of T2DM when they exceed this body weight, and their diabetes is more likely to go into remission when they drop below this body weight.  

The personal fat threshold itself is thought to be determined mainly by genetics. On one hand, a disorder causing people to have little to no fat tissue (called lipodystrophy) will bias a very low personal fat threshold, and T2DM will be extremely difficult to avoid.¹³ On the other hand, despite approximately 90% of type 2 diabetics being overweight or obese, approximately 70% of individuals with morbid obesity (BMI above 40) still do not have T2DM and likely have a high personal fat threshold.^14,15 Between these extremes, personal fat thresholds seem to be highly variable, with ethnicity as one of its primary determinants. When accounting for other factors, Black and Asian ethnic groups have around double the risk of developing T2DM than white ethnic groups. ¹⁵

Although research is ongoing, the personal fat threshold is also thought to be partly influenced by lifestyle factors. Exercise, for example, might increase the personal fat threshold by shuttling more energy to muscle instead of fat cells.¹⁶ A high saturated fat intake, as another example, might lower the personal fat threshold by storing greater amounts of excess energy as liver fat when compared to unsaturated fats.¹⁷ A lack of sleep and high stress levels also tend to be associated with T2DM for reasons still under investigation.^18,19  So while genetics is probably going to keep an individual’s personal fat threshold within a fairly narrow range, it is likely (slightly) modifiable by certain lifestyle factors.

Treatments for Type 2 diabetes?

Various treatment options exist for managing type 2 diabetes. Some treatment options target the primary underlying cause of the disease (excess body weight), such as a lifestyle changes that lower energy intake and increase energy expenditure. However, considering that many people struggle to sustain changes to their diet and activity levels, certain medications and surgeries that support weight loss efforts are demonstrably effective and viable options.^20,21 Medications such as metformin and insulin, for instance, have shown to potentially improve the handling of blood sugar, reduce symptoms of the disease, and reduce the risk of other diseases relating to T2DM.²²

We recommend anyone concerned with T2DM to speak with their doctor. The best approach to preventing and treating T2DM can vary from one person to another, and it is important to discuss all options with a healthcare professional.

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References

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16. Kirwan JP, et al. Cleve Clin J Med 2018;84(1):S15–S21.  

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18. Antza C, et al. J Endrocrinol 2021;252(2):125–141.

19. Kelly SJ, et al. Annu Rev Public Health 2015;36:441–62.

20. Avgerubis I, et al. Diabetes Obes Metab 2020;22(3):335–345.  

21. McGlone ER, et al. PLoS Med 2020;17(12):e1003228.  

22. Pfeiffer AFH, et al. Dtsch Arztebl Int 2014;111(5):69–82.