What causes type 2 diabetes?

In considering what causes type 2 diabetes it is important to understand that the development of type 2 diabetes is a complex process involving:

• a genetic predisposition that may dictate how someone responds to environmental influences on insulin production and insulin resistance, ^{1, 2}
• a defect in the function of the pancreatic beta-cells (β-cell) that are responsible for insulin secretion,^{1, 3, 4} and
• a decrease in the responsiveness of insulin-sensitive tissues to the insulin produced by the body, such as the liver, gastrointestinal tract, and skeletal muscle.^{5, 6, 7}

While genetic predisposition can play a role, the recent surge in type 2 diabetes suggests that environmental factors are a key contributor to the current epidemic.^{7, 8, 9} Lifestyle factors such as obesity, physical inactivity, and an unhealthy diet are strongly associated with the development of type 2 diabetes.⁷

Genetic predisposition

While it is not fully understood how genetic factors impact the development of type 2 diabetes, studies have identified numerous genetic variants that can increase an individual’s chance of developing insulin resistance and impaired pancreatic beta-cell function.^{6, 7, 10} This genetic predisposition is believed to interact with environmental factors, such as diet and physical activity, to contribute to the development of type 2 diabetes. This can also explain why some people with obesity do not have type 2 diabetes, while others do.

Pancreatic beta-cell dysfunction

Insulin is produced and secreted by beta-cells in the pancreas. In people with type 2 diabetes, the pancreatic beta-cells gradually lose their ability to produce and secrete enough insulin to maintain normal blood glucose levels. This defect in beta-cell function is a critical component in the development of the disease.^{11, 12}

The causes of beta-cell dysfunction in type 2 diabetes include: genetic predisposition, chronic exposure to high blood glucose levels (glucotoxicity), and abnormalities in lipid metabolism (lipotoxicity).^{13, 14}

Insulin Resistance

Insulin resistance is a hallmark feature of type 2 diabetes, and occurs when the body’s cells become less responsive to the effects of insulin, leading to increased blood glucose levels.

Obesity and a lack of exercise are strongly associated with insulin resistance, as excess body weight and physical inactivity can contribute to the body’s reduced sensitivity to insulin. At the molecular level, insulin resistance is caused by impairment in the signaling pathways that mediate the biological effects of insulin, such as glucose uptake, glycogen synthesis, and lipid metabolism.^{12, 15}

The development of insulin resistance is a complex process that often involves:

• an increased production of free fatty acids from adipose tissue, which can interfere with insulin signalling^{16, 17}

• inflammation, which can impair the ability of insulin to stimulate glucose uptake^{18, 19}
• mitochondrial dysfunction, which can reduce the efficiency of glucose and fat metabolism^{5, 15}
• the accumulation of ectopic fat in organs such as the liver and skeletal muscle, which can impair insulin action^{19, 20}

Summary

The cause of type 2 diabetes involves the interplay of genetic predisposition with environmental and lifestyle factors, ultimately resulting in insulin resistance and subsequent pancreatic β-cell dysfunction.

However, the good news is that research has shown type 2 diabetes can be reversed.²¹

Lifestyle interventions such as weight loss, healthy eating, and regular physical activity can improve insulin sensitivity, lower blood glucose levels, and reduce the need for medication.²²

Additional research is ongoing to develop new treatments and prevention strategies for type 2 diabetes, as well as to better understand the genetic and environmental factors that contribute to the disease.

References

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3. Y. Kido, “Gene–environment interaction in type 2 diabetes,” Dec. 16, 2016, Springer Science+Business Media. doi: 10.1007/s13340-016-0299-2.
4. O. Ozougwu, “The pathogenesis and pathophysiology of type 1 and type 2 diabetes mellitus,” Sep. 30, 2013, Academic Journals. doi: 10.5897/jpap2013.0001.
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6. W. A. Al-Shammari, M. Al-Ateeq, S. Alshubrami, A. A.- Jabreen, M. A. Al-Shammari, and M. Al-Jasir, “Epidemiological Profile of Diabetes Mellitus Patients in Diabetes Center in King Salman Specialist Hospital Hail Region Saudi Arabia,” Mar. 02, 2021. doi: 10.24018/ejmed.2021.3.2.516.
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8. X. Lv et al., “Identifying diagnostic indicators for type 2 diabetes mellitus from physical examination using interpretable machine learning approach,” Mar. 18, 2024, Frontiers Media. doi: 10.3389/fendo.2024.1376220.
9. S. Subramaniam, J. S. Dhillon, and W. F. W. Ahmad, “Behavioral Theory-Based Framework for Prediabetes Self-Care System—Design Perspectives and Validation Results,” Aug. 31, 2021, Multidisciplinary Digital Publishing Institute. doi: 10.3390/ijerph18179160.
10. J. C. Lynch, “Prevention of Type 2 Diabetes Mellitus,” Feb. 01, 1999, SAGE Publishing. doi: 10.1177/089719009901200104.
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12. P. V. Dludla et al., “Pancreatic β-cell dysfunction in type 2 diabetes: Implications of inflammation and oxidative stress,” World Journal of Diabetes, vol. 14, no. 3. p. 130, Mar. 15, 2023. doi: 10.4239/wjd.v14.i3.130.
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14. D. Himanshu, W. Ali, and M. Wamique, “Type 2 diabetes mellitus: pathogenesis and genetic diagnosis,” Journal of Diabetes & Metabolic Disorders, vol. 19, no. 2. Springer Nature, p. 1959, Sep. 22, 2020. doi: 10.1007/s40200-020-00641-x.
15. J. Son and D. Accili, “Reversing pancreatic β-cell dedifferentiation in the treatment of type 2 diabetes,” Experimental & Molecular Medicine, vol. 55, no. 8. Springer Nature, p. 1652, Aug. 01, 2023. doi: 10.1038/s12276-023-01043-8.
16. V. Saini, “Molecular mechanisms of insulin resistance in type 2 diabetes mellitus,” Jan. 01, 2010. doi: 10.4239/wjd.v1.i3.68.
17. J. Capeau, “Insulin resistance and steatosis in humans,” Diabetes & Metabolism, vol. 34, no. 6. Elsevier BV, p. 649, Dec. 01, 2008. doi: 10.1016/s1262-3636(08)74600-7.
18. H. Yaribeygi, F. R. Farokhi, A. E. Butler, and A. Sahebkar, “Insulin resistance: Review of the underlying molecular mechanisms,” Journal of Cellular Physiology, vol. 234, no. 6. Wiley, p. 8152, Oct. 14, 2018. doi: 10.1002/jcp.27603.
19. H. Joost, “Pathogenesis, Risk Assessment and Prevention of Type 2 Diabetes mellitus,” Obesity Facts, vol. 1, no. 3. Karger Publishers, p. 128, Jan. 01, 2008. doi: 10.1159/000137673.
20. V. T. Samuel and G. I. Shulman, “Mechanisms for Insulin Resistance: Common Threads and Missing Links,” Cell, vol. 148, no. 5. Cell Press, p. 852, Mar. 01, 2012. doi: 10.1016/j.cell.2012.02.017.
21. R. Taylor, A. Al-Mrabeh, and N. Sattar, “Understanding the mechanisms of reversal of type 2 diabetes,” The Lancet Diabetes & Endocrinology, vol. 7, no. 9. Elsevier BV, p. 726, May 13, 2019. doi: 10.1016/s2213-8587(19)30076-2.
22. G. Smushkin and A. Vella, “What is type 2 diabetes?,” Oct. 22, 2010, Elsevier BV. doi: 10.1016/j.mpmed.2010.08.008.