New studies in mice may pave the way to new ways to treat type 1 diabetes. The insulin-producing cells in the pancreas are destroyed in people with the disease, who typically inject insulin, normalizing their blood sugar. But the treatment can lead to unwanted effects such as buildup of fat, leading to heart disease and obesity. Using a mouse model of the disease, May-yun Wang et al.1 tested the effects of treating diabetes with another hormone, leptin. Leptin is secreted by fat cells and is known for modulating energy expenditure and fat metabolism. Leptin stabilized blood sugar levels in these mice as well as insulin did, and leptin combined with insulin resulted in steadier, long-term blood glucose control—findings in sync with previous studies supporting a role for leptin in glucose metabolism. The researchers went on to show that leptin also has a more favorable effect than insulin on lipid and cholesterol metabolism. How might the approach work—and is it time to test it in people?
Martin G. Myers Jr.:
Wang et al.1 have extended the role for leptin in glucose homeostasis by demonstrating that leptin alone prevents high blood sugar in insulin-deficient diabetic mice—perhaps through suppressing the production of glucagon, an islet hormone that elevates blood glucose. Questions raised by this study include whether leptin acts in the brain, on the islet or elsewhere to mediate these effects. Additionally, it will be important to carry out longer-term studies of leptin, alone or in combination with insulin, in a variety of models to determine the utility of suppressing glucagon secretion in long-standing type 1 diabetes, as glucagon production is lost over time in this disease. Such studies could also help in understanding the chronic impact of the accompanying decrease in adiposity.
Associate Professor of Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA.
C. Ronald Kahn:
What we need now is a simple, direct study to determine whether leptin works to improve metabolism in humans with type 1 diabetes. —C. Ronald Kahn
This study extends previous research suggesting that leptin can potentiate the effects of insulin by showing that high-dose leptin normalizes glucose and hemoglobin A1c (glycosylated hemoglobin), as well as a number of intermediary metabolites, in a mouse model of type 1 diabetes. Leptin even seems to have more favorable effects on lipids and cholesterol than insulin itself. However, the doses of leptin used were high and would clearly suppress appetite and potentially induce side effects such as local inflammation. Nonetheless, the data are extremely compelling. So, what we need now is less speculation about the merits or weaknesses of this and other rodent studies and a simple, direct study to determine whether leptin works to improve metabolism and lower glucose and lipid levels in humans with type 1 diabetes. If positive, such a study would stimulate additional research to determine the value of leptin as a therapy for individuals with difficult to control type 1 diabetes. If negative, then we might have another example of differences between humans and mice.
Professor, Joslin Diabetes Center and Harvard Medical School, Boston, Massachusetts, USA.
Domenico Accili:
Wang et al.1 should be commended for thinking outside the box regarding insulin adjuvant therapy in type 1 diabetes. There is a long-felt need to ease the burden of care in individuals forced to live by the glucose meter and insulin pump. But there are caveats. Untreated type 1 diabetes leads to a complete loss of adipose tissue, and trying to restore leptin levels makes sense, given previous work in lipoatrophic individuals. Indeed, the authors report more substantial improvements of lipid levels with leptin than with insulin1. Lowering lipid levels improves glucose use. But in clinical practice, insulin therapy protects patients with type 1 diabetes from the loss of adipose tissue and normalizes their leptin levels, raising the question of whether they would benefit from leptin supplementation. The authors put much stock in the glucagon hypothesis, but in my mind the data are not totally convincing—their readout for glucagon action, cAMP response element–binding (CREB) protein phosphorylation, is not specific for glucagon, and the reduction of glucagon abundance could be an effect of lower lipid levels, rather than a cause. Given that the main effect of leptin is suppression of appetite, my interpretation is that reduced food intake in the leptin-treated mice is likely to have an important role in this outcome.
Professor of Medicine, Columbia University, New York, New York, USA.
References
Wang, M.-Y. et al. Leptin therapy in insulin-deficient type 1 diabetes. Proc. Natl. Acad. Sci. USA 107, 4813–4819 (2010).
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Leptin therapy for type 1 diabetes gains traction. Nat Med 16, 380 (2010). https://doi.org/10.1038/nm0410-380
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DOI: https://doi.org/10.1038/nm0410-380