Editors' ChoiceDiabetes

Autophagy Protects the Tired, the Poor, the Huddled (β Cell) Masses

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Science Translational Medicine  30 Jul 2014:
Vol. 6, Issue 247, pp. 247ec130
DOI: 10.1126/scitranslmed.3009817

Many factors drive the development of type 2 diabetes (T2D), including increasing weight, inactivity, and dysregulated sleep. To compensate for these changes, the pancreas makes a stand by trying to increase β cell mass and secrete more insulin. But this defense can only hold back the diabetes tide for so long, and eventually, blood sugars start to rise. During this process, the poor pancreatic β cell is subject to a rich beating from all sides. Excess glucose, lipid, inflammation, and oxidative stress all contribute to the dysfunction and death of the β cell. Now, Rivera et al. provide clear and elegant evidence that autophagy—“self eating”— pathways provide a relief valve for keeping β cells healthy.

This group originally identified pancreatic amyloid plaques as a diabetes precursor lesion in humans. The plaques contain islet amyloid polypeptide (IAPP, or amylin), which is normally co-secreted with insulin from the β cell. Rodents do not develop these lesions because of species-specific protein-folding properties, but a transgenic rodent model that expresses human IAPP (h-IAPP) develops plaques and then diabetes. The first clue that autophagy modulates plaque development came from the observation that autophagy activators diminish h-IAPP deposition in primary human islets, insulinoma cells, and the transgenic animal model of diabetes. Conversely, inhibitors of autophagy increased the h-IAPP load. The authors showed that β cell h-IAPP interacts with an autophagosome anchor, p62, which selectively helps clear aggregated proteins. This insoluble complex was targeted specifically to lysosomes and was polyubiquitinated, demonstrating that β cells dispose of h-IAPP by means of degradative pathways.

Autophagy-deficient mice were not inherently diabetic, but they become so when forced to express h-IAPP. These mice have increased fasting blood sugars, impaired glucose tolerance, impaired β cell function, less β cell mass, and increased β cell apoptosis. Nitrotyrosine, a marker of oxidative stress, was elevated in their β cells, prompting the authors to consider whether autophagy normally induces antioxidative responses in β cells. The antioxidant transcription factor Nrf2 and one of its specific target genes were increased in autophagy-deficient mice, but not in mice expressing h-IAPP alone. When h-IAPP accumulates in the setting of impaired autophagy, the Nrf2 pathway is shut off, demonstrating a specific role for Nrf2 protection of β cells against oxidative stresses induced by h-IAPP.

Diabetes therapy has traditionally focused on replacing insulin, increasing its secretion, or potentiating its action. These results are exciting because they highlight an additional pathway for preventing, or at least prolonging, the onset of diabetes. This paper opens the door for enhancing an endogenous compensatory response in prediabetic patients, the very population to target for maximum health benefit and cost-saving. It also raises the intriguing possibility of developing markers of islet damage in prediabetic patients for risk stratification. Exploiting β cell protective strategies may also benefit patients with diabetes and recipients of islet cell transplants.

J. F. Rivera et al., Autophagy defends pancreatic β cells from human islet amyloid polypeptide-induced toxicity. J. Clin. Invest. 10.1172/JCI71981 (2014). [Full Text]

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