Biochem. J. (2013) 456, e1–e3 (Printed in Great Britain)
e1
doi:10.1042/BJ20131282
READERS’ CHOICE
Autophagy: a two-edged sword in diabetes mellitus
Suguru YAMAMOTO*, Junichiro J. KAZAMA* and Masafumi FUKAGAWA†1
*Division of Clinical Nephrology and Rheumatology, Niigata University Graduate School of Medical and Dental Science, Niigata, Japan, and †Division of Nephrology, Endocrinology
and Metabolism, Tokai University School of Medicine, Isehara, Japan
A fragility fracture is a serious complication in patients with
diabetes mellitus as a result of hyperglycaemia, insulin resistance
and the production of AGEs (advanced glycation end-products).
In their paper published in the Biochemical Journal, Bartolomé
et al. identified a role for autophagy in the differentiation,
function and survival of osteoblastic cells in a high-glucose
environment, and they also demonstrated that osteoblastic
cell survival was limited by chemical and genetic inhibition
of autophagy. These novel findings show the possibility of
investigating a therapeutic strategy of maintaining autophagy
in osteoblasts to lead to the prevention of diabetes-related
osteopaenia. Autophagy is one of the common functions for
maintaining cellular health, and the regulation of autophagy
that is perturbed by diabetes mellitus may induce improvement
of cellular functions not only for diabetes-related osteopaenia,
but also for other systemic complications. However, systemic
activation of autophagy may not always induce beneficial
effects for non-targeted healthy cells, and autophagy should be
controlled at a proper level at each disease stage in each target
organ.
A fragility fracture is a serious complication in patients with
diabetes mellitus. It induces impairment of activities of daily
living, quality of life and survival in the affected population. The
risk of fragility fractures increases not only in diabetes mellitus
(Type 1 and Type 2), but also in rheumatoid arthritis, inflammatory
bowel disease, coeliac disease, cystic fibrosis, hyperthyroidism
and kidney disease [1]. In diabetes mellitus, hyperglycaemia,
insulin resistance and the production of AGEs (advanced
glycation end-products) induce a decrease in bone mineral density
and reduce bone quality [2,3]. The mechanism of fragility fracture
in patients with diabetes mellitus is not completely understood.
In volume 455 (part 3) of the Biochemical Journal, Bartolomé
et al. [4] describe the protective role of autophagy for the
differentiation, function and survival of osteoblastic cells in a
high-glucose environment. Osteoblastic cell survival is impaired
by high glucose and worsened by chemical and genetic inhibition
of autophagy. These novel findings show the possibility of
investigating the therapeutic strategy of maintaining autophagy
in osteoblasts to lead to the prevention of diabetes-related
osteopaenia. The role of autophagy in the interaction between
osteoblasts and osteoclasts in diabetes-related osteopaenia is still
unclear; however, the intervention to autophagy may provide
beneficial strategies not only for diabetes mellitus, but also for
other systemic diseases and complications.
To prevent fragility fractures, intervention should focus on
each systemic disease-specific factor and common pathway, such
as autophagy in bone cells. In diabetic mellitus, high-glucose
exposure induced the production of ROS (reactive oxygen species)
as well as protein oxidation, and there was a decrease in survival
of osteoblastic cells [4]. One study describes how the AGEs that
are formed after prolonged hyperglycaemia inhibit osteoblastic
differentiation and increase apoptosis even without a high-glucose
environment [5]. Advanced chronic kidney disease increases the
accumulation of uraemic toxins, such as indoxyl sulfate and pcresyl sulfate, which induce increases in free radical production
and ROS from osteoblastic cells [6,7]. These reports suggest that
various disease-related factors react with osteoblasts directly and
induce cellular dysfunction, which leads to a reduction in bone
quality. The treatment of systemic disease induces improvement
of osteoblastic cellular function. In a uraemic environment, a
reduction in serum indoxyl sulfate in rats with oral charcoal
adsorbent shows improvement of kidney-damage-induced bone
disorders with improvement of bone storage modulus and
bone histomorphometry, such as an increase in the number of
osteoblasts [8].
Autophagy is an important factor in maintaining cellular
function and viability, and is related to cellular/organ damage
owing to malnutrition, hypoxia, infection and various systemic
diseases. Impairment of autophagy by knockdown of Atg7,
an autophagy-related protein, in MC3T3-E1 cells induced cell
dysfunction and inhibited osteoblast differentiation in a highglucose environment [4]. Ablation of FIP200 [200 kDa FAK
(focal adhesion kinase) family-interacting protein] also impairs
autophagy in osteoblasts, which leads to terminal differentiation
as well as nodule formation in vitro and leads to osteopaenia
in vivo [9].
The regulation of autophagy that is perturbed by diabetes
mellitus in all cell types may induce dramatic benefits not only
for diabetes-related osteopaenia, but also for other systemic
complications (Figure 1). Diabetes mellitus is characterized
by insulin resistance and failure of pancreatic β-cells to
produce insulin. The aggregation of ubiquitinated protein
is increased in pancreatic β-cells during oxidative-stressassociated hyperglycaemia and is regulated by autophagy [10].
Pancreatic β-cell-specific Atg7-knockout mice show impairment
of autophagy, and induced hyperglycaemia, glucose intolerance
and hypoinsulinaemia [11]. The pathophysiology of some
diabetes-related complications is also related to autophagy [12–
14]. In kidneys, podocytes exhibit an unusually high level of
autophagy as compared with inner medullary collecting duct cells
[15]. Podocyte-specific deletion of Atg5 induced accumulation
of oxidized and ubiquitinated proteins, and ER (endoplasmic
Abbreviations used: AGE, advanced glycation end-product; mTOR, mammalian target of rapamycin; ROS, reactive oxygen species.
1
To whom correspondence should be addressed (email [email protected]).
c The Authors Journal compilation c 2013 Biochemical Society
e2
Figure 1
S. Yamamoto, J. J. Kazama and M. Fukagawa
Role of impaired autophagy in the development of diabetic complications
reticulum) stress, which leads to late-onset glomerulosclerosis in
aging mice [15]. Also, mTOR (mammalian target of rapamycin),
a major suppressant of autophagy, in podocytes is activated
in human diabetic nephropathy, and tightly balanced mTOR
activity requires podocyte homoeostasis in diabetic nephropathy
[16]. These reports suggest that a high level of autophagy
is needed to maintain podocyte function, and the inadequate
balance of autophagy is related to diabetic nephropathy. In
cardiovascular disorders, macrophage foam cell formation is
a hallmark of progressive atherosclerosis in patients with
diabetes mellitus, obesity and so forth. Deficiency of Wip1
phosphatase, a negative regulator of Atm-dependent signalling,
inhibits the progression of atherosclerosis in apolipoprotein
E-knockout mice. This inhibitory effect is due to resistance
of macrophage foam cell formation through up-regulation of
autophagy [17]. In addition, macrophage-specific Atg5-knockout
mice show increased atherosclerotic plaque formation, with an
increase in both apoptosis and oxidative stress, and decreased
efferocytosis [18]. These reports suggest that the control of
autophagy in macrophages is crucial for determining macrophage
pro-inflammatory and anti-inflammatory phenotypes, and for
regulating the progression of atherosclerosis. Thus the impairment
of autophagy in all cells is thought to play an important role in the
onset and progress of diabetes mellitus and its complications, and
the regulation of autophagy is a therapeutic target. Bartolomé
et al. [4] reported that it is possible to maintain autophagy
with treatments that lead to the improvement of osteoblastic
cellular function under high-glucose situations. Furthermore,
the activation of autophagy in dysfunctional osteoblasts may
improve diabetes-related osteopaenia. Systemic intervention for
autophagy will also have potential for the treatment of not only
bone disorders, but also other complications, such as retinopathy,
neuropathy, nephropathy and cardiovascular disease in patients
with diabetes mellitus.
However, systemic activation of autophagy may not always
induce beneficial effects for non-targeted healthy cells, and
activation or inactivation of autophagy may need to be selected
according to the disease situation. In fact, genetic deletion
of mTOR in mouse podocytes induced glomerulosclerosis;
however, mTOR activation is found in the glomerulus in diabetic
nephropathy [16]. Furthermore, genetically reducing the mTOR
c The Authors Journal compilation c 2013 Biochemical Society
copy number in podocytes prevented glomerulosclerosis and
significantly ameliorated the progression of glomerular disease in
diabetic nephropathy [16]. These results suggest that autophagy
should be controlled at a proper level at each disease stage in
each target organ. The mechanism and regulation of autophagy
may be different in detail in each cell type [19], and the target for
organ-specific regulation of autophagy will become a realistic
intervention. We need to understand much more specifically
the characteristics of the autophagy induced by disease-specific
disorders in each cell and organ on the basis of further studies.
REFERENCES
1 Kanis, J. A., on behalf of the World Health Organisation Scientific Group (2007)
Assessment of osteoporosis at the primary health care level. WHO Scientific Technical
Report, WHO Collaborating Centre for Metabolic Bone Diseases, University of Sheffield,
Sheffield, U.K.
2 Hamann, C., Kirschner, S., Gunther, K. P. and Hofbauer, L. C. (2012) Bone, sweet bone:
osteoporotic fractures in diabetes mellitus. Nat. Rev. Endocrinol. 8, 297–305
3 Leslie, W. D., Rubin, M. R., Schwartz, A. V. and Kanis, J. A. (2012) Type 2 diabetes and
bone. J. Bone Miner. Res. 27, 2231–2237
4 Bartolomé, A., Lopez-Herradon, A., Portal-Nunez, S., Garcia-Aguilar, A., Esbrit, P., Benito,
M. and Guillen, C. (2013) Autophagy impairment aggravates the inhibitory effects of high
glucose on osteoblast viability and function. Biochem. J. 455, 329–337
5 Okazaki, K., Yamaguchi, T., Tanaka, K., Notsu, M., Ogawa, N., Yano, S. and Sugimoto, T.
(2012) Advanced glycation end products (AGEs), but not high glucose, inhibit the
osteoblastic differentiation of mouse stromal ST2 cells through the suppression of osterix
expression, and inhibit cell growth and increasing cell apoptosis. Calcif. Tissue Int. 91,
286–296
6 Iwasaki, Y., Yamato, H. and Fukagawa, M. (2011) Treatment with pravastatin attenuates
oxidative stress and protects osteoblast cell viability from indoxyl sulfate. Ther. Apheresis
Dial. 15, 151–155
7 Tanaka, H., Iwasaki, Y., Yamato, H., Mori, Y., Komaba, H., Watanabe, H., Maruyama, T. and
Fukagawa, M. (2013) p -Cresyl sulfate induces osteoblast dysfunction through activating
JNK and p38 MAPK pathways. Bone 56, 347–354
8 Iwasaki, Y., Kazama, J. J., Yamato, H., Shimoda, H. and Fukagawa, M. (2013)
Accumulated uremic toxins attenuate bone mechanical properties in rats with chronic
kidney disease. Bone 57, 477–483
9 Liu, F., Fang, F., Yuan, H., Yang, D., Chen, Y., Williams, L., Goldstein, S. A., Krebsbach,
P. H. and Guan, J. (2013) Suppression of autophagy by FIP200 deletion leads to
osteopenia in mice through the inhibition of osteoblast terminal differentiation. J. Miner.
Bone Res. 28, 2414–2430
Readers’ Choice
10 Kaniuk, N. A., Kiraly, M., Bates, H., Vranic, M., Volchuk, A. and Brumell, J. H. (2007)
Ubiquitinated-protein aggregates form in pancreatic β-cells during diabetes-induced
oxidative stress and are regulated by autophagy. Diabetes 56, 930–939
11 Ebato, C., Uchida, T., Arakawa, M., Komatsu, M., Ueno, T., Komiya, K., Azuma, K., Hirose,
T., Tanaka, K., Kominami, E. et al. (2008) Autophagy is important in islet homeostasis and
compensatory increase of β-cell mass in response to high-fat diet. Cell Metab. 8,
325–332
12 Towns, R., Kabeya, Y., Yoshimori, T., Guo, C., Shangguan, Y., Hong, S., Kaplan, M.,
Klionsky, D. J. and Wiley, J. W. (2005) Sera from patients with type 2 diabetes and
neuropathy induce autophagy and colocalization with mitochondria in SY5Y cells.
Autophagy 1, 163–170
13 Kume, S., Thomas, M. C. and Koya, D. (2012) Nutrient sensing, autophagy, and diabetic
nephropathy. Diabetes 61, 23–29
14 Fu, D., Wu, M., Zhang, J., Du, M., Yang, S., Hammad, S. M., Wilson, K., Chen, J. and
Lyons, T. J. (2012) Mechanisms of modified LDL-induced pericyte loss and retinal injury
in diabetic retinopathy. Diabetologia 55, 3128–3140
e3
15 Hartleben, B., Godel, M., Meyer-Schwesinger, C., Liu, S., Ulrich, T., Kobler, S., Wiech, T.,
Grahammer, F., Arnold, S. J., Lindenmeyer, M. T. et al. (2010) Autophagy influences
glomerular disease susceptibility and maintains podocyte homeostasis in aging mice.
J. Clin. Invest. 120, 1084–1096
16 Godel, M., Hartleben, B., Herbach, N., Liu, S., Zschiedrich, S., Lu, S., Debreczeni-Mor, A.,
Lindenmeyer, M. T., Rastaldi, M. P., Hartleben, G. et al. (2011) Role of mTOR in podocyte
function and diabetic nephropathy in humans and mice. J. Clin. Invest. 121, 2197–2209
17 Le Guezennec, X., Brichkina, A., Huang, Y. F., Kostromina, E., Han, W. and Bulavin, D. V.
(2012) Wip1-dependent regulation of autophagy, obesity, and atherosclerosis. Cell
Metab. 16, 68–80
18 Liao, X., Sluimer, J. C., Wang, Y., Subramanian, M., Brown, K., Pattison, J. S., Robbins,
J., Martinez, J. and Tabas, I. (2012) Macrophage autophagy plays a protective role in
advanced atherosclerosis. Cell Metab. 15, 545–553
19 Komatsu, M., Waguri, S., Koike, M., Sou, Y. S., Ueno, T., Hara, T., Mizushima, N., Iwata,
J., Ezaki, J., Murata, S. et al. (2007) Homeostatic levels of p62 control cytoplasmic
inclusion body formation in autophagy-deficient mice. Cell 131, 1149–1163
Received 27 September 2013/15 October 2013; accepted 22 October 2013
Published on the Internet 22 November 2013, doi:10.1042/BJ20131282
c The Authors Journal compilation c 2013 Biochemical Society