Recent estimates by the International Diabetes Federation suggest that the incidence of diabetes soared to an all-time high of 382 million in 2013, compared with 371 million in 2012. The federation predicts that by 2035 the number of individuals afflicted with this disease will increase to 592 million. Furthermore, an alarmingly high number of individuals (∼175 million) is as yet undiagnosed (1). Therefore, efforts to understand the pathophysiology of diabetes are critical for forward movement toward development of novel therapeutic strategies for this disease. Against this backdrop, original investigations by Unger and colleagues (2,3) suggested that chronic exposure and stimulation of the islet β-cell to glucose (glucotoxicity) or free fatty acids (FFAs) (lipotoxicity) result in β-cell dysfunction. Numerous studies using both in vitro and in vivo models have implicated ceramide, a sphingolipid derived from palmitate, in islet dysfunction and death (46). Sphingolipids have also been implicated in the metabolic dysfunction of cells and tissues that are also associated with hypertension and atherosclerosis (7,8).

Recently, Othman et al. (9) reported significantly higher plasma levels of deoxysphingolipids (1-deoxySLs) in patients with metabolic syndrome, suggesting that these atypical sphingolipids might serve as biomarkers for diagnosis and treatment of these patients. It has been shown that mutations in genes encoding specific subunits of serine palmitoyl transferase (SPT), which mediates the de novo biosynthesis of ceramide from palmitoyl CoA and serine, lead to alterations in the amino acid specificity of SPT from serine to alanine (9). From a cellular standpoint, 1-deoxySLs do not undergo the canonical sphingolipid degradation pathway; rather, they accumulate intracellularly and adversely affect cellular metabolism and function (9,10). It has been demonstrated that 1-deoxySLs are cytotoxic in various model systems, and more important, they are implicated in the pathology of neuronal functional impairment in hereditary sensory and autonomic neuropathy in patients with type 1 diabetes (HSAN1) (10).

In this issue, Zuellig et al. (11) provide the first direct evidence implicating 1-deoxySLs in induction of metabolic dysfunction of insulin-secreting Ins-1 cells and primary rodent islets. They report that exposing these cells to 1-deoxysphinganine (dSA) induced significant defects in glucose-stimulated insulin secretion (GSIS), cellular dysfunction, and cell death. dSA also promoted activation of Rac1, a small G-protein, and caused alterations in cytoskeletal makeup, including intracellular accumulation of F-actin, and activation of stress kinases. Evidence is also presented that indicates upregulation of ceramide synthase 5 activity in dSA-treated cells resulted in its conversion to 1-deoxydihydroceramide. Pharmacological inhibition of intracellular trafficking of sphingolipids partially restored the cytotoxic effects of dSA. Together, these findings demonstrate that dSA and its metabolic intermediate 1-deoxydihydroceramide exert deleterious effects on islet β-cell function, including inhibition of GSIS and induction of loss in metabolic cell viability. These observations are both novel and timely. It is noteworthy that the cytotoxic effects of dSA are demonstrable at much lower concentrations (1–5 µmol/L) compared with known cellular effects of cell permeable analogs of ceramide (10–50 µmol/L) and FFAs (0.1–0.5 mmol/L). Based on their longer half-lives (due to limited intracellular degradation), 1-deoxySLs indeed represent a novel class of biolipids that induce metabolic stress and defects in the islet β-cell. Interestingly, cellular effects of 1-deoxySLs, ceramides, and FFAs appear to involve activation of overlapping signaling pathways including activation of Rac1, stress kinases, and caspase-3 culminating in cell death (Fig. 1).

Taken together, the observations by Zuellig et al. (11) offer significant advances in the area of sphingolipid-induced metabolic dysregulation and demise of the islet β-cell. Future studies will undoubtedly validate this model and the significance of the findings. Ideally, these findings will need to be reproduced in human islets to demonstrate their translational significance. It is hoped that future studies will decipher the intermediate signaling steps that couple the Rac1-p38 MAP kinase-Caspase-3 cascade in the onset of β-cell metabolic dysfunction under conditions of dSA-induced stress. One attractive candidate is phagocyte-like NADPH oxidase that is activated in islet β-cells following exposure to high glucose, FFAs, ceramides, and proinflammatory cytokines (1215). Moreover, high glucose, FFAs, cytokines, and ceramides have been shown to activate Rac1 (13,14,1619), a member of the NADPH oxidase holoenzyme complex. These points need to be addressed further. As appropriately pointed out by the authors, elevated levels of 1-deoxySLs in patients with HSAN1 and metabolic syndrome do not result in overt diabetes. This suggests that additional metabolic signals, presumably derived from established chronic hyperglycemia (glucotoxicity), may be necessary to elicit maximal damaging effects of 1-deoxySLs on the islet β-cell. From a therapeutic standpoint, recent findings by Garofalo et al. (20) demonstrated a significant reduction in the production of neurotoxic 1-deoxySLs in mice and humans with HSAN1 following oral supplementation of L-serine. This intervention improved motor and sensory performance indices in mice, suggesting that channeling the sphingolipid biosynthetic pathway away from 1-deoxySLs via serine supplementation might prove to be beneficial. Similar approaches can be tested in the model systems used by Zuellig et al. (11) to further validate this model in the context of 1-deoxySL–induced metabolic dysfunction. It should be noted that although these studies are focused on the islet β-cell, it is likely that this class of cytotoxic sphingolipids might exert unfavorable effects and induce metabolic dysfunction in other cell types and target tissues, a consideration that has potential implications for conditions other than diabetes. In conclusion, the findings reported in the study by Zuellig et al. (11) will likely serve as stepping stones for immediate investigations in this area. Pursuit of this line of investigation will not only promote further understanding of underlying metabolic signaling cascades, but it will also aid in identification of novel drug targets to halt β-cell dysfunction and the onset of diabetes and associated complications.

See accompanying article, p. 1326.

Funding. This work was supported by grants from the Department of Veterans Affairs (1BX000469), National Institutes of Health (DK-74921 and EY-022230), and Juvenile Diabetes Research Foundation (5-2012-257). A.K. is the recipient of a Senior Research Career Scientist Award from the Department of Veterans Affairs (13S-RCS-006).

Duality of Interest. No potential conflicts of interest relevant to this article were reported.

1.
International Diabetes Federation
.
IDF Diabetes Atlas
. 6th ed.
Brussels, Belgium
,
International Diabetes Federation
,
2013
2.
Unger
RH
,
Grundy
S
.
Hyperglycaemia as an inducer as well as a consequence of impaired islet cell function and insulin resistance: implications for the management of diabetes
.
Diabetologia
1985
;
28
:
119
121
[PubMed]
3.
Unger
RH
.
Lipotoxicity in the pathogenesis of obesity-dependent NIDDM. Genetic and clinical implications
.
Diabetes
1995
;
44
:
863
870
[PubMed]
4.
Veluthakal
R
,
Palanivel
R
,
Zhao
Y
,
McDonald
P
,
Gruber
S
,
Kowluru
A
.
Ceramide induces mitochondrial abnormalities in insulin-secreting INS-1 cells: potential mechanisms underlying ceramide-mediated metabolic dysfunction of the beta cell
.
Apoptosis
2005
;
10
:
841
850
[PubMed]
5.
Lang
F
,
Ullrich
S
,
Gulbins
E
.
Ceramide formation as a target in beta-cell survival and function
.
Expert Opin Ther Targets
2011
;
15
:
1061
1071
[PubMed]
6.
Boslem
E
,
Meikle
PJ
,
Biden
TJ
.
Roles of ceramide and sphingolipids in pancreatic β-cell function and dysfunction
.
Islets
2012
;
4
:
177
187
[PubMed]
7.
Chavez
JA
,
Summers
SA
.
A ceramide-centric view of insulin resistance
.
Cell Metab
2012
;
15
:
585
594
[PubMed]
8.
Galadari
S
,
Rahman
A
,
Pallichankandy
S
,
Galadari
A
,
Thayyullathil
F
.
Role of ceramide in diabetes mellitus: evidence and mechanisms
.
Lipids Health Dis
2013
;
12
:
98
[PubMed]
9.
Othman
A
,
Rütti
MF
,
Ernst
D
, et al
.
Plasma deoxysphingolipids: a novel class of biomarkers for the metabolic syndrome?
Diabetologia
2012
;
55
:
421
431
[PubMed]
10.
Penno
A
,
Reilly
MM
,
Houlden
H
, et al
.
Hereditary sensory neuropathy type 1 is caused by the accumulation of two neurotoxic sphingolipids
.
J Biol Chem
2010
;
285
:
11178
11187
[PubMed]
11.
Zuellig
RA
,
Hornemann
T
,
Othman
A
, et al
.
Deoxysphingolipids, novel biomarkers for type 2 diabetes, are cytotoxic for insulin-producing cells
.
Diabetes
2014;63:1326–1339
12.
Syed
I
,
Jayaram
B
,
Subasinghe
W
,
Kowluru
A
.
Tiam1/Rac1 signaling pathway mediates palmitate-induced, ceramide-sensitive generation of superoxides and lipid peroxides and the loss of mitochondrial membrane potential in pancreatic beta-cells
.
Biochem Pharmacol
2010
;
80
:
874
883
[PubMed]
13.
Kowluru
A
.
Friendly, and not so friendly, roles of Rac1 in islet β-cell function: lessons learnt from pharmacological and molecular biological approaches
.
Biochem Pharmacol
2011
;
81
:
965
975
[PubMed]
14.
Subasinghe
W
,
Syed
I
,
Kowluru
A
.
Phagocyte-like NADPH oxidase promotes cytokine-induced mitochondrial dysfunction in pancreatic β-cells: evidence for regulation by Rac1
.
Am J Physiol Regul Integr Comp Physiol
2011
;
300
:
R12
R20
[PubMed]
15.
Morgan
D
,
Oliveira-Emilio
HR
,
Keane
D
, et al
.
Glucose, palmitate and pro-inflammatory cytokines modulate production and activity of a phagocyte-like NADPH oxidase in rat pancreatic islets and a clonal beta cell line
.
Diabetologia
2007
;
50
:
359
369
[PubMed]
16.
Syed
I
,
Kyathanahalli
CN
,
Jayaram
B
, et al
.
Increased phagocyte-like NADPH oxidase and ROS generation in type 2 diabetic ZDF rat and human islets: role of Rac1-JNK1/2 signaling pathway in mitochondrial dysregulation in the diabetic islet
.
Diabetes
2011
;
60
:
2843
2852
[PubMed]
17.
Cacicedo
JM
,
Benjachareowong
S
,
Chou
E
,
Ruderman
NB
,
Ido
Y
.
Palmitate-induced apoptosis in cultured bovine retinal pericytes: roles of NAD(P)H oxidase, oxidant stress, and ceramide
.
Diabetes
2005
;
54
:
1838
1845
[PubMed]
18.
Kim
BC
,
Kim
JH
.
Exogenous C2-ceramide activates c-fos serum response element via Rac-dependent signalling pathway
.
Biochem J
1998
;
330
:
1009
1014
[PubMed]
19.
Brenner
B
,
Koppenhoefer
U
,
Weinstock
C
,
Linderkamp
O
,
Lang
F
,
Gulbins
E
.
Fas- or ceramide-induced apoptosis is mediated by a Rac1-regulated activation of Jun N-terminal kinase/p38 kinases and GADD153
.
J Biol Chem
1997
;
272
:
22173
22181
[PubMed]
20.
Garofalo
K
,
Penno
A
,
Schmidt
BP
, et al
.
Oral L-serine supplementation reduces production of neurotoxic deoxysphingolipids in mice and humans with hereditary sensory autonomic neuropathy type 1
.
J Clin Invest
2011
;
121
:
4735
4745
[PubMed]
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