Decreased ADP-ribosyl cyclase activity in peripheral blood mononuclear cells from diabetic patients with nephropathy.
ABSTRACT ADP-ribosyl-cyclase activity (ADPRCA) of CD38 and other ectoenzymes mainly generate cyclic adenosine 5'diphosphate-(ADP-) ribose (cADPR) as a second messenger in various mammalian cells, including pancreatic beta cells and peripheral blood mononuclear cells (PBMCs). Since PBMCs contribute to the pathogenesis of diabetic nephropathy, ADPRCA of PBMCs could serve as a clinical prognostic marker for diabetic nephropathy. This study aimed to investigate the connection between ADPRCA in PBMCs and diabetic complications.
PBMCs from 60 diabetic patients (10 for type 1 and 50 for type 2) and 15 nondiabetic controls were fluorometrically measured for ADPRCA based on the conversion of nicotinamide guanine dinucleotide (NGD(+)) into cyclic GDP-ribose.
ADPRCA negatively correlated with the level of HbA1c (P = .040, R(2) = .073), although ADPRCA showed no significant correlation with gender, age, BMI, blood pressure, level of fasting plasma glucose and lipid levels, as well as type, duration, or medication of diabetes. Interestingly, patients with nephropathy, but not other complications, presented significantly lower ADPRCA than those without nephropathy (P = .0198) and diabetes (P = .0332). ANCOVA analysis adjusted for HbA1c showed no significant correlation between ADPRCA and nephropathy. However, logistic regression analyses revealed that determinants for nephropathy were systolic blood pressure and ADPRCA, not HbA1c.
Decreased ADPRCA significantly correlated with diabetic nephropathy. ADPRCA in PBMCs would be an important marker associated with diabetic nephropathy.
[show abstract] [hide abstract]
ABSTRACT: Diabetes-specific microvascular disease is a leading cause of blindness, renal failure and nerve damage, and diabetes-accelerated atherosclerosis leads to increased risk of myocardial infarction, stroke and limb amputation. Four main molecular mechanisms have been implicated in glucose-mediated vascular damage. All seem to reflect a single hyperglycaemia-induced process of overproduction of superoxide by the mitochondrial electron-transport chain. This integrating paradigm provides a new conceptual framework for future research and drug discovery.Nature 01/2002; 414(6865):813-20. · 36.28 Impact Factor
Article: Treatment of type 2 diabetic patients with kidney disease with AT1-receptor antagonists: lessons from recent trials[show abstract] [hide abstract]
ABSTRACT: Background. As the incidences of type 2 diabetes (non-insulin dependent diabetes mellitus; NIDDM) and associated nephropathy increase worldwide at epidemic rates, the occurrence of serious renal outcomes such as end-stage renal disease has become a critical burden to patients and health care systems. Methods. The Irbesartan Diabetic Nephropathy Trial (IDNT), Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL), and Losartan Intervention For Endpoint reduction in hypertension (LIFE) trials are reviewed. Results. In the IDNT trial, treatment with irbesartan significantly reduced the composite primary endpoint [doubling of serum creatinine (SCr), end-stage renal disease (ESRD; dialysis, transplantation, or SCr ≥ 6 mg/dl), or death] by 20% compared with placebo (P = 0.02), and by 23% compared with amlodipine (P = 0.006). In the RENAAL study, treatment with losartan resulted in a significant risk reduction of 16% in the primary composite endpoint [doubling of SCr, ESRD (dialysis or transplantation), or death]; P = 0.02. In the diabetic subgroup of LIFE, losartan reduced the risk of the primary composite endpoint of cardiovascular morbidity and mortality by 24% (P = 0.031). The risk of cardiovascular mortality was 37% lower in the losartan group than in the atenolol group (P = 0.028). These benefits in IDNT, RENAAL, and LIFE appeared to be beyond the blood pressure effect. Conclusions. The findings from recent clinical trials support the use of angiotensin receptor antagonists in patients with nephropathy due to type 2 diabetes, and have shown a significant reduction in the progression towards ESRD (losartan) and proteinuria (losartan, irbesartan), effects that were independent of blood pressure lowering achieved with these agents. Reduction in cardiovascular morbidity and mortality have also been shown in a trial with losartan in diabetics. Collectively, these studies will have worldwide beneficial impact on the treatment of this devastating disease.Clinical and Experimental Nephrology 01/2002; 6(4):0175-0181. · 1.37 Impact Factor
[show abstract] [hide abstract]
ABSTRACT: Despite recent medical advances, the number of patients beginning dialysis annually is increasing in both the United States and Japan. The ethnically homogeneous population of Japan presents an opportunity to study the presence of factors other than race/ethnicity that might contribute to incidence of end-stage renal disease (ESRD). To determine if and where regional differences exist in ESRD in Japan. Analysis of data reported by the Japanese Society for Dialysis Therapy based on the annual number of patients with ESRD beginning maintenance dialysis therapy in all 47 prefectures of Japan from 1982 to 1998. Mean annual ESRD incidence and increasing rate of ESRD in each of 11 predefined areas making up the entire country. Incidence of ESRD increased approximately 3-fold in Japan during the study years, from 81.3 per 1 million in 1982 to 237.6 per 1 million in 1998. Significant regional differences were found in both measures. The mean (SEM) annual ESRD incidence (P<.01) and increasing rate of ESRD (P<.01), respectively, were significantly different across Japan. Koshinetsu (140  per 1 million and 9.1 [0.6] per 1 million/y) and Hokuriku (141  per 1 million and 9.7 [0.5] per 1 million/y) were the areas with the lowest incidence and increasing rate of incidence, while Okinawa (188  per 1 million and 13.4 [0.6] per 1 million/y) and Kyushu (179  per 1 million and 12.0 [0.6] per 1 million/y) were the areas with the highest incidence and increasing rate of incidence. We found definite and significant regional differences in incidence and increasing rate of incidence of ESRD in Japan. Further analyses are needed to identify factors that contribute to these regional differences and thereby improve strategies for treatment of renal disease. JAMA. 2000;284:2622-2624.JAMA The Journal of the American Medical Association 284(20):2622-4. · 30.03 Impact Factor
Hindawi Publishing Corporation
Experimental Diabetes Research
Volume 2008, Article ID 897508, 8 pages
Decreased ADP-Ribosyl Cyclase Activity in Peripheral Blood
Mononuclear Cells from Diabetic Patients with Nephropathy
Michio Ohtsuji,1Kunimasa Yagi,1Miyuki Shintaku-Kubota,1Yukiko Kojima-Koba,1Naoko Ito,1
Masako Sugihara,1Naoto Yamaaki,1Daisuke Chujo,1Atsushi Nohara,2Yoshiyu Takeda,1
Junji Kobayashi,1Masakazu Yamagishi,2and Haruhiro Higashida3
1Division of Endocrinology and Diabetology, Kanazawa University Graduate School of Medicine, 13-1 Takaramachi,
Kanazawa 920 8640, Japan
2Division of Cardiovascular Medicine, Department of Internal Medicine, Kanazawa University Graduate School of Medicine,
13-1 Takaramachi, Kanazawa 920 8640, Japan
3Department of Biophysical Genetics, Kanazawa University Graduate School of Medicine, 13-1 Takaramachi,
Kanazawa 920 8640, Japan
Correspondence should be addressed to Kunimasa Yagi, email@example.com
Received 30 September 2008; Accepted 12 December 2008
Recommended by Andreas Pf¨ utzner
Aims/hypothesis. ADP-ribosyl-cyclase activity (ADPRCA) of CD38 and other ectoenzymes mainly generate cyclic adenosine
5’diphosphate-(ADP-) ribose (cADPR) as a second messenger in various mammalian cells, including pancreatic beta cells and
peripheral blood mononuclear cells (PBMCs). Since PBMCs contribute to the pathogenesis of diabetic nephropathy, ADPRCA
of PBMCs could serve as a clinical prognostic marker for diabetic nephropathy. This study aimed to investigate the connection
between ADPRCA in PBMCs and diabetic complications. Methods. PBMCs from 60 diabetic patients (10 for type 1 and 50
for type 2) and 15 nondiabetic controls were fluorometrically measured for ADPRCA based on the conversion of nicotinamide
guanine dinucleotide (NGD+) into cyclic GDP-ribose. Results. ADPRCA negatively correlated with the level of HbA1c (P = .040,
R2= .073), although ADPRCA showed no significant correlation with gender, age, BMI, blood pressure, level of fasting plasma
glucose and lipid levels, as well as type, duration, or medication of diabetes. Interestingly, patients with nephropathy, but
not other complications, presented significantly lower ADPRCA than those without nephropathy (P = .0198) and diabetes
(P = .0332). ANCOVA analysis adjusted for HbA1c showed no significant correlation between ADPRCA and nephropathy.
However, logistic regression analyses revealed that determinants for nephropathy were systolic blood pressure and ADPRCA, not
HbA1c. Conclusion/interpretation. Decreased ADPRCA significantly correlated with diabetic nephropathy. ADPRCA in PBMCs
would be an important marker associated with diabetic nephropathy.
Copyright © 2008 Michio Ohtsuji et al.ThisisanopenaccessarticledistributedundertheCreativeCommonsAttributionLicense,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Diabetes mellitus is characterized by chronic hyperglycemia
and the development of diabetes-specific microvascular
complications. As a consequence of these complications,
diabetes is a leading cause of end stage renal disease
common cause of ESRD in Japan . Recent epidemiologic
data indicated that the number of Japanese type 2 diabetic
patients on renal replacement therapy has tripled within
less than 15 years, and Japanese type 2 diabetic patients
might be particularly predisposed to nephropathy [3, 4].
Therefore, earlier detection of high-risk Japanese subjects
for the diabetic nephropathy is quite important for early
intervention to prevent ESRD.
Chronic low-grade inflammation and activation of the
innate immune system are closely involved in the patho-
genesis of diabetes and its microvascular complications [5,
6]. Inflammatory events are central to the pathogenesis of
diabetic nephropathy [7–9], and inflammatory cytokines
are involved in its development and progression .
Macrophages derived from circulating monocytes have been
recently focused on as playing central roles in the pro-
gression of diabetic nephropathy [11, 12]. Since PBMCs
2Experimental Diabetes Research
mainly consist of lymphocytes and monocytes, both of
which contribute to the progression of diabetic nephropathy,
intracellular regulatory signals involved in the activation of
PBMCs could serve as a possible therapeutic target and/or
clinical prognostic marker for diabetic nephropathy.
Cyclic adenosine 5’diphosphate-ribose (cADPR) plays
a second messenger role in a variety of mammalian cells,
including pancreatic beta cells, kidney mesangial cells, and
PBMCs . The rapid release of Ca2+from the smooth
endoplasmic reticulum (SER), the most characterized Ca2+
organelle, is evoked by stimulation of two kinds of receptors
on the SER for ryanodine and inositol (1,4,5)-triphosphate.
cADPR is catalyzed from beta-NAD+by ADP-ribosyl-
cyclase activity (ADPRCA) of CD38, CD157, and other
ectocellular membrane-bound enzymes [14–18]. cADPR
has been recently demonstrated to stimulate a variety of
contraction, and vasodilation [19–25]. For example, several
studies have examined ADPRCA in kidney mesangial cells
[26, 27], and cADPR has been reported to induce smooth
muscle contraction in small renal arteries .
Since cADPR modulates adaptive immune recognition
process of PBMCs , we hypothesized that impaired
regulatory signals of ADPRCA in PBMCs would result in
the progression of diabetic vascular complications. However,
no clinical studies have been performed to examine the
relationship between CD38 and diabetic complications.
Based on this background, this study investigates the
connection between ADPRCA in PBMCs and diabetic
vascular complications, especially nephropathy.
2. MATERIALS AND METHODS
Patients were eligible for the study if they exhibited diabetes
mellitus. Diabetes mellitus was diagnosed and classified
according to World Health Organization (WHO) criteria
renal and/or hepatic diseases were excluded. The study,
approved by the ethics committee of Kanazawa University
Graduate School of Medical Science, was conducted in
accordance with the Declaration of Helsinki (1964), and all
patients gave written informed consent before participating
in the study.
ssessment and diagnosis of diabetic complications were
performed as below . Nephropathy was diagnosed as
the existence of albuminuria, proteinuria, and/or creati-
nine clearance <60mL/min. Albuminuria was defined as
urinary albumin excretion between 20 and 200mg/24hr
or urinary albumin to urinary creatinine ratio between
30 and 300mg/gCr. Proteinuria was defined as Albustix
[Ames] positive. Creatinine clearance values were calculated
by the Cockroft-Gault formula. Retinopathy was diagnosed
on the basis of direct ophthalmoscopy (through a dilated
pupil) by an experienced ophthalmologist and/or by flu-
orescein angiography. Peripheral neuropathy was assessed
by questioning patients about symptoms of neuropathy,
including paresthesia, dulled sensation, and pain in legs
and feet and was based on clinical examination (i.e.,
measuring abnormal knee/ankle reflexes and a Semmes-
conduction velocities of ulnar (motor and sensory), tibial,
peroneal, and sural nerves. Macroangiopathy was considered
in subjects who met the following three conditions: (1)
a history of a cardiovascular event and/or the presence
of angina and/or permanent ischemic electrocardiogram
(usually combined with a cardiac noninvasive imaging tech-
nique); (2) claudication and/or abolished peripheral pulses
and/or foot lesions due to vascular disease demonstrated
by Doppler echography and/or angiography; or (3) carotid
vascular disease, as assessed by Doppler echography.
Medication for type 2 diabetics was classified into three
tion, and oral hypoglycemic agents including sulphonylureas
and alpha-glucosidase inhibitors. No type 2 diabetic subjects
being treated with insulin sensitizers (including thiazolidine-
diones and biguanides) were enrolled in this study.
Body mass index (BMI) was calculated as weight (in
kilograms) divided by height (in meters) squared. Venous
blood samples were obtained after a 12-hour overnight
fast. Blood glucose was measured with the glucose oxidase
method and HbA1c by high-pressure liquid chromatogra-
phy. Serum total cholesterol (TC) and triglycerides (TG)
were determined by enzymatic methods, and high-density
lipoprotein cholesterol (HDL-C) levels were measured by a
polyanion-polymer/detergent method. Low-density lipopro-
tein cholesterol(LDL-C)wascalculatedusingthe Friedewald
After obtaining written informed consent, peripheral blood
samples were collected. PBMCs were isolated using Ficoll-
Paque PLUS (Sigma) [33–35] and centrifuged. Isolated
with 5mM MgCl2 (2 mL for each sample) at 4◦C for 30
minutes. The suspension was homogenized in a Teflon-glass
homogenizer; the resultant homogenate was centrifuged at
4◦C for 5 minutes at 1000×g to remove unbroken cells
and nuclei. Crude membrane fractions were prepared by
centrifugation (twice) of homogenates at 105000×g for 15
minutes. The supernatant was removed, and precipitates
Michio Ohtsuji et al.3
For each experiment, membranes were freshly prepared and
used immediately for enzymatic reactions.
based on measurement of the conversion of β-NGD+into
the fluorescent product cGDP-ribose [36–39]. In brief,
2.5mL of reaction mixtures containing 60μM β-NGD+,
50mM Tris/HCl, pH 6.6, 100mM KCl, 10μM CaCl2, and
membranes (62–297μg of protein) were maintained at 37◦C
under constant stirring. The samples were then excited
at 300nm, and fluorescence emission was continuously
monitored at 410nm in a Shimadzu RF-5300PC spectroflu-
orophotometer (Kyoto, Japan). Activity was calculated from
protein as reported previously .
All data are shown as mean ± SD. Continuous variables
were compared by one-way analyses of variance (ANOVA)
or covariance (ANCOVA) after being adjusted for age, BMI,
and sex. Normality of the distribution of Ln(ADPRCA) was
confirmed by Shapiro-Wilk’s W-test. Differences between
the two groups were compared by chi2analysis (categorical
variables) or nonparametric Mann-Whitney U-test (contin-
uous variables). Logistic regression analyses were performed
to clarify the clinical parameters contributing to categorical
variables. Stepwise multivariate regression analyses were
performed to clarify the clinical parameters contributing to
the level of continuous variable. All statistical analyses were
conducted with JMP 6.03 for Macintosh OS-X 10.5 (SAS
Institute Inc, Cary, NC, USA). A P-value of less than .05 was
considered statistically significant.
In total, sixty Japanese diabetic patients (31 males and 29
females) and fifteen nondiabetic controls (6 males and 9
females) were enrolled in this study. The baseline char-
acteristics of the subjects are shown in Table 1. ADPRCA
showed statistically significant negative correlation with
the level of HbA1c (P = .040, R2= 0.073, Figure 1). As
shown in Table 2, no significant correlation was observed
between ADPRCA and other clinical parameters (level of
fasting plasma glucose, systolic and diastolic blood pressure,
serum total cholesterol, logarithm of serum TG, HDL-C,
LDL-C, age, duration of diabetes, BMI, gender difference,
type of diabetes (Figure 2(a)), or medication for diabetes
Figure 3 shows the relationship between ADPRCA and
the diabetic vascular complications. ADPRCA was signif-
icantly lower in subjects with nephropathy than those
Figure 1: ADP-ribosyl cyclase activities and the level of HbA1c.
and HbA1c (P = .040, R2= 0.073, Ln(ADPRC) =3.4277567–
without (P = .0198) and nondiabetic controls (P = .0332)
(Figure 3(a)). Subjects with other complications also showed
similar tendencies; however, no significant correlations
giopathy were observed (Figures 3(b)–3(d)). Although
HbA1c level showed relationship with ADPRCA, no signif-
icant difference was observed in ADPRCA between subjects
with any diabetic complications (data not shown).
As HbA1c was significantly related to ADPRCA, we
examined whether HbA1c contributed to the relationship
showed that the difference just failed to meet statistical
significance after adjusting for HbA1c (Table 3). Next,
to examine whether ADPRCA could be an independent
contributor to the existence of nephropathy, we performed
blood pressure, TG, HDL, LDL, gender, type of diabetes,
duration of diabetes, medication for diabetes, HbA1c, and
BMI. Systolic blood pressure and ADPRCA contributed
significantly to the existence of nephropathy (Table 4).
The main finding of this study was that diabetic subjects
with nephropathy showed decreased ADPRCA. However,
PBMCs in proinflammatory states like diabetic vasculopathy
might be relating to increased ADPRCA as several cytokines
including IL-8, IFN-gamma upregulate intracellular CD38
activity , our results interestingly showed decreased
ADPRCA in PBMCs. Logistic analysis revealed that only
systolic blood pressure and ADPRCA, but not HbA1c, were
significantly related to the incidence of nephropathy. There-
fore, contribution of HbA1c to the relationship between
ADPRCA and nephropathy should be considered small
in extent. ADPRCA’s correlation with nephropathy seems
4Experimental Diabetes Research
CTL Type 1 DM Type 2 DM
Figure 2: (a) ADP-ribosyl cyclase activities and type of diabetes. No significant relationship was observed between ADPRCA and type of
diabetes. (b) ADP-ribosyl cyclase activities and medication for type 2 diabetes. No significant relationship was observed between ADPRCA
and medication for type 2 diabetes. CTL: control; OHA: oral hypoglycemic agent.
CTLNephropathy (−)Nephropathy (+)
P = .0332
N.S. (P = .7942)
P = .0198
ANOVA: F-value = 3.5126, P-value = .0352
CTLRetinopathy (−)Retinopathy (+)
N.S. (P = .1334)
N.S. (P = .5481)N.S. (P = .2543)
ANOVA: F-value = 1.2896, P-value = .2818
CTL Neuropathy (−)Neuropathy (+)
N.S. (P = .1862)
N.S. (P = .4877)N.S. (P = .4427)
ANOVA: F-value = 0.9207, P-value = .4030
CTLMacroangiopathy (−) Macroangiopathy (+)
ANOVA: F-value = 2.3347, P-value = .1043
N.S. (P = .0526)
N.S. (P = .5814) N.S. (P = .0704)
Figure 3: Relationship between logarithm of ADP-ribosyl-cyclase activity Ln(ADPRCA) and diabetic vascular complications. Figures show
relationship between nondiabetic control, subjects with each complication, and those without. (a) Subjects with nephropathy showed lower
ADPRCA than those without nephropathy (P = .0198) and nondiabetic controls (P = .0332). (b)–(d) No significant difference in ADPRCA
was observed in subjects with retinopathy, neuropathy, and macroangiopathy. CTL: control.
Michio Ohtsuji et al.5
Table 1: Baseline characteristics of subjects. Results are expressed as mean ± S.D.
Type 1 diabetesType 2 diabetes
164 ± 54
81 ± 12
Number of subjects
Duration of diabetes (years)
Fasting plasma glucose (mg/dl)
Medication for diabetes
Oral hypoglycemic agents
ADP-ribosyl cyclase activity (nmol/min/mg protein)
36.0 ± 14.2
244 ± 130
8.0 ± 1.5
16.9 ±7.516.6 ±7.6 17.8 ±4.6
Table 2: Correlation of ADP-ribosyl-cyclase activity with subject
parameters (calculated with logarithm-transformed TG).
Fasting plasma glucose
Systolic blood pressure
Diastolic blood pressure
Total cholesterol (TC)
Duration of diabetes
Table 3: Comparison of ADPRCA influence on nephropathy,
adjusted for HbA1c.
First, to discuss the role of cADPR-mediated signals in
PBMCs, since ADPRCA could be stimulated by angiotensin-
II , kidney tissue with diabetic nephropathy could show
increased ADPRCA. Recent report by Kim et al. showed
increased ADPRCA in the kidney of STZ-induced diabetes
ancy could be acceptable. Interestingly, the roles of CD38 on
Table 4: Logistic analysis between nephropathy and parameters
in diabetic subjects. Carrier of complication = 1, noncarrier = 0;
medication: insulin =2, OHA = 1, diet = 0; gender: male = 1,
female = 0; type of diabetes: type 2 =1, type 1 = 0.
Systolic blood pressure
PBMCs, binding of agonistic anti-CD38 antibodies, which
stimulate ADPRCA, induces release of proinflammatory
cytokines including IL-1, IL-6, and TNF-alpha over the short
term . Cytokine release could make an important con-
tribution to inflammation responsible in the early stages of
CD38 ligation inhibits cell growth and induces apoptosis
in B-cell precursors  mediating phosphatidylinositol 3-
kinase signaling , although having stimulatory effects
on mature lymphocytes. The suppressive effect mediated by
CD38 was also observed in experiments with patient-derived
myeloid leukemia cells and with the murine cell line . In
addition, CD38 expression has been reported in circulating
monocytes but not in resident macrophages and dendritic
cells [44, 45]. Differentiation of monocytes to macrophages
. CD38 is strongly expressed in lymphocyte precursors,
declined during differentiation, and then upregulated again
in mature plasma cells . CD157 was suggested to display
a similar expression tendency in myeloid cells . Since
hyperglycemia directly enhances protein ADP-ribosylation
in cultured neuroblastoma cells , resulting in increased
ADPRCA in diabetic subjects, we speculate that decreased
ADPRCA in PBMCs could reflect decreased suppressive
6Experimental Diabetes Research
effects of CD38 and CD157 and increased numbers of
Second, let us consider the agonistic effects of autoan-
tibodies against CD38, which is shown to exert insulin
secretion from cultured human islets  through ADPRCA
activation. In humans, the majority of anti-CD38 autoanti-
bodies (∼60%) display agonistic properties [51, 52], which
demonstrate the capability to trigger Ca2+release in lym-
phocytic cell lines . In agreement with these functional
features, the presence of anti-CD38 autoantibodies in type
2 diabetic patients was associated with significantly higher
levels of fasting plasma C-peptide and insulin, as compared
with anti-CD38 negative subjects. Thus, anti-CD38 autoim-
munity might indicate a relative protection against beta-
cell failure and a lower risk of insulin requirement [52, 54,
55]. Previous reports on the clinical characteristics of anti-
CD38 autoantibodies carriers have not gone into depth on
diabetic complications, although the possible exacerbation
of diabetic complications by the agonistic effect of anti-
CD38 autoantibodies on PBMCs was noted by Mallone et
al. . However, several discussions should be needed for
the relationship between CD38 autoantibodies and diabetic
vasculopathy as agonistic CD38 autoantibodies possibly
stimulate both insulin rsecretion resulting in hyperinsuline-
mia, the prominent risk factor for diabetic macroangiopathy,
and angiotensin-II induced renal artery contraction. We just
speculate that those with anti-CD38 autoantibodies should
show lower frequencies of diabetic nephropathy, and other
vascular complications in long-term follow-up studies due
to better glycemic control and increased ADPRCA reflecting
less maturated PBMCs.
Third, as all of our subjects were diabetic, it behooves
us mention the Okamoto model of diabetes pathogenesis.
CD38-related signal has been well documented in dia-
betes mellitus [18, 56–58]. Our results showing decreased
ADPRCA being significantly correlated to increased HbA1c
is compatible with previous studies reflecting to some degree
the Okamoto model [59–61]. Interestingly, in our study,
no significant relationship was observed between ADPRCA
and fasting plasma glucose. We suggest that ADPRCA
might be more related to postprandial than fasting plasma
glucose level, the former being strongly responsive to insulin
secretion [27, 29].
Finally, the clinical significance of our results: CD38
expression, representative of ADP-ribosyl cyclase, is already
used clinically as a prognostic marker for HIV infected
subjects [62, 63] and chronic lymphoid leukemia (CLL)
[13, 56, 64]. Since other ADP ribosyl cyclases including
CD157 reside on the cell surface of PBMCs, restricting
examination to CD38 would not entirely cover cADPR-
mediated signaling impairment. Measuring ADPRCA would
thus be a better approach in flagging up groups at risk
for diabetic nephropathy from among general diabetic
introduced into clinical settings for detecting subjects at
high-risk for diabetic nephropathy and thus prompting early
intervention to prevent ESRD.
This study had a number of limitations. First, we did
not have data on anti-CD38 autoantibodies. ADPRCA in
each subject is partly determined by preexisting factors inde-
and autoantibodies against CD38. We speculate that higher
ADPRCA values might reflect possession of anti-CD38
autoantibodies. Second, we did not examine any markers of
lymphocyte or monocyte maturation/differentiation. Both
should be examined in further studies.
In conclusion, our findings suggest that decreased
ADPRCA in PBMCs is significantly correlated with diabetic
nephropathy and that measurement of ADPRCA in PBMCs
could serve as an important marker associated with diabetic
nephropathy. Further prospective studies should be intro-
duced to clarify the mechanism and predictive significance
of decreased ADPRCA in diabetic complications.
The authors would like to thank Mrs. Reiko Ikeda for
her technical assistance in data analyses and comments
regarding this manuscript. K. Yagi and M. Shintaku-Kubota
contributed equally to this work.
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