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Early Diabetic Nephropathy
A complication of reduced insulin sensitivity in type 1 diabetes
PETTER BJORNSTAD, MD
1
JANET K. SNELL-BERGEON, PHD, MPH
1,2
MARIAN REWERS, MD, PHD
1,2
DIANA JALAL, MD
3
MICHEL B. CHONCHOL, MD
3
RICHARD J. JOHNSON, MD
3
DAVID M. MAAHS, MD, PHD
1,2,3
OBJECTIVE dDiabetic nephropathy (DN) is a major cause of morta lity in type 1 diabetes.
Reduced insulin sensitivity is a well-documented component of type 1 diabete s. We hypothe-
sized that baseline insulin sensitivity would predict development of DN over 6 years.
RESEARCH DESIGN AND METHODSdWe as sessed the relationship between in-
sulin sensitiv ity at baseline and development of early phenotype s of DNdmicroalbuminuria
(albumin-creatinine ratio [ACR] $30 mg/g) and rapid renal fu nction decline (glomerular filtra-
tion rate [GFR] loss .3 mL/mi n/1.73 m
2
per year)dwith three Chronic Kidney Disease Epide-
miology Collaboration (CKD-EP I) equations over 6 years. Subjects with diabetes (n =449)and
without diabetes (n = 565) in the Coronary Artery Calcification in Type 1 Diabetes study had an
estimated insulin sensitivity index (ISI ) at baseline and 6-year follow-up.
RESULTSdThe ISI was lower in subjects with diabetes than in those withou t diabete s (P ,
0.0001). A higher ISI at baseline predicted a lower odds of developing an ACR $30 mg/g (odds
ratio 0.65 [95% CI 0.49–0. 85], P = 0.00 3) univariately and after adjus ting for HbA
1c
(0.69 [0.51–
0.93], P = 0.01). A higher ISI at baseline conferred prote ction from a rapid decline of GFR as
assessed by CKD-EPI cystatin C (0.77 [0.64 –0.92], P = 0.004) and remained significant after
adjusting for HbA
1c
and age (0.80 [0.67–0.97], P = 0.02). We found no relation between ISI and
rapid GFR decline estimated by CKD-EPI creatinine (P = 0.38) or CKD-EPI combined cystatin
C and creatinine (P = 0.50).
CONCLUSIONSdOver 6 years, a higher I SI independently predicts a lower odds of devel-
oping microalbuminuria and rapid GFR de cline as estimated with cystatin C, suggesting a re-
lationship between insulin sensi tivity and early phenotypes of DN.
Diabetes Care 36:3678–3683, 2013
D
iabetic nephr opathy (DN) is a com-
mon and serious complication of
diabetes. Its incidence is rising rap-
idly (1), and it is the most common cause
of end-stage renal di sease in the U.S. and
Europe (2). The 2011 U.S. R enal Data
System showed that DN accounted for
44.5% of all cases of end-stage renal dis-
ease in 2009 (3). Despite improvements
in the outlook of this complication in past
decades, it continues to be one of the ma-
jor causes of morbidity and mortality in
type 1 diabetes (4,5). DN is an important
risk factor for coronary artery disease (6–8)
and overall mortality (6,9). These find-
ings highlight the need for improved
methods of identifying persons at high
risk for DN (10).
The role of insulin sensitivity in the
development and progression of macro-
(7,11,12) and microvascular complications
(12,13) in type 1 diabetes is increasingly
recognized. Reduced insulin sensitivity
also is a plausible mechanism linking renal
disease with excess mortality in type 1 di-
abetes. Historically, when glyc emic con-
trol is poor, reduced insulin sensitivity
was believed to be directly related to
body weight and HbA
1c
(14,15), but
more recent data suggest that reduced in-
sulin sensitivity cannot simply be explained
by weight or poor glycemic control. In fact,
reduced insulin sensitivity has been docu-
mented in type 1 diabetic subjects with
normal BMI and HbA
1c
compared with
nondiabetic individuals (16). The Coro-
nary Artery Calcification in Type 1 Diabe-
tes (CACTI) longitudinal cohort study of
adults with type 1 diabetes investigated
the determinants of early and accelerated
atherosclerosis and found that insulin sen-
sitivity independently predicted coronary
artery calcification (17,18). Reduced insu-
lin sensitivity has also been shown to pre-
dict diabetic retinopathy, neuropathy,
and nephropathy in subjects with type 1
diabetes (13).
Despite advances in the estimation of
insulin sensitivity (insulin sensitivity in-
dex[ISI])(19)andglomerularfiltration
rate (GFR) (20), research in the associa-
tion of insulin sensitivity with DN has
been limited since the Pittsburgh Epide-
miology of Diabetes Complications
(EDC) cohort showed more than a decade
ago that the estimated glucose disposal
rat e (eGDR) predicts ov ert nephropathy
(13). To readdress this relationship with
contemporary data and estimat ing equa-
tions, we hy pothesized that higher insuli n
sensitivity measured by ISI at baseline
wouldbeassociatedwithdecreased
odds of developing two early phenotypes
of DNdmicroalbuminuria (albumin-
creatinine ratio [ACR] $30 mg/g) and
rapid renal function decline (GFR l oss
.3mL/min/1.73m
2
per year) (21–23)d
calculated by the three Chronic Kidney Dis-
ease Epidemiology Collaboration (CKD-
EPI) equations (20) over 6 years in the
CACTI study.
RESEARCH DESIGN AND
METHOD S dThe CACTI study en-
rolled subjects 19–56 years of age with
and without type 1 diabetes who were
asympto matic for cardiovascular disease
at the baseline visit in 2000–2002 and
then wer e reexamined 3 and 6 years later
as previously described (24). Subjects
with type 1 diabetes had to have a disease
duration of at least 10 years at enro llment,
with the exce ptio n of 109 su bjects w ho
had taken part in a pilot study in 1997–
1998 and had 2–48 years of diabetes du-
ration. Subjects with serum creatinine
levels .2 mg/dL were excluded at baseline
cccccccccccccccccccccccccccccccccccccccccccccccc c
From the
1
Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado; the
2
Barbara Davis Center for Diabetes, University of Colorado Denver, Aurora, Colorado; and the
3
Department
of Nephrology, University of Colorado Denver, Aurora, Colorado.
Corresponding author: Petter Bjornstad, petter.bjornstad@childrenscolorado.org.
Received 14 March 2013 and accepted 7 June 2013.
DOI: 10.2337/dc13-0631
© 2013 by the American Diabetes Association. Readers may use this article as long as the work is properly
cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/
licenses/by-nc-nd/3.0/ for details.
3678 DIABETES CARE, VOLUME 36, NOVEMBER 201 3 care.diabetesjournals.org
Pathophysiology/Complications
ORIGINAL ARTICLE
unless they were participants in the pilot
study. All subjects with the data needed to
calculate ISI and GFR at the baseline and
6-year visits were included in this analysis
(n = 449 with type 1 diabetes, n =565
wit hout diabetes). Among subjects with
type 1 diabetes, those with missing data
had slightly worse baseline renal function
(e.g., CKD-EPI cystatin C eGFR 108 6 18
vs. 100 6 30 mL/min/1.73 m
2
) and fasting
lipid profile than those with complete
data. In contrast, nondiabetic control sub-
jects with missing data were younger
(35 6 9 vs. 40 6 9 years) and had better
renal function (CKD-EPI cystatin C eGFR
111 6 13 vs. 108 6 12 mL/min/1.73 m
2
).
The study was approved by the Colorado
Multiple Institutional Review Board, and
all subjects provided informed consent.
We measured heig ht and we ight and
calculated B MI as kilograms pe r meter
squared. Resting systolic blood pressure
(SBP) and fifth phase diastolic blood
pressure (DBP) were measured three
times while the subj ect was seate d, and
the second and third measurements were
averaged. Hypertension was defined as
current antihypertensive therapy or un-
treated hypertension (blood pressure
$140/90 mmHg) at the time of the study
visit. A ntihypertension medicati on use
was determined by a medication inven-
tory as previously described (24), and
use of an angio tensin-convert ing enzyme
inhi bitor (ACEi) or an angiotensin recep-
tor blocker (ARB) was combined for these
anal yses.
After an overnight fast, blood was
collected, centrifuged, a nd separated.
Plasma was stored at 48C until assayed.
Total plasma cholesterol and triglyceride
levels were measured by standard enzy-
matic meth ods, HDL cholesterol was sep-
arated with the use of dextran sulfate, and
LDL cholest erol was calculated by the
Friedewald equation. High-performance
liquid chromatography (Bio-Rad variant)
was used to measure HbA
1c
.
Ove rnight urine samples were col-
lected in duplicate, and urine creatinine
and albumin levels were measured by
radioimmunoassay (Dia gnostic Pro ducts)
and averaged. In sub jects (n = 35) who did
not have two timed overnight urine sam-
ples, only one timed overnight urine sam-
ple was collected. Two subjects did not
provide a timed overnight urine sample,
and instead, spot urine was collected.
Early DN was defined as microalbu-
minuria (ACR $30 mg/g) and rapid GFR
decline (.3 mL/min/1.73 m
2
per year)
(23,25) by all three CKD-EPI equations.
Twenty-five type 1 diabetic subjects had
an ACR ,30 mg/g at the first visit (V1) ,
and ACR $30 mg/g developed in them by
the third visit (V3). In contrast, 284 sub-
jects had ACR ,30 mg/g at both V1 and
V3. The analysis compa red t hese two
groups of subjects. Microalbuminuria de-
veloped in only five control subjects, so
we did not have sufficient power to run
anal yses on this outcome.
GFR was determined wi th the use of
the CKD-EPI serum creatinine, serum
cystatin C, and combined equations re-
cently published by Inker et al. (2 0) for
the CKD-EPI Investigators Group. Cystatin
C was measured in the University of Col-
orado Hospital clinical laboratory accord-
ing to the package insert instructions
of a commercially available assay (Dade-
Behring) on a BN II or Prospec nephelom-
eter. The coefficient of variation was 3.3%.
Intraassay precision is 2.3–4.1%, and in-
terassay precision is 2.6–3.3% according
to the package insert. Results are reported
in milligrams per liter, with a sensitivity
cutoff of 0.23 mg/L. Because of a system-
atic shift in the Dade-Behring cystatin C
assay over the period of the study, cystatin
C levels were standardized to V3 levels by
Deming regression equations, as previ-
ously described (26).
Serum cr eati nine level was measured
according to package insert instructions
on a Roche Mira Plus II an alyzer until
2006 and then an Olympus AU400e (r =
0.9999 between methodologies) trace-
able to the National Institute of Standards
and Technol ogy standard reference mate-
rial at the U niversity of Colorado Clinical
Translational Res earch L aboratory. Intra-
and interassay precision are 1.6 and 3.3%,
respect ively. Because of the longitudinal
design of CACTI and to assess for any po-
tential c hang e over time in the serum cre-
atinine assay, 100 samples each from all
three visits w ere remeasured as a single
batch. Deming regression equations
were u sed to standardize serum creatinine
level by the same methodology as previ-
ously described for cystatin C (26).
With the use of the CKD-EPI creati-
nine equation to estimate GFR, 122 sub-
jects with type 1 diabetes experienced a
GFR loss .3 mL/min/1.73 m
2
per year
compared with 327 who had a stable re -
nal function (GFR loss ,3 mL/min/1.73
m
2
per year). In contrast, by CKD-EPI
cystatin C equa tion, rapid GFR decline
developed in only 58 subjects with type
1 diabetes compared with 391 with stable
renal function. By combined CKD-EPI
creatin ine and cyst atin C equation, rapid
GFR decline developed in 64 subjects
with type 1 diabetes compared with 385
with stabl e renal function on foll ow-up.
We compared subjects with rapid GFR
decl ine with those with stable renal func-
tion over the 6 years of the study. Rapi d
GFR decline developed in only 29 control
subjects per CKD-EPI cystatin C equation
compared with 135 and 4 7 control sub-
jects per CKD-EPI creatinine and combined
creatinine and cystatin C equations,
respective ly.
CACTI clamp cohort: ISI
The ISI is derived from previous euglycemic-
hyperinsulinemic clamp studies in a sub-
set of 87 subjects (40 with and 47 without
diabetes frequency matched for age, sex,
and weight) of the CACTI cohort, as
previously described i n detail (18). The
best-fi t ISI model for subjects with type
1 diabetes comprises waist circumfer-
ence, daily insulin dose per kilogram
body weight, triglyceride levels, and
DBP and explained 63% of the variance
in GDR. The equation to calculate the ISI
is as follows: exp(4.1075 – 0.01299 3
waist [cm] – 1.05819 3 insuli n dos e
[daily units/kg] – 0.00354 3 triglycer-
ide level [mg/dL] – 0.00802 3 DBP
[mmHg]) (19).
Statistical analysis
Anal yses were perfor med with SAS ver-
sion 9.2 for Windows (SAS Institute,
Cary, NC) software. Differences between
type 1 diabetic subjects and control sub-
jects at baseline and follow-up were as-
sessed by x
2
test for categorical variables
and t test for continuous v ariables. Non -
parametric variables (e.g., ACR and tri-
glyceride leve l) w ere log transforme d to
compute geometric means. U nivariate lo-
gistic regres sion was perfo rmed to evalu-
ate the associations between variables at
baseline and the development of micro-
albuminuria and rapid renal function de-
cline c alculated by the CKD-EPI
crea tinine, cystatin C, and combined cre-
atinine and cystatin C equ ations. The fol-
lowing variables wer e tested for univariate
associations with the dependent out-
comes: LDL cholesterol, HDL cholesterol,
total cholester ol, SBP, HbA
1c
, type 1 di-
abetes duration, and age. DBP and triglyc-
eride level were not included because t hey
are part of the ISI. Only variables s ignifi-
cantly associated with the dependent var-
iables in univariate analyses were eligible
for selection in the multivariable models,
with a significance level of P , 0.05 for
inclusion. Stepwise logistic regression
care. diabetesjournals.org DIABETES CARE, VOLUME 36, NOVEMBER 2013 3679
Bjornstad and Associates
was used to determine which variables re-
mained in multivariable models predicting
microalbuminuria and rapid GFR de-
cline. Only variables with P , 0.1 in step-
wiseselectionwereincludedinthe
models. We further evaluated the inde-
pendence of the association of ISI to renal
outcomes by adjusting the multivariable
models for the dichotomous variabl es of
sex, smoking status, and ACEi/ARB use.
All analyses were stratified by type 1 dia-
betes status, and significance was based on
an a of 0.05.
RESULTSdData, including ISI, were
available for 449 subjects with type 1
diabetes and 565 control subjects at base-
line (V1) and follow-up (V3). Among type
1 diabetic subjects, 76 had an ACR $30
mg/g, and 15–21 (depending on which
eGFR calculation was used) had a GFR
,60 mL/min/1.73 m
2
at V1; all were ex-
cluded from the analyses. Twenty-five
subjects progressed from normoalbumi-
nuria at V1 to microalbuminuria at V3,
and there were 12–14 new cases of GFR
,60 mL/min/1.73 m
2
.Conversely,
among control subjects, ACR $30 mg/g
developed in only six, and GFR ,60 mL/
min/1.73 m
2
developed in only two t o
four at V3.
The mean ISI at V1 among type 1 di-
abetic subjects was 4.4 6 1.6 mg z kg
21
z
min
21
vs. 15.4 6 6.7 mg z kg
21
z min
21
in control subjects (P , 0.0001). Simi-
larly at V3, the mean was 4.7 6 1.8 and
15.6 6 6.6 mg z kg
21
z min
21
among type
1 diabetic and cont rol subjects, respec-
tively (P , 0.0001). In addition, among
both subject groups, the mean differences
in HbA
1c
; age; total cholesterol, HDL cho-
lesterol, LDL cholesterol, and triglyceride
levels; SBP and DBP; and the proportions
of hypertension, ACEi/ARB use, and non-
Hispanic whites were all statistically sig-
nificantly different (Table 1). There was a
significant overall decline in eGFR over 6
years i n the enti re cohort as calculated by
CKD-EPI creatinine (P , 0.000 1), cysta-
tin C (P , 0.0001), and combined creat-
inine a nd cystatin C (P , 0.0001).
In univariate analysis, only ISI at
baseline predicted a lower odds of de-
veloping ACR $30 mg/g (od ds ratio 0.65
[95% CI 0.49–0.85], P = 0.003), and
HbA
1c
predicted a higher od ds of devel-
oping ACR $30 mg/g (1.45 [1.10–1.92],
P = 0.009). ISI remained in the model af-
ter adjusting for HbA
1c
in a multivar iable
logistic regression (0.69 [0.51–0.93], P =
0.013) (Table 2). Moreover, the associa-
tion rem ained significant with additional
adjustments for sex, smok ing status, and
ACEi /ARB use (P =0.018).
In univariate analysis, ISI was associ-
ated with a d ecrease d odds (0.77 [0.64–
0.92], P = 0.004) and HbA
1c
(P ,
0.0001), age (P = 0.04), SBP (P = 0.02),
and BMI (P = 0.01 ) w ere associated with
an increased odds of developing r apid
GFR decline as calculated by CKD-EPI
cystatin C. In the ste pwise model, ISI re-
mained significant after adjusting for
HbA
1c
and age (0.80 [0.67–0.97], P =
0.02) (Table 3). Moreover, the association
rema ine d unchanged with additional ad-
justments for both sex and smoking sta-
tus, but a djusting for ACEi/ARB use at
baseline a ttenuated the s ignificance of
the association (0.831 [0.686–1.006],
P = 0.058). We found no associations
Table 1dSubject characteristics
V1 V3
Variable
Type 1 diabetes
(n = 449)
No diabetes
(n =565) P value
Type 1 diabetes
(n =449)
No diabetes
(n = 565) P value
Age (years) 36.7 6 8.7 40.2 6 8.8 ,0.0001 43.3 6 8.7 46.8 6 8.8 ,0.0 001
Sex 0.31 0.12
Male 47 51 46 50
Female 53 49 54 50
Non-Hispa nic whites 95 85 ,0.0001 95 85 ,0.0 001
Type 1 diabetes duration (years) 22.9 6 8.9 NA NA 29.2 6 8.9 NA NA
HbA
1c
(%) 7.9 6 1.2 5.5 6 0.4 ,0.0001 7.9 6 1.2 5.5 6 0.5 ,0.0001
HbA
1c
(mmol/mol) 63 6 10.8 37 6 2 ,0.0001 63 6 10.8 37 6 3.1 ,0.0001
BMI (kg/m
2
)26.16 4 .3 26.0 6 4.8 0.75 26.7 6 4.6 26.5 6 4.9 0.47
ISI (mg z kg
21
z min
21
)4.46 1 .6 15.4 6 6.7 ,0.0001 4.7 6 1.8 15.6 6 6.6 ,0.0001
Cystatin C (mg/L) 0.81 6 0.21 0.78 6 0.10 0.03 0.85 6 0.34 0.78 6 0.12 ,0.0 001
Serum creatinine (mg/dL) 0.83 6 0.34 0.83 6 0.24 0.89 0.86 6 0 .38 0.83 6 0.18 0.13
CKD-EPI equation
Creatinine (mL/m in/1.73 m
2
) 105 6 24 102 6 20 0.08 97.9 6 21.4 96.5 6 14.5 0.22
Cystatin C (mL/min/1.73 m
2
) 108 6 18 108 6 12 0.84 102 6 22 106 6 14 0.006
Combined (mL/min/1.73 m
2
) 103 6 23 101 6 18 0.14 101 6 22 102 6 13 0.39
MA or greater 18 3 ,0.0001 17 2 ,0.0 001
ACEi/ARB use 32 3 ,0.0001 46 8 ,0.0 001
Lipid medications 16 7 ,0.0001 47 19 ,0.0 001
Hypertension 39 16 ,0.0001 54 24 ,0.0001
SBP (mmHg) 116 6 13 114 6 12 0.03 116 6 13 116 6 13 0.35
DBP (mmHg) 77 6 9796 9 0.00 03 74 6 9786 9 ,0.0 001
Total cholesterol (mg/dL) 174 6 33 192 6 37 ,0.0001 163 6 33 186 6 33 ,0.0 001
HDL choleste rol (mg/dL) 56 6 16 51 6 15 ,0.0001 61 6 20 56 6 19 ,0.0001
LDL cholesterol (mg/dL) 99 6 28 116 6 33 ,0.0001 86 6 30 108 6 31 ,0.0001
Triglycerides (mg/dL)* 81 (41–190) 111 (52–298) ,0.0001 68 (35–168) 98 (47–263) ,0.0001
Data are mean 6 SD or % unless otherwise indicate d. MA, microalbuminuria; NA, not applicable. *Geometric mean (5th–95th percentile).
3680 DIABETES CARE, VOLUME 36, NOVEMBER 201 3 care.diabetesjournals.org
Reduced insulin resistance and DN
between ISI or HbA
1c
and rapid G FR de-
cline when calculated by CKD-EP I creat-
inine (P = 0.38) or combined creatinine
and cystatin C (P = 0.50).
CONCLUSIONSdA major challenge
in preventing DN is the difficulty in
accurately identifyin g high-risk patients
and the need for additional therapeutic
tar gets. The aim of this study was to
evaluate the association of insulin sensi-
tivi ty and DN. The data show that greater
insulin sensitivity at baseline indepen-
dently predicts lower risk of developing
ACR $30 mg/g and confers protection
from a rapid decline of GFR as calculated
by CKD-EPI cysta tin C.
The association betw een reduced in-
sulin sensitivity and diabetes complica-
tions is increasingly recogn ized, but it is
not a recent discovery. In 1968, Martin
and Stocks (27) showed that microvascu-
lar complicat ions were associ ate d with re-
duced insulin sensitivity in long-standing
type 1 diabetes. In 1993, Yip et al. (28)
explored insulin resistance as an underlying
factor in type 1 diabetes and found reduced
insulin sensitivity, measured by GDR, in
asmallgroupwithmicroalbuminuria,
whereas Orchard et al. (13) later demon-
strated that eGDR (a marker of insulin sen-
sitivity) predicted overt nephropathy in
type 1 diabetic subjects in the Pittsburgh
EDC cohort. The utility of eGDR as a
marker of microvascular complications
in type 1 diabetes was also confirmed by
Chillarón et al. (29) and Girgis et al. (30) in
two smaller cross-sectional studies in 91
and 61 subjects, respectively.
The exact mechanism of reduced in-
sulin sensitivity in type 1 diabetes is
poorly understoo d. One hypothesis sug-
gests that reduced insulin sensitivity is
secondary to prolonged exposure to su-
praphysiologic levels of exogenous insulin,
which has been shown to be associated
with increased ectopic fat accumulation in
the liver and skeletal muscles, increased
oxidative stress, and decreased mitochon-
drial biogenesis (31,32). One possible
mechanistic pathway linking reduced insu-
lin sensitivity to DN in type 1 diabetes is
through reduced insulin sensitivity effects
on overall nonessential fatty acid exposure
and lipotoxicity in the development of
macro- and microangiopathy.
The present study is similar to that of
Orchard et al. (13) but with a larger
sample and contemporary equations for
estimating GFR and insulin sensitivity
and the inclusion of nondiabetic subjects
in the analyses. The present study popu-
lation was also 10 years older than the
Pittsburgh EDC study population and
had a lower mean HbA
1c
of 7.9%. In ad-
dition, the present study uses the ISI, an
equation derived from the study of Snell-
Bergeon et al. (19), which is the largest
euglycemic-hyperinsulinemic clamp
study in adults with and without type 1
diabetes and improves on the adjusted R
2
increase from the Pittsbur gh EDC study
(from 0.57–0.63). Microalbuminuria is
still recognized as the earliest stage of
DN in type 1 diabetes (33), but evidence
shows that ACR $30 mg/g does not in-
exorably lead to prog ression of DN (34).
For that reason, we decided to add a sec-
ond recognized phenotype of early DN:
rapid G FR decline, which some believe
to be a better marker of trajectory toward
impaired renal fun ction (25). Annual
screening for albuminuria a nd eGFR is
recommended by the American Diabetes
Association (35).
We calculated a rapid decline in
kidney function with all three of the
CKD-EPI equations (20). Concordance
between CKD-EPI cystatin C and creati-
nine eGFR has been reported to be as low
as 62% (36), and CKD-EPI cystatin C
eGFR is considered to be less biased by
age and weight than creatinine-based
measurements (22). Consistent with the
present data, cystatin C has been shown
to be more accurate in detecting rapid
GFR d ecline than creatinine-based mea-
surements in type 1 diabetic subjects with
normal GFR levels (37). Furthermore,
rapid GFR decline esti mated by cystatin
C has also been shown to be associated
with a higher risk for cardiovascular com-
plications and mortality than GFR esti-
mated by creatinine (21,36). This is also
consistent with our findings from the
CACTI cohort, where eGFR calculated
by cystatin C predicted coronary art ery
calcification progress ion better than
eGFR calculated by the CKD-EPI creatinine
or combined equations (8). These findings
agree with the present data, where only
rapid GFR decline calculated by CKD-EPI
cystatin C eGFR was associated with ISI in
subjects with type 1 diabetes.
There are limitations to the current
study, including the observational design
and no direct measurements of GFR or
insulin sensitivity because of the large co-
hort size. However, we used all three of
the recently published CKD-EPI equations.
Table 2dMultivariable analysis predicting development of microalbuminuria
Microalbuminuria (ACR $30 mg/g) P value
LDL cholesterol Did not enter model d
HDL choleste rol Did not enter model d
Total cholesterol Did not enter model d
SBP Did not enter model d
BMI Did not enter model d
HbA
1c
1.31 (0.98–1.75) 0.07
Duration of diabetes Did not enter model d
Age Did not enter model d
ISI 0.69 (0.51–0.93) 0.01
Data are odds ratio (95% CI).
Table 3dMultivariable analysis predicting development of rapid GFR decline
(>3 mL/min/1.73 m
2
/year)
CKD-EPI cystatin C P value
LDL cholesterol Did not enter model d
HDL choleste rol Did not enter model d
Total cholesterol Did not enter model d
SBP Did not enter model d
BMI Did not enter model d
HbA
1c
1.49 (1.20–1.87) 0.0004
Duration of diabetes Did not enter model d
Age 1.05 (1.01–1.08) 0.006
ISI 0.80 (0.67–0.97) 0.02
Data are odds ratio (95% CI).
care. diabetesjournals.org DIABETES CARE, VOLUME 36, NOVEMBER 2013 3681
Bjornstad and Associates
It should be noted that eGFR at higher
levels is associated with greater variability;
however, these equations are state of the
art and used by such studies as the Di-
abetes Control and Complications Trial/
Epidemiology of Diabetes Interventions
and Complications (DCCT/EDIC) (38).
Moreover, cystatin C–based equations
have been shown to estimate GFR well in
diabetic subjects with normal and elevated
renal function (37,39). In addition, the ISI
has strong agreement with GDR measured
by the gold standard method in the CACTI
clamp study (R
2
= 0.63), thereby support-
ing its role as a true reflection of insulin
sensitivity. There was insufficient power
to assess the ability of ISI to predict risk
of developing microalbuminuria in con-
trol subjects and the categorical develop-
ment of eGFR ,60 mL/min/1.73 m
2
in
both groups because these end points de-
veloped in very few subjects in the cohort.
The subjects with type 1 diabetes without
complete data at baseline had worse renal
function and lipid panel findings, which
may bias the results to the null because less
healthy subjects with type 1 diabetes were
not included in the analyses.
In summary, greater insulin sensitiv-
ity as measured by ISI at baseline appears
to be protective against the development
of microalbuminuria and rapid eGFR de-
cline as estimated b y cystatin C. Des pit e
the Bypass Angi opla sty Revasculari zati on
Investigati on 2 Diabetes (BARI 2D) study
(40) showing no benefit of an insulin sen-
sitizing strategy on nephropathy in sub -
jects with type 2 diabetes, modification of
insu lin sensi tivity holds promise as a ther-
apeutic target to reduce vascular compli-
cations in type 1 diabetes because both
lifestyle c hanges (diet and exercise) and
medications, such as metformin, can im-
prove insulin sensitivity. Further research
is requ ired to bett er assess the role of in-
sulin sensitivity in DN i n typ e 1 diabetes,
especially given the increased incidence of
obesity in people with type 1 diabetes.
AcknowledgmentsdSupport for this study
was provided by National Heart, Lung, and
Blood Institute grant R01 HL113029, Diabetes
Endocrinology Research Center Clinical
Investigation Core grant P30-DK-57516,
and JDRF grant 17-2013-313. The study was
performed at the Adult Clinical and Trans-
lational Research Center at the University of
Colorado Denver with support from National
Institutes of Health grant M01-RR-00051, at
the Barbara Davis Center for Childhood Di-
abetes, and at the Colorado Heart Imaging
Center in Denver. J.K.S.-B. was supported by
an American Diabetes Association Junior Fac-
ulty Award (1-10-JF-50). D.M.M. was sup-
ported by a grant from the National Institute of
Diabetes and Digestive and Kidney Diseases
(DK-075360).
R.J.J. has patent applications related to th e
lowering of uric acid and blocking fructose
metabolism as a me ans for slowing DN or
improving insulin resistanc e and has shares
with XORT Therapeutic s related to these pat-
ents. No othe r potential conflicts of interest
relevant to this article were reported.
P.B. contributed to the research and dis-
cussion and wrote, reviewed, and edited the
manuscript. J.K.S.-B. formulated the I SI
model, contributed to the research and dis-
cussion, and reviewe d and edited the manu-
script. M.R. designed the CACTI study,
contributed to the research and discussion,
and reviewed and edited the manus cript. D.J.,
M.B.C., and R.J.J. contributed to the disc us-
sion and reviewed and edited the ma nuscript.
D.M.M. contributed to th e research and dis-
cussion and revie wed and edited the manu-
script. D.M.M. is the guarantor of this work
and, as such, had full access to all the data in
the study and takes responsibility f or the in-
tegrity of the data and the accuracy of the data
analysis.
Parts of this study were presented in ab stract
form at the 73rd Scientific Sessions of the
American Diabetes Association, Chicago, Illinois,
21–25 June 2013.
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