Role of Glycemia in Insulin Sensitivity in Adolescents
with
Type
1
and
Type
2
Diabetes
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Suhyla Alam (Eastern Virginia Medical School),
Amy West, Maura Downey, Jane EB Reusch, Kristen Nadeau
University of Colorado Denver and Children’s Hospital Colorado
Introduction
Methods
• Interest in the role of insulin resistance (IR) in type 1
diabetes (T1D) and its potential mechanisms is
increasing, especially because of its correlation with
cardiovascular disease in type 2 diabetes (T2D)
• Previously, we used a hyperinsulinemic euglycemic
clamp to measure IR in adolescents, and as expected,
found IR in obese and T2D youth (see graph below)
• Of note, we also found IR in T1D youth, unrelated to
obesity (BMI similar to lean controls, see graph below)
Results
CGMS RESULTS*
STUDY DESIGN
• 15 subjects with T2D and 23 subjects with T2D
were included in the study; all were aged 12-19
years and classified as sedentary
Accelerometer
for one week
72 hour CGMS,
study diet
DEXA,
overnight stay,
clamp
Nadeau KJ et al, JCEM 2010
• Our previous studies assessing HbA1c and fasting
glucose on the day of the clamp failed to find an
association with IR in T1D, but these measures
lacked information on glycemic variability
Study Goals
• We aimed to assess the relationship between 3 day
glycemia and glycemic variability, as measured by
continuous glucose monitoring (CGMS), and IR in
adolescents with T1D
• We also aimed to extend this analysis between
glycemia and IR to adolescents with T2D
Methods
SUBJECT CHARACTERISTICS*
Male (n,%)
Tanner Stage
White (n,%)
Hispanic (n,%)
Black (n,%)
Asian (n,%)
Age (years)
BMI (kg/m2)
BMI Percentile
Diabetes Duration (mo)
Type 1 (N=23)
10 (43%)
4.39 (.84)
18 (78%)
3 (13%)
1 (4%)
1 (4%)
15.4 (1.8)
22.0 (4.7)
57.0 (28.0)
65.5 (53.2)
Type 2 (N=15)
3 (20%)
5 (0)
3 (20%)
10 (67%)
2 (13%)
0
15.8 (2.5)
32.8 (5.5)
96.4 (6.1)
31.8 (26.5)
*All numbers in tables represent Value (Standard Deviation) unless otherwise noted
Summary
• Sedentary status, defined as <3 hours of
physical activity/week, was determined by an
accelerometer worn for 7 days and a physical
activity questionnaire
• A CGMS iPro 2.0A then recorded blood glucose
values every 5 minutes for approximately 72
hours while subjects consumed a weight
maintenance study diet (7 kcal/kg; 55%
carbohydrates, 30% fat, and 15% protein)
• For the duration of the study diet, metformin (if
taken) was withdrawn
• Subjects were admitted overnight to ensure
fasting and had a DEXA scan to determine fatfree mass
• In the morning, subjects underwent a
80mU/m2/min
hyperinsulinemic
euglycemic
clamp to assess IR
• IR was determined using glucose infusion rate
(GIR) in the final 30 minutes, normalized to fat
free mass
• Data was evaluated with linear regression
analysis. Potential confounders (duration of
diabetes, tanner stage, BMI, percentage of
sensor values occurring during the daytime)
were assessed and remained in the final model
if they significantly impacted the outcome
Results
CLAMP RESULTS
Insulin Sensitivity
(mg/kg/min)
Insulin Sensitivity
(mg/lean kg/min)
A1C on day of clamp (%)
Fasting YSI Glucose on
day of clamp (mg/dL)
Number of CGM sensors
values
Average Blood Glucose^
(mg/dL)
% time spent over
250 mg/dL
% time spent below
60 mg/dL
Type 1
Type 2
734 (206)
816 (167)
166.13 (30.88) 167.2
(80.73)
15.52 (11.07) 20.4 (33.73)
3.52 (5.53)
0.93 (2.40)
*All numbers in tables represent Value (Standard Deviation) unless
otherwise noted
^Approximately 71% of the CGMS recordings were taken during the
daytime period (7am-11pm) in both the T1D and T2D groups
T1D RELATIONSHIPS
Outcome
Insulin
Sensitivity
(mg/fat
free
mass/min)
Parameter
Estimate (95% p-value
CI)
-0.020 (-0.091,
0.57
0.051)
Predictor of
Interest
Fasting YSI
Glucose
A1C on Day of
-0.19 (-1.7,1.3)
Clamp
CGMS Measures
Average Blood
0.042 (-0.013,
Glucose
0.096)
SD of Ave. Blood
Glucose
0.066 (-0.023,
0.15)
% Duration
Below 60
% Duration above
250
0.10 (-0.25,
0.46)
0.17 (0.037,
0.307)
0.78
0.12
0.14
0.56
0.02
T2D RELATIONSHIPS
Predictor of
Outcome
Interest
Insulin
Fasting YSI
Sensitivity Glucose
(mg/fat free A1C on Day of
mass/min) Clamp
Parameter
p-value
Estimate (95% CI)
-0.23 (-0.33, -0.12) 0.0004
-1.9 (-3.8, -0.093)
CGMS Measures
Average Blood
-0.059 (-0.12,
Glucose
0.002)
0.04
0.06
Type 1
7.9 (3.3)
Type 2
4.5 (2.9)
10.6 (3.9)
8.0 (5.1)
% Duration
below 60
-1.1 (-3.1, 0.85)
0.24
8.2 (1.2)
119 (26.8)
7.9 (2.3)
111 (21.9)
% Duration
above 250
-0.085 (-0.18,
0.007)
0.07
SD of Ave
-0.11 (-0.30, 0.081)
Blood Glucose
• In adolescents with T1D, insulin sensitivity
corrected for fat free mass was independently
associated with percentage of time spent in
the hyperglycemic range (blood sugars above
250 mg/dl) during the 72 hour CGMS period
• Stated differently, in T1D adolescents, for
each 10% increase in duration of CGMS time
spent above 250 mg/dL, there is a 1.6 point
increase in insulin sensitivity
• In contrast, insulin sensitivity in the T2D
group corrected for fat free mass was
independently negatively associated with
fasting YSI glucose and HbA1c on the day of
the clamp, and tended to be independently
negatively associated with average glycemia
and percentage of time spent with blood
sugars above 250 mg/dl during the prior 3
days as measured by CGMS
• In both groups, insulin sensitivity corrected
for lean mass was not significantly associated
with standard deviation of the average CGMS
blood sugar or with the percentage of CGMS
time spent in the hypoglycemic range (blood
sugars below 60mg/dl)
0.23
Conclusion
• As expected, in the T2D cohort, insulin
sensitivity was negatively associated with
hyperglycemia
• Unexpectedly, in the T1D cohort, insulin
sensitivity was positively associated with
hyperglycemia, implying a unique mechanism
of IR than seen in T2D
• A potential explanation for these findings in the
T1D cohort is that peripheral insulin delivery
worsens IR, and therefore subjects who are
underinsulinized may be more insulin sensitive
• This relationship between glycemic control and
insulin sensitivity in T1D merits future research
ACKNOWLEDGEMENTS
• CGMS instruction provided by Terry Hernandez
• Clinical study support provided by Children’s Hospital Colorado
Pediatric CTRC
• Study also funded by grants of Nadeau, Kristen: NIH/NCRR K23
RR020038-05, JDRF 11-2010-343, NIH/NIDDK 1R56DK088971-01, JDRF52008-291, M01 RR00069-42, 5 P30 DK48520-10