Role of Glycemia in Insulin Sensitivity in Adolescents with Type 1 and Type 2 Diabetes You can put a logo here or on the other side of your title.

Suhyla Alam (Eastern Virginia Medical School), Amy West, Maura Downey, Jane EB Reusch, Kristen Nadeau University of Colorado Denver and Children’s Hospital Colorado Methods Results Summary Introduction

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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) Nadeau KJ et al, JCEM 2010

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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

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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* Type 1 (N=23) Type 2 (N=15)

Male (n,%) Tanner Stage 10 (43%) 4.39 (.84) 3 (20%) 5 (0) White (n,%) Hispanic (n,%) Black (n,%) Asian (n,%) Age (years) BMI (kg/m 2 ) BMI Percentile Diabetes Duration (mo) 18 (78%) 3 (13%) 1 (4%) 1 (4%) 15.4 (1.8) 22.0 (4.7) 57.0 (28.0) 65.5 (53.2) 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

STUDY DESIGN

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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

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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 maintenance subjects study consumed diet (7 a kcal/kg; weight 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 fat free mass In the morning, 80mU/m 2 /min subjects hyperinsulinemic underwent a 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 Type 1

7.9 (3.3) 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) 10.6 (3.9) 8.2 (1.2) 119 (26.8)

Type 2

4.5 (2.9) 8.0 (5.1) 7.9 (2.3) 111 (21.9)

CGMS RESULTS* Type 1 Type 2

Number of CGM sensors values Average Blood Glucose^ (mg/dL) % time spent over 250 mg/dL 734 (206) 15.52 (11.07) 816 (167) 166.13 (30.88) 167.2 (80.73) 20.4 (33.73) % time spent below 60 mg/dL 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)

Predictor of Parameter Estimate (95% Interest

Fasting YSI Glucose A1C on Day of

CI)

-0.020 (-0.091, 0.051) -0.19 (-1.7,1.3) Clamp CGMS Measures Average Blood 0.042 (-0.013, Glucose 0.096)

p-value

0.57

0.78

0.12

SD of Ave. Blood Glucose % Duration Below 60 % Duration above 250 0.066 (-0.023, 0.15) 0.10 (-0.25, 0.46) 0.17 (0.037, 0.307) 0.14

0.56

0.02

T2D RELATIONSHIPS Outcome Predictor of Interest

Insulin Sensitivity (mg/fat free mass/min) Fasting YSI Glucose A1C on Day of Clamp

Parameter Estimate (95% CI)

-0.23 (-0.33, -0.12) -1.9 (-3.8, -0.093) CGMS Measures Average Blood Glucose -0.059 (-0.12, 0.002) SD of Ave Blood Glucose % Duration below 60 % Duration above 250 -0.11 (-0.30, 0.081) -1.1 (-3.1, 0.85) -0.085 (-0.18, 0.007)

p-value

0.0004

0.04

0.06

0.23

0.24

0.07

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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)

Conclusion

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As expected, sensitivity was in the T2D negatively hyperglycemia Unexpectedly, sensitivity was in the T1D positively cohort, associated insulin with cohort, associated insulin 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

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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, JDRF5 2008-291, M01 RR00069-42, 5 P30 DK48520-10