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Understanding the Ups and Downs of Blood Glucose Irl B. Hirsch, M.D. University of Washington.

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Presentation on theme: "Understanding the Ups and Downs of Blood Glucose Irl B. Hirsch, M.D. University of Washington."— Presentation transcript:

1 Understanding the Ups and Downs of Blood Glucose Irl B. Hirsch, M.D. University of Washington

2 Question Who has the greatest risk of proliferative diabetic retinopathy (PDR) over the next 10 years A 55 y/o man with type 2 diabetes for 5 years, on oral agents, A1c = 9.0% An 18 y/o man with 5 years of type 1 diabetes, on BID NPH/R, A1c = 9.0% An 18 y/o man with 5 years of type 1 diabetes, on CSII, A1c = 9.0% Why are the risks of PDR different?

3 Postprandial hyperglycemia glycemic variability Dont forget about the ups and downs!

4 Oxidative Stress What Should You Know? Oxygen is critical for life: respiration and energy Oxygen is also implicated in many disease processes, ranging from arthritis, cancer, Lou Gehrigs disease as well as aging –This dangerous form of oxygen is from the formation of free radicals or reactive oxygen species, or pro-oxidants –Normally, pro-oxidants are neutralized by anti- oxidants

5 Oxidative Stress: What You Should Know Oxidative Stress = Imbalance between pro-oxidants (free radicals, reactive oxygen species) and anti-oxidants

6 Oxidative Stress: Why is it Important? Free radicals (reactive oxygen species) are known to fuel diabetic vascular complications

7 OK, What Turns On Oxidative Stress, Free Radicals, and Reactive Oxygen Species High blood glucose Science is confirmed on this point Variability in blood glucose Science is highly suggestive on this point

8 How Does One Measure…? Oxidative Stress Urinary isoprostanes: best marker of oxidative stress in total body HbA1c of oxidative stress Glycemic variability Mean Amplitude of Glycemic Excursions (MAGE) Standard deviation on SMBG meter download I Hirsch

9 Correlation Between Urinary 8-iso-PGF2 alpha and MAGE in T2DM Urinary 8-SO-PGF2 alpha Excretion Rates (pg/mg creatinine) MAGE (mg glucose/dL) R=0.86, p< JAMA 295: , 2006 I. Hirsch

10 Why This Study is So Important Oxidative stress not related to A1c, fasting glucose, fasting insulin, mean blood glucose Stronger correlation of oxidative stress to MAGE than to postprandial glucose levels! MAGE = both the UPS and the DOWNS of blood glucose I. Hirsch

11 So What Is The Significance of the Understanding of GV? …it suggests that different therapeutic strategies now in use should be evaluated for their potential to minimize glycemic excursion, as well as their ability to lower A1c. …wider use of real-time continuous glucose monitoring in clinical practice would provide the required monitoring tool to minimize glycemic variability and superoxide overproduction. Brownlee M, Hirsch IB: JAMA: 295:1707, 2006 I. Hirsch

12 What About Long-Term Glycemic Variability? Pittsburgh Epidemiology of Diabetes Complications 16-year follow-up of childhood T1DM, N=408 Results: Risks of coronary disease over time related to A1c and variability of A1c! Diabetes 55 (Supp 1): A1, 2006

13 What We KNOW Risk of complications are related to Glycemic exposure as measured as A1c over time Proven Genetic risks Clearly true, but little understanding Glycemic variability Supported by most but not all studies

14 Conclusion 1 Glycemic variability may be an important mechanism increasing oxidative stress and vascular complications So how do we best measure glycemic variability in our patients with diabetes? I. Hirsch

15 Whats a better way to assess glycemic variability? I. Hirsch

16 Which Patient Has More Variable Fasting Glucose Data? Joe: HbA1c = 6.5%; on CSII with insulin aspart Mary: HbA1c = 6.5%; on HS glargine and prandial lispro Mean = 123 mg% SD = 51 SD = 63 I. Hirsch

17 Standard Deviation A measurement of glycemic variability Can determine both overall and time specific SD Need sufficient data points Minimum 5 but prefer 10 I. Hirsch

18 Calculation To Determine SD Target Ideally SD X 3 < mean, but extremely difficult with type 1 patients SD X 2 < MEAN I. Hirsch

19 Significance of a High SD Insulin deficiency (especially good with fasting blood glucose) Poor matching of calories (especially carbohydrates) with insulin Gastroparesis Giving mealtime insulin late (or missing shots completely) Erratic snacking Poor matching of basal insulin, need for CSII? I. Hirsch

20 Other Significance of a High SD I. Hirsch

21 Caveats of the SD Need sufficient SMBG data Low or high averages makes the 2XSD

22 Caveats of the SD: Low Mean Mean = 81; SD = 29 I. Hirsch

23 Caveats of SD: High Mean Mean = 217; SD = 82 I. Hirsch

24 Putting it all together Typical new patient visit to UW DCC 27 y/o woman on CSII for 5 years Testing 4 to 5 times daily, A1c=6.4% Major problems with hypoglycemia unawareness Poor understanding of basic concepts of insulin use despite seen by specialists for 20 years (last appointment with endocrinologist was no more than 12 min for her new patient appointment)

25 Question Who has the greatest risk of PDR over the next 10 years? A 55 y/o man with T2DM for 5 years, on oral agents, A1c = 9.0%; Mean/SD = 210/50; An 18 y/o man with 5 years of T1DM, on BID N/R, A1c = 9%; Mean/SD = 210/100; An 18 y/o man with 5 years of T1DM, on CSII, A1c = 9% Mean/SD = 210/75; After thinking about glycemic variability and oxidative stress

26 The Future of Glycemic Variability: Measurements For the Future SD: used with SMBG for over a decade with meter downloads; underutilized Interquartile ratio: the range where the middle 50% of the values in a distribution falls, calculated by subtracting the 25 th from the 75 th percentile Compared to SD, IQR not influenced by outliers MAGE: gold standard (?) but requires continuous glucose sensing. May be more useful as we move into the CGM era I. Hirsch

27 What We Need Data comparing these tools to markers of oxidative stress! I. Hirsch

28 Conclusions Although there is no definitive proof from a randomized controlled trial, the data suggests that glycemic variability is a risk factor for microvascular complications We have the opportunity to quantitate GV now with meter downloads I. Hirsch

29 What You Should Take Away From This Discussion A1c is not the only factor contributing to the complications of diabetes

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