understanding the ups and downs of blood glucose

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

Understanding the Ups and Downs of Blood

Glucose

Irl B Hirsch, M.D.

University of Washington

♦ 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,

Postprandial hyperglycemia ≠ glycemic variability

Don’t forget about the

“ups” and “downs”!

“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

Gehrig’s 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

Oxidative Stress:

Why is it Important?

Free radicals (reactive oxygen species) are known to fuel diabetic vascular complications

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

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

Correlation Between Urinary 8-iso-PGF2

alpha and MAGE in T2DM

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

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:

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

What We KNOW

♦ Risk of complications are related to

♦ Glycemic exposure as measured as A1c

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

What’s a better way to assess

glycemic variability?

I Hirsch

Which Patient Has More Variable

Fasting Glucose Data?

Joe: HbA1c = 6.5%; on CSII

with insulin aspart

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

Calculation To Determine SD Target

• Ideally SD X 3 < mean, but extremely

difficult with type 1 patients

SD X 2 < MEAN

I Hirsch

Significance of a High SD

♦ Insulin deficiency (especially good with fasting

blood glucose)

♦ Poor matching of calories (especially

carbohydrates) with insulin

Other Significance of a High SD

I Hirsch

Caveats of the SD

♦ Need sufficient SMBG data

♦ Low or high averages makes the

2XSD<mean rule irrelevant

I Hirsch

Caveats of the SD: Low Mean

56 85 98 106 110 113 46 60 59 128

Mean = 81; SD = 29

I Hirsch

Caveats of SD: High Mean

210 249 294 112 77 302 288 259 321 193

Mean = 217; SD = 82

I Hirsch

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”)

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/

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 25th from the 75th 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

What We Need

Data comparing these

tools to markers of oxidative stress!

I Hirsch

• 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

What You Should Take Away From

This Discussion

A1c is not the only factor contributing to the complications of

diabetes

A1c is not the only factor contributing to the complications of

diabetes