The Variability of Blood Glucose in Diabetics

Summarized by Robert W. Griffith, MD
May 22, 2006

Summary

Research shows that variability in blood glucose levels is important in determining the likelihood of well-known diabetic complications.

Introduction

Over a third of those born in the year 2000 will develop diabetes in their lifetime. That sobering thought has encouraged scientists to look beyond the HbA1c level to try to determine what factors are responsible for the oft-lethal vascular complications of diabetes. One of these is the variability seen in blood glucose levels during the day. Drs Brownlee and Hirsch, both expert diabetologists, have written a thoughtful editorial in the Journal of the American Medical Associationand we summarize the main points from it here.

HbA1c

HbA1c is shorthand for a type of hemoglobin, the oxygen-carrying element in red blood cells. (Hb stands for hemoglobin, and A1c is the designation of the subtype.) Glucose binds to HbA1c and is only released very slowly, so that the proportion of HbA1c represents the average blood glucose level over the previous 4 weeks. This makes its measurement more valuable than a single blood sugar measurement, which can vary a lot depending on when the last meal was, and what it contained.

There's a strong relationship between the HbA1c level and diabetic complications.

In non-diabetic persons the formation and breakdown of HbA1c reach a 'steady state' with about 3.0% to 6.5% of the hemoglobin being the A1c subtype. The recommended treatment goal for diabetics is to keep their HbA1c level below 7%, or (better) below 6.5%, but few patients achieve this.

Using blood sugar levels to reduce complications

To help patients reach and keep a low HbA1c, they are encouraged to test their own blood sugar at intervals throughout the 24 hours. It's been shown that people who tested their glucose level regularly had, on average, an HbA1c that was 0.4% lower than those who didn't. This translated into a reduction in the risk of complications to only 12.5% for those whose initial HbA1c was 8%.

Further steps to reduce complications

A common path in the development of vascular complications is overproduction of a free radical molecule, superoxide. Superoxide production can be stimulated in a number of ways - including high blood sugar and increased fatty acid oxidation. A new study¹ has explored the role of variability in blood glucose levels in affecting free radical production. Type 2 diabetics with poor control of their blood sugar underwent continuous blood glucose monitoring and 24-hour excretion of free radicals in the urine.

There was no correlation between free radical production and 24-hour average glucose level, fasting glucose level, and HbA1c. However, production was 4 times higher in patients with the greatest hour-to-hour variability in blood glucose levels. But one should note that postprandial blood glucose was not related to increased free radical excretion.

A supportive finding

The Diabetes Control and Complications Trial provided results that support the need for intensive treatment of 'individual' blood sugar levels. Diabetic retinopathy risk was assessed in tow groups of patients with sustained high levels of HbA1c - 9%, in fact. The risk of retinopathy was reduced by half with intensive blood glucose control, even though the two groups had the same HbA1c². Relying on HbA1c levels for monitoring treatment is clearly inadequate.

Value of self-monitoring blood glucose levels

The findings from the first study above show clearly that frequent monitoring of blood glucose should be done to monitor the effectiveness of treatment, regardless of the HbA1c level. There's no doubt that a type 2 diabetic with an HbA1c level in the 6.5% to 7% range is today likely to be regarded as 'well-controlled', both by the physician and the patient. But this is clearly wrong. And it's not enough to consider 'ironing out' the natural post-prandial elevation by taking drugs designed for that purpose; as the study showed, post-prandial high values did not translate into increased free radical excretion. Another important result of these findings: new diabetic drugs should be designed and evaluated on their ability to reduce the variations encountered in blood glucose levels.

Future trends

It's likely that more patients will be encouraged to undergo continuous glucose monitoring (like the more frequent use of Holter monitoring in cardiology these days). More research will be done to determine how wide the variations in glucose levels are in a patient, and how constant they are in an individual. What, for instance, stimulates an increase in variatiability? And, of course, diabetics will have to be educated in this relatively new 'risk factor' they may have with regard to the development of complications.

Source

• Glycemic variability: a haemoglobin A1c-independent risk factor for diabetic complications. M. Brownlee, IB. Hirsch, Editorial, 2006, vol. 295, pp. 1707--1708

Footnotes
1. Activation of oxidative stress by acute glucose fluctuations compared with sustained chronic hyperglycemia in patients with type 2 diabetes. L. Monnier, E. Mas, C. Ginet,  et al., JAMA, 2006, vol. 265, pp. 1681--1687
2. The relationship of glycemic exposure (HbA1c) to the development and progression of retinopathy in the Diabetes Control and Complications Trial.  The Diabetes Control and Complications Trial Research Group., Diabetes, 1995, vol. 44, pp. 968--983

Related Links
Type 2 Diabetes Complications
WebMD: How to Test Your Blood Glucose
Post-Prandial Glucose in Diabetes

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