1,5-Anhydroglucitol

Structure of 1,5-anhydroglucitol

1,5-Anhydroglucitol, also known as 1,5-AG, is a naturally occurring monosaccharide found in nearly all foods. Blood concentrations of 1,5-anhydroglucitol decrease during times of hyperglycemia above 180 mg/dL, and return to normal levels after approximately 2 weeks in the absence of hyperglycemia. As a result, it can be used for people with either type-1 or type-2 diabetes mellitus to identify glycemic variability or a history of high blood glucose even if current glycemic measurements such as hemoglobin A1c (HbA1c) and blood glucose monitoring have near normal values. Despite this possible use and its approval by the FDA, 1,5-AG tests are rarely ordered. There is some data suggesting that 1,5-AG values are useful to fill the gap and offer complementary information to HbA1c and fructosamine tests.[1]

History

The role of 1,5-AG was first inferred by Akanuma in 1981 [2] when he demonstrated decreased 1,5-AG levels in diabetic patients. This observation was enhanced in 1983 when it was seen that plasma 1,5-AG fell to undetectable levels in diabetic patients who did not receive insulin.[3] Further studies[4] showed that patients receiving medication to lower blood glucose had lasting improvement in 1,5-AG levels. If medication stopped, 1,5-AG decreased to pre-treatment levels. In 2003, 1,5-AG began to be looked at by researchers in the United States and was shown to be a valuable short-term glycemic monitor.[5][6] In 2006, 1,5-AG showed its most compelling clinical use when it was demonstrated that an assay (GlycoMark, developed by Nippon Kayaku, Inc.) for postprandial hyperglycemia was able to differentiate two patients who had similar, near goal, hemoglobin A1c values, yet very different glucose profiles as shown by continuous blood glucose monitoring - one of the patients having excessive glycemic variability.[7]

Underlying physiology

The assay measures blood levels of 1,5-anhydroglucitol. 1,5-AG is ingested from nearly all foods during the course of a regular diet. It is nearly 100% non metabolized and remains in a relatively constant amount in the blood and tissues. 1,5-AG is carried in the blood stream and filtered by the glomerulus, where it enters the kidney. Once in the kidney, 1,5-AG is re-absorbed back into the blood through the renal proximal tubule. A small amount, equal to the amount ingested, of 1,5-AG is released in the urine to maintain a constant amount in the blood and tissue. This process occurs in people who do not have their blood glucose values rising over 180 mg/dL.

When a diabetic person's blood glucose exceeds 180 mg/dL for any period of time, the kidney cannot re-absorb all glucose back into the blood. The rest is excreted in the urine (glucosuria). The additional glucose in the kidney blocks 1,5-AG from being re-absorbed into the blood and 1,5-AG is excreted in the urine at a higher rate then normal. Blood levels of 1,5-AG decrease immediately, and continue to decrease until glucose values go below 180 mg/dL. Once hyperglycemia is corrected, 1,5-AG begins to be re-absorbed from the kidney back into the blood at a steady rate. If a person's glucose levels remain below 180 mg/dL for approximately 4 weeks, 1,5-AG will return to its normal levels.

It is this competitive inhibition of 1,5-AG from glucose which allows the assay to accurately reflect any hyperglycemic episodes over 180 mg/dL

Measuring 1,5-AG

A comprehensive evaluation of the assay has been described in the literature.[8]

The assay can be run on almost any open chemistry analyzer, including those found in physician office laboratories. Two reactions take place during the measurement:

Reaction 1 is a pretreatment of the sample performed by adding glucokinase to convert glucose to glucose 6-phosphate in the presence of adenosine triphosphate, pyruvate kinase, and phosphoenol pyruvate. The purpose of this step is to alter glucose, which is found in the blood sample, so that it can not react during reaction 2.

Reaction 2 uses pyranose oxidase to oxidize the second hydroxyl of 1,5-AG, generating hydrogen peroxide. The amount of hydrogen peroxide is detected by colorimetry using peroxidase, and is in direct relationship to the serum 1,5-AG concentration.

Interpretation of results

Results are in µg/mL. Lower values indicate worsening glucose control, with more frequent and prolonged glucose values over 180 mg/dL. 10 µg/mL of 1,5-AG correlates to an average post meal glucose of 185 mg/dL, and is the target value in people with diabetes. Values over 10 µg/mL indicate glucose on average is below 180 mg/dL. Those with values below 10 µg/mL could benefit from nutritional counseling, and medications which target post meal glucose spikes, such as pramlintide, exenatide, sitagliptin, saxagliptin, repaglinide or rapid acting insulins.

GlycoMark
(µg/mL) 		Approximate Mean Postmeal
Maximum Glucose (mg/dL)
> 12 < 180
10 185
8 190
6 200
4 225
< 2 > 290

Indications and use

The test is cleared by the FDA to be sold and marketed for the intermediate term monitoring of glycemic control in people with diabetes. GlycoMark is available through most major reference laboratories, including Quest Diagnostics and Labcorp or may be performed in a hospital or physician's office.

See also

References

  1. ↑ "1,5-anhydroglucitol (GlycoMark) as a marker of short-term glycemic control and glycemic excursions.". Expert Rev Mol Diagn 8 (1): 9–19. Jan 2008. doi:10.1586/14737159.8.1.9. PMID 18088226.
  2. ↑ Akanuma Y, Ogawa K, Yamanouchi T, Mashiko S, Oka Y, Kosaka K, Akanuma H (1981). "Decreased plasma 1,5-anhydroglucitol in diabetic patients". Diabetes 30 (Suppl. 1): 124A.
  3. ↑ Yoshioka S, Saitoh S, Negishi C, Fujisawa T, Takatani O, Imura M, Funagashi M (1983). "Variations of 1-deoxyglucose (1,5-anhydroglucitol) content in plasma from patients with insulin-dependent diabetes mellitus.". Clin. Chem. 29 (7): 1396–8. PMID 6345028.
  4. ↑ Yamanouchi T, er al. (1996). "Clinical usefulness of serum 1,5-anhydroglucitol in monitoring glycemic control.". The Lancet 347 (9014): 1514–8. doi:10.1016/S0140-6736(96)90672-8. PMID 8684103.
  5. ↑ Buse JB, Freeman JL, Edelman SV, Jovanovic L, McGill JB (2003). "Serum 1,5-anhydroglucitol(GlycoMarkTM): a short-term glycemic marker.". Diabetes Technol Ther. 5 (3): 355–63. doi:10.1089/152091503765691839. PMID 12828817.
  6. ↑ McGill JB, Cole TG, Nowatzke W, Houghton S, Ammirati EB, Gautille T, Sarno MJ (2004). "Circulating 1,5-anhydroglucitol levels in adult patients with diabetes reflect longitudinal changes of glycemia: a U.S. trial of the GlycoMarkTM assay.". Diabetes Care 27 (8): 1859–65. doi:10.2337/diacare.27.8.1859. PMID 15277408.
  7. ↑ Dungan KM, Buse JB, Largay J, Kelly MM, Button EA, Wittlin S (2006). "1,5-anhydroglucitol and postprandial hyperglycemia as measured by continuous glucose monitoring system in moderately controlled patients with diabetes.". Diabetes Care 29 (6): 1214–9. doi:10.2337/dc06-1910. PMID 16731998.
  8. ↑ Nowatzke W, Sarno MJ, Birch NC, Stickle DF, Eden T, Cole TG (2004). "Evaluation of an assay for serum 1,5-anhydroglucitol (GlycoMarkTM) and determination of reference intervals on the Hitachi 917 analyzer.". Clin Chim Acta 350 (1–2): 201–9. doi:10.1016/j.cccn.2004.08.013. PMID 15530479.

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