The Fate of Aldose Reductase Inhibition and Sorbitol Dehydrogenase Activation

Special Article - Diabetic Complications

Austin J Endocrinol Diabetes. 2019; 6(1): 1064.

The Fate of Aldose Reductase Inhibition and Sorbitol Dehydrogenase Activation

Patil KK1 and Gacche RN2*

¹School of Life Sciences, Swami Ramanand Teerth Marathwada University, India

²Department of Biotechnology, Savitribai Phule Pune University, India

*Corresponding author: Rajesh N Gacche, Department of Biotechnology, Savitribai Phule Pune University, India

Received: March 27, 2019; Accepted: April 26, 2019; Published: May 06, 2019


Diabetic complications are the unavoidable ailment in hyperglycaemic condition. The polyol pathway mediated adverse effects of hyperglycemia are responsible for development of severe health ailments. Aldose reductase and sorbitol dehydrogenase are the important cytosolic enzymes involved in polyol pathway. In diabetic state, owing to higher glucose flux generates bulk amount of intracellular sorbitol through the polyol pathway. The intracellular accumulation of sorbitol is proved to be deleterious to tissue microenvironment that leads to development of secondary complications of diabetes. The reduction of sorbitol level in the tissue is therapeutically important in the management of polyol mediated diabetic complications. A variety of structurally diverse Aldose Reductase Inhibitors (ARIs) have been developed for inhibiting the generation of sorbitol, some are in clinical practice but majority of the newly synthesized molecules failed in clinical trial studies and thus not approved by FDA. On the other hand, Sorbitol dehydrogenase, the second enzyme of polyol pathway has a role of metabolizing harmful sorbitol to fructose is least focused as a therapeutic target. In this review an alternative strategy is proposed for minimizing the tissue sorbitol level that may be useful for the management of diabetes and its related complications. This review will provide an overview of importance of sorbitol dehydrogenase activation over the aldose reductase inhibition. Furthermore, in future it may find applications in the design and development of activators of sorbitol dehydrogenase.

Keywords: Diabetic complication; Polyol pathway; Aldose reductase; Sorbitol dehydrogenase; ARI’s


Diabetes Mellitus (DM) is a complex metabolic syndrome characterised by elevation of blood glucose level beyond its glucose tolerance threshold. The condition arises as a result of defects in insulin secretion, action or a combination of both that results into long-lasting hyperglycemia [1]. World Health Organization (WHO report 2015) highlighted diabetes as the leading cause of mortality (1.6 million deaths in 2015) and ranking seventh position among the top ten causes of deaths in the world [2]. The incidence of diabetes is more in undeveloped and developing countries like India: a capital of diabetes and put a serious concern to the health care professionals [3]. The International Diabetes Federation (IDF 2016) reported 415 million people have diabetes and it may affect over 640 million people in 2040. A plethora of studies evidenced that the degree and duration of hyperglycemic state is the basis for development of secondary complications of diabetes [4]. The most inevitable complications of DM include both microvascular complications (nephropathy, retinopathy and neuropathy) and macrovascular complications (cardiovascular disease) that affecting many organs of the body [5].

So far many attempts have been taken for mitigating the DM and its associated complications; but none of them demonstrated effective repercussion to treat DM completely. The currently available therapeutic drugs for diabetes mellitus includes glucose lowering agents like insulin, biguanides, sulphonylureas, glinides, thiazolidinediones, alpha-glucosidases inhibitors, DPP-4 inhibitors, SGLT2 inhibitors and GLP-1 agonists etc [6,7]. Moreover, tightly controlled diet and increased physical activities improves the blood glucose level considerably. But at present, even with the finest therapeutic prophylaxis available for the management of DM, it is practically impossible for a diabetic individual to keep up normal glycemia at all times throughout the life [8]. Therefore, novel, effective and safe strategies is needed to nullify the threatening effects of hyperglycemia. In this regards the research thrust continues across the world; in search of new agents and targets to develop long term effective antidiabetic drugs that eventually reduces the diabetes risks and its associated complications.

In this review we mainly focus the polyol pathway and its associated diabetes complications. Moreover, the structural details of polyols enzymes, its inhibitors and future therapeutic prospective is highlighted that have applications in the management of diabetes complications.

The polyol pathway

The polyol pathway is the alternative to the glycolysis and pentose phosphate pathways which contributes very small portion of carbohydrate metabolism. The schematic showing in Figure 1 illustrates the complete polyol pathway that converting intracellular glucose into fructose via sorbitol within the cell. Under the normal glycemic condition, the polyol enzymes function as general housekeeping enzymes, but in case of diabetic state these enzymes activated exponentially that result into increased glucose flux to this pathway [9].

Citation: Patil KK and Gacche RN. The Fate of Aldose Reductase Inhibition and Sorbitol Dehydrogenase Activation. Austin J Endocrinol Diabetes. 2019; 6(1): 1064.