Cardiovascular Risk Factors
Nicole M. Farmer, Andres Victor Ardisson Korat in Cooking for Health and Disease Prevention, 2022
AGEs can also form non-Maillard reactions. The second formation pathway occurs from the autooxidation of glucose and the peroxidation of lipids, known an α-oxaldehydes (Figure 5.3). And the third pathway for formation of AGEs involves the polyol pathway, where glucose is converted to sorbitol by the enzyme aldose reductase and then to fructose through enzymatic action of sorbitol dehydrogenase (Figure 5.3). Fructose metabolites (as fructose 3-phosphate) then are converted into α-oxaldehydes and interact with monoacids to form AGEs. The formation of AGEs leads to several biomarkers for in vivo formation. The most widely known AGEs are carboxymethyl-lysine (CML) (found in Maillard reactions), pentosidine and pyrraline (found in Maillard reactions), and methylglyoxal (an α-oxaldehyde).
Neuropathic Pain †
Gary W. Jay in Chronic Pain, 2007
Insulin is not responsible for glucose uptake in the peripheral nerves. For this reason, high glucose levels in the blood cause high nerve glucose concentrations. The polyol pathway, via reactions catalyzed by aldose reductase, converts glucose to sorbitol. Nerve fructose levels are also increased. Excess fructose and sorbitol induce a decrement in the expression of the sodium/myoinositol cotransporter, which causes decreased myoinositol levels. This, in turn, creates decreased levels of Na/K ATPase activity. Aldose reductase, when activated, depletes its cofactor nicotinamide adenine dinucleotide phosphate (NADPH), which causes decreased levels of nitric oxide and glutathione, which work to stop oxidative injury. The lack of nitric oxide stops vascular relaxation, which helps in the induction of chronic ischemia (60–65).
Apiaceae Plants Growing in the East
Mahendra Rai, Shandesh Bhattarai, Chistiane M. Feitosa in Ethnopharmacology of Wild Plants, 2021
C. cyminum is able to reduce blood glucose levels without initiating hypoglycaemia or β-cell burn out. This antidiabetic activity was validated in the petroleum ether fraction of C. cyminum distillate through in vitro and in vivo studies. The hypoglycaemic effect was ascribed to cuminal and cuminol in the essential oil. The latter compounds were identified as potent glucose-dependent insulinotropic agents with 3.34-and 3.85-fold increase in insulin secretion, for cuminal and cuminol, respectively, compared to the 11.8 mM glucose control. This action was mediated by blocking the ATP-sensitive K+ channels and increasing the intracellular Ca2+ concentration in cultured rat pancreatic cells. In addition, both compounds exert antioxidant protective effects on insulin-secreting β cells (Patil et al. 2013). Furthermore, cuminal has been proved to inhibit aldose reductase and α-glucosidase enzymes with IC50 values of 0.00085 mg/mL and 0.5 mg/mL, respectively (Lee 2005). Aldose reductase is a key enzyme in the onset of most of the diabetic complications. On the other hand, inhibition of α-glucosidase can delay carbohydrate digestion and decrease the absorption rate of glucose (Kalita et al. 2018).
Biomarkers in diabetic neuropathy
Published in Archives of Physiology and Biochemistry, 2023
Kaveri M. Adki, Yogesh A. Kulkarni
Hyperglycaemia activates the polyol pathway. Aldose reductase utilises excess glucose and converts into sorbitol. Similarly, sorbitol dehydrogenase converts sorbitol into fructose. This cellular mechanism depletes nicotinamide adenine dinucleotide phosphate (NADPH), which causes the generation of glutathione. Glutathione is the primary antioxidant in nerve tissue. The depletion of glutathione leads to oxidative stress and slows down nerve conduction. A study by Varkonyi et al. showed that AGEs play a prime role in the progression of various diabetic complications such as duplication of basal lamina around endothelial cells results in thickening of walls of small blood vessels (Várkonyi et al. 2017). The AGEs result in excess glucose and protein complex formation. These AGEs form a complex network with collagen and harm nerves (Grisold et al. 2017).
Targeting oxidative stress through antioxidants in diabetes mellitus
Published in Journal of Drug Targeting, 2018
Parul Thakur, Ashwini Kumar, Awanish Kumar
The polyol pathway comprises two enzymes viz. Aldose reductase (AR) and Sorbitol dehydrogenase (SDH) [15]. Aldose reductase is found in tissues such as nerve, retina, lens, glomeruli and vascular cells. In many of these tissues, glucose uptake is mediated by insulin-independent GLUTs; intracellular glucose concentrations, therefore, rise in parallel with hyperglycaemia [10]. In euglycemic condition, glucose in not reduced by AR, reason being lower affinity of AR for glucose; and normal glycolytic pathway is carried on. However, under hyperglycaemic conditions, AR reduces glucose to sorbitol, which is then oxidised to fructose by SDH. With chronic hyperglycaemia, the AR pathway becomes enhanced leading to increased formation of sorbitol. As a result of activated AR pathway, there is increased consumption of NADPH (as an obligate co-factor) by AR. The glutathione reductase enzyme also requires NADPH as co-factor for the regeneration of glutathione (GSH), an endogenous scavenger of ROS. Therefore, increased utilisation of NADPH caused by enhanced activity of AR reduces intracellular concentration of GSH which is an antioxidant. This impairs the antioxidant defence network and increases cellular susceptibility to oxidative stress. Second, intracellular accumulation of sorbitol is harmful. It causes cell damage potently activates stress-sensitive signalling pathways including P3 MAPK and JNK [16].
Potential molecular mechanism of action of sodium-glucose co-transporter 2 inhibitors in the prevention and management of diabetic retinopathy
Published in Expert Review of Ophthalmology, 2022
Lia Meuthia Zaini, Arief S Kartasasmita, Tjahjono D Gondhowiardjo, Maimun Syukri, Ronny Lesmana
The polyol pathway plays a significant role in the development of diabetic complications, including retinopathy (Figure 4). Chronic hyperglycemia causes the hexokinase enzyme to become saturated, diverting the excess glucose from the glycolysis pathway. As a result, an increased flux of blood glucose (~30%) enters the polyol pathway, producing a large amount of sorbitol catalyzed by the enzyme aldose reductase. The expression of aldose reductase mRNA is high in the primary target organs of diabetic complications, including the lens, retina, and sciatic nerve. Pericyte degradation, a hallmark of DR, has also been linked to the increased aldose reductase activity in the retinal capillary [53]. The upregulation of the polyol pathway also increases cell susceptibility to oxidative stress. In the polyol pathway, the depletion of nicotinamide adenine dinucleotide phosphate (NADPH) by aldose reductase leads to failure in regenerating glutathione, a critical intracellular antioxidant, hampering the antioxidant mechanism [54].
Related Knowledge Centers
- Catalysis
- Enzyme
- Galactitol
- Galactose
- Glucose
- Nicotinamide Adenine Dinucleotide Phosphate
- Polyol Pathway
- Sorbitol
- Oxidoreductase
- Sorbitol Dehydrogenase