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Featured Article: Inhibition of diabetic cataract by glucose tolerance factor extracted from yeast.

 

Supplementary

Diabetes is the most common metabolic disease. It is the third leading cause of death in developed countries, and is currently considered as epidemic in the third world. Globally, an estimated 422 million people are diabetics according to the 2016 data from the World Health Organization (WHO). The number of diabetic patients is expected to almost double between the years 2000-2030.

There are many severe complications related to diabetes, which decrease life expectancy by third. Among them: blindness, renal failure, cardio vascular diseases, strokes, neuropathy, and a much higher prevalence of cataract.

Cataract is the major cause of visual loss in older diabetic subjects and occurs at an earlier age than in non-diabetics. There is fivefold frequency of cataract in diabetic subjects compared with non-diabetic population in the same age group.

Cataract occurs when the eye lens loses its transparency, causing a reduction of passage of light. The lens becomes opaque and vision is disturbed. The transparency of the lens is achieved by structural proteins called crystallins, which survive in the lens for entire life time. In mammals they comprise of three families: α, β and Ɣ. Damage to lens crystallins by high glucose or oxidative stress creates aggregates and reduces transparency and optic quality

The mechanism of development of diabetic cataract is not fully known. Most of the studies indicate that chronic elevation of blood glucose in diabetes (hyperglycemia) is the major cause for diabetic cataract.

Hyperglycemia brings to glycation of lens proteins, causing them alteration in structure and aggregation. Hyperglycemia induces also production of reactive oxygen species, development of oxidative stress, and decreased activity of antioxidant enzymes in the lens.

During hyperglycemic conditions a considerable portion of blood glucose is converted to sorbitol by the enzyme aldose reductase (AR) via polyol pathway. Sorbitol accumulates in the lens, increases the osmotic pressure and protein agregation . All the above cause a reduction in lens transparency and the development of cataract.

Many efforts have been invested in development of anti-cataract medications. Aldose reductase (AR) inhibitors, vitamins, and antioxidants have been examined throughout the years with only partial effects. Up to date, there is no medication to prevent the development of diabetic cataract, and surgical removal of the damaged lens is the only available treatment. Cataract treatment poses an enormous health and economic burden particularly in developing countries where diabetes treatment is insufficient and cataract surgery often inaccessible. As a result, There is a high need for new medications to treat diabetic cataract.

During the recent years many investigators have shown that natural products are a potential source for new drug candidates for many diseases in general, and diabetes in particular. A research aimed at revealing new natural sources to treat diabetes and its complications is of high importance.

The Glucose Tolerance Factor (GTF) is a dietary agent that can be extracted from several sources: the richest among them is Brewer’s yeast. GTF reversed the impaired glucose tolerance of both diabetic rats and diabetic patients. In vitro studies done with GTF showed remarkable increase in glucose transport into variety of cells including, fat and cardiac muscle cells. An increase in glucose incorporation into glycogen in liver cells was also found when GTF was added.

Despite the high anti diabetic activity of this natural substance, GTF has not been fully characterized yet, mainly due to the instability of the purified fractions. Our laboratory succeeded in extraction and partial purification of an active and stable GTF preparation from brewer’s yeast. We examined GTF effects in animal models for both types of diabetes. An oral dose of GTF administered to diabetic rats decreased glucose and lipids levels in their blood. Figure 1 presents the effect of an oral dose of GTF on decreasing blood glucose of diabetic rats. When GTF was administered in concert with marginal insulin doses, the reduction in blood glucose was much higher than for each agent alone, demonstrating a synergy between GTF and insulin [1,2].

We also examined the effect of GTF on lipid peroxidation in several major organs (heart, kidneys, liver and the eye lens). A significant reduction in lipid peroxidation level was detected in organs of diabetic rats treated with GTF. Our results show that GTF can inhibit the deleterious elevation in lipid peroxides induced by diabetes [3,4].

We also studied the effect of GTF on diabetic nephropathy in rat model. Urine protein levels that were very high in diabetic rats were significantly reduced following treatment with GTF. Decreased levels of lipid peroxidation were also detected in the renal cortex of rats treated with GTF. Histology and immune histochemistry studies done on the kidneys revealed beneficial effects of GTF treatment on preventing diabetic renal damage [4]. GTF treatment also protected diabetic retinas from retinal damage imposed by diabetes [3].

Our aim in the present study was to explore the preventive effects of GTF on the development of diabetic cataract both in vivo, in diabetic rat model, and in vitro in organ culture of lenses incubated in high glucose conditions.

The in vivo study included: control healthy rats, streptozotocin (STZ) diabetic rats, and STZ diabetic rats orally treated with 15 doses of GTF. The diabetic untreated rats developed cataracts, whereas the development of cataract was totally or partially prevented in diabetic animals treated with GTF. Figure 2 shows eyes of untreated diabetic rats where opacity of lens is clearly seen, versus eyes of diabetic rats treated with GTF where cataract development was prevented and the lens remained clear.

We examined the activity of lens Aldose Reductase (AR) at the end of the study and found that while AR activity significantly increased in lenses removed from diabetic rats, the activity of this enzyme was reduced to normal values in lenses taken from animals treated with GTF.

In vitro studies were done on bovine lenses incubated for 14 days in a special lens organ culture system developed in our laboratory [5]. Half of the lenses were incubated in normal glucose conditions, and half in high glucose conditions. To one group of the normal or high glucose conditions GTF was added. The optical quality of all the lenses was measured daily by an automated scanning laser system [6]. Figure 3 presents the organ culture system and the automated scanning system.The control lenses, whether with or without GTF addition, stayed clear and kept a good optical quality through all the study. High glucose conditions induced optical damage to the lenses. Addition of GTF to high glucose conditions prevented this damage.

We also showed that high glucose conditions affected the activity of aldose reductase and Na/K ATPase in lens epithelial cells. Addition of GTF decreased these destructive changes induced by high glucose conditions.

As mentioned above, development of cataract also results in major changes to lens proteins (crystallins). We found in our study that the amount of soluble cortical lens proteins was decreased and structural changes were detected in these proteins while incubating lenses in high glucose medium. These changes were prevented when GTF was added to high glucose medium.

We showed in our previous studies [2] that GTF activated key proteins along insulin signaling pathway, exhibiting insulin mimetic potential. These insulin –like effects can explain the direct influence of GTF on protecting lens crystallins from glycation, formation of reactive oxygen species and degradation.

Our findings show that GTF, which was found as anti-diabetic agent both in vivo and in vitro, and exhibited also a cataract preventive activity, can serve as a source for developing a novel anti diabetic drug in general, and an anti-cataract treatment in particular.

References

1. Mirsky N. Glucose tolerance factor reduces blood glucose and free fattyacids levels in diabetic rats (1993) J Inorg Biochem 49:123–128
2. Weksler-Zangen S, Mizrahi T, Raz I, Mirsky N (2012). Glucose tolerancefactor (GTF) extracted from yeast: oral insulin mimetic and insulinpotentiating agent In vivo and in vitro studies. Br J Nutr108:875–882
3. Mirsky N. Glucose tolerance factor – insulin mimetic and potentiating agent – a source for a novel anti diabetic medication (2012), In: Chackrewarthy S (ed.). Glucose tolerance. Croatia: InTech Open Science pp. 165–188
4. Nakhoul F, Abassi Z, Morgan M, Sussan S, Mirsky N. (2006). Inhibition ofdiabetic nephropathy in rats by an oral anti diabetic material extracted from yeast. J Am Soc Nephrol 17:127–131
5. Dovrat A, Sivak JG, Gershon D. (1986). Novel approach to monitoring lens function during organ culture. Lens Res 3:207–215
6. Sivak JG, Gershon D, Dovrat A, Weerheim J. (1986). Computer assisted scanning laser monitor of optical quality of the excised crystalline lens. Vision Res 26:1873–1879