Mitochondrial nutrients improve immune dysfunction in the type 2 diabetic Goto‐Kakizaki rats

Abstract

The development of type 2 diabetes is accompanied by decreased immune function and the mechanisms are unclear. We hypothesize that oxidative damage and mitochondrial dysfunction may play an important role in the immune dysfunction in diabetes. In the present study, we investigated this hypothesis in diabetic Goto-Kakizaki rats by treatment with a combination of four mitochondrial-targeting nutrients, namely, R-α-lipoic acid, acetyl-L-carnitine, nicotinamide and biotin. We first studied the effects of the combination of these four nutrients on immune function by examining cell proliferation in immune organs (spleen and thymus) and immunomodulating factors in the plasma. We then examined, in the plasma and thymus, oxidative damage biomarkers, including lipid peroxidation, protein oxidation, reactive oxygen species, calcium and antioxidant defence systems, mitochondrial potential and apoptosis-inducing factors (caspase 3, p53 and p21). We found that immune dysfunction in these animals is associated with increased oxidative damage and mitochondrial dysfunction and that the nutrient treatment effectively elevated immune function, decreased oxidative damage, enhanced mitochondrial function and inhibited the elevation of apoptosis factors. These effects are comparable to, or greater than, those of the anti-diabetic drug pioglitazone. These data suggest that a rational combination of mitochondrial-targeting nutrients may be effective in improving immune function in type 2 diabetes through enhancement of mitochondrial function, decreased oxidative damage, and delayed cell death in the immune organs and blood.

l-Carnitine mediates protection against DNA damage in lymphocytes of aged rats

“…The protective role of L-carnitine could also be attributed to its antioxidant role as observed by us and others (Rani and Panneerselvam 2002;Gulcin 2006) and thereby this could have contributed to its protective role on DNA. This is also supported by recent studies by Hao et al (2008) where in they observed 12 week long treatment of diabetic rats with a combination of mitochondrial targeting nutrients like L-carnitine enhanced immune functions, inhibited oxidative damage and apoptosis process.…”

Mitochondrial dysfunction in the liver of type 2 diabetic Goto–Kakizaki rats: improvement by a combination of nutrients

“…These treatments also produced a non-significant decrease in p53 and p21 (Fig. 5), consonant with the statistically significant reduction in these two proteins seen in GK rat thymocytes reported earlier (15) . As evidence indicating a possible increase in oxidative stress and consequent cell death/tissue damage in GK rat mitochondria, amounts of oxidised proteins were clearly elevated in GK rats, and total antioxidant capacity, total superoxide dismutase, glutathione S-transferase and NAD(P)H:quinone oxidoreductase 1 activities were substantially decreased.…”

“…It is thus an appropriate model to study events occurring at the onset of diabetes, compared with obese diabetic rats which present severe hyperglycaemia and hyperlipidaemia (13) . Treatment of GK rats with mitochondrial nutrients significantly improves glucose tolerance, insulin release, plasma NEFA levels, skeletal muscle mitochondrial biogenesis (14) and immune function (15) . The rationale for the selection and dosage levels of these nutrients, as detailed earlier (14,15) , targets substances that influence mitochondrial processes either synergistically or by mechanisms as widely disparate as possible.…”

“…Treatment of GK rats with mitochondrial nutrients significantly improves glucose tolerance, insulin release, plasma NEFA levels, skeletal muscle mitochondrial biogenesis (14) and immune function (15) . The rationale for the selection and dosage levels of these nutrients, as detailed earlier (14,15) , targets substances that influence mitochondrial processes either synergistically or by mechanisms as widely disparate as possible. Briefly, acetyl-L-carnitine and LA were selected for the ability of each to ameliorate mitochondrial dysfunction: acetyl-L-carnitine by its ability to facilitate the transport of long-chain fatty acids across the mitochondrial membrane and LA by its ability to improve insulin sensitivity by adenosine monophosphate-activated protein kinase (AMPK) activation.…”

Modeling Chick to Assess Diabetes Pathogenesis and Treatment

“…We attempted to cryopreserve isolated chick islets following an established protocol used for cryopreservation of mouse islets [57]. The islets were cryopreserved in a medium consisting of DMEM:Ham's F.12 (1:1) (Gibco, Brazil), supplemented with 10% FCS, riboflavin, and nicotinamide as cryoprotectants [58][59][60][61][62][63][64]. We found that it is possible to cryopreserve chick islets without losing viability and insulin secretory activity [13].…”