Journal of Diabetes and Its Complications
Volume 25, Issue 1 , Pages 31-38, January 2011

Role of lipoic acid on insulin resistance and leptin in experimentally diabetic rats

  • Mohammed A. Kandeil

      Affiliations

    • Biochemistry Department, Faculty of Veterinary Medicine, Beni Suef University, Egypt
    • ,
  • Kamal A. Amin

      Affiliations

    • Biochemistry Department, Faculty of Veterinary Medicine, Beni Suef University, Egypt
    • Corresponding Author InformationCorresponding author. Biochemistry Department, College of Veterinary Medicine, Beni Suef University, Egypt. Fax: +20 00220822327982.
    • ,
  • Kamel A. Hassanin

      Affiliations

    • Biochemistry Department, Faculty of Veterinary Medicine, Beni Suef University, Egypt
    • ,
  • Kalid M. Ali

      Affiliations

    • Physiology Department, Faculty of Veterinary Medicine, Beni Suef University, Egypt
    • ,
  • Eman T. Mohammed

      Affiliations

    • Biochemistry Department, Faculty of Veterinary Medicine, Beni Suef University, Egypt

Received 12 August 2009; received in revised form 11 September 2009; accepted 28 September 2009. published online 30 October 2009.

Article Outline

Abstract 

Objective

We aimed to examine the changes in serum insulin and leptin levels in induced type 1 diabetes mellitus in relationship to glycemic state and lipid profiles and to clarify the role of lipoic acid (LA).

Methods

Ninety-six male rats were equally divided into the following: a control group (normal, nondiabetic), a diabetic group induced by subcutaneous injection of alloxan (non-LA-treated), and an LA-treated diabetic group (for 4 weeks). Body weight, serum lipid profile, glucose, insulin, homeostasis model assessment–insulin resistance (HOMA-IR), and leptin were measured.

Results

This study showed a significant increase in serum triacylglycerol (TG), total cholesterol, glucose levels, and HOMA-IR and a significant decrease in body weight gain, insulin, and leptin levels in the diabetic group compared to the control group. LA treatment induced a significant decrease in glucose, TG, and total cholesterol levels and significantly increased serum insulin and leptin levels in comparison with the diabetic group.

Conclusion

Induced diabetes resulted in insulin resistance, hyperlipidemia, and hypoleptinemia, while LA ameliorates these changes and improves insulin sensitivity.

Keywords: Insulin, Leptin, Alloxan-induced diabetes, Lipoic acid, Rat

 

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1. Introduction 

Diabetes is a metabolic disorder that is known to produce various dysfunctions in the body and the central nervous system (CNS). Some of the diabetes-related CNS disturbances include hyperphagia, polydipsia, and activation of the hypothalamo–pituitary–adrenal axis (Biessels, Kappelle, Bravenboer, Erkelens, & Gispen, 1994).

The sustained hyperglycemia leads to a further impairment of insulin production by β-cells—the so-called glucose toxicity (Del Prato & Marchetti, 2004). In addition, the elevated serum triacylglycerol (TG) and its accumulation in pancreatic islets during the development of diabetes have been associated with impaired β-cell secretory responses—the so-called lipotoxicity (Hirose, Lee, Inman, Nagasawa, & Unger, 1996)—and are causally related to type 2 diabetes. Szkudelski, Kandulska, and Okulicz (1998) reported that the decrease in insulin concentration after alloxan injection was accompanied by a rise in blood glucose concentration and a decrease in the content of free fatty acids, suggesting that the use of lipids as a source of energy is enhanced. This assumption is additionally supported by a slight decrease in blood TG in alloxan-treated rats. In contrast, Sheela and Augusti (1992) reported a significant increase in serum total cholesterol, TG, and total lipids in alloxan- and streptozotocin-induced diabetic animals. Also, Sobenin, Tertov, and Orekhov (1994) found an elevated total cholesterol level in plasma of diabetic patients.

The most important hormones produced by adipose tissue are leptin and adiponectin. Leptin plays a significant role in the regulation of lipid and carbohydrate metabolism. Leptin is a cytokine that decreases appetite, increases energy expenditure, suppresses insulin synthesis and secretion, and increases insulin sensitivity (Yildiz & Haznedaroglu, 2006). Changes in the secretion or sensitivity to leptin may contribute to the development of type 1 and type 2 diabetes (Huerta, 2006). Leptin is produced in proportion to the amount of adipose tissue and acts in specific brain hypothalamic nuclei to reduce food intake and in rodents to activate thermogenesis (Friedman, 2000). Leptin also has actions outside the brain, one of which is the stimulation of fatty acid oxidation in muscles and liver, at least in part through AMP-activated protein kinase (AMPK) activation (Minokoshi et al., 2002). The secretion of leptin hormone is affected by food consumption, insulin, fasting, and cold exposure. It is known that the increased ATP and malonyl-CoA contents in adipocytes enhance secretion of leptin (Szkudelski, 2006).

It was found that the insulin-induced rise in leptin secretion is accompanied by an initial decrease in the intracellular leptin content, probably due to its augmented release from fat cells (Barr, Malid, Zarnowski, Taylor, & Cushman, 1997). Glucose seems to be the most important source of ATP in adipocytes during leptin secretion. Insulin promotes the translocation of glucose transporter-4 from the intracellular pool to the plasma membrane and thereby accelerates glucose transport into adipocytes (Khan & Pessin, 2002).

Insulin also shifts glucose metabolism from anaerobic to mitochondrial oxidation, generating ATP and finally augmenting secretion of leptin (Levy & Stevens, 2001). Compounds enhancing glucose uptake but potentiating its metabolism to lactate (e.g. metformin) were found to restrict secretion of leptin (Mueller, Stanhope, Gregoire, Evans, & Havel, 2000).

Diabetics have increased levels of lipid hydroperoxides and protein carbonyls (Packer, Kraemer, & Rimbach, 2001). α-Lipoic acid (ALA) is a naturally occurring short-chain fatty acid with sulfhydryl groups that has potent unique antioxidative activity in a wide variety of experimental systems and is clinically used to treat diabetic neuropathy (Biewenga et al., 1997, Packer et al., 2001, Wollin and Jones, 2003). Lipoic acid (LA) scavenges hydroxyl radicals, hypochlorous acid, nitric oxide, peroxynitrite, hydrogen peroxide, and singlet oxygen. It also chelates iron, copper, and other transition metals (Packer, Witt, & Tritschler, 1995). Therefore, LA and dihydrolipoic acid take central positions in the antioxidant network (Packer et al., 2001). LA may also increase nerve growth factor levels (Hounsom, Horrobin, Tritschler, Corder, & Tomlinson, 1998) and promote nerve fiber sprouting (Dimpfel, Spüler, Pierau, & Ulrich, 1990). In addition, it was recently reported that LA reduced the body weight gain of rodents by suppressing food intake and increasing energy expenditure (Lee et al., 2005, Song et al., Jan 7 2005).

Leptin, insulin, glucose, and ALA have been shown to reduce food intake by lowering hypothalamic AMPK activity (Lee et al., 2005). Short-term administration of LA at a high dose to normal and diabetic rats causes an inhibition of gluconeogenesis secondary to an interference with hepatic fatty acid oxidation. This may render LA an anti-hyperglycemic agent for the treatment of diabetic rats that display glucose overproduction as a major metabolic abnormality (Khamaisi et al., 1999).

In this study, we aimed to examine changes in serum insulin and leptin levels in induced type 1 diabetes mellitus in relation to concomitant changes in body weight, glycemic state, and lipid profiles in rats. Moreover, we aimed to clarify whether the treatment with LA is capable of reversing these effects or not.

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2. Materials and methods 

2.1. Materials 

2.1.1. Experimental animals 

Ninety-six male albino rats (100–180 g body weight, 10 weeks old) were used in this study. Rats were kept for 2 weeks on balanced ration with water ad libitum for acclimatization.

2.1.2. Alloxan (diabetogenic agent) 

5,6-Dioxyuracil was purchased from Sigma Chemical Company (USA). It was dissolved in citrate buffer (pH 4.4) immediately before use.

2.1.3. Lipoic acid 

1,2-Dithiolane-3-pentanoic acid is marketed as thioctic acid by EVA Pharma for Pharmaceuticals and Medical Appliances (Egypt). The tablets were crushed and suspended in distilled water and each tablet contains 300 mg thioctic acid.

2.2. Methods 

2.2.1. Experimental diabetes 

It was induced in overnight fasted rats (16 h) by subcutaneous injection of a single dose of alloxan (120 mg/kg body weight). Then, after 4–5 days of alloxan injection, rats were screened for blood glucose levels. Rats with a serum postprandial glucose level of 180–300 mg/dl were considered as mildly diabetic and were included in the experiment (n=64 rats) cited by Abdel-Reheim (1997).

2.2.2. Animal grouping 

Normal, nondiabetic rats (n=32, not treated with LA) make up the control group. The rats that belong to the diabetic group (n=32, not treated with LA) were orally given isotonic solution via a stomach tube daily for four successive weeks. The rats that belong to the LA-treated diabetic group (n=32) were treated with LA (100 mg/kg body weight daily) via a stomach tube for four successive weeks (Arivazhagan, Panneerselvam, & Panneerselvam, 2003).

2.2.3. Sampling and preparations 

At the end of the experimental period, blood samples were collected from the rats in each group (fasting and postprandial) for determination of glucose level and other biochemical parameters.

2.2.4. Biochemical assay 

Fasting serum TG concentration was determined by enzymatic method (Young & Pestaner, 1975), serum total cholesterol concentration was determined by enzymatic method (Richmond, 1973), and serum glucose concentration was enzymatically estimated according to the method of Trinder (1969). Serum leptin concentration was estimated according to Considine et al. (1996) using DSL (Diagnostic system Laboratory, Inc.) active Leptin ELISA Kit, Catalog No. DSL-10-24100. Serum insulin was measured according to Turkingto et al. (1982) using Insulin AccuBind ELISA Microwells from Monobind Inc. (Costa Mesa, CA). Homeostasis model assessment–insulin resistance (HOMA-IR) score was calculated to show the insulin resistance by using the following formula: [insulin (μIU/ml)×fasting glucose (mmol/L)]/22.5 (Haffner, Miettinen, & Stern, 1997); higher HOMA-IR scores denote lower insulin (insulin resistance). The obtained data during the experimental period were statistically analyzed by t test, and the correlation between variables was evaluated using correlation coefficient (Snedecor & Cochran, 1980).

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3. Results 

The obtained data revealed that there was a significant decrease in the mean body weight and body weight gain in the rats of the diabetic group compared with those of the control group (Table 1; Fig. 1). LA was found to significantly increase the mean body weight gain in the LA-treated diabetic group as compared with the diabetic group. Data of Table 1 showed a significant increase in serum TG and total cholesterol concentrations in the diabetic group when compared with the control group. In the LA-treated diabetic group, significant lower levels of both TG and total cholesterol were recorded as compared with the diabetic group (Table 1).

Table 1. Mean body weight, body weight gain (g), serum TG, and total cholesterol concentrations (mg %) in control, diabetic, and LA-treated diabetic groups
GroupsMean body weight (g)Mean body weight gain (g)TG (mg %)Total cholesterol (mg %)
Control180.37±6.75a29.32±1.77a81.69±2.32a80.42±2.26a
Diabetic131.81±3.84b6.68±2.97b92.60±2.08b86.76±2.03b
LA-treated diabetic172.04±5.75a16.49±1.15c78.48±5.001a80.98±0.90a

Different superscript letters indicate significant variation at P<.05, while same superscript letters indicate nonsignificant variation.

Comparison of the diabetic group versus the control group showed a significant increase in both fasting and postprandial glucose levels in the diabetic group, which was significantly decreased after treatment with LA (Table 2; Fig. 2). There was a significant decrease in the serum levels of insulin and leptin hormones in the diabetic group compared with the control group. LA administration significantly increased the serum levels of insulin and leptin hormones (Table 2; Fig. 3, Fig. 4). On the other hand, there was a significant increase in HOMA-IR in the diabetic group compared with the control group, but LA treatment could increase the insulin sensitivity as reflected by low HOMA-IR levels in the LA-treated diabetic group (Table 2; Fig. 3).

Table 2. Mean serum levels of fasting and postprandial glucose, insulin, leptin, and HOMA-IR in control, diabetic, and LA-treated diabetic groups
GroupsFasting glucose (mg %)Postprandial glucose (mg %)Insulin (μIU/ml)HOMA-IR (μIU/ml)Leptin (ng/ml)
Control86.82±1.83a108.42±1.41a14.57±0.99a3.12±0.16a4.04±0.37a
Diabetic259.19±19.17b355.67±11.72b7.4±0.38b4.73±0.37b1.80±0.16b
LA-treated diabetic195.90±5.66c290.13±7.46c8.88±0.45c4.05±0.36ab2.83±0.25c

Different superscript letters indicate significant variation at P<.05, while same superscript letters indicate nonsignificant variation.

The present study revealed a positive correlation coefficient between leptin and mean body weight as well as a positive correlation coefficient between leptin and insulin and between insulin and mean body weight (Table 3). HOMA-IR was found to be negatively correlated with leptin, insulin, and body weight (Table 3).

Table 3. Correlation coefficient between insulin, leptin, and mean body weight
GroupsLeptin (ng/ml)Insulin (μIU/ml)Mean body weight (g)
Leptin––0.347
Insulin0.504–0.4244
HOMA-IR−0.5−0.6937−0.41811

Negative values indicate negative correlation, while positive values indicate positive correlation.

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4. Discussion 

The present study showed a significant decrease in mean body weight and body weight gains in the diabetic group compared with the control group. Schedl and Wilson (1971) explained the loss in body weight by enhanced transport of sugar and amino acids associated with alloxan-induced diabetes. In addition, brush border enzymes, namely, disaccharidases, are increased in chemically induced diabetes (Younsozai & Schedl, 1972). Thus, it appears that both the absorptive and digestive functions of small intestinal mucosa are altered in diabetes.

Our results showed a significant increase in mean body weight gain in the diabetic rats treated with LA compared with the diabetic group but still lower than that in the control group. LA is an insulin sensitizer—it can improve insulin-stimulated glucose uptake and improve insulin sensitivity (Moini, Packer, & Saris, 2002). LA, by its ability to improve insulin sensitivity and accelerate recovery of pancreatic β-cells, can nearly restore the metabolic alterations associated with diabetes.

The current data showed that serum TG concentrations were elevated in the diabetic group compared to the control group. These results are in accordance with those of Sheela and Augusti (1992) and Abdel-Azim, Bader, and Barakat (2002). The observed triglyceredemia in diabetic rats resulted from hepatic overproduction of TG that is probably a consequence of increased flux of glucose and free fatty acids to the liver (Abdel-Azim et al., 2002), and impaired clearance of TG-rich lipoproteins resulted from lowered lipoprotein lipase (LPL) activity (Quaschning et al., 1999). LPL is an enzyme on the surface of endothelial cells lining the vessels. The activity of this enzyme requires insulin, and in its absence, hypertriglyceredemia results.

Our results showed that serum total cholesterol levels increased significantly in the diabetic group than in the control group. These results agreed with those of Monnier, Colette, Percheron, and Descomps (1995). They attributed the increase in total cholesterol level to the increased β-oxidation of long-chain FA and increased oxidation of ketogenic amino acids producing an excess of hepatic acetyl-coA that is used for cholesterol synthesis (Abdel-Azim et al., 2002). It could be also due to depressed hepatic phenol 2-monooxygenase activity, the key enzyme responsible for the catabolism of cholesterol to bile acids (O' Meara, Devery, Owens, Johnson, & Tomkin, 1990). Moreover, decreased LDL receptor activity with a consequent delayed clearance of the glycated cholesterol LDL particles could be another cause of the increased total serum cholesterol level (Mazzone et al., 1984, Monnier et al., 1995).

The decrease in serum TG and total cholesterol after administration of LA is in agreement with the findings of Kocak et al. (2000) and Song et al. (2005). This result could be attributed to the effect of LA in reducing TG accumulation in skeletal muscles, pancreatic islets, and adipose tissue where LA increases fatty acid oxidation by activating the AMPK in skeletal muscles (Lee et al., 2005). The antioxidative action of LA may suggest its preventive effect on LDL cholesterol oxidation, thus enhancing its catabolism. From the previous results, it could be concluded that LA has an anti-hyperlipidemic effect on diabetic rats.

The present work revealed that serum insulin levels significantly decreased in the diabetic group compared to the control group. These results are in agreement with those of Kocak et al. (2000), Melhem, Craven, Liachenko, and DeRubertis (2002), and Szkudelski et al. (1998). Alloxan and streptozotocin are widely used as inducers of diabetes mellitus in experimental animals. Both chemicals cause selective destruction of pancreatic islet β-cells and can induce chronic or permanent diabetes in these animals (Mathe, 1995).

The current results showed that both fasting and postprandial serum glucose concentrations were significantly increased in the diabetic group compared to control rats. The chronic hyperglycemia and glucose intolerance could arise from a defect in insulin secretion as in the case of IDDM (Caro, 1990). In experimental diabetes that may represent a model of IDDM, alloxan generates some types of oxygen radicals that attack DNA, inducing DNA strand breaks in β-cells. The breaks induce DNA repair involving the activation of poly(ADP-ribose) polymerase, which uses NAD+ as a substrate. As a result, the intracellular levels of NAD+ fall. The fall in NAD+ inhibits ATP synthesis and cellular functions including insulin synthesis and secretion, and thus, the β-cell ultimately dies (Ohkuwa et al., 1995, Pusztai et al., 1996). This will lead to reduced uptake of glucose by peripheral tissues like muscles and adipose tissue (Beck-Nielsen, 2002), glycogenolysis (Gold, 1970), and increased gluconeogenesis and hepatic glucose production (Caro, 1990, Raju et al., 2001).

The present data demonstrated that serum glucose levels significantly decreased while serum insulin levels significantly increased in the diabetic group administrated LA in comparison with the diabetic group. These data are in agreement with Mazzone et al., 1984, Packer et al., 2001 who reported that LA increases glucose uptake through translocation of the glucose transporter to plasma membranes, a mechanism that is shared with insulin-stimulated glucose uptake. In experimental and clinical studies, LA markedly reduced the symptoms of diabetic pathologies, including cataract formation, vascular damage, and polyneuropathy (Packer et al., 2001), indicating the role of LA as a glucose-lowering agent. In this context, Moini et al. (2002) reported that the insulin receptor is a potential cellular target for LA action, and they explained the mechanism of action of LA as an insulin sensitizer. This mechanism occurs by autophosphorylation of insulin receptors and oxidation of thiol groups present in insulin receptor β-subunits by the oxidized form of LA, which, in turn, may be required for insulin-stimulated glucose transport. In addition, Bitar, Wahid, Pilcher, Al-Saleh, and Al-Mulla (2004) and Cho et al. (2003) stated that LA activates the insulin-signaling pathway and exerts insulin-like actions in adipocytes and muscle cells by the phosphorylation of insulin receptor. The mechanism of action of LA recently attributed its blocking effect on interleukin-1β that is secreted by activated macrophages in response to an immune-mediated process causing islet cell death in IDDM (Schroeder, Belloto, Hudson, & McInerney, 2005). In addition to this action of LA in the protection of pancreatic β-cells from death in IDDM, Song et al. (2005) reported another role of LA in protecting pancreatic β-cell by reducing TG accumulation in such cells. This accumulated metabolite is considered as a factor contributing to insulin resistance in obesity and is causally related to NIDDM. Thus, it can be concluded that LA can improve insulin-stimulated glucose transport, reduce insulin resistance (Jacob et al., 1996), and protect pancreatic islet cells from destruction.

Over the past few years, our understanding of leptin biology has significantly expanded. A more detailed clarification of the mechanisms of both leptin and insulin interaction in the setting of diabetes with hypoleptinemia may ultimately provide a novel therapeutic target for treating this disease.

One of the results of this current study was the significant decrease of serum leptin level in the diabetic group compared with the control group. These results are in agreement with those of Barber et al. (2003), Hathout et al. (1999), and Kirel et al. (2000). These authors indicated that diabetes causes marked decrease in serum leptin level. Our data support a direct relationship between the circulating insulin concentration and leptin secretion. Patients with type 1 diabetes (during insulinopenia) had significant lower leptin concentration compared with normal ones (Soliman et al., 2002). Also, streptozotocin-treated mice had low leptin levels (Cusin et al., 1995). Decreased leptin secretion is expected to stimulate appetite and contribute to hyperphagia in those patients. This was confirmed by a study of Sindelar et al. (1999) who showed that administration of leptin in diabetic animals could indeed reverse diabetes-induced hyperphagia. In other words, the beneficial effects of insulin on diabetes-induced hyperphagia may be mediated through leptin (Barber et al., 2003); thereby, these observations provide an insight into the therapeutic implication of leptin as an antidiabetic agent (Miyanaga et al., 2003).

The observed low serum leptin levels in type 1 diabetic rats in the present study may be due to insulin deficiency.

The present data demonstrated that treatment with LA significantly increased serum leptin levels in the LA-treated diabetic group when compared with the diabetic group.

Overall, insulin and glucose appear to increase leptin secretion. In turn, leptin increases peripheral insulin sensitivity while it decreases insulin secretion from pancreatic β-cells. Leptin increases skeletal muscle glucose uptake and oxidation and suppresses hepatic glucose output. Effects of leptin on lipid metabolism might reduce lipotoxicity and, therefore, contribute to the improvement of hepatic, skeletal, and whole-body insulin sensitivity (Yildiz & Haznedaroglu, 2006).

This work showed a positive correlation coefficient between leptin and body weight. Previous studies reported a strong positive correlation between leptin and body mass index in patients with type 1 diabetes mellitus (Lauszus, Schmitz, Vestergaard, Klebe, & Pedersen, 2001) and in patients with insulin resistance (Rudzka-Kocjan, Szarras-Czapnik, B, & Ginalska-Malinowska, 2006). Human obesity is suggested to be, in part, due to desensitization of leptin receptors within the hypothalamus resulting in hyperphagia (Frederich et al., 1995, Smith, 1996). Leptin, which has a dual nature as a hormone and as a cytokine, plays an important role in the regulation of body weight and energy balance. Interestingly, serum leptin and TG levels were independently associated with insulin resistance (Taniguchi et al., 2002). Leptin and insulin may have complementary roles in maintaining a stable body weight (Kirel et al., 2000).

In addition, a positive correlation coefficient was found between insulin and leptin concentrations. These data are in agreement with the results obtained by Hathout et al. (1999) and Malmstroem et al. (1996).

The present study indicates that ALA has an effective protective role in diabetic rats. This role has been concluded from its reduction to plasma glucose level and an accelerated recovery of pancreatic insulin-producing cells, which is deduced from the significantly increased serum level of insulin in the LA-treated diabetic group.

LA treatment effectively reversed body weight, blood glucose, plasma insulin, cholesterol, TG, and lipid peroxidation levels of streptozotocin-induced diabetic animals (Mazzone et al., 1984). Moreover, LA, a potent antioxidant, improves renal function in diabetes by lowering oxidative stress (Bhatti et al., 2005, El Sawalhy and Raffat, 2007). LA could be considered as an adjuvant therapy in diabetic cardiomyopathy (Strödter et al., 1995, Yi and Maeda, 2006).

It could be concluded that ALA treatment effectively reversed body weight, TG, total cholesterol, blood glucose, plasma insulin, HOMA-IR, and leptin, suggesting a potential therapeutic approach. In conclusion, LA stimulates basal glucose transport, has a positive effect on insulin-stimulated glucose uptake, and improves insulin sensitivity. Moreover, dietary ALA is a promising protective agent for reducing cardiovascular complications of diabetes.

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Acknowledgments 

This work was financially supported by grants from Beni Suef University. We acknowledge the support offered by Prof. Dr. Abd El-Salam, S.A., head of the department, for our research work.

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PII: S1056-8727(09)00098-1

doi:10.1016/j.jdiacomp.2009.09.007

Journal of Diabetes and Its Complications
Volume 25, Issue 1 , Pages 31-38, January 2011

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