Carla G. Taylor

Zinc, the Pancreas, and Diabetes: Insights from Rodent Studies and Future Directions

Molecular and cellular studies have demonstrated several roles for zinc (Zn) in insulin production and the consequent actions of insulin on metabolism. Clinical and epidemiological studies suggest that reduced Zn status is associated with diabetes. Investigations of Zn in rodent models of diabetes have provided a valuable link for understanding the molecular, cellular, clinical and epidemiological observations in the context of inter-organ metabolism and the metabolic disturbances of diabetes. This review highlights some of the current knowledge and future research directions for the role of Zn in the pancreas and diabetes based on rodent studies and experimental manipulations of Zn. Overall, Zn supplementation is effective for preventing or ameliorating diabetes in several rodent models of Type 1 and Type 2 diabetes. Studies with chemically-induced Type 1 diabetes indicate that the protective effects of Zn involve antioxidant mechanisms whether it is Zn alone (as an antioxidant), Zn induction of metallothionein or Zn inhibition of redox-sensitive transcription factors. Further studies are needed to identify the mechanism(s) for Zn protection in Type 2 diabetes, including pancreatic and peripheral effects. Experimental manipulations of Zn status in rodent models of diabetes provide a valuable approach to explore mechanisms for the protective effects of Zn; however, long term clinical studies establishing safety (lack of toxicity) and efficacy are required before any recommendations can be made for people with diabetes.

Dietary zinc supplementation attenuates hyperglycemia in db/db mice.

Although zinc (Zn) deficiency has been associated with insulin resistance, and altered Zn metabolism (e.g., hyperzincuria, low-normal plasma Zn concentrations) may be present in diabetes, the potential effects of Zn on modulation of insulin action in Type II diabetes have not been established. The objective of this study was to compare the effects of dietary Zn deficiency and Zn supplementation on glycemic control in db/db mice. Weanling db/db mice and lean littermate controls were fed Zn-deficient (3 ppm Zn; dbZD and InZD groups), Zn-adequate control (30 ppm Zn; dbC and InC groups) or Zn-supplemented (300 ppm Zn; dbZS and InZS groups) diets for 6 weeks. Mice were assessed for Zn status, serum and urinary indices of diabetes, and gastrocnemius insulin receptor concentration and tyrosine kinase activity. Fasting serum glucose concentrations were significantly lower in the dbZS group compared with the dbZD group (19.3 ± 2.9 and 27.9 ± 4.1 mM, respectively), whereas the dbC mice had an intermediate value. There was a negative correlation between femur Zn and serum glucose concentrations (r = −0.59 for lean mice, P = 0.007). The dbZS group had higher pancreatic Zn and lower circulating insulin concentrations than dbZC mice. Insulin-stimulated tyrosine kinase activity in gastrocnemius muscle was higher in the db/db genotype, and insulin receptor concentration was not altered. In summary, dietary Zn supplementation attenuated hyperglycemia and hyperinsulinemia in db/db mice, suggesting that the roles of Zn in pancreatic function and peripheral tissue glucose uptake need to be further investigated.

Effects of dietary fat and zinc on adiposity, serum leptin and adipose fatty acid composition in C57BL/6J mice☆

Zinc (Zn) has been implicated in altered adipose metabolism, insulin resistance and obesity. The objective of this study was to investigate the effects dietary Zn deficiency and supplementation on adiposity, serum leptin and fatty acid composition of adipose triglycerides and phospholipid in C57BL/6J mice fed low-fat (LF) or high-fat (HF) diets for a 16 week period. Weanling C57BL/6J mice were fed LF (16% kcal from soybean oil) or HF (39% kcal from lard and 16% kcal from soybean oil) diets containing 3, 30 or 150 mg Zn/kg diet (ZD = Zn-deficient, ZC = Zn control and ZS = Zn-supplemented, respectively). HF-fed mice had higher fat pad weights and lower adipose Zn concentrations than the LF-fed mice. The ZD and ZS groups had a reduced content of fatty acids in adipose triglycerides compared to the ZC group, suggesting that zinc status may influence fatty acid accumulation in adipose tissue. Serum leptin concentration was positively correlated with body weight and body fat, and negatively correlated with adipose Zn concentration. Dietary fat, but not dietary Zn, altered the fatty acid composition of adipose tissue phospholipid and triglyceride despite differences in Zn status assessed by femur Zn concentrations. The fatty acid profile of adipose triglycerides generally reflected the diets. HF-fed mice had a higher percentage of C20:4 n-6, elevated ratio of n-6/n-3, lower ratio of PUFA/SAT and reduced percentage of total n-3 fatty acids in adipose phospholipid, a fatty acid profile associated with obesity-induced risks for insulin resistance and impaired glucose transport. In summary, the reduced adipose Zn concentrations in HF-fed mice and the negative correlation between serum leptin and adipose Zn concentrations support an interrelationship among obesity, leptin and Zn metabolism.

Dietary milled flaxseed and flaxseed oil improve N-3 fatty acid status and do not affect glycemic control in individuals with well-controlled type 2 diabetes.

Objective: To determine the effects of dietary consumption of milled flaxseed or flaxseed oil on glycemic control, n-3 fatty acid status, anthropometrics, and adipokines in individuals with type 2 diabetes. Design: Thirty-four participants were randomized into a parallel, controlled trial. Subjects: The participants were adults with type 2 diabetes (age 52.4 ± 1.5 years, body mass index 32.4 ± 1.0 kg/m2, n  =  17 men and 17 women). Interventions: Participants consumed a selection of bakery products containing no flax (control group [CTL], n  =  9), milled flaxseed (FXS, n  =  13; 32 g/d), or flaxseed oil (FXO, n  =  12; 13 g/d) daily for 12 weeks. The FXS and FXO groups received equivalent amounts of alpha-linolenic acid (ALA; 7.4 g/day). Measures of Outcome: The primary outcome measures were fasting plasma hemoglobin A1c, glucose, insulin, and phospholipid fatty acid composition. The secondary outcome measures were fasting circulating leptin and adiponectin, as well as body weight, body mass index, and waist circumference. Dietary intake assessment and calculations for homeostasis model assessment for insulin resistance and quantified insulin sensitivity check were also completed. Results: The FXS and FXO groups had increases in plasma phospholipid n-3 fatty acids (ALA, eicosapentaenoic acid [EPA], or decosapentaenoic acid [DPA], but not docosahexaenoic acid), and the FXO group had more EPA and DPA in plasma phospholipids compared to the FXS group. All groups had similar caloric intakes; however, the CTL group experienced a 4% weight gain compared to baseline (p < 0.05), while both flax groups had constant body weights during the study period. All other parameters, including glycemic control, were unchanged by dietary treatment. Conclusions: Milled FXS and FXO intake does not affect glycemic control in adults with well-controlled type 2 diabetes. Possible prevention of weight gain by flax consumption warrants further investigation.

Resveratrol Arrests and Regresses the Development of Pressure Overload- but Not Volume Overload-Induced Cardiac Hypertrophy in Rats

Cardiac hypertrophy is a compensatory enlargement of the heart due to either volume overload (VO) and/or pressure overload (PO) that develops into heart failure if left untreated. The polyphenol resveratrol has been reported to regress PO-induced cardiac hypertrophy in rats. Our aim in this study was to assess the effectiveness of resveratrol on VO-induced cardiac hypertrophy. Sprague Dawley rats were subjected to aortocaval shunt and abdominal aortic banding surgeries to create VO and PO, respectively; sham-operated rats served as controls. To arrest the development of cardiac hypertrophy, daily resveratrol treatment (2.5 mg/kg body weight) was started 2 d postsurgery for 26 d and assessed by echocardiography at 2, 14, and 28 d postsurgery. Similarly, to regress cardiac hypertrophy resveratrol treatment was started after structural and functional abnormalities developed (14 d postsurgery) for 14 d and assessed by echocardiography at 14 and 28 d postsurgery. VO surgeries induced eccentric hypertrophy characterized by increased left ventricle internal dimensions (LVID) without wall thickening. Conversely, PO induced concentric hypertrophy with increased wall thickness without change in LVID. Lipid peroxidation, a marker for oxidative stress, was significantly elevated in both PO and VO rats. Resveratrol treatment arrested the development and regressed abnormalities in cardiac structure and function in PO but not VO rats. Treatment with resveratrol also significantly reduced oxidative stress in cardiac tissue of PO and VO rats. The results on cardiac structure and function demonstrate a potential for resveratrol in the treatment of cardiac hypertrophy due to PO but not VO.

Enhancement of tissue glutathione for antioxidant and immune functions in malnutrition

Glutathione (t-y-glutamyl-L-cysteinyl-glycine, GSHT), a cysteine-containing tripeptide and the most abundant non-protein thiol in mammalian cells, is receiving considerable research attention (over 1200 citations in the Medline Database for 1992). The structural uniqueness of GSH, conferred by the y-glutamyl bond, contributes to its intracellular stability (resistance to intracellular peptidases) and determines tissue specificity for uptake of extracellular GSH via y-glutamyl transpeptidase. Tissue concentrations of GSH, like many other metabolically important compounds, are highly regulated. For example, it is difficult to deplete hepatic GSH to less than 30% of control values even with xenobiotic challenge or prolonged starvation [l-6]. Also, it is difficult to exceed the physiological ma~mum concentration for hepatic GSH with supplementation of GSH precursors unless hepatic GSH stores have been depleted previously with xenobiotics or by fasting [4,6]. GSH, a substrate for GSH-S-transferase (EC 2.5.1.18) and GSH peroxidase (EC 1.11.1.9), was initially studied for its role in detoxification of xenobiotics and antioxidation of reactive oxygen species and free radicals, This also led to an appreciation of GSH for transport and storage of cysteine, and for the effects of nutritional status (e.g. sulfur amino acid deficiency) and physiological state on tissue GSH concentrations. With increasing knowledge, the recognized functions of GSH have been expanded to include many aspects of cell biology, such as regulation of cellular redox balance, leukotriene and prostaglandin metabolism, deoxyribonucleotide synthesis, immune function and cell proliferation [for recent GSH reviews, see Refs. 7-111. At the same time, there has been increased interest in the potential therapeutic use of GSH or GSH precursors for treatment of toxicity or diseases, especially those conditions that are believed to be free radical-mediated and that have depleted stores of tissue GSH. The concept of using GSH or GSH precursors

Adipose Tissue: The Link Between Obesity and Cardiovascular Disease

The ever-increasing prevalence of cardiovascular disease (CVD) associated with obesity is linked through signaling pathways within adipose tissue. Adipose tissue functions as an endocrine organ, producing and secreting a variety of bioactive molecules. In obesity, the adipose tissue itself undergoes changes in cell size which alters its normal physiological function. Altered adipocyte function changes production and secretion of adipokines, such as leptin, adiponectin, angiotensinogen, plasminogen activator inhibitor-1, resistin, and several inflammatory molecules. Adipokines interact with other tissues and cells in the body, including many pathways linked to CVD. Future research in the area of obesity-related CVD requires further investigation into a combination of lifestyle and pharmacological therapies that alter adipokine production by reducing adipocyte size.

Nutritional and hormonal regulation of glutathione homeostasis.

Publisher Summary This chapter discusses the regulation of tissue GSH homeostasis, by nutrition and hormones, and to assess the physiological relevance of altered thiol status, using the vicious cycle of disease, infection, and malnutrition as an example. The chapter describes that the nutritional and hormonal regulation of GSH homeostasis is important for developing strategies to enhance the tissue GSH and to intervene in this cycle of disease, infection, and malnutrition. It has been demonstrated that cellular processes, such as signal transduction and gene transcription, are dependent on the redox status of critical sulfhydryl groups for interactions among proteins and between the transcription factors and DNA. Although many factors influence GSH status, the regulation of tissue GSH, by nutrition and hormones, is important for understanding in vivo GSH homeostasis, particularly when malnutrition and oxidative stress are present. Malnutrition is a complication of many diseases and occurs during prolonged or repeated bouts of infection. The chapter discusses various glutathione synthesis and interorgan homeostasis, and it concludes with the regulation of glutathione by hormones.

Elevation of lung glutathione by oral supplementation of L-2-oxothiazolidine-4-carboxylate protects against oxygen toxicity in protein-energy malnourished rats.

The objectives of this study were to investigate whether oral supplementation of l‐2‐oxothiazolidine‐4‐carboxylate (OTC) is effective for increasing tissue glutathione (GSH) concentrations in rats fed a diet very low (0.5%) in protein — a model of wasting malnutrition — and to determine the efficacy of OTC for protection against pulmonary oxygen toxicity. Weanling rats, fed a 0.5 or 15% protein diet for 2 wk, were given an oral supplement of OTC, and tissue GSH concentrations were measured over a 24 h period. OTC supplementation to rats fed 0.5% protein significantly increased GSH concentrations in liver and lung, but not in kidney and blood, when compared with the 0.5% protein unsupplemented group. The liver GSH concentration in the 0.5% protein OTC‐supplemented group was higher than the 15% control group. Daily supplementation of OTC protected rats from pulmonary oxygen toxicity during 4 days of 85% oxygen exposure as determined by lung‐to‐body weight ratios and in vivo proton magnetic resonance imaging. Although hyperoxia exposure increased lung GSH concentrations in all groups, OTC supplementation was effective for increasing lung GSH concentration in rats fed the 0.5% protein diet. This study demonstrated that oral administration of OTC to wasting malnourished rats is an effective procedure to increase GSH concentration rapidly in target organs such as lung, and that daily supplementation of a low dose of OTC has a sustained effect to protect against pulmonary oxygen toxicity during 4 days of hyperoxia exposure.— Taylor, C. G.; Bauman, P. F., Sikorski, B., Bray, T. M. Elevation of lung glutathione by oral supplementation of L‐2‐oxothiazolidine‐4‐carboxylate protects against oxygen toxicity in protein energy malnourished rats. FASEB J. 6: 3101‐3107; 1992.

Variations in Adipokine Genes AdipoQ, Lep, and LepR are Associated with Risk for Obesity-Related Metabolic Disease: The Modulatory Role of Gene-Nutrient Interactions

Obesity rates are rapidly increasing worldwide and facilitate the development of many related disease states, such as cardiovascular disease, the metabolic syndrome, type 2 diabetes mellitus, and various types of cancer. Variation in metabolically important genes can have a great impact on a populations susceptibility to becoming obese and/or developing related complications. The adipokines adiponectin and leptin, as well as the leptin receptor, are major players in the regulation of body energy homeostasis and fat storage. This paper summarizes the findings of single nucleotide polymorphisms in these three genes and their effect on obesity and metabolic disease risk. Additionally, studies of gene-nutrient interactions involving adiponectin, leptin, and the leptin receptor are highlighted to emphasize the critical role of diet in susceptible populations.