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.

Werner syndrome (WS) is a premature aging disorder caused by mutations in a RecQ-like DNA helicase. Mice lacking the helicase domain of the WRN homologue exhibit many phenotypic features of WS, including a prooxidant status and a shorter mean life span compared to wild-type animals. Here, we show that Wrn mutant mice also develop premature liver sinusoidal endothelial defenestration along with inflammation and metabolic syndrome. Vitamin C supplementation rescued the shorter mean life span of Wrn mutant mice and reversed several age-related abnormalities in adipose tissues and liver endothelial defenestration, genomic integrity, and inflammatory status. At the molecular level, phosphorylation of age-related stress markers like Akt kinase-specific substrates and the transcription factor NF-κB, as well as protein kinase Cδ and Hif-1α transcription factor levels, which are increased in the liver of Wrn mutants, were normalized by vitamin C. Vitamin C also increased the transcriptional regulator of lipid metabolism PPARα. Finally, microarray and gene set enrichment analyses on liver tissues revealed that vitamin C decreased genes normally up-regulated in human WS fibroblasts and cancers, and it increased genes involved in tissue injury response and adipocyte dedifferentiation in obese mice. Vitamin C did not have such effect on wild-type mice. These results indicate that vitamin C supplementation could be beneficial for patients with WS.

The antihyperglycemic effects of chemically synthesized d-chiro-inositol (d-CI), a component of an insulin mediator, have been demonstrated in rats. Buckwheat contains relatively high levels of d-CI: thus, it has been proposed as a source of d-CI for reducing serum glucose concentrations in diabetics. The present study evaluates the effects of a buckwheat concentrate, containing d-CI, on hyperglycemia and glucose tolerance in streptozotocin (STZ) rats. In fed STZ rats, both doses of the buckwheat concentrate (containing 10 and 20 mg of d-CI/kg of body weight) were effective for lowering serum glucose concentrations by 12-19% at 90 and 120 min after administration. Findings from this study demonstrate that a buckwheat concentrate is an effective source of d-CI for lowering serum glucose concentrations in rats and therefore may be useful in the treatment of diabetes.

The murine Hox 1.3 gene is one of six homeo box genes clustered on chromosome 6. Our analysis of Hox 1.3 cDNA and genomic clones indicates that the gene is organized into two exons and encodes a 270-amino-acid homeo domain protein. The predicted protein is rich in serine, glycine, and proline residues, and its homeo domain is identical to the Hox 2.1 domain. During embryogenesis, the gene is maximally expressed at midgestation but is also expressed to a lesser extent in many adult tissues possessing different cell lineages. Hox 1.3 transcripts are also present in cultured fibroblasts. The Hox 1.3 protein accumulates in the nuclei of nonconfluent cultured fibroblasts but is greatly diminished in contact-inhibited nongrowing cells. Thus, the expression of the Hox 1.3 gene correlates with growth in embryos and cultured cells. Paradoxically, it is also expressed in certain subsets of postmitotic, fully differentiated neurons, most notably the Purkinje neurons of the cerebellum, the pyramidal and dentate neurons of the hippocampus, and the motor neurons of the spinal cord. This complex pattern of expression suggests that Hox 1.3 may provide a function required by many cell types in addition to any role it may have in morphogenesis.

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.

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.

Analysis of oxylipins derived from fatty acids may provide insight into the biological effects of dietary lipids beyond their effects on tissue fatty acid profiles. We have previously observed that diets with higher amounts of α-linolenic acid (ALA; 18:3n3) are associated with reduced obesity-related glomerulopathy (ORG). Therefore, to examine the renal oxylipin profile, the effects of dietary linoleic acid (LA; 18:2n6) and ALA on oxylipins and renal phospholipid fatty acid composition, and the relationship between oxylipins and ORG, diet-induced obese rats displaying ORG were fed 8 different diets for 8 wk as follows (oil/oil = combination of two oils) [shown as ALA/LA (in g) per 100 g oil]: canola/flax (20/18), canola (8/18), soy (9/53), high-oleic canola/canola (5/16), high-oleic canola (2/15), lard/soy (1/8), and safflower (0.2/73). Targeted lipidomic analysis by HPLC-tandem mass spectrometry revealed that LA and ALA oxylipins comprised 60% of the total renal oxylipin profile examined. Of the >60 oxylipins screened, only those derived either directly or indirectly from ALA were associated with less glomerulomegaly, indicative of reduced ORG progression. Both the amount and ratio of dietary LA and ALA influenced renal polyunsaturated fatty acids (PUFAs); in contrast, only fatty acid amount altered oxylipins derived from these fatty acids, but there was no apparent competition by LA or ALA on their formation. Dietary LA incorporation into renal phospholipids was higher than for ALA, but ALA oxylipin:ALA ratios were higher than the analogous LA ratios for select lipoxygenase reactions. This indicates that the effect of dietary ALA on renal oxylipins exceeded what was reflected in renal PUFA composition. In conclusion, dietary LA and ALA have differential effects on renal oxylipins and PUFAs, and ALA-derived oxylipins are associated with renoprotection in this model of ORG.

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