Dongmin Liu

Recent advances in understanding the anti-diabetic actions of dietary flavonoids

Flavonoids are polyphenolic compounds that are abundant in fruits and vegetables, and increasing evidence demonstrates a positive relationship between consumption of flavonoid-rich foods and disease prevention. Epidemiological, in vitro and animal studies support the beneficial effects of dietary flavonoids on glucose and lipid homeostasis. It is encouraging that the beneficial effects of some flavonoids are at physiological concentrations and comparable to clinically-used anti-diabetic drugs; however, clinical research in this field and studies on the anti-diabetic effects of flavonoid metabolites are limited. Flavonoids act on various molecular targets and regulate different signaling pathways in pancreatic β-cells, hepatocytes, adipocytes and skeletal myofibers. Flavonoids may exert beneficial effects in diabetes by (i) enhancing insulin secretion and reducing apoptosis and promoting proliferation of pancreatic β-cells; (ii) improving hyperglycemia through regulation of glucose metabolism in hepatocytes; (iii) reducing insulin resistance, inflammation and oxidative stress in muscle and fat and (iv) increasing glucose uptake in skeletal muscle and white adipose tissue. This review highlights recent findings on the anti-diabetic effects of dietary flavonoids, including flavan-3-ols, flavanones, flavonols, anthocyanidins, flavones and isoflavones, with particular emphasis on the studies that investigated the cellular and molecular mechanisms involved in the beneficial effects of the compounds.

Genistein Induces Pancreatic β-Cell Proliferation through Activation of Multiple Signaling Pathways and Prevents Insulin-Deficient Diabetes in Mice

Genistein, a flavonoid in legumes and some herbal medicines, has various biological actions. However, studies on whether genistein has an effect on pancreatic beta-cell function are very limited. In the present study, we investigated the effect of genistein on beta-cell proliferation and cellular signaling related to this effect and further determined its antidiabetic potential in insulin-deficient diabetic mice. Genistein induced both INS1 and human islet beta-cell proliferation after 24 h of incubation, with 5 mum genistein inducing a maximal 27% increase. The effect of genistein on beta-cell proliferation was neither dependent on estrogen receptors nor shared by 17beta-estradiol or a host of structurally related flavonoid compounds. Pharmacological or molecular intervention of protein kinase A (PKA) or ERK1/2 completely abolished genistein-stimulated beta-cell proliferation, suggesting that both molecules are essential for genistein action. Consistent with its effect on cell proliferation, genistein induced cAMP/PKA signaling and subsequent phosphorylation of ERK1/2 in both INS1 cells and human islets. Furthermore, genistein induced protein expression of cyclin D1, a major cell-cycle regulator essential for beta-cell growth. Dietary intake of genistein significantly improved hyperglycemia, glucose tolerance, and blood insulin levels in streptozotocin-induced diabetic mice, concomitant with improved islet beta-cell proliferation, survival, and mass. These results demonstrate that genistein may be a natural antidiabetic agent by directly modulating pancreatic beta-cell function via activation of the cAMP/PKA-dependent ERK1/2 signaling pathway.

Flavonoids influence epigenetic-modifying enzyme activity: structure - function relationships and the therapeutic potential for cancer.

Epigenetic modifications result in heritable changes in gene expression without changes to the DNA sequence. The most common forms of epigenetic regulation of gene expression are DNA methylation and histone acetylation or methylation, all of which are associated with chromatin remodeling. Results from recent studies suggest that epigenetic changes are some of the primary contributory factors of tumor-suppressor gene silencing in cancer cells. Compounds that target epigenetic regulators in the body may represent an attractive target for chemoprevention. Flavonoids are polyphenolic phytochemicals that exert a multitude of beneficial effects on human health. In recent years, isoflavones, flavonols and catechins have received much attention due to their ability to influence activity of chromatin-modifying enzymes. Epigallocatechin-3-gallate, for example, was shown to inhibit activity of histone acetyltransferase and DNA methyltransferase. In this review, we will highlight the structure-function relationship between flavonoids and epigenetic modifications, with an emphasis on the isoflavones, flavonols and catechins, and their potential as anti-cancer agents in this regard.

Epigenetics: the missing link to understanding β-cell dysfunction in the pathogenesis of type 2 diabetes.

Type 2 diabetes (T2D) is a growing health problem worldwide. While peripheral insulin resistance is common during obesity and aging in both animals and people, progression to T2D is largely due to insulin secretory dysfunction and significant apoptosis of functional β-cells, leading to an inability to compensate for insulin resistance. It is recognized that environmental factors and nutrition play an important role in the pathogenesis of diabetes. However, our knowledge surrounding molecular mechanisms by which these factors trigger β-cell dysfunction and diabetes is still limited. Recent discoveries raise the possibility that epigenetic changes in response to environmental stimuli may play an important role in the development of diabetes. In this paper, we review emerging knowledge regarding epigenetic mechanisms that may be involved in β-cell dysfunction and pathogenesis of diabetes, including the role of nutrition, oxidative stress and inflammation. We will mainly focus on the role of DNA methylation and histone modifications but will also briefly review data on miRNA effects on the pancreatic islets. Further studies aimed at better understanding how epigenetic regulation of gene expression controls β-cell function may reveal potential therapeutic targets for prevention and treatment of diabetes.

Dietary Epicatechin Promotes Survival of Obese Diabetic Mice and Drosophila melanogaster

The lifespan of diabetic patients is 7-8 y shorter than that of the general population because of hyperglycemia-induced vascular complications and damage to other organs such as the liver and skeletal muscle. Here, we investigated the effects of epicatechin, one of the major flavonoids in cocoa, on health-promoting effects in obese diabetic (db/db) mice (0.25% in drinking water for 15 wk) and Drosophila melanogaster (0.01-8 mmol/L in diet). Dietary intake of epicatechin promoted survival in the diabetic mice (50% mortality in diabetic control group vs. 8.4% in epicatechin group after 15 wk of treatment), whereas blood pressure, blood glucose, food intake, and body weight gain were not significantly altered. Pathological analysis showed that epicatechin administration reduced the degeneration of aortic vessels and blunted fat deposition and hydropic degeneration in the liver caused by diabetes. Epicatechin treatment caused changes in diabetic mice that are associated with a healthier and longer lifespan, including improved skeletal muscle stress output, reduced systematic inflammation markers and serum LDL cholesterol, increased hepatic antioxidant glutathione concentration and total superoxide dismutase activity, decreased circulating insulin-like growth factor-1 (from 303 ± 21 mg/L in the diabetic control group to 189 ± 21 mg/L in the epicatechin-treated group), and improved AMP-activated protein kinase-α activity in the liver and skeletal muscle. Consistently, epicatechin (0.1-8 mmol/L) also promoted survival and increased mean lifespan of Drosophila. Therefore, epicatechin may be a novel food-derived, antiaging compound.

Development of a Nongenetic Mouse Model of Type 2 Diabetes

Insulin resistance and loss of β-cell mass cause Type 2 diabetes (T2D). The objective of this study was to generate a nongenetic mouse model of T2D. Ninety-six 6-month-old C57BL/6N males were assigned to 1 of 12 groups including (1) low-fat diet (LFD; low-fat control; LFC), (2) LFD with 1 i.p. 40 mg/kg BW streptozotocin (STZ) injection, (3), (4), (5), (6) LFD with 2, 3, 4, or 5 STZ injections on consecutive days, respectively, (7) high-fat diet (HFD), (8) HFD with 1 STZ injection, (9), (10), (11), (12) HFD with 2, 3, 4, or 5 STZ injections on consecutive days, respectively. After 4 weeks, serum insulin levels were reduced in HFD mice administered at least 2 STZ injections as compared with HFC. Glucose tolerance was impaired in mice that consumed HFD and received 2, 3, or 4 injections of STZ. Insulin sensitivity in HFD mice was lower than that of LFD mice, regardless of STZ treatment. Islet mass was not affected by diet but was reduced by 50% in mice that received 3 STZ injections. The combination of HFD and three 40 mg/kg STZ injections induced a model with metabolic characteristics of T2D, including peripheral insulin resistance and reduced β-cell mass.

Genistein Prevents Hyperglycemia-Induced Monocyte Adhesion to Human Aortic Endothelial Cells through Preservation of the cAMP Signaling Pathway and Ameliorates Vascular Inflammation in Obese Diabetic Mice

Hyperglycemia-induced vascular inflammation resulting in the enhanced monocyte-endothelial cell (EC) interaction is the key event in the pathogenesis of atherosclerosis in diabetes. Here, we investigated the effect of isoflavone genistein on hyperglycemia-stimulated vascular inflammation. Human aortic EC (HAEC) were pretreated with genistein before the addition of high glucose (HG; 25 mmol/L) for 48 h. Genistein at a physiological concentration (0.1 μmol/L) significantly inhibited HG-induced adhesion of monocytes to HAEC and suppressed endothelial production of monocyte chemotactic protein-1 (MCP-1) and IL-8. Inhibition of adenylate cyclase or protein kinase A (PKA) significantly attenuated the antiadhesion effect of genistein. Consistently, genistein improved HG-impaired intracellular cAMP production and PKA activity in HAEC. Six-week-old diabetic db/db mice were untreated (db/db) or treated with a diet containing 1 g genistein/kg diet (db/db+G) for 8 wk. Their nondiabetic db/+ mice were used as normal controls. Circulating concentrations of MCP-1/JE and KC were significantly greater, whereas IL-10 concentrations were lower in db/db mice than those in normal mice. Dietary supplementation of genistein did not normalize but significantly suppressed the elevated serum concentrations of MCP-1/JE from 286 ± 30 ng/L to 181 ± 35 ng/L and KC from 321 ± 21 ng/L to 232 ± 20 ng/L while increasing that of IL-10 from 35 ± 4 ng/L to 346 ± 35 ng/L in db/db+G mice. Further, genistein treatment suppressed diabetes-induced adhesion of monocytes to EC by 87% and endothelial secretion of adhesion molecules. We conclude that genistein improves diabetes-caused vascular inflammation, which may be mediated through promoting the cAMP/PKA pathway.

Genistein ameliorates hyperglycemia in a mouse model of nongenetic type 2 diabetes.

While peripheral insulin resistance is common during obesity and aging in mice and people, the progression to type 2 diabetes (T2D) is largely due to loss of β-cell mass and function through apoptosis. We recently reported that genistein, a soy derived isoflavone, can improve glycemic control and β-cell function in insulin-deficient diabetic mice. However, whether it can prevent β-cell loss and diabetes in T2D mice is unknown. Our current study aimed to investigate the effect of dietary supplemented genistein in a nongenetic T2D mouse model. Nongenetic, middle-aged obese diabetic mice were generated by high fat diet and a low dose of streptozotocin injection. The effect of dietary supplementation of genistein on glycemic control and β-cell mass and function was determined. Dietary intake of genistein (250 mg·kg(-1) diet) improved hyperglycemia, glucose tolerance, and blood insulin level in obese diabetic mice, whereas it did not affect body weight gain, food intake, fat deposit, plasma lipid profile, and peripheral insulin sensitivity. Genistein increased the number of insulin-positive β-cell in islets, promoted islet β-cell survival, and preserved islet mass. In conclusion, dietary intake of genistein could prevent T2D via a direct protective action on β-cells without alteration of periphery insulin sensitivity.

Dietary antiaging phytochemicals and mechanisms associated with prolonged survival.

Aging is well-known an inevitable process that is influenced by genetic, lifestyle and environmental factors. However, the exact mechanisms underlying the aging process are not well understood. Increasing evidence shows that aging is highly associated with chronic increase in reactive oxygen species (ROS), accumulation of a low-grade proinflammatory phenotype and reduction in age-related autophagy, suggesting that these factors may play important roles in promoting aging. Indeed, reduction of ROS and low-grade inflammation and promotion of autophagy by calorie restriction or other dietary manipulation can extend lifespan in a wide spectrum of model organisms. Interestingly, recent studies show that some food-derived small molecules, also called phytochemicals, can extend lifespan in various animal species. In this paper, we review several recently identified potential antiaging phytochemicals that have been studied in cells, animals and humans and further highlight the cellular and molecular mechanisms underlying the antiaging actions by these molecules.

Ranolazine Increases β-Cell Survival and Improves Glucose Homeostasis in Low-Dose Streptozotocin-Induced Diabetes in Mice

In addition to its anti-ischemic and antianginal effects, ranolazine has been shown to lower hemoglobin A1c (HbA1c) in patients with coronary artery disease and diabetes. The present study was undertaken to test the hypothesis that ranolazine lowers HbA1c because of improved glucose homeostasis in an animal model. Diabetes in mice was induced by giving multiple low doses of streptozotocin. Ranolazine was given twice daily via an oral gavage (20 mg/kg) for 8 weeks. Fasting plasma glucose levels were significantly lower in the ranolazine-treated group (187 ± 19 mg/dl) compared with the vehicle group (273 ± 23 mg/dl) at 8 weeks. HbA1c was 5.8 ± 0.4% in the vehicle group and 4.5 ± 0.2% in the ranolazine-treated group (p < 0.05). Glucose disposal during the oral glucose tolerance test (OGTT) and insulin tolerance test were not different between the two groups; however, during OGTT, peak insulin levels were significantly (p < 0.05) higher in ranolazine-treated mice. Mice treated with ranolazine had healthier islet morphology and significantly (p < 0.01) higher β-cell mass (69 ± 2% per islet) than the vehicle group (50 ± 5% per islet) as determined from hematoxylin and eosin staining. The number of apoptotic cells was significantly (p < 0.05) less in the pancreas of the ranolazine-treated group (14 ± 2% per islet) compared with the vehicle group (24 ± 4% per islet). In addition, ranolazine increased glucose-stimulated insulin secretion in rat and human islets in a glucose-dependent manner. These data suggest that ranolazine may be a novel antidiabetic agent that causes β-cell preservation and enhances insulin secretion in a glucose-dependent manner in diabetic mice.