James W. Daily

Antidiabetic effects of fermented soybean products on type 2 diabetes

Historically, the incidence of type 2 diabetes has been lower in Asian populations compared with those in Western countries. One possible reason for the lower incidence among Asians is that they consume fermented soybean products, which are unique to the traditional Asian diet. Some have hypothesized that dietary phytoestrogens and soy peptides in fermented soybean foods consumed in traditional Asian diets may help prevent and slow the progression of type 2 diabetes. This review evaluates the existing evidence from animal studies and clinical and epidemiologic investigations on fermented soybeans in the prevention and treatment of type 2 diabetes. Nutritional studies performed in animals and intervention studies with humans suggest that the ingestion of soy protein with isoflavones improves glucose control and reduces insulin resistance. Korean fermented soybean products such as doenjang, kochujang, and chungkookjang contain alterations in the structures and content of isoflavonoids and small bioactive peptides, which are produced during fermentation. Several studies revealed improvements in insulin resistance and insulin secretion with the consumption of these fermented products. Therefore, fermented soybean products may help prevent or attenuate the progression of type 2 diabetes. Although the lack of human intervention trials does not permit definitive conclusions, the evidence does suggest that fermented soy products may be better for preventing or delaying the progression of type 2 diabetes compared with nonfermented soybeans.

A high-fat diet increases angiogenesis, solid tumor growth, and lung metastasis of CT26 colon cancer cells in obesity-resistant BALB/c mice.

We evaluated whether high‐fat diet (HFD), in the absence of increased calorie intake, increases colon cancer growth and metastasis. Four‐week‐old male BALB/c mice were fed on an HFD (60 kcal% fat) or control diet (10 kcal% fat) for 16 wk, after which CT26 colon cancer cells were subcutaneously injected into the right flank. Solid tumor growth and the number and volume of tumor nodules in the lung were increased markedly in the HFD group with only a slight increase in body weight (5.9%). HFD feeding increased tumor tissue levels of Ki67, cyclin A, cyclin D1, CDK2, Bcl‐xL, and Bcl‐2; reduced p53 levels and TUNEL‐positive apoptotic cells; increased the levels of CD45, CD68, CD31, VEGF, P‐VEGF receptor‐2, iNOS, and COX‐2 as well as hemoglobin content; and increased the levels of HIF‐1α, P‐STAT3‐Y705, P‐STAT3‐S727, P‐IκB‐α, P‐p65, p65, P‐c‐Jun, P‐Akt, P‐ERK1/2, P‐p38, and P‐SAPK/JNK. HFD feeding increased the serum levels of EGF, insulin, IGF‐I, IFN‐γ, leptin, RANTES, MCP‐1, IL‐1ra, and SDF‐1α and media conditioned by epididymal fat tissue explants from HFD‐fed mice caused an increase in microvessel outgrowth from the mouse aorta and tube formation of human umbilical vein endothelial cells. These results indicate that the chronic consumption of an HFD increases colon cancer cell proliferation, tumor angiogenesis, and lung metastasis in mice in the absence of discernible weight gain. HFD feeding increases the levels of growth factors which activate transcription factors, thereby inducing the expression of many genes involved in the stimulation of inflammation, angiogenesis, and cellular proliferation.

Anesthetics and cardiocentesis increase urinary carnitine excretion in rats and guinea pigs

Our interest in carnitine homeostasis lead us to determine effects of several commonly used anesthetics and blood sampling procedures on serum and urinary carnitine concentrations. Serum and urine samples were collected from male rats and guinea pigs prior to and after anesthesia with and without cardiocentesis and assayed for carnitine and acylcarnitine. Methoxyflurane alone increased urinary carnitine excretion in guinea pigs but not in rats. Methoxyflurane plus cardiocentesis increased urinary carnitine and acylcarnitine in both species, and isoflurane mimicked methoxyflurane in rats. Cardiocentesis with phenobarbital or pentobarbital increased carnitine and acylcarnitine in serum but not in urine. Ketamine plus acepromazine increased total carnitine only in the serum of rats. A combination of ketamine and xylazine increased serum carnitine and urinary acylcarnitine. It is concluded that anesthesia and cardiocentesis increased serum and urinary carnitine and acylcarnitines differently depending on the species and the anesthetic administered.

Low gestational weight gain improves infant and maternal pregnancy outcomes in overweight and obese Korean women with gestational diabetes mellitus.

Objective. The aim of the study was to retrospectively assess what was the optimal gestational weight gain to have better maternal and neonatal outcomes in overweight and obese Korean women with gestational diabetes mellitus (GDM) who maintained normoglycemia throughout pregnancy by dietary modification, exercise, and/or insulin treatment. Study design. We performed a hospital-based study of 215 GDM women with prepregnancy BMI ≥ 25 kg/m2. Body weight, glucose homeostasis, lipid profiles, insulin treatment, and maternal outcomes were collected as predictors of neonatal birth weight. We divided the subjects into three groups according to modified Institute of Medicine (IOM) guidelines for weight gain during pregnancy: inadequate (n = 42), normal (n = 96), and excessive (n = 77) groups. Results. Excessive weight gain resulted in increased macrosomia, HbA1c at delivery, and postprandial blood glucose levels, but fasting blood glucose levels were not significantly different among the groups. The inadequate weight gain group (2.4 kg weight gain during pregnancy) had better neonatal outcomes and better maternal glycemic control with fewer requiring insulin treatment. Conclusion. Minimal weight gain, well below IOM recommendations, and tight control of blood glucose levels during pregnancy with proper medical management and dietary modification may eliminate most of the adverse pregnancy outcomes experienced by obese GDM Asian women.

Serum prolactin concentrations determine whether they improve or impair β-cell function and insulin sensitivity in diabetic rats

Prolactin improves glucose homeostasis by increasing β‐cell mass under certain conditions such as pregnancy, whereas hyperprolactinaemia due to a pituitary gland adenoma tumour exacerbates insulin resistance. However, previous studies have not evaluated how prolactin modulates β‐cell function and insulin sensitivity at different dosages. Here, we determined that chronic intraperitoneal injections of different dosages of prolactin have opposite effects on insulin resistance and β‐cell function and mass in 90% pancreatectomized diabetic male rats, and the mechanisms were explored.

Choline supplementation increases tissue concentrations of carnitine and lowers body fat in guinea pigs

Abstract It has been documented that choline supplementation results in urinary conservation of carnitine in both humans and guinea pigs. This conservation in guinea pigs is associated with increased concentrations of carnitine in skeletal muscle for which no functional consequences have been reported. The objective of this study was to evaluate changes in fat metabolism and body composition as a consequence of the increased tissue carnitine in choline-supplemented guinea pigs. Guinea pigs were given free access to commercial diet without or with 3 g choline/kg diet. Using indirect calorimetry, the respiratory exchange ratios (RER) of the animals were determined under normal, exercise, and unfed conditions. There were no differences in RER between supplemented and nonsupplemented groups under any of the conditions. The RER data lead to the conclusion that choline–carnitine did not promote oxidation of fat over carbohydrates for energy. However, proximate analysis of carcass revealed significantly lower total body fat and higher body proteins in the choline-supplemented animals compared with the nonsupplemented animals. These apparently contradictory results are explained by the hypothesis that the acetates generated by the β-oxidation of fatty acids are transferred to carnitine and not oxidized to carbon dioxide, resulting in little or no shift in RER.

Central infusion of ketone bodies modulates body weight and hepatic insulin sensitivity by modifying hypothalamic leptin and insulin signaling pathways in type 2 diabetic rats.

Although the effects of ketogenic diets on energy and glucose homeostasis have been controversial, elevation of serum ketone levels by subcutaneous injection of β-hydroxybutyrate (BHB) can improve glucose homeostasis. Ketones may work through the brain; therefore, we evaluated whether the intracerebroventricular (ICV) infusion of β-hydroxybutyrates would also modulate peripheral energy and glucose homeostasis, and through what mechanisms, in diabetic rats fed a high fat diet in short- and long-term studies. Short-term (3h) central injection of BHB (50 μg/h) improved serum glucose levels and peripheral insulin sensitivity compared to the artificial cerebrospinal fluid (CSF) group among 90% pancreatectomized (Px) diabetic rats, but not in non-diabetic Sham rats. In addition to short-term infusion, long-term (28 days) central infusion of BHB (12 μg/h) elevated serum BHB levels. Long-term infusion of BHB potentiated leptin and insulin signaling in the hypothalamus to slightly decrease body weight in Px rats. Central BHB infusion had a greater effect on peripheral glucose metabolism than overall energy metabolism. Hepatic insulin signaling (tyrosine phosphorylation of IRS2→serine phosphorylation of Akt→reduced expression of PEPCK) was potentiated and hepatic glucose production in the hyperinsulinemic state was suppressed in the diabetic rats. In addition, glucose tolerance was improved by central BHB infusion through enhanced whole body glucose disposal rates, but insulin secretion was not affected in the diabetic rats. In conclusion, mild ketosis by central infusion of ketones improves energy and glucose metabolism through the potentiation of leptin and insulin signaling in the hypothalamus of diabetic rats.

Leptin: Making It Live Up to Its Promise Using Natural Products

Leptin was discovered in 1994 as the missing factor causing morbid obesity in ob/ob mice. 1 It was quickly recognized to be the most important regulator of energy stores in the body, and there was much excitement about its promise to be the ‘‘magic bullet’’ for obesity. However, it was soon recognized that most obese people have very high leptin levels, that leptin resistance is a critical component of most cases of obesity, and that it cannot be overcome by giving leptin. Therefore, much subsequent research has been dedicated to overcoming leptin resistance, but thus far there has been little success in humans in either treating obesity with leptin or finding strategies for reversing leptin resistance. The research presented in this issue of the Journal of Medicinal Food by Choi et al. demonstrates a very promising approach to the problem of obesity by modulating leptin metabolism. Food consumption can become dysregulated either by inadequate leptin secretion or by leptin resistance due to impaired leptin signaling in the hypothalamus. The potentiation of leptin signaling enhances the regulation of energy homeostasis. These authors used two natural compounds available from herbal preparations in combination to increase the endogenous secretion of leptin and to inhibit protein tyrosine phosphatase 1B, which is best known as a negative regulator of insulin signaling but also attenuates leptin signaling, resulting in leptin resistance. Because not only leptin resistance, but also insulin resistance, is an important contributor to the pathophysiology of obesity, this is an especially elegant approach as it uses one natural product that increases both insulin and leptin sensitivity and another that is a leptin secretagogue. The effectiveness of these substances remains to be demonstrated in obese humans, but even if they prove ineffective, this approach to treating human obesity should serve as a model for future studies.

A ketogenic diet impairs energy and glucose homeostasis by the attenuation of hypothalamic leptin signaling and hepatic insulin signaling in a rat model of non-obese type 2 diabetes

Ketogenic diets (KTD) are reported to have beneficial effects on the regulation of energy and glucose homeostasis, but remain controversial. We investigated the effects of KTD and ketones on insulin resistance and secretion in non-obese type 2 diabetic rats and their mechanism. KTD (82% energy as fat), intraperitoneal injection of β-hydroxybutyrate (IHB; 150 mg/kg bw/12 h) with a control diet (COD; 20% energy as fat) or saline injection with COD was given to 90% pancreatectomized (Px) diabetic rats for five weeks. KTD increased epididymal fat pads and serum leptin levels without increasing energy intake, but IHB decreased them. KTD, but not IHB, attenuated hypothalamic signal transducer and activator of transcription 3 and 5′-adenosine monophosphate-activated protein kinase (AMPK) phosphorylation in KTD. Serum glucagon levels were markedly higher in the KTD group than in other groups. During an oral glucose tolerance test, serum glucose levels slowly increased until 80 min in the KTD group and then decreased very slowly. Insulin secretion capacity during a hyperglycemic clamp was significantly lower in the IHB group than in other groups. However, a euglycemic hyperinsulinemic clamp revealed that KTD decreased glucose infusion rates and increased hepatic glucose output in hyperinsulinemic states while IHB had opposite effects to KTD. The increased hepatic glucose output in KTD was associated with increased hepatic phosphoenolpyruvate carboxykinase expression through attenuated tyrosine phosphorylation of IRS2 and phosphorylation of AktSer473. Hepatic AMPKThr172 phosphorylation was reduced in KTD. In conclusion, KTD impairs energy and glucose homeostasis by exacerbating insulin resistance and attenuating hypothalamic leptin signaling in non-obese type 2 diabetic rats. These changes are not associated with increased serum ketone levels.

Standardized chungkookjang, short-term fermented soybeans with Bacillus lichemiformis, improves glucose homeostasis as much as traditionally made chungkookjang in diabetic rats

As the traditional homemade chungkookjang is replaced by standardized chungkookjang fermented by inoculating Bacillus spp., it is desirable to maintain the anti-diabetic efficacy of the most potent traditional varieties. Preliminary in vitro research suggested that anti-diabetic efficacy can be achieved by using B. lichemiformis as a starter and fermenting for 48 h. Experimental type 2 diabetic male rats induced by partial pancreatectomy and high fat diets were administered either control diet, 10% cooked soybeans, 10% traditional chungkookjang with potent anti-diabetic efficacy, or standardized chungkookjang fermented with B. lichemiformis for 48 h. Rats were fed their respective diets for 8 weeks after surgery. Cooked soybeans as well as both chungkookjangs partially restored fasting serum glucose concentrations, but only the chungkoojangs increased fasting insulin levels. That trend was also seen in the glucose-stimulated insulin secretion during hyperglycemic clamp and was explained by the greater β-cell mass and BrdU incorporation indicating increased proliferation of β-cells. The euglycemic hyperinsulinemic clamp indicated that all soy products improved insulin sensitivity. Phosphorylation of Akt and AMPK in the liver increased in an ascending order of the control, cooked soybeans, traditional chungkookjang and standardized chungkookjang while PEPCK expression was lowered in a descending order of the control, cooked soybeans, traditional chungkookjang and standardized chungkookjang. These results indicate that standardized chungkookjang is most effective for improving hepatic insulin signaling. In conclusion, chungkookjang fermented with B. lichemiformis retains the anti-diabetic properties of the most efficacious traditional chungkookjang and it may be even more effective for improving insulin function than traditionally prepared chungkookjang.