ROMK inward-rectifier K ⁺ channels control renal K ⁺ secretion. The activity of ROMK is regulated by protein kinase A (PKA), but the molecular mechanism for regulation is unknown. Having found that direct interaction with membrane phosphatidylinositol 4,5-bisphosphate (PIP ₂ ) is essential for channel activation, we investigate here the role of PIP ₂ in regulation of ROMK1 by PKA. By using adenosine-5′-[γ-thio]triphosphate) (ATP[γS]) as the substrate, we found that PKA does not directly activate ROMK1 channels in membranes that are devoid of PIP ₂ . Rather, phosphorylation by PKA + ATP[γS] lowers the concentration of PIP ₂ necessary for activation of the channels. In solution-binding assays, anti-PIP ₂ antibodies bind PIP ₂ and prevent PIP ₂ –channel interaction. In inside-out membrane patches, antibodies inhibit the activity of the channels. PKA treatment then decreases the sensitivity of ROMK1 for inhibition by the antibodies, indicating an enhanced interaction between PIP ₂ and the phosphorylated channels. Conversely, mutation of the PKA phosphorylation sites in ROMK1 decreases PIP ₂ interaction with the channels. Thus, PKA activates ROMK1 channels by enhancing PIP ₂ –channel interaction.

Nicotinamide overload may play a role in the development of type 2 diabetes

Over the past few decades, food fortification and infant formula supplementation with high levels of vitamins have led to a sharp increase in vitamin intake among infants, children and adults. This is followed by a sharp increase in the prevalence of obesity and related diseases, with significant disparities among countries and different groups within a country. It has long been known that B vitamins at doses below their toxicity threshold strongly promote body fat gain. Studies have demonstrated that formulas, which have very high levels of vitamins, significantly promote infant weight gain, especially fat mass gain, a known risk factor for children developing obesity. Furthermore, ecological studies have shown that increased B vitamin consumption is strongly correlated with the prevalence of obesity and diabetes. We therefore hypothesize that excess vitamins may play a causal role in the increased prevalence of obesity. This review will discuss: (1) the causes of increased vitamin intake; (2) the non-monotonic effect of excess vitamin intake on weight and fat gain; and (3) the role of vitamin fortification in obesity disparities among countries and different groups within a country.

Ecological evidence suggests that niacin (nicotinamide and nicotinic acid) fortification may be involved in the increased prevalence of obesity and type 2 diabetes, both of which are associated with insulin resistance and epigenetic changes. The purpose of the present study was to investigate nicotinamide-induced metabolic changes and their relationship with possible epigenetic changes. Male rats (5 weeks old) were fed with a basal diet (control group) or diets supplemented with 1 or 4 g/kg of nicotinamide for 8 weeks. Low-dose nicotinamide exposure increased weight gain, but high-dose one did not. The nicotinamide-treated rats had higher hepatic and renal levels of 8-hydroxy-2′-deoxyguanosine, a marker of DNA damage, and impaired glucose tolerance and insulin sensitivity when compared with the control rats. Nicotinamide supplementation increased the plasma levels of nicotinamide,N¹-methylnicotinamide and choline and decreased the levels of betaine, which is associated with a decrease in global hepatic DNA methylation and uracil content in DNA. Nicotinamide had gene-specific effects on the methylation of CpG sites within the promoters and the expression of hepatic genes tested that are responsible for methyl transfer reactions (nicotinamideN-methyltransferase and DNA methyltransferase 1), for homocysteine metabolism (betaine–homocysteineS-methyltransferase, methionine synthase and cystathionine β-synthase) and for oxidative defence (catalase and tumour protein p53). It is concluded that nicotinamide-induced oxidative tissue injury, insulin resistance and disturbed methyl metabolism can lead to epigenetic changes. The present study suggests that long-term high nicotinamide intake (e.g. induced by niacin fortification) may be a risk factor for methylation- and insulin resistance-related metabolic abnormalities.

The global increased prevalence of obesity and diabetes occurred after the worldwide spread of B-vitamins fortification, in which whether long-term exposure to high level of B vitamins plays a role is unknown. Our aim was to examine the relationships between B-vitamins consumption and the obesity and diabetes prevalence.

The body’s total antioxidant capacity represents a sum of the antioxidant capacity of various tissues/organs. A decrease in the body’s antioxidant capacity may induce oxidative stress and subsequent metabolic syndrome, a clustering of risk factors for type 2 diabetes and cardiovascular disease. The skin, the largest organ of the body, is one of the major components of the body’s total antioxidant defense system, primarily through its xenobiotic/drug biotransformation system, reactive oxygen species-scavenging system, and sweat glands- and sebaceous glands-mediated excretion system. Notably, unlike other contributors, the skin contribution is variable, depending on lifestyles and ambient temperature or seasonal variations. Emerging evidence suggests that decreased skin’s antioxidant and excretory functions (e.g., due to sedentary lifestyles and low ambient temperature) may increase the risk for metabolic syndrome. This review focuses on the relationship between the variability of skin-mediated detoxification and elimination of exogenous and endogenous toxic substances and the development of metabolic syndrome. The potential role of sebum secretion in lipid and cholesterol homeostasis and its impact on metabolic syndrome, and the association between skin disorders (acanthosis nigricans, acne, and burn) and metabolic syndrome are also discussed.