Foreword

The global obesity and overweight pandemic that causes the increasing number of patients with type 2 diabetes (T2D) is a major challenge for healthcare systems worldwide. With its cardiovascular complications, this metabolic disorder is one of the major causes of morbidity and mortality worldwide. On top of lifestyle and dietary recommendations to prevent or control T2D, a tremendous amount of research has been invested in understanding disease mechanisms better and developing novel drugs. Even if new pharmaceuticals have entered the clinical arena in recent years, metformin is still the first-line option, even after more than 60 years. This points to the necessity to develop therapeutic strategies based on biological pathways that have not previously been the center focus of diabetes research. Such an area is nitric oxide research.

Nitric oxide (NO) is one of the universal signaling molecules in mammalian species. When discovered in the 1980s, it portrayed a completely novel principle, where a small, unstable, and reactive free radical gas was involved in cell signaling. Its chemical nature makes it react with other radicals and transition metals; one example of the latter is how NO activates soluble guanylyl cyclase to generate cGMP, a classical form of NO signaling that, e.g., induces vasodilation. Binding to heme in cytochrome c oxidase, leading to inhibition of mitochondrial respiration, is another example. In addition, post-translational nitrosation of many proteins, which regulates their function, is another signaling modality of NO. This pluripotency of NO explains why it is involved in regulating such diverse processes as cardiovascular function, metabolism, inflammation, and nerve signaling. The canonical pathway for NO generation involves the substrates L-arginine and molecular oxygen and specific NO synthases (N.O.S.s), of which there are three isoforms. Two of them are more constitutively expressed (endothelial N.O.S. and neuronal N.O.S.), while an inducible isoform (inducible N.O.S.) is involved during inflammatory conditions. The half-life of NO is within seconds due to binding to heme or to rapid oxidation, which forms the inorganic anions nitrite and nitrate that are widely used both in vitro and in vivo as more stable surrogate measures of NO.

Interestingly, discoveries in the mid-1990s revealed that these supposedly inert anions could be recycled back to bioactive NO and other reactive nitrogen species. The first step in this nitrate-nitrate-NO pathway involves active uptake of circulating nitrate in the salivary glands, after which nitrate in the saliva is reduced to nitrite by oral commensal bacteria, a function that mammalian cells are poor in performing. Swallowed salivary nitrite is rapidly absorbed in the gut, and then there are several pathways for further reduction to NO. Of interest is that the nitrate-nitrite-NO pathway can be fueled by a diet where certain vegetables contain high levels of nitrate. This pathway can be viewed as a parallel backup system to the L-arginine-NOS-NO pathway, perhaps with more importance during hypoxic and ischemic conditions.

This book, to my knowledge, is the first of its kind, Asghar Ghasemi and collaborators present a comprehensive and detailed overview of our current knowledge on the role of NO in T2D. The rationale for this book is the growing evidence of the involvement of the NO system in diabetes. An impressive amount of research has clarified that NO is deeply involved on many levels to uphold metabolic homeostasis and that NO signaling is negatively affected in T2D. Of interest is that several of the pharmaceuticals used in T2D affect the NO system and perhaps even more so by the drugs we use to treat diabetic cardiovascular complications. Experimental works in animal models of obesity or T2D show promising results with interventions aimed to increase NO signaling. However, translation into human studies has so far been less successful, but larger and more prolonged studies are clearly needed. There is an intriguing dietary aspect here since NO bioavailability can be boosted by nitrate in our diet, which is supported by epidemiological studies showing that green leafy vegetables, which are high in nitrate, stand out as particularly protective against the development of T2D and cardiovascular disease. Clearly, more research on the role of NO in metabolic regulation and T2D is needed, and in this context, the present book is of great value to anyone interested in this field of research.