Current Diabetes Reviews - Volume 11, Issue 1, 2015

Pancreatic β-cells secrete insulin when blood glucose levels become high. However, when β-cells are chronically exposed to hyperglycemia, their function gradually deteriorates. Although such phenomena are called as β-cell glucose toxicity, its molecular mechanism remained unclear. This manuscript describes the possible mechanism for such β-cell dysfunction. In the diabetic state, nuclear expression levels of pancreatic transcription factors PDX-1 and MafA are decreased. In addition, incretin receptor expression in β- cells is decreased, which is likely involved in the impairment of incretin effects in diabetes. Taken together, it is likely that down-regulation of pancreatic transcription factors and/or incretin receptors are involved in β-cell dysfunction observed in type 2 diabetes.

The objective of this paper is to review the evidence testing the possible benefit of vitamin D replacement on diabetes control and complications. Type 2 diabetes mellitus (DM 2) has become a significant global health care problem and its reported incidence is increasing at an alarming rate. Despite the improvement in therapy and development of new drugs, treatment is still not optimal especially with the associated adverse effects of most of the available drugs. New efforts are shifted toward disease prevention and a search for safer drugs. New mounting evidence is associating low vitamin D to diabetes mellitus and as such many studies were conducted to test the effect of vitamin D replacement on incidence of diabetes, diabetes control as well as diabetes complications. Although these studies present several limitations, vitamin D replacement seems to have beneficial effect on all aspects of diabetes: incidence, control and complications. Further longer term and more powered controlled trials are necessary to draw firmer conclusions on this beneficial role of vitamin D treatment on DM.

The global burden of type 2 diabetes is increasing worldwide, and successful treatment of this disease needs constant provision of new drugs. Twelve classes of antidiabetic drugs are currently available, and many new drugs are under clinical development. These include compounds with known mechanisms of action but unique properties, such as once-weekly DPP4 inhibitors or oral insulin. They also include drugs with new mechanisms of action, the focus of this review. Most of these compounds are in Phase 1 and 2, with only a small number having made it to Phase 3 at this time. The new drug classes described include PPAR agonists/modulators, glucokinase activators, glucagon receptor antagonists, anti-inflammatory compounds, G-protein coupled receptor agonists, gastrointestinal peptide agonists other than GLP-1, apical sodium-dependent bile acid transporter (ASBT) inhibitors, SGLT1 and dual SGLT1/SGLT2 inhibitors, and 11beta- HSD1 inhibitors.

There is a close association of chronic tissue damage, inflammation and cancer. A chronic injury may contribute to sustained healing response leading to fibrosis, organ failure and carcinogenesis. Wounds created due to mechanical or patho-physiological insults, generally follow a sophisticated series of mutually coherent steps leading to the re-establishment of the affected tissue or organ. The process of wound healing resembles fundamental processes like embryogenesis and tissue regeneration. All the stages in the wound healing process are tightly regulated and any sort of imbalance may lead to either non healing chronic ulcers or excessively healed hypertrophic scars. Diabetic wounds are also very tough to heal and in many cases they do not heal, ultimately resulting in the amputation of that body part. The non-healing property of diabetic wounds may be due to combined effect of intrinsic and extrinsic factors. In this review, we aimed to explore the steps involved in diabetic wound healing and compare it with the process of carcinogenesis. This review demonstrates that both carcinogenesis and the diabetic wound healing follow a similar path of latent healing in an abnormal exaggerated manner.

Milk, the secretory product of the lactation genome, promotes growth of the newborn mammal. Milk delivers insulinotropic amino acids, thus maintains a molecular crosstalk with the pancreatic β-cell of the milk recipient. Homeostasis of β-cells and insulin production depend on the appropriate magnitude of mTORC1 signaling. mTORC1 is activated by branched-chain amino acids (BCAAs), glutamine, and palmitic acid, abundant nutrient signals of cow´s milk. Furthermore, milk delivers bioactive exosomal microRNAs. After milk consumption, bovine microRNA-29b, a member of the diabetogenic microRNA-29- family, reaches the systemic circulation and the cells of the milk consumer. MicroRNA-29b downregulates branchedchain α-ketoacid dehydrogenase, a potential explanation for increased BCAA serum levels, the metabolic signature of insulin resistance and type 2 diabetes mellitus (T2DM). In non-obese diabetic mice, microRNA-29b downregulates the antiapoptotic protein Mcl-1, which leads to early β-cell death. In all mammals except Neolithic humans, milk-driven mTORC1 signaling is physiologically restricted to the postnatal period. In contrast, chronic hyperactivated mTORC1 signaling has been associated with the development of age-related diseases of civilization including T2DM. Notably, chronic hyperactivation of mTORC1 enhances endoplasmic reticulum stress that promotes apoptosis. In fact, hyperactivated β-cell mTORC1 signaling induced early β-cell apoptosis in a mouse model. The EPIC-InterAct Study demonstrated an association between milk consumption and T2DM in France, Italy, United Kingdom, Germany, and Sweden. In contrast, fermented milk products and cheese exhibit an inverse correlation. Since the early 1950´s, refrigeration technology allowed widespread consumption of fresh pasteurized milk, which facilitates daily intake of bioactive bovine microRNAs. Persistent uptake of cow´s milk-derived microRNAs apparently transfers an overlooked epigenetic diabetogenic program that should not reach the human food chain.