Undernutrition is still a recurring nutritional problem in low and middle-income countries. It is directly associated with the social and economic sphere, but it can also negatively impact the health of the population. In this sense, it is believed that undernourished individuals may be more susceptible to the development of non-communicable diseases, such as diabetes mellitus, throughout life. This hypothesis was postulated and confirmed until today by several studies that demonstrate that experimental models submitted to protein undernutrition present alterations in glycemic homeostasis linked, in part, to the reduction of insulin secretion. Therefore, understanding the changes that lead to a reduction in the secretion of this hormone is essential to prevent the development of diabetes in undernourished individuals. This narrative review aims to describe the main molecular changes already characterized in pancreatic β cells that will contribute to the reduction of insulin secretion in protein undernutrition. So, it will provide new perspectives and targets for postulation and action of therapeutic strategies to improve glycemic homeostasis during this nutritional deficiency.

Electrical mechanosensing is a process mediated by specialized ion channels, gated directly or indirectly by mechanical forces, which allows cells to detect and subsequently respond to mechanical stimuli. The activation of mechanosensitive (MS) ion channels, intrinsically gated by mechanical forces, or mechanoresponsive (MR) ion channels, indirectly gated by mechanical forces, results in electrical signaling across lipid bilayers, such as the plasma membrane. While the functions of mechanically gated channels within a sensory context (e.g., proprioception and touch) are well described, there is emerging data demonstrating functions beyond touch and proprioception, including mechanoregulation of intracellular signaling and cellular/systemic metabolism. Both MR and MS ion channel signaling have been shown to contribute to the regulation of metabolic dysfunction, including obesity, insulin resistance, impaired insulin secretion, and inflammation. This review summarizes our current understanding of the contributions of several MS/MR ion channels in cell types implicated in metabolic dysfunction, namely, adipocytes, pancreatic β-cells, hepatocytes, and skeletal muscle cells, and discusses MS/MR ion channels as possible therapeutic targets. © 2024 American Physiological Society. Compr Physiol 14:5269-5290, 2024.

We compared the impact of 2 lifestyle modifying physical activities, yoga (YBLM) or walking (WBLM) on impaired beta cell function (IBF) or insulin resistance (IR) in restoring acute phase insulin release (APIR) among prediabetes at high risk for type 2 diabetes (HRDM).

Male and female adults (N = 42, 38.1 ± 4.8 years) with abdominal obesity (Male:103 ± 8.1 cm) Female: 92 ± 11.1 cm), randomized into YBLM (n = 20) and WBLM (n = 22), were monitored for the practice of the intervention, 45 min a day/5 days a week for 12 weeks. Blood sample was collected at 0th minute to estimate the level of Fasting Blood Glucose (FBG), Sr. Insulin and lipid profile and at 10th minute (APIR). IBF, IR and sensitivity (IS) reading were checked in HOMA-2 calculator.

Wilcoxon sign rank t-test denoted an improved APIR among the subjects with IBF (p = 0.008) and not among the subjects with IR (p = 0.332). However, regression analysis yielded an improved APIR among subjects with IBF (F(1,10) = 7.816, p = 0.002) with the management of body weight and lipid profile and IR (F(1,13) = 17.003, p = 0.001) being found influenced with selected lipid components. In all, during the post assessment period, an impressive boost in APIR was manifested among people shifted to Normoglycemia (n = 14, 35.9%).

Intriguingly, we postulate the potential role of YBLM over WBLM in the management of lipid profile and body weight on accelerating APIR either through improved Beta cell compensation or by sensitizing skeletal muscles regulating IR, helping improve glucose tolerance resulting in either remission or management of prediabetes.

Lipotoxicity is a significant element in the development of type 2 diabetes mellitus (T2DM). Since pro-diabetic nutritional patterns are associated with hyperglycemia as well as hyperlipidemia, the study analyzes the effects of combining these lipid and carbohydrate components with a special focus on the structural fatty acid properties such as increasing chain length (C16-C20) and degree of saturation with regard to the role of glucolipotoxicity in human EndoC-βH1 β-cells.

β-cell death induced by saturated FFAs is potentiated by high concentrations of glucose in a chain length-dependent manner starting with stearic acid (C18:0), whereas toxicity remains unchanged in the case of monounsaturated FFAs. Interference with FFA desaturation by overexpression and inhibition of stearoyl-CoA-desaturase, which catalyzes the rate-limiting step in the conversion of long-chain saturated into corresponding monounsaturated FFAs, does not affect the potentiating effect of glucose, but FFA desaturation reduces lipotoxicity and plays an important role in the formation of lipid droplets. Crucial elements underlying glucolipotoxicity are ER stress induction and cardiolipin peroxidation in the mitochondria.

In the context of nutrition, the data emphasize the importance of the lipid component in glucolipotoxicity related to the development of β-cell dysfunction and death in the manifestation of T2DM.

Elevated plasma concentrations of saturated free fatty acids (SFAs) are involved in pancreatic β-cell dysfunction and apoptosis, referred to as lipotoxicity. However, in contrast to apoptosis, the involvement of ferroptosis, as a distinct type of oxidative regulated cell death in β-cell lipotoxicity remains elusive. Therefore, the aim of this study was to determine the effects of various free fatty acids on ferroptosis induction in rat insulin-producing β-cells. Herein, rat insulin-producing β-cells underwent lipid peroxidation in the presence of long-chain SFAs and ω-6-polyunsaturated fatty acids (PUFAs), but only the latter induced ferroptosis. On the other hand, ω-3-polyunsaturated fatty acid α-linolenate did not induce ferroptosis but sensitized insulin-producing β-cells to SFA-mediated lipid peroxidation. While the monounsaturated fatty acid oleate, overexpression of glutathione peroxidase 4 (GPx4), and the specific ferroptosis inhibitor ferrostatin-1 significantly abrogated lipid peroxidation, neither GPx4 nor ferrostatin-1 affected palmitate-mediated toxicity. Site-specific expression of catalase in cytosol, mitochondria, and ER attenuated lipid peroxidation, indicating the contribution of metabolically generated H₂O₂ from all three subcellular compartments. These observations suggest that only ω-6-PUFAs reach the thresholds of lipid peroxidation required for ferroptosis, whereas SFAs favour apoptosis in β-cells. Hence, avoiding an excessive dietary intake of ω-6-PUFAs might be a crucial prerequisite for prevention of reactive oxygen species-mediated ferroptosis in insulin-producing cells.

The toxic potential of H₂O₂ is limited, even if intracellular concentrations of H₂O₂ under conditions of oxidative stress increase to the micromolar concentration range. Its toxicity is mostly restricted to the oxidation of highly reactive thiol groups, some of which are functionally very important. Subsequently, the HO^· radical is generated spontaneously from H₂O₂ in the Fenton reaction. The HO^· radical is extremely toxic and destroys any biological structure. Due to the high reactivity, its action is limited to a locally restricted site of its generation. On the other hand, H₂O₂ with its stability and long half-life can reach virtually any site and distribute its toxic effect all over the cell. Thereby HO^·, in spite of its ultra-short half-life (10^-9 s), can execute its extraordinary toxic action at any target of the cell. In this oxidative stress scenario, H₂O₂ is the pro-radical, that spreads the toxic action of the HO^· radical. It is the longevity of the H₂O₂ molecule allowing it to distribute its toxic action from the site of origin all over the cell and may even mediate intercellular communication. Thus, H₂O₂ acts as a spreader by transporting it to sites where the extremely short-lived toxic HO^· radical can arise in the presence of "free iron". H₂O₂ and HO^· act in concert due to their different complementary chemical properties. They are dependent upon each other while executing the toxic effects in oxidative stress under diabetic metabolic conditions in particular in the highly vulnerable pancreatic beta cell, which in contrast to many other cell types is so badly protected against oxidative stress due to its extremely low H₂O₂ inactivating enzyme capacity.

Hydrogen peroxide (H2O2) is the most abundant reactive oxygen species (ROS) within mammalian cells. At low concentrations, H2O2 serves as a versatile cell signaling molecule that mediates vital physiological functions. Yet at higher concentrations, H2O2 can be a toxic molecule by promoting pathological oxidative stress in cells and tissues. Within normal cells, H2O2 is differentially distributed in a variety of subcellular locales. Moreover, many redox-active enzymes and their substrates are themselves differentially distributed within cells. Numerous reports have described the biological and biochemical consequences of adding exogenous H2O2 to cultured cells and tissues, but many of these observations are difficult to interpret: the effects of exogenous H2O2 do not necessarily replicate the cellular responses to endogenous H2O2. In recent years, chemogenetic approaches have been developed to dynamically regulate the abundance of H2O2 in specific subcellular locales. Chemogenetic approaches have been applied in multiple experimental systems, ranging from in vitro studies on the intracellular transport and metabolism of H2O2, all the way to in vivo studies that generate oxidative stress in specific organs in living animals. These chemogenetic approaches have exploited a yeast-derived d-amino acid oxidase (DAAO) that synthesizes H2O2 only in the presence of its d-amino acid substrate. DAAO can be targeted to various subcellular locales, and can be dynamically activated by the addition or withdrawal of its d-amino acid substrate. In addition, recent advances in the development of highly sensitive genetically encoded H2O2 biosensors are providing a better understanding of both physiological and pathological oxidative pathways. This review highlights several applications of DAAO as a chemogenetic tool across a wide range of biological systems, from analyses of subcellular H2O2 metabolism in cells to the development of new disease models caused by oxidative stress in vivo.

Aquaporin-8 (AQP8) is a peroxiporin, a transmembrane water and hydrogen peroxide (H₂O₂) transport protein expressed in the mitochondrial and plasma membranes of pancreatic β-cells. AQP8 protein expression is low under physiological conditions, but it increases after cytokine exposure both, in vitro and in vivo, possibly related to a NF-κB consensus sequence in the promoter. AQP8 knockdown (KD) insulin-producing RINm5F cells are particularly susceptible to cytokine-mediated oxidative stress. Cytokine (a mixture of IL-1β, TNF-α, and IFN-γ) treated AQP8 KD cells exhibited pronounced sensitivity to reactive oxygen and nitrogen species (ROS and RNS), resulting in a significant loss of β-cell viability due to enhanced toxicity of the increased concentrations of H₂O₂ and hydroxyl radicals (^●OH) in mitochondria of AQP8 KD cells. This viability loss went along with increased caspase activities, reduced nitrite concentration (representative of nitric oxide (NO^●) accumulation) and increased lipid peroxidation. The explanation for the increased toxicity of the proinflammatory cytokines in AQP8 KD cells resides in the fact that efflux of the H₂O₂ generated during oxidative stress in the β-cell mitochondria is hampered through the loss of the peroxiporin channels in the mitochondrial membranes of the AQP8 KD cells. The increased proinflammatory cytokine toxicity due to loss of AQP8 expression in the KD β-cell mitochondria is thus the result of increased rates of apoptosis. This decreased cell viability is caused by increased levels of oxidative stress along with a ferroptosis-mediated cell death component due to decreased NO^● generation.