Natural killer cell-derived exosomal miR-1249-3p attenuates insulin resistance and inflammation in mouse models of type 2 diabetes

Natural killer (NK) cells have been suggested to be associated with type 2 diabetes by regulating systemic inflammation. However, the mechanism by which NK cells regulate insulin sensitivity remains unknown. This study shows that NK-derived exosomes from lean mice attenuate obesity-induced insulin resistance and inflammation in mice of type 2 diabetes. Moreover, lean NK-derived exosomes enhance insulin sensitivity and relieve inflammation in adipocytes and hepatocytes. MiR-1249-3p, which is significantly upregulated in lean NK-derived exosomes, can be transferred from NK cells to adipocytes and hepatocytes via exosomes. NK-derived exosomal miR-1249-3p dramatically induces cellular insulin sensitivity and relieves inflammation. Mechanistically, exosomal miR-1249-3p directly targets SKOR1 to regulate the formation of ternary complex SMAD6/MYD88/SMURF1, which mediates glucose homeostasis by suppressing the TLR4/NF-κB signaling pathway. This study reveals an emerging role for NK-derived exosomal miR-1249-3p in remission of insulin resistance, and provides a series of potential therapeutic targets in type 2 diabetes.

A Novel PTP1B Inhibitor-Phosphate of Polymannuronic Acid Ameliorates Insulin Resistance by Regulating IRS-1/Akt Signaling

Protein tyrosine phosphatase 1B (PTP1B) is a critical negative modulator of insulin signaling and has attracted considerable attention in treating type 2 diabetes mellitus (T2DM). Low-molecular-weight polymannuronic acid phosphate (LPMP) was found to be a selective PTP1B inhibitor with an IC50 of 1.02 ± 0.17 μM. Cellular glucose consumption was significantly elevated in insulin-resistant HepG2 cells after LPMP treatment. LPMP could alleviate oxidative stress and endoplasmic reticulum stress, which are associated with the development of insulin resistance. Western blot and polymerase chain reaction (PCR) analysis demonstrated that LPMP could enhance insulin sensitivity through the PTP1B/IRS/Akt transduction pathway. Furthermore, animal study confirmed that LPMP could decrease blood glucose, alleviate insulin resistance, and exert hepatoprotective effects in diabetic mice. Taken together, LPMP can effectively inhibit insulin resistance and has high potential as an anti-diabetic drug candidate to be further developed.

355 Mineral Metabolism

This presentation will highlight historic discoveries in mineral metabolism in ruminants. At least 15 minerals can be classified as essential based on their involvement in one or more metabolic functions in mammals. Deficiencies of all essential minerals have occurred naturally or have been induced experimentally in ruminants. Cobalt was shown to be essential for ruminants in 1935 based on its ability to correct naturally occurring deficiency signs in Australia. This discovery occurred 13 years before cobalt was shown to a component of vitamin B12. Low serum magnesium concentrations also were associated with grass tetany in cattle before magnesium was found to be essential for the rat in 1931. The value of supplemental salt for cattle was demonstrated in the 1800’s and a salt deficiency was experimentally induced in dairy cows in 1905. Over 50 years later sodium was identified as the mineral primarily responsible for salt deficiency. Naturally occurring deficiencies of phosphorus and copper were observed in grazing ruminants shortly after they were reported to be essential for rats. Copper toxicosis also became recognized as a practical problem, especially in some breeds of sheep. Selenium was shown to prevent white muscle disease in 1958. Because of its known toxicity and lack of a specific metabolic function, it was not until 1979 that Food and Drug Administration approved the addition of 0.1 mg Se/kg DM (later increased to 0.3 mg/kg) from inorganic sources to ruminant diets. This approval occurred after the identification of glutathione peroxidase as a selenium metalloenzyme in 1972. In 2009, the Food and Drug Administration approved the use of chromium propionate as a source of supplemental chromium for cattle at levels up to 0.5 mg Cr/kg DM. The approval of chromium propionate was based on its safety and ability to enhance insulin sensitivity in cattle.

Association between Dietary Pattern and Insulin Resistance

The current evidence supports the fact that obesity is directly involved in a significant correlation with insulin resistance and type 2 diabetes mellitus (T2DM). Many studies have been published to report the role of many micronutrients, including carbohydrate, lipids and proteins which enhance or worsen the sensitivity of insulin. Thus, this literature review aims to assess the potential association between the different dietary components and insulin resistance based on the findings from the current studies in the literature. It has been suggested that replacing the consumption of fructose with other carbohydrates substances as fibers and starch might reduce such events and enhance insulin sensitivity as these substances pass intact through the gastrointestinal tract to the colon where they begin to be fermented. Additionally, carbohydrates substances reduce the utilization of free fatty acids by enhancing G-coupling through inhibition of the hormone-sensitive lipase, while the effect of overconsumption of glucose and fructose on insulin resistance is still controversial. Moreover, the quality of lipids is far more important than the quantity. Therefore, frequent ingestion of vegetable oils is suggested to enhance the sensitivity. As for proteins, high protein diets have been proposed for their useful effects. However, they should be carefully described to avoid their potential adverse events.

Therapeutic Effect of Folate and Cobalamin in Diabetics

Diabetes Mellitus type 2 is a metabolic ailment. It is a condition when insulin is produced by our body but, it is not used properly by us. The number of diabetic patients is increasing in the whole world. The problem of obesity is also very closely related to it, which itself is expanding. The individuals diagnosed with type 2 Diabetes Mellitus have high chance of microvascular problems (like nephropathy, retinopathy and neuropathy). They are also at the verge of facing macrovascular ailments (like cardiovascular comorbidities). This indicates that many antidiabetic agents should be administered in combination, to maintain normal sugar level in blood. The management for the patients suffering from diabetes should be effective and harmless for them. It should also improve the general well-being of the patients. So many remedies have been developed for the management of diabetes. Several of them are being developed. We should enhance insulin sensitivity to let our body use insulin effectively. We also must stop the increasing pancreatic β-cell failure which is a specific characteristic of Diabetes Mellitus type 2. The microvascular complications must also be avoided or revoked. Our direst need is to develop agents which may help us in achieving goals mentioned earlier. Many micronutrients are involved in combating the Diabetes Mellitus and complication associated to the malady. These micronutrients are vitamins. Our main focus in this chapter are Vitamins B9 (Folate) and B12 (Cobalamin). Many researches have shown that the said parameters were decreased in patients suffering from Diabetes Mellitus. The level of these two vitamins should be maintained to the normal level and not toward the border line. The maintained level of these vitamins will help in controlling the main problems in patients suffering from Diabetes Mellitus like neuropathy, anemia and many others. By taking these vitamins along with other preventive measures, Diabetes Mellitus can be controlled and can be less dangerous.

SorCS1 binds the insulin receptor to enhance insulin sensitivity

Type II diabetes mellitus (T2DM) has reached endemic levels and comprises a substantial burden to the patient and the society. Along with lifestyle factors, a number of genetic loci predisposing to T2DM have been suggested including SORCS1 that encodes a type-1 transmembrane receptor. Here we establish SorCS1 as a high-affinity binding partner for the insulin receptor (IR) that increases insulin affinity, Akt activation, and peripheral glucose uptake. Mice lacking full-length SorCS1 develop age-dependent insulin resistance characterized by increased plasma glucose and insulin levels and a blunted response to exogenous insulin. SorCS1 exists in three forms; as a transmembrane monomer and dimer, and as a truncated soluble form (sol-SorCS1) produced in adipose tissue and is present in plasma. Whereas dimeric SorCS1 engages the proform of the insulin receptor (proIR) during biosynthesis and supports its maturation, the monomeric form stabilizes the mature IR at the plasma membrane. In its soluble form, SorCS1 positively correlates with body mass index and inversely with plasma glucose in diabetic patients, and in mouse models of insulin resistance, overexpression or exogenous administration of the monomeric soluble receptor domain restores insulin sensitivity. We conclude that SorCS1 is a critical regulator of peripheral insulin sensitivity operating in both a cell autonomous and endocrine manner, and we propose sol-SorCS1 as a novel adipokine.

Mesenchymal Stem Cell-conditioned Medium Alleviates High Fat-induced Hyperglucagonemia via miR-181a-5p and its Target PTEN/AKT Signaling

Background: Pancreatic α-cells are critical to glucose homeostasis because they release glucagon and stimulate the liver to produce glucose. Dysregulation of α-cells gives rise to fasting and postprandial hyperglycemia in type 2 diabetes mellitus(T2DM). Mesenchymal stem cells (MSCs) or their conditioned medium can improve islet function and enhance insulin sensitivity in target tissues. However, studies showing the direct effect of MSCs on islet α-cell dysfunction are limited. Methods: In this study, we used high-fat diet (HFD)-induced mice and α-cell line exposure to palmitate (PA) to determine the effects of bone marrow-derived MSC-conditioned medium (bmMSC-CM) involved in glucagon secretion. To investigate the potential signaling pathways, phosphatase and tensin homolog deleted on chromosome 10 (PTEN) , AKT and phosphorylated AKT(p-AKT) were assessed by Western blotting.Results: In vivo, bmMSC-CM infusion protected against HFD-induced hyperglycemia and hyperglucagonemia. Consistently, bmMSC-CM decreased PA-induced glucagon secretion in α-cells and isolated islets. Additionally, bmMSC-CM reduced intracellular PTEN expression and rescued AKT signaling. Previous studies and the TargetScan database indicate that miR-181a and its target PTEN play vital roles in ameliorating α-cell dysfunction. We observed that miR-181a-5p is highly expressed in BM-MSCs but prominently lower in αTC1-6 cells. Overexpression or downregulation of miR-181a-5p respectively alleviates or aggravates glucagon secretion in αTC1-6 cells via the PTEN/AKT signaling pathway. Conclusions: Our observations suggest that MSC-secreted miR-181a-5p mitigates glucagon secretion of α-cells by regulating PTEN/AKT signaling. These findings might provide a novel understanding of MSC-based treatment.

Mitochondrial-derived peptides in energy metabolism

Mitochondrial-derived peptides (MDPs) are small bioactive peptides encoded by short open-reading frames (sORF) in mitochondrial DNA that do not necessarily have traditional hallmarks of protein-coding genes. To date, eight MDPs have been identified, all of which have been shown to have various cyto- or metaboloprotective properties. The 12S ribosomal RNA ( MT-RNR1) gene harbors the sequence for MOTS-c, whereas the other seven MDPs [humanin and small humanin-like peptides (SHLP) 1–6] are encoded by the 16S ribosomal RNA gene. Here, we review the evidence that endogenous MDPs are sensitive to changes in metabolism, showing that metabolic conditions like obesity, diabetes, and aging are associated with lower circulating MDPs, whereas in humans muscle MDP expression is upregulated in response to stress that perturbs the mitochondria like exercise, some mtDNA mutation-associated diseases, and healthy aging, which potentially suggests a tissue-specific response aimed at restoring cellular or mitochondrial homeostasis. Consistent with this, treatment of rodents with humanin, MOTS-c, and SHLP2 can enhance insulin sensitivity and offer protection against a range of age-associated metabolic disorders. Furthermore, assessing how mtDNA variants alter the functions of MDPs is beginning to provide evidence that MDPs are metabolic signal transducers in humans. Taken together, MDPs appear to form an important aspect of a retrograde signaling network that communicates mitochondrial status with the wider cell and to distal tissues to modulate adaptative responses to metabolic stress. It remains to be fully determined whether the metaboloprotective properties of MDPs can be harnessed into therapies for metabolic disease.

Research Progress of 70 kDa Ribosomal Protein S6 Kinase (P70S6K) Inhibitors as Effective Therapeutic Tools for Obesity, Type II Diabetes and Cancer

At present, diseases such as obesity, type Ⅱ diabetes and cancer have brought serious health problems, which are closely related to mTOR pathway. 70 kDa ribosomal protein S6 kinase (p70S6K), as a significant downstream effector of mTOR, mediates protein synthesis, RNA processing, glucose homeostasis, cell growth and apoptosis. Inhibiting the function of p70S6K can reduce the risk of obesity which helps to treat dyslipidemia, enhance insulin sensitivity, and extend the life span of mammals. Therefore, p70S6K has become a potential target for the treatment of these diseases. So far, except for the first p70S6K specific inhibitor PF-4708671 developed by Pfizer and LY2584702 developed by Lilai, all of them are in preclinical research. This paper briefly introduces the general situation of p70S6K and reviews their inhibitors in recent years, which are mainly classified into two categories: natural compounds and synthetic compounds. In particular, their inhibitory activities, structure-activity relationships (SARs) and mechanisms are highlighted.

Glucagon-dependent suppression of mTORC1 is associated with upregulation of hepatic FGF21 mRNA translation

Fibroblast growth factor 21 (FGF21) is a peptide hormone that acts to enhance insulin sensitivity and reverse many of the metabolic defects associated with consumption of a high-fat diet. Recent studies show that the liver is the primary source of FGF21 in the blood and that hepatic FGF21 expression is upregulated by glucagon. Interestingly, glucagon acts to upregulate FGF21 production by primary cultures of rat hepatocytes and H4IIE and HepG2 hepatocarcinoma cells independent of changes in FGF21 mRNA abundance, suggesting that FGF21 protein expression is regulated posttranscriptionally. Based on these observations, the goal of the present study was to assess whether or not FGF21 mRNA is translationally regulated. The results show that FGF21 mRNA translation and secretion of the hormone are significantly upregulated in H4IIE cells exposed to 25 nM glucagon, independent of changes in FGF21 mRNA abundance. Furthermore, the glucagon-induced upregulation of FGF21 mRNA translation is associated with suppressed activity of the mechanistic target of rapamycin in complex 1 (mTORC1). Similarly, the results show that rapamycin-induced suppression of mTORC1 leads to upregulation of FGF21 mRNA translation with no change in FGF21 mRNA abundance. In contrast, activation of mTORC1 by refreshing the culture medium leads to downregulation of FGF21 mRNA translation. Notably, refeeding fasted rats also leads to downregulation of FGF21 mRNA translation concomitantly with activation of mTORC1 in the liver. Overall, the findings support a model in which glucagon acts to upregulate FGF21 production by hepatocytes through suppression of mTORC1 and subsequent upregulation of FGF21 mRNA translation.