Decreased Plasma Glucose Levels Research Articles

Integrated mRNA and miRNA analysis reveals the regulatory network of oxidative stress and inflammation in Coilia nasus brains during air exposure and salinity mitigation

BackgroundAir exposure is an inevitable source of stress that leads to significant mortality in Coilia nasus. Our previous research demonstrated that adding 10‰ NaCl to aquatic water could enhance survival rates, albeit the molecular mechanisms involved in air exposure and salinity mitigation remained unclear. Conversely, salinity mitigation resulted in decreased plasma glucose levels and improved antioxidative activity. To shed light on this phenomenon, we characterized the transcriptomic changes in the C. nasus brain upon air exposure and salinity mitigation by integrated miRNA-mRNA analysis.ResultsThe plasma glucose level was elevated during air exposure, whereas it decreased during salinity mitigation. Antioxidant activity was suppressed during air exposure, but was enhanced during salinity mitigation. A total of 629 differentially expressed miRNAs (DEMs) and 791 differentially expressed genes (DEGs) were detected during air exposure, while 429 DEMs and 1016 DEGs were identified during salinity mitigation. GO analysis revealed that the target genes of DEMs and DEGs were enriched in biological process and cellular component during air exposure and salinity mitigation. KEGG analysis revealed that the target genes of DEMs and DEGs were enriched in metabolism. Integrated analysis showed that 24 and 36 predicted miRNA-mRNA regulatory pairs participating in regulating glucose metabolism, Ca2+ transport, inflammation, and oxidative stress. Interestingly, most of these miRNAs were novel miRNAs.ConclusionIn this study, substantial miRNA-mRNA regulation pairs were predicted via integrated analysis of small RNA sequencing and RNA-Seq. Based on predicted miRNA-mRNA regulation and potential function of DEGs, miRNA-mRNA regulatory network involved in glucose metabolism and Ca2+ transport, inflammation, and oxidative stress in C. nasus brain during air exposure and salinity mitigation. They regulated the increased/decreased plasma glucose and inhibited/promoted antioxidant activity during air exposure and salinity mitigation. Our findings would propose novel insights to the mechanisms underlying fish responses to air exposure and salinity mitigation.

Long-Term Consumption of Sucralose Induces Hepatic Insulin Resistance through an Extracellular Signal-Regulated Kinase 1/2-Dependent Pathway.

Sugar substitutes have been recommended to be used for weight and glycemic control. However, numerous studies indicate that consumption of artificial sweeteners exerts adverse effects on glycemic homeostasis. Although sucralose is among the most extensively utilized sweeteners in food products, the effects and detailed mechanisms of sucralose on insulin sensitivity remain ambiguous. In this study, we found that bolus administration of sucralose by oral gavage enhanced insulin secretion to decrease plasma glucose levels in mice. In addition, mice were randomly allocated into three groups, chow diet, high-fat diet (HFD), and HFD supplemented with sucralose (HFSUC), to investigate the effects of long-term consumption of sucralose on glucose homeostasis. In contrast to the effects of sucralose with bolus administration, the supplement of sucralose augmented HFD-induced insulin resistance and glucose intolerance, determined by glucose and insulin tolerance tests. In addition, we found that administration of extracellular signal-regulated kinase (ERK)-1/2 inhibitor reversed the effects of sucralose on glucose intolerance and insulin resistance in mice. Moreover, blockade of taste receptor type 1 member 3 (T1R3) by lactisole or pretreatment of endoplasmic reticulum stress inhibitors diminished sucralose-induced insulin resistance in HepG2 cells. Taken together, sucralose augmented HFD-induced insulin resistance in mice, and interrupted insulin signals through a T1R3-ERK1/2-dependent pathway in the liver.

Nocturnal melatonin increases glucose uptake via insulin-independent action in the goldfish brain.

Melatonin, a neurohormone nocturnally produced by the pineal gland, is known to regulate the circadian rhythm. It has been recently reported that variants of melatonin receptors are associated with an increased risk of hyperglycemia and type 2 diabetes, suggesting that melatonin may be involved in the regulation of glucose homeostasis. Insulin is a key hormone that regulates circulating glucose levels and cellular metabolism after food intake in many tissues, including the brain. Although cells actively uptake glucose even during sleep and without food, little is known regarding the physiological effects of nocturnal melatonin on glucose homeostasis. Therefore, we presume the involvement of melatonin in the diurnal rhythm of glucose metabolism, independent of insulin action after food intake. In the present study, goldfish (Carassius auratus) was used as an animal model, since this species has no insulin-dependent glucose transporter type 4 (GLUT4). We found that in fasted individuals, plasma melatonin levels were significantly higher and insulin levels were significantly lower during the night. Furthermore, glucose uptake in the brain, liver, and muscle tissues also significantly increased at night. After intraperitoneal administration of melatonin, glucose uptake by the brain and liver showed significantly greater increases than in the control group. The administration of melatonin also significantly decreased plasma glucose levels in hyperglycemic goldfish, but failed to alter insulin mRNA expression in Brockmann body and plasma insulin levels. Using an insulin-free medium, we demonstrated that melatonin treatment increased glucose uptake in a dose-dependent manner in primary cell cultures of goldfish brain and liver cells. Moreover, the addition of a melatonin receptor antagonist decreased glucose uptake in hepatocytes, but not in brain cells. Next, treatment with N1-acetyl-5-methoxykynuramine (AMK), a melatonin metabolite in the brain, directly increased glucose uptake in cultured brain cells. Taken together, these findings suggest that melatonin is a possible circadian regulator of glucose homeostasis, whereas insulin acquires its effect on glucose metabolism following food intake.

Long-term effects of canagliflozin treatment on the skeleton of aged UM-HET3 mice.

Sodium glucose cotransporter-2 inhibitors (SGLT2is) promote urinary glucose excretion and decrease plasma glucose levels independent of insulin. Canagliflozin (CANA) is an SGLT2i, which is widely prescribed, to reduce cardiovascular complications, and as a second-line therapy after metformin in the treatment of type 2 diabetes mellitus. Despite the robust metabolic benefits, reductions in bone mineral density (BMD) and cortical fractures were reported for CANA-treated subjects. In collaboration with the National Institute on Aging (NIA)-sponsored Interventions Testing Program (ITP), we tested skeletal integrity of UM-HET3 mice fed control (137 mice) or CANA-containing diet (180ppm, 156 mice) from 7 to 22months of age. Micro-computed tomography (micro-CT) revealed that CANA treatment caused significant thinning of the femur mid-diaphyseal cortex in both male and female mice, did not affect trabecular bone architecture in the distal femur or the lumbar vertebra-5 in male mice, but was associated with thinning of the trabeculae at the distal femur in CANA-treated female mice. In male mice, CANA treatment is associated with significant reductions in cortical bone volumetric BMD by micro-CT, and by quantitative backscattered scanning electron microscopy. Raman microspectroscopy, taken at the femur mid-diaphyseal posterior cortex, showed significant reductions in the mineral/matrix ratio and an increased carbonate/phosphate ratio in CANA-treated male mice. These data were supported by thermogravimetric assay (TGA) showing significantly decreased mineral and increased carbonate content in CANA-treated male mice. Finally, the sintered remains of TGA were subjected to X-ray diffraction and showed significantly higher fraction of whitlockite, a calcium orthophosphate mineral, which has higher resorbability than hydroxyapatite. Overall, long-term CANA treatment compromised bone morphology and mineral composition of bones, which likely contribute to increased fracture risk seen with this drug.

The Effect of the Sodium-Glucose Cotransporter Inhibitor on Cognition and Metabolic Parameters in a Rat Model of Sporadic Alzheimer's Disease.

Type 2 diabetes mellitus increases the risk of sporadic Alzheimer's disease (sAD), and antidiabetic drugs, including the sodium-glucose cotransporter inhibitors (SGLTI), are being studied as possible sAD therapy. We have explored whether the SGLTI phloridzin may influence metabolic and cognitive parameters in a rat model of sAD. Adult male Wistar rats were randomized to a control (CTR), an sAD-model group induced by intracerebroventricular streptozotocin (STZ-icv; 3 mg/kg), a CTR+SGLTI, or an STZ-icv+SGLTI group. Two-month-long oral (gavage) SGLTI treatment (10 mg/kg) was initiated 1 month after STZ-icv and cognitive performance tested prior to sacrifice. SGLTI treatment significantly decreased plasma glucose levels only in the CTR group and failed to correct STZ-icv-induced cognitive deficit. In both the CTR and STZ-icv groups, SGLTI treatment diminished weight gain, decreased amyloid beta (Aβ) 1-42 in duodenum, and decreased the plasma levels of total glucagon-like peptide 1 (GLP-1), while the levels of active GLP-1, as well as both total and active glucose-dependent insulinotropic polypeptide, remained unchanged, compared to their respective controls. The increment in GLP-1 levels in the cerebrospinal fluid and its effect on Aβ 1-42 in duodenum could be one of the molecular mechanisms by which SGLTIs indirectly induce pleiotropic beneficial effects.

Saikosaponin d (SSD) alleviates diabetic peripheral neuropathy by regulating the AQP1/RhoA/ROCK signaling in streptozotocin-induced diabetic rats.

Diabetic peripheral neuropathy (DPN) is one of the most important complications of diabetes with a poor prognosis. Saikosaponin d (SSD) is a triterpenoid saponin isolated from Radix Bupleuri that has multiple pharmacological activities. However, whether SSD affects DPN is unclarified. Sprague Dawley rats were treated with streptozotocin (STZ) and high-fat diet (HFD) to induce DPN, in the presence or absence of SSD, with or without transfection of lentivirus vectors carrying siRNA targeting aquaporin 1 (si-AQP1). The body weight, plasma glucose levels, mechanical and thermal hyperalgesia, and nerve conductive velocity (NCV) of rats were measured. Hematoxylin-Eosin staining was used for histopathological observation of sciatic nerves. RT-qPCR and western blotting were utilized for measuring expression levels of AQP1 and ras homolog family member A/Rho-associated protein kinase (RhoA/ROCK) signaling pathway-related markers in dorsal root ganglion (DRG) of rats. SSD increased the body weight, decreased plasma glucose levels, attenuated mechanical and thermal hyperalgesia, enhanced NCV and reduced proinflammatory cytokine levels in DPN rats. AQP1 displayed a high level in DPN rats and SSD treatment repressed the expression of AQP1. SSD enhanced the protective effect of AQP1 knockdown on the pathological changes of DPN. AQP1 depletion suppressed the activation of RhoA/ROCK signaling pathway in DPN rats. SSD alleviates STZ/HFD-induced DPN in rats by inhibiting the AQP1/RhoA/ROCK signaling pathway.

Effect of abrupt and gradual calorie restriction regimens on biochemical and behavioral markers in obese mice model.

Background: Although Calorie Restriction (CR) is primarily considered in obesity management, behavioral studies of CR and its methodology of implementation are not well-defined. Objective: The study aimed to determine the efficacy of the extensively researched method of CR-abrupt calorie restriction (ACR) and a newly proposed gradual calorie restriction (GCR) in terms of body weight, behavioral and biochemical parameters in the obese animal model-C57BL/6J mice. Design: Male obese mice were subjected to GCR regimen for 14 weeks which was compared and evaluated for anxiety-like behavior and stress levels with ACR. Plasma corticosterone was measured before initiation of CR and every three weeks following GCR and ACR, whereas plasma insulin was measured twice-after obesity induction and post 14 weeks of CR. The behavioral assessments were conducted before inducing CR and every three weeks following ACR and GCR. Results: A significant anxiety-like behavior and an increase in plasma corticosterone were observed in mice on GCR during the critical initial six weeks of CR (p < 0.05). Both groups showed a decrease in plasma glucose levels; however, the GCR group showed a significant reduction (p < 0.01). There was a significant decrease in social interaction in both groups with an increase in the latency period and a decrease in time spent with the stranger animal during the social interaction test (p < 0.05). Conclusion: The mice on GCR regimen demonstrated lesser anxiety-like behavior and low plasma corticosterone levels compared to those on ACR. This gives us a new avenue in CR research to evaluate the methodologies of implementing CR.

Upregulation of Antioxidative Gene Expression by Lasia spinosa Organic Extract Improves the Predisposing Biomarkers and Tissue Architectures in Streptozotocin-Induced Diabetic Models of Long Evans Rats.

Plants are an entity essential to the function of the biosphere as well as human health. In the context of human health, this research investigated the effect of Lasia spinosa (Lour) leaf methanolic extracts (LSML) on antioxidative enzymes and gene expression as well as biochemical and histological markers in a streptozotocin (STZ)-induced diabetes model. Fructose-fed streptozotocin (STZ)-induced diabetic animals were subjected to a four-week intervention followed by the assessment of the animal's blood and tissues for enzymatic, biochemical, histological, and genetic changes. LSML-treated groups were shown to decrease plasma glucose levels and improve body and organ weights compared to the untreated group in a dose-dependent manner. At the doses of 125 and 250 mg/kg b.w., LSML were able to normalize serum, hepatic, and renal biochemical parameters and restore the pancreas, kidney, liver, and spleen tissue architectures to their native state. A considerable increase (p &lt; 0.01) of liver antioxidant enzymes CAT, SOD, GSH, and a decrease of MDA level in LSML-treated groups were found at higher doses. The improved mRNA expression level of antioxidant genes CAT, SOD2, PON1, and PFK1 was also found at the doses of 125 mg/kg and 250 mg/kg BW when compared to untreated control groups. The results demonstrate that LSML impacts the upregulation of antioxidative gene expressions, thus improving the diabetic complications in animal models which need to be affirmed by compound-based antioxidative actions for therapeutic development.

In vivo and in silico evaluation of analgesic and hypoglycemic activities of Amaranthus blitum L.

Amaranthus blitum L. is a worldwide weed that originated in the Mediterranean region and now grows from the tropics to temperate zones, from Asian to southern African countries. It is commonly consumed as a cooked vegetable item. Amaranthus blitum L., on the other hand, has never been extensively investigated for its medicinal properties like analgesic and hypoglycemic potentials. Hence, using an in vivo and in silico method, assess the analgesic and hypoglycemic efficacy of Amaranthus blitum L. methanolic extract and its key phytoconstituents is the primary aim of this study. The acetic acid-induced writhing test and the hot plate test protocol were employed to assess the in vivo analgesic effectiveness of Amaranthus blitum L. methanolic extract (ABME) in Swiss albino mice of either sex. In a Stretozotocin (STZ) induced anti-diabetic test, the hypoglycemic activity was investigated. Admet-SAR web server and PyMOL (Version 1.7.4) software package were used to perform in silico activity of the isolated compounds and ADME analysis. The research employed methanolic extracts (ME) at dosages of 250 mg/kg and 500 mg/kg to assess analgesic and hypoglycemic effects. ME (250 mg/kg) and ME (500 mg/kg) showed substantial outcomes in the acetic acid-induced writhing test, with 39.48 ± 5.66% and 51.20 ± 3.78%, respectively. ME at a dosage of 500 mg/kg caused the highest latency time increase of 16.92 ± 0.94s in the hot plate test. In the context of in silico assessment, eleven chemicals fit Lipinski's five-condition criteria. The best docking score was for glycidyl oleate which is 6.3 kcal/mol against cyclooxygenase-2 enzyme (PDB ID: 5KIR) among these safe chemicals, which was practically identical to Celecoxib's (8.5 kcal/mol). In streptozotocin induced hypoglycemic test, significant decrease in plasma glucose level was observed for 500 mg/kg of methanolic extract. In silico study showed best docking score of 2,2-di‑tert-butylphenol with − 6.4 kcal/mol against sulfonylurea protein (PDB ID: 6JB3), compared to glibenclamide (− 9.4 kcal/mol). Our research demonstrates that phytoconstituents of Amaranthus blitum L. are very potential analgesic and hypoglycemic candidates. These compounds might be employed to develop an effective analgesic and anti-diabetic medication from a natural resource using advanced technologies.

Impact of healthy lifestyle on the risk of type 2 diabetes mellitus in southwest China: A prospective cohort study

To explore the influence of nine healthy lifestyle factors on the risk of type 2 diabetes mellitus in adults in Guizhou, China. Data were obtained from a large population-based prospective cohort study in Guizhou Province, China. A total of 7,319 participants aged ≥18 years without diabetes at baseline were included in this study and were followed up from 2016 to 2020. A healthy lifestyle score was calculated based on the number of healthy lifestyle factors. During an average of 7.1 person-years of follow-up, 764 participants were diagnosed with type 2 diabetes mellitus. Compared with those of participants who scored 0-3 for a healthy lifestyle, the hazard ratios (95% confidence intervals) of those who scored 4, 5, 6, and ≥7 were 0.676 (0.523-0.874), 0.599 (0.464-0.773), 0.512 (0.390-0.673), and 0.393 (0.282-0.550), respectively, showing a gradual downward trend (P for trend <0.01). More importantly, they had lower fasting and 2 h post-load plasma glucose levels and fewer changes in plasma glucose levels during follow-up. If ≥7 healthy lifestyle factors were maintained, 33.8% of incident diabetes cases could have been prevented. Never smoking was the strongest protective factor against type 2 diabetes mellitus. A healthy lifestyle can effectively decrease plasma glucose levels and reduce the incidence of type 2 diabetes mellitus in adults in Guizhou, China. In addition, not smoking may be an effective way to prevent type 2 diabetes mellitus.

The endocrine pancreas during exercise in people with and without type 1 diabetes: Beyond the beta-cell.

Although important for digestion and metabolism in repose, the healthy endocrine pancreas also plays a key role in facilitating energy transduction around physical exercise. During exercise, decrements in pancreatic β-cell mediated insulin release opposed by increments in α-cell glucagon secretion stand chief among the hierarchy of glucose-counterregulatory responses to decreasing plasma glucose levels. As a control hub for several major glucose regulatory hormones, the endogenous pancreas is therefore essential in ensuring glucose homeostasis. Type 1 diabetes (T1D) is pathophysiological condition characterised by a destruction of pancreatic β-cells resulting in pronounced aberrations in glucose control. Yet beyond the beta-cell perhaps less considered is the impact of T1D on all other pancreatic endocrine cell responses during exercise and whether they differ to those observed in healthy man. For physicians, understanding how the endocrine pancreas responds to exercise in people with and without T1D may serve as a useful model from which to identify whether there are clinically relevant adaptations that need consideration for glycaemic management. From a physiological perspective, delineating differences or indeed similarities in such responses may help inform appropriate exercise test interpretation and subsequent program prescription. With more complex advances in automated insulin delivery (AID) systems and emerging data on exercise algorithms, a timely update is warranted in our understanding of the endogenous endocrine pancreatic responses to physical exercise in people with and without T1D. By placing our focus here, we may be able to offer a nexus of better understanding between the clinical and engineering importance of AIDs requirements during physical exercise.

A Randomized Controlled Trial of R-Form Verapamil Added to Ongoing Metformin Therapy in Patients with Type 2 Diabetes

ContextThere is a medical need for effective insulin-independent antidiabetic drugs that can promote pancreatic β-cell function and have a low risk of hypoglycemia in type 2 diabetes mellitus (T2DM) patients. R-form verapamil (R-Vera), which is able to enhance the survival of β-cells and has higher cardiovascular safety margin compared with racemic verapamil, was developed as a novel approach for T2DM treatment.ObjectiveThis randomized, double-blind, placebo-controlled clinical trial was designed to evaluate the efficacy and safety of 3 dosages of R-Vera added to ongoing metformin therapy in T2DM patients who had inadequate glycemic control on metformin alone.MethodsParticipants were randomly assigned in an equal ratio to receive R-Vera 450, 300, or 150 mg per day, or matching placebo, in combination with metformin. The primary endpoint was change in hemoglobin A1c (HbA1c) after 12 weeks of treatment.ResultsA total of 184 eligible participants were randomized to receive either R-Vera or placebo plus metformin. At week 12, significant reductions in HbA1c were observed for R-Vera 300 mg/day (−0.36, P = 0.0373) and 450 mg/day (−0.45, P = 0.0098) compared with placebo. The reduction in HbA1c correlated with decreasing fasting plasma glucose levels and improved HOMA2-β score. Treatment with R-Vera was well tolerated with no hypoglycemic episodes occurring during the trial.ConclusionAddition of R-Vera twice daily to ongoing metformin therapy significantly improved glycemic control in T2DM patients. The favorable efficacy and safety profile of R-Vera 300 mg/day can be considered as the appropriate dose for clinical practice.

Interleukin-1b and Interferon-g are Associated with Malaria-Induced Hypoinsulinemic Hypoglycemia in Plasmodium berghei Anka-Infected Mice

Malaria-induced hypoglycemia is recognized as a serious complication of malaria and has one of the strongest associations with mortality in children. It has been speculated that oxidative stress and pro-inflammatory response during parasite infection were involved in its pathophysiology. Hence, this study aimed to investigate the development of malaria-induced hypoglycemia during Plasmodium berghei ANKA (PbANKA) infection with particular attention to the involvement of c-peptide, interleukin-1b (IL-1b), and interferon-g (IFN-g). ICR mice were infected with 1×107 parasitized erythrocytes of PbANKA, and parasitemia was monitored, and the development of hypoglycemia was assessed by measuring plasma glucose levels. The change of c-peptide level was evaluated. The pro-inflammatory response of IL-1b and IFN-g were also quantified in plasma. It was found that PbANKA infection resulted in hypoglycemia as indicated by a significantly (P &lt; 0.05) decrease in plasma glucose levels on day 4 post-infection and associated with parasitemia. The c-peptide was slightly increased at day 2 post-infection, and then significantly (P &lt; 0.05) decreased since day 4. Furthermore, we observed a significantly (P &lt; 0.05) increased IL-1b, firstly responded, at day 2 post-infection followed by increasing the IFN-g level at day 4 in PbANKA-induced hypoglycemia. Our findings support the idea that hypoinsulinemic hypoglycemia in the PbANKA infected mice may be involved in the high IL-1b and IFN-g against the parasite infection.

Effect of low-dose Piscirickettsia salmonis infection on haematological-biochemical blood parameters in Atlantic salmon (Salmo salar).

Piscirickettsia salmonis is the etiological agent of Piscirickettsiosis, a severe disease that affects Atlantic salmon (Salmo salar) farmed in Chile and many other areas (Norway, Scotland, Ireland, Canada and the USA). This study investigated the effects of low-dose P. salmonis infection (1 × 102 CFU/ml) on Atlantic salmon. In this study, we challenged fish with an isolated representative of the EM-90 genogroup via intraperitoneal injection for 42 days. Infected fish displayed decreased haematocrit and haemoglobin levels at day 13 post-infection, indicating erythropenia, haemolysis and haemodilution. Conversely, their white blood cell counts increased on days 13 and 21 post-infection. Additionally, their iron levels decreased from day 2 post-infection, indicating iron deficiency and an inability to retrieve stored iron before infection. Their magnesium levels also decreased at day 28 post-infection, possibly due to osmoregulatory problems. Also, we observed an increase in lactate dehydrogenase activity on days 5, 21, and 28 post-infection, suggesting early symptoms of hepatotoxicity. Later analyses determined a decrease in plasma glucose levels from day 2 post-infection. This may be attributed to the hypoxic conditions caused by P. salmonis, leading to an excess utilization of stored carbohydrates. Our results suggest that the blood parameters we studied are useful for monitoring the physiological status of Atlantic salmon infected with P. salmonis.

Dose Response Effect of Photobiomodulation on Hemodynamic Responses and Glucose Levels in Men with Type 2 Diabetes: A Randomized, Crossover, Double-Blind, Sham-Controlled Trial

This study verifies the acute dose response effect of photobiomodulation (PBM) by light emitting diodes (LEDs) on hemodynamic and metabolic responses in individuals with type 2 diabetes mellitus (T2DM). Thirteen participants with T2DM (age 52 ± 7 years) received PBM by a light-emitting diode array (50 GaAIAs LEDs, 850 ± 20 nm, 75 mW per diode) on the rectus and oblique abdomen, quadriceps femoris, triceps surae, and hamstring muscle areas, bilaterally, using different energy treatments (sham, 75, 150, 300, 450, and 600 Joules) in random order with a washout of at least 15 days apart. The PBM by LEDs statistically decreased plasma glucose levels (primary outcome) in 15 min after application of the 75 and 450 J irradiation protocol, reduced blood lactate levels 15 min after application of the 75, 450, and 600 J irradiation protocol, increased cardiac output (Q˙) and cardiac index (CI) in the 1st minute after application of the 75 and 300 J irradiation protocol, and reduced Q˙ and heart rate (HR) in the 15 min after application of the 300 J and 600 J irradiation protocol, respectively. For hemodynamic variables, including Q˙, total peripheral resistance (TPR), and HR, we observed that the ideal therapeutic window ranged between 75 and 300 J, while for metabolic variables, glucose and lactate, the variation was between 450 and 600 J.

Review of SGLT2i for the Treatment of Renal Complications: Experience in Patients with and Without T2D

The management of type 2 diabetes (T2D) involves decreasing plasma glucose levels and reducing cardiovascular and microvascular complications. Diabetic kidney disease (DKD), defined as presence of albuminuria, impaired glomerular filtration, or both, is an insidious microvascular complication of diabetes that generates a substantial personal and clinical burden. The progressive reduction in renal function and increased albuminuria results in an increase of cardiovascular events. Thus, patients with DKD require exhaustive control of the associated cardiovascular risk factors. People with diabetes and renal impairment have fewer options of antidiabetic drugs because of contraindications, adverse effects, or altered pharmacokinetics. Sodium–glucose cotransporter type 2 inhibitors (SGLT2i) reduce blood glucose concentrations by blocking the uptake of sodium and glucose in the proximal tubule and promoting glycosuria, and these agents now have an important role in the management of T2D. The results of several cardiovascular outcomes trials suggested that SGLT2i are associated with improvements in renal endpoints in addition to their reduction in cardiovascular events and mortality, which represents a major advance in the care of this population. The dedicated kidney outcomes trials have confirmed the renoprotective action of SGLT2i across different glomerular filtration and albuminuria values, even in patients with non-diabetic chronic kidney disease. Notably, this improvement in kidney function may indirectly benefit cardiac function through multifaceted interorgan cross talk, which can break the cardiorenal vicious circle linked to T2D. In this article, we briefly review the different mechanisms of action that may explain the renal beneficial effects of SGLT2i and disclose the results of the key renal outcome trials and the subsequent update of related clinical guidelines.

Effects of dietary palmitoleic acid on vascular function in aorta of diabetic mice

BackgroundChronic hyperglycemia in diabetes causes atherosclerosis and progresses to diabetic macroangiopathy, and can lead to coronary heart disease, myocardial infarction and cerebrovascular disease. Palmitoleic acid (POA) is a product of endogenous lipogenesis and is present in fish and vegetable oil. In human and animal studies, POA is reported as a beneficial fatty acid related to insulin sensitivity and glucose tolerance. However, few studies have reported its effects on aortic function in diabetes. Here, we investigated the effects of POA administration on vascular function in KKAy mice, a model of type 2 diabetes.MethodsMale C57BL/6 J (control) and KKAy (experimental) mice at the age of 14 weeks were used in the present study. For each mouse strain, one group was fed with reference diet and a second group was fed POA-containing diet for 2 weeks. The vascular reactivities of prepared aortic rings were then measured in an organ bath to determine if POA administration changed vascular function in these mice.ResultsKKAy mice treated with POA exhibited decreased plasma glucose levels compared with mice treated with reference diet. However, endothelium-dependent vasorelaxant responses to acetylcholine and protease-activated receptor 2 activating protein, which are attenuated in the aorta of KKAy mice compared to C57BL/6 J mice under a reference diet, were not affected by a 2-week POA treatment. In addition, assessment of vasoconstriction revealed that the phenylephrine-induced vasoconstrictive response was enhanced in KKAy mice compared to C57BL/6 J mice under a reference diet, but no effect was observed in KKAy mice fed a POA-containing diet. In contrast, there was an increase in vasoconstriction in C57BL/6 J mice fed the POA-containing diet compared to mice fed a reference diet. Furthermore, the vasoconstriction in aorta in both C57BL/6 J and KKAy mice fed a POA-containing diet were further enhanced under hyperglycemic conditions compared to normal glucose conditions in vitro. In the hyperinsulinemic, and hyperinsulinemic combined with hyperglycemic conditions, vasoconstriction was increased in KKAy mice fed with POA.ConclusionThese results suggest that POA intake enhances vasoconstriction under hyperglycemic and hyperinsulinemic conditions, which are characteristics of type 2 diabetes, and may contribute to increased vascular complications in diabetes.

No effect of resveratrol on fatty acid oxidation or exercise capacity in patients with fatty acid oxidation disorders: A randomized clinical cross-over trial.

The objective was to investigate whether resveratrol (RSV) can improve exercise capacity in patients with fatty acid oxidation (FAO) disorders. The study was a randomized, double-blind, cross-over trial. Nine patients with very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency or carnitine palmitoyl transferase (CPT) II deficiency were randomized to receive either 8 weeks of 1000 mg day-1 RSV or placebo (P) followed by a 4-weeks wash-out period and subsequently 8 weeks of the opposite treatment. Primary outcome measures were heart rate and FAO as measured via stable isotope technique during constant workload exercise. Secondary outcome measures included fat and glucose metabolism; perceived exertion; as well as subjective measures of energy expenditure, fatigue, and daily function. Eight participants completed the trial. Heart rate did not differ at the end of exercise after treatment with RSV vs placebo (P=.063). Rate of oxidation of palmitate at end of exercise was not different with 1.5 ± 0.8 (RSV) vs 1.3 ± 0.6 (P) μmol kg-1 min-1 (P=.109). Secondary outcomes did not change except for increased plasma glycerol and decreased plasma glucose levels at the end of exercise after treatment with RSV vs placebo. A daily dose of 1000 mg resveratrol does not improve exercise capacity or FAO during exercise in patients with CPTII or VLCAD deficiencies.

Update on the Cardiovascular Benefits of Sodium-Glucose Co-Transporter-2 Inhibitors: Mechanism of Action, Available Agents and Comprehensive Review of Literature

Despite the currently established treatment for heart failure (HF), HF remains a growing public healthcare problem with an increasing burden. Therefore, novel therapeutic innovations are needed to overcome this issue and improve HF prognosis. Sodium-glucose co-transporter-2 inhibitors (SGLT2i) are state-of-the-art in type 2 diabetes mellitus management. They inhibit the reabsorption of glucose from the proximal renal tubules, leading to increased glycosuria and decreased plasma glucose levels. SGLT2i use is growing significantly, especially after recent clinical trials demonstrating favorable cardiovascular and renal protective effects independently of blood glucose-lowering. The mechanisms by which SGLT2i demonstrate their cardio-renal protective effects remain incompletely understood but are thought to be related to potential diuretic and natriuretic effects along with other mechanisms that will be discussed in this article. Over the past few years, there has been significant research on the safety, efficacy, and quality of this class of medications. Here, we review the current guideline-directed medical therapy for HF, focus on SGLT2i mechanism of action and potential role in HF patients, and finally summarize the cardiovascular clinical trials with SGLT2.

Cover Image, Volume 23, Issue 5

The cover image is based on the Original Article A decrease in plasma glucose levels is required for increased endogenous glucose production with a single administration of a sodium-glucose co-transporter-2 inhibitor tofogliflozin by Nozomu Yamasaki et al., https://doi.org/10.1111/dom.14312.