Insulin Action Research Articles

A Systematic Review of Gut Microbiota Diversity: A Key Player in the Management and Prevention of Diabetes Mellitus.

Diabetes mellitus represents a significant global health challenge, characterized by impaired insulin production and action, leading to elevated blood glucose levels. This systematic review investigates the association between gut microbiota composition and diversity, along with the structural and functional characteristics of the gut microbiome, and their implications for the risk, prevention, and management of both type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM). Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines, a comprehensive search across multiple databases yielded 16 studies that met the inclusion criteria. The findings highlight the potential of gut microbiota interventions, such as fecal microbiota transplantation and probiotic supplementation, in improving metabolic parameters and glycemic control. Notably, the review underscores the importance of dietary interventions and the role of specific microbial populations in influencing diabetes outcomes. Despite the promising results, the variability in study designs, sample sizes, and methodologies poses challenges for generalizability and interpretation. This review emphasizes the need for further research to elucidate the mechanisms underlying these associations and to explore personalized microbiome-based therapies in diabetes management. The insights gained could pave the way for innovative therapeutic strategies aimed at harnessing gut health to mitigate the burden of diabetes mellitus.

Role of Serum Magnesium on Insulin Resistance in Overweight and Obese Children.

Background Childhood obesity has become a global epidemic, with projections indicating it could affect 25% of children under 16 by 2050. This rise poses significant health risks, including early onset of type 2 diabetes and cardiovascular diseases. Recent research has shown a correlation between insulin action and magnesium levels, highlighting the link between low serum magnesium levels and obesity. This study aimed to investigate the relationship between serum magnesium levels and obesity in children aged 5-16 years, to compare overweight and obese adolescents with age- and gender-matched controls, and to determine the association between insulin resistance and decreased serum magnesium levels. Methodology At a tertiary hospital, this 1.5-year cross-sectional comparativestudy investigated the relationship between magnesium levels in the blood and insulin resistance in children aged 5-16. Cases met the 2015 revised Indian Academy of Pediatrics (IAP) growth charts for overweight or obesity in comparison to age-matched healthy controls. Exclusions included secondary causes of obesity and medical complications affecting magnesium. Assessments involved clinical history, examination, and fasting blood tests for insulin resistance indices. Results Compared to the controls, overweight children showed that mean serum magnesium levels are lower (1.03 mEq/l vs. 1.85 mEq/l, p<0.001); they were also reflected in higher anthropometric measures, which include body mass index (BMI) and body fat percentage. Cases had significantly higher metabolic markers like fasting insulin, Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) index, and lipid profiles, whereas systolic blood pressure although showing recognized differences did not significantly differ. Conclusion The study underscored the importance of detecting magnesium levels on insulin resistance in overweight and obese children.

Biomarkers of Oxidative Stress in Diabetic Microvascular Complications Review Article

Reactive oxygen species (ROS) are produced as a result of biochemical processes that are not in balance with the body's antioxidant defense mechanism. This metabolic dysfunction is referred to the oxidative stress (OS). Metabolic dysfunction-associated diseases are affected by changes in the redox balance. It is now widely recognized that oxidative stress significantly affects diabetes mellitus (DM), particularly type 2 diabetes. The biochemical changes associated with DM could disturb the oxidative milieu, leading to several microvascular complications in diabetic patients. Thus, DM is a perfect disease to explore the harmful consequences of oxidative stress and how to treat it. Oxidative stress triggered by hyperglycemia is an important contributor to the effects of diabetic microvascular diseases. Uncontrolled hyperglycemia carried by deficiencies in insulin secretion or action produces a number of problems, such as peripheral vascular disorders, nephropathy, neuropathy, retinopathy, increased morbidity and/or mortality, as well as the incidence of diabetes mellitus (DM) are rising globally. The development and progression of diabetic problems are strongly correlated with reactive oxygen species and oxidative stress, according to a wide body of research. This review aims to explore various markers of oxidative stress and the role of ROS in the pathogenesis and progression of late diabetic microvascular complications.

CNPAS2 induced β cell dysfunction by regulating KANK1 expression in type 2 diabetes.

Diabetes mellitus type 2 (T2DM) is formed by defective insulin secretion with the addition of peripheral tissue resistance of insulin action. It has been affecting over 400 million people all over the world. To explore the pathogenesis of T2DM and to develop and implement new prevention and treatment strategies for T2DM. Receiver operating characteristic (ROC) curve analysis was used to conduct diagnostic markers. The expression level of genes was determined by reverse transcription-PCR as well as Western blot. Cell proliferation assays were performed by cell counting kit-8 (CCK-8) tests. At last, T2DM mice underwent Roux-en-Y gastric bypass surgery. We found that NPAS2 was significantly up-regulated in islet β cell apoptosis of T2DM. The ROC curve revealed that NPAS2 was capable of accurately diagnosing T2DM. NPAS2 overexpression did increase the level of KANK1. In addition, the CCK-8 test revealed knocking down NPAS2 and KANK1 increased the proliferation of MIN6 cells. At last, we found that gastric bypass may treat type 2 diabetes by down-regulating NPAS2 and KANK1. This study demonstrated that NPAS2 induced β cell dysfunction by regulating KANK1 expression in type 2 diabetes, and it may be an underlying therapy target of T2DM.

A Single Dose of Phosphoinositide-3-kinase Inhibitor Alpelisib Induces Insulin Resistance in Healthy Adults: A Randomized Feasibility Study.

Our objective is to test a single dose of the phosphoinositide-3-kinase (PI3K) inhibitor alpelisib as a tool for acute modeling of insulin resistance in healthy volunteers. This single-center, double-blind, phase 1 clinical trial randomized healthy adults to take a single oral dose of alpelisib 300 mg (n = 5) or placebo (n = 6) at bedtime, followed by measurement of glucose, insulin, and C-peptide levels after an overnight fast and during a 3-hour, 75-g oral glucose tolerance test. Fasting plasma glucose trended higher with alpelisib (mean ± S.D.: 93 ± 11 mg/dL) versus placebo (84 ± 5 mg/dL), while mean fasting serum insulin increased nearly fivefold (23 ± 12 µU/mL vs. 5 ± 3 µU/mL, respectively) and Homeostasis Model Assessment of Insulin Resistance scored 5.4 ± 3.1 for alpelisib and 1.1 ± 0.6 for placebo. During OGTT, incremental area under the curve (AUC) for insulin was over fourfold greater with alpelisib (22 ± 15 mU/mL x min) than placebo (5 ± 2 mU/mL x min); glucose AUC trended higher with alpelisib. Single-dose alpelisib was well tolerated and produced metabolic alterations consistent with acute induction of IR, validating its use for mechanistic study of insulin action in humans. (ClinicalTrials.gov registration: NCT05733455).

Asuhan Keperawatan Keluarga pada Tn. A dengan Diabetes Melitus di Desa Kalibuntu RT 02 RW 02 Kecamatan Losari Kabupaten Berebes

Diabetes Mellitus (DM) is a chronic metabolic disease that often occurs in the elderly, characterized by hyperglycemia due to impaired insulin secretion or action. This research focuses on family nursing care for Mr. A, a DM sufferer, in Kalibuntu Village, Losari District, Brebes Regency. Based on data, the prevalence of diabetes in Indonesia is very high, with Indonesia ranking third in Southeast Asia. In Brebes Regency, the prevalence of DM is also significant, requiring special attention in management. The Friedman model is used in family nursing care, which emphasizes the role of the family in supporting the patient's health management. The care process includes assessment, diagnosis, planning, implementation, and evaluation. The assessment is carried out by collecting family data using clear and simple language. Nursing diagnoses are established based on data analysis, while nursing interventions are designed to meet the patient's specific needs. Implementation is carried out by carrying out the plans that have been prepared, followed by ongoing evaluation to assess the effectiveness of the intervention and make necessary adjustments. Management of DM in Mr. A involves five main pillars: education, meal planning, physical exercise, pharmacological interventions, and blood sugar checks. A positive attitude towards treatment plays an important role in achieving good glucose control and improving quality of life. These findings emphasize the importance of family involvement in DM care to ensure effective and sustainable management.

Synthesis, Antimicrobial, DNA Interactions, In Vitro Cytotoxicity, and Cell Cycle Analysis Efficiency of Newly Nano‐Sized Cu (II), Ni (II), Co (II), and Zn (II) Thio‐Schiff Base Complexes of 2‐((E)‐((4,5‐Dimethyl‐2‐(((E)‐4‐Methylbenzylidene)Amino)Phenyl)imino)Methyl)‐Benzenethiol

ABSTRACTNano‐sized bivalent metal complexes, specifically [M(L)2] with L = 2‐((E)‐((4,5‐dimethyl‐2‐(((E)‐4‐methylbenzylidene)amino)phenyl)‐imino)methyl)benzenethiol] (C23H22N2S) and M = Cu (II) (C1), Co (II) (C2), Ni (II) (C3), and Zn (II) (C4), underwent synthesis and subsequent characterization. Elemental analyses, infrared, NMR, mass, electronic, magnetic susceptibility, conductivity assessments, and X‐ray diffraction studies were used to assess our bivalent metal complexes. DFT studies were used to study the tautomeric equilibrium of the tridentate thio‐Schiff base ligand (HL), via the DFT\B3LYP method in connection with a 6–311G* correlation consistent basis set. Two tautomers, which are thione and thiol forms, were studied to estimate the predominant one. The metal formed four coordinated with the tridentate N2S donor thio‐Schiff base to form octahedral geometry complexes. The SEM, TEM, XRD, AFM, and EDX of the studied complexes unveiled distinct and strong diffraction peaks, signifying their crystalline nature and providing evidence of their particle sizes being within the nano‐size. The crystal sizes calculated for all complexes were determined to be ranging from 27.73 to 76.39 nm. The interactions between metal complexes and calf thymus DNA, and their potential for mimicking insulin activity, were investigated in a controlled lab setting by measuring their ability to inhibit alpha‐amylase. The antimicrobial potential of thio‐Schiff base ligand (HL) plus complexes (C1–C4) were tested. The viscosity and UV–Vis absorption determinations were utilized to assess the calf thymus DNA (CT‐DNA) interaction with the nano‐sized metal (II) chelates. Our flow cytometry data indicate significant levels of apoptosis and cell cycle arresting in both liver and breast cancer cell lines.

Lipid Profile in Type 2 Diabetes Mellitus Patients with and without Diabetic Retinopathy

Diabetes mellitus (DM) is a group of metabolic diseases characterized by hyperglycemia due to abnormalities in insulin secretion, insulin action, or both. Diabetic retinopathy is the most common microangiopathic complication of DM and one of the leading causes of blindness in the world. Poor lipid profile levels are one of the risk factors for diabetic retinopathy. Objective: To analyze differences in the proportion of lipid profile categories in type 2 DM patients with and without diabetic retinopathy. Methods: This was a hospital-based cross-sectional study with 45 samples. The independent variables assessed were the lipid profile, including LDL, HDL, triglycerides, and total cholesterol levels. The dependent variable assessed was the incidence of diabetic retinopathy. The analysis used were univariate and bivariate (Chi-square and Fisher exact). Results: The prevalence of diabetic retinopathy was 37.8%, consist of 17.8% of NPDR and 20% of PDR. There were significant differences in the proportion of LDL categories (p=0.007) and total cholesterol (p=0.038) in type 2 DM patients with and without diabetic retinopathy, and there were no significant differences in the proportion of HDL categories (p=0.719) and triglycerides (p=1) in type 2 DM patients with and without diabetic retinopathy. Conclusion: There were significant differences in the proportion of LDL categories and total cholesterol in type 2 DM patients with and without diabetic retinopathy.

DURASI MENDERITA DM MEMENGARUHI KONTROL GLIKEMIK JANGKA PANJANG YANG DIUKUR MELALUI HbA1c PADA PASIEN DIABETES MELITUS TIPE 2

Diabetes mellitus (DM) is a metabolic disorder characterized by hyperglycemia due to abnormalities in insulin secretion or action. In West Java, the prevalence of DM reached 1.9%, with a significant increase in Tasikmalaya City, which recorded 7,436 cases in 2022. This study aimed to explore the relationship between individual characteristics, nutritional status, comorbidities, and duration of DM with HbA1c levels in type 2 diabetes patients at one of the private hospitals in Tasikmalaya City.This study evaluated medical records of 210 patients with type 2 DM. The Spearman's rank correlation test was used to analyse the relationships between variables and a p&lt;0.05 was considered as statistically significant. The research design used is cross sectional with purposive sampling technique.The result showed there was a statistically significant relationship between the duration of illness and HbA1c levels (p = 0.001 and r = 0,072). However, the relationship between nutritional status or comorbidities and HbA1c levels were not statistically significant (p = 0.471 and 0.187, respectively), indicating no relationship between nutritional status and HbA1c levels. The study concluded there was no significant relationship between nutritional status and comorbidities with HbA1c levels. Namun, ada hubungan antara durasi penyakit dengan kadar HbA1c

Murine nuclear tyrosyl-tRNA synthetase deficiency leads to fat storage deficiency and hearing loss

Aminoacyl-tRNA synthetases are fundamental to the translation machinery with emerging roles in transcriptional regulation. Previous cellular studies have demonstrated tyrosyl-tRNA synthetase (YARS1 or TyrRS) as a stress response protein through its cytosol-nucleus translocation to maintain cellular homeostasis. Here, we established a mouse model with a disrupted TyrRS nuclear localization signal, revealing its systemic impact on metabolism. Nuclear TyrRS deficiency (YarsΔNLS) led to reduced lean mass, reflecting a mild developmental defect, and reduced fat mass, possibly due to increased energy expenditure. Consistently, YarsΔNLS mice exhibit improved insulin sensitivity and reduced insulin levels, yet maintain normoglycemia, indicative of enhanced insulin action. Notably, YarsΔNLS mice also develop progressive hearing loss. These findings underscore the crucial function of nuclear TyrRS in the maintenance of fat storage and hearing and suggest that aminoacyl-tRNA synthetases' regulatory roles can affect metabolic pathways and tissue-specific health. This work broadens our understanding of how protein synthesis interconnects metabolic regulation to ensure energy efficiency.

Effectiveness of Earthworm Extract on the Lipid Profile of Diabetic Wistar Rats

Various metabolic diseases, such as diabetes mellitus, are characterized by hyperglycemia, stemming from decreased insulin action, secretion, or both. The use of chemical medicines for diabetes mellitus, especially acarbose, involves regulating the digestion and absorption of complex carbohydrates. However, acarbose may disrupt liver function, prompting exploration into alternative sources for treatment, such as earthworm extract. The purpose of this study was to identify the effectiveness of ethanol extract and coelomic fluid from earthworms (E. eugeniae) on the lipid profile of male diabetic wistar rats (R. norvegicus) in vivo. The research hypothesis is that earthworm extracts could effectively lower the lipid profile of diabetic Wistar rats. This research is experimental research with pre-test and post-test control study group design, using an in vivo method. The results of the one-way ANOVA test of HDL were p=0.441; p=0.441; p=0.000; for LDL were p=0.691; p=0.101; p=0.049; for total cholesterol were p=0.107; p=0.347; p=0.486; and for triglycerides were p=0.028; p=0.926; p=0.553 on days 0, 7, and 14, respectively. Based on the research data, both ethanol extract and a combination of ethanol extract and coelomic fluid were able to reduce lipid profile levels on the 7th and 14th days. Earthworm extract has the potential to promote repair of β cells and is anti-inflammatory which can be used to reduce lipid profile levels.

Insulin receptors in vascular smooth muscle cells regulate plaque stability of atherosclerosis.

Increased prevalence of acute myocardial infarction related to diabetes and insulin resistance is associated with elevated risk for unstable atherosclerotic plaques, which are characterized by reduced vascular smooth muscle cells (VSMC) and extracellular matrix (ECM) and increased inflammation. Thus, insulin resistance may reduce plaque stability as deleting insulin receptors (IR) in VSMC decreased their proliferation and enhanced apoptosis. Direct effects of insulin on VSMC to alter plaque composition were studied using mice with double knockout of ApoE and IR genes in VSMC with SMIRKO/ApoE-/- and Myh11-CreERT2EYFP+/ApoE-/- and Myh11-CreERT2EYFP+IRKO/ApoE-/- mice, which were also used for lineage tracing studies. Compared to ApoE-/- mice, SMIRKO/ApoE-/-- mice exhibited more atherosclerotic plaques, which contained less VSMC and collagen, but increased levels of VSMC apoptosis and necrotic areas. Lineage tracing studies showed that Icam1+ Vcam1+ VSMC was inflammatory VSMC, which increased in aortas of Myh11-CreERT2EYFP+IRKO/ApoE-/- mice compared to control mice. Isolated VSMC lacking IR expressed higher inflammatory cytokines than cells with IR. Cell based studies indicated that insulin's anti-apoptotic and pro-proliferative effects in VSMC were mediated via activation of IR/Akt pathway, which were decreased in VSMC from SMIRKO or high fat diet (HFD) mice. Analysis of IR targets that regulated inflammatory cytokines in VSMC showed that thrombospondin 1 (Thbs1) and Mmp2 were consistently increased with loss of IR. Insulin inhibited Thbs1 expression, but not Mmp2, by p-Akt/p-FoxO1 pathways in VSMC from ApoE-/- mice, which was impaired in cells from SMIRKO/ApoE-/-- mice. Thbs1 further induced Icam1 and Mmp2 expressions in VSMC. Insulin via IR has significant actions in VSMC to decrease inflammation, apoptosis and ECM turnover via the activation of Akt and FoxO1 pathways. Inhibition of insulin actions and related pathways related to insulin resistance and diabetes may contribute to the formation of unstable atherosclerotic plaques.

Role of SGLT2 inhibitors in improving cardiac functions (on Echocardiography) in patients having Diabetes Mellitus and ischemic heart disease

BACKGROUND &amp; OBJECTIVE: Sodium-glucose cotransporter-2 inhibitors (SGLT2i or SGLT2 inhibitors) have a distinctive mechanism of action unrelated to insulin secretion or action. By causing glucosuria, they reduce plasma glucose by inhibiting SGLT2 in the proximal tubules of the kidneys. This mechanism of action corrects several metabolic abnormalities, which are, in fact, CVD risks in addition to normoglycemia. This study was conducted to assess the average change in ejection fraction resulting from the use of SGLT2 inhibitors in enhancing cardiac function in patients with Diabetes Mellitus and ischemic heart disease. METHODOLOGY: This is a descriptive case series conducted from 10th December 2022 to 9th May 2023 in the Department of Medicine, Faisalabad Medical University; 435 type II diabetes mellitus patients were selected, according to inclusion and exclusion criteria. All received a daily dose of 20 mg of SGLT2 for three months. Echocardiography was done before and after the treatment period left ventricular ejection fraction (EF) was evaluated, and improvement in cardiac function was noted. RESULTS: In this study, the mean age of participants was 46.54±8.52 years. 314 (72.18%), or the majority, were between 30 and 50. The male-to-female ratio was 1.1:1, with 228 (52.41%) men and 207 (47.59%) women. The mean ejection fraction at baseline was 53.45 ± 4.12. The mean change in ejection fraction of SGLT2 inhibitors in improving cardiac functions among patients having Diabetes Mellitus and ischemic heart disease was 50.79 ± 3.76.( p-value ≤0.001). CONCLUSION: SGLT2 inhibitors effectively improve cardiac functions among patients with Diabetes Mellitus type II and ischemic heart insult

Evaluation of Prothrombin and Activated Partial Thromboplastin Time in Patients with Diabetes Mellitus

Diabetes mellitus (DM) is a metabolic disease accompanied by high blood glucose due to a defect in insulin secretion, insulin activity, or both. High blood glucose levels may lead to serious damage to some organs of the body, mainly blood vessels and nerves. Therefore, this study was conducted to evaluate prothrombin time (PT) and activated partial thromboplastin time (APTT) in diabetic patients. 100 venous blood samples were collected from diabetic patients attending the diabetes clinic in Sebha. Of them, 57 were males and 53 were females, and their ages ranged between 15-88 years. out of 100, 48 Were treated with insulin-regulating tablets and 52 Were treated with insulin injections. 34 blood samples were collected from healthy people (15 females and 19 males). They were used as a control group, aged between 14-55 years. 4 ml of venous blood was drawn, and 2 ml was placed in containers containing the anticoagulant sodium citrate to perform the PT and APTT. Place 2 ml of sample in tubes containing sodium fluoride anticoagulant to perform a fasting blood sugar (FBS). Place the tubes in a centrifuge at 3000 rpm to obtain plasma. The results showed the mean of PT in patients was (19.4 ± 3.6), the mean APTT was (35.9 ± 1.5) and the Mean FBS was (229.7 ± 80.39), whereas the mean PT, APTT, and FBS in control were (12.8 ± 1.6), (25.4 ± 2.1), and (91.9 ± 12.5) respectively. there was a significant increase of PT and APTT in patients compared to control (P&lt;0.05), PT and FBS were higher in patients who used insulin injection with significant differences(P&lt;0.05), while no significant differences were in APTT (P &gt; 0.05). The present study observed a statistically significant increase in PT and APTT among patients compared to controls, it would be helpful to incorporate coagulation screening as a routine investigation for the better management of diabetic patients.

Molecular Aspects in the Development of Type 2 Diabetes and Possible Preventive and Complementary Therapies.

The incidence of diabetes, including type 2 diabetes (T2DM), is increasing sharply worldwide. To reverse this, more effective approaches in prevention and treatment are needed. In our review, we sought to summarize normal insulin action and the pathways that primarily influence the development of T2DM. Normal insulin action involves mitogenic and metabolic pathways, as both are important in normal metabolic processes, regeneration, etc. However, through excess energy, both can be hyperactive or attenuated/inactive leading to disturbances in the cellular and systemic regulation with the consequence of cellular stress and systemic inflammation. In this review, we detailed the beneficial molecular changes caused by some important components of nutrition and by exercise, which act in the same molecular targets as the developed drugs, and can revert the damaged pathways. Moreover, these induce entire networks of regulatory mechanisms and proteins to restore unbalanced homeostasis, proving their effectiveness as preventive and complementary therapies. These are the main steps for success in prevention and treatment of developed diseases to rid the body of excess energy, both from stored fats and from overnutrition, while facilitating fat burning with adequate, regular exercise in healthy people, and together with necessary drug treatment as required in patients with insulin resistance and T2DM.

Loss of Insulin Signaling in Microglia Impairs Cellular Uptake of Aβ and Neuroinflammatory Response Exacerbating Alzheimer-like Neuropathology.

Insulin receptors are present on cells throughout the body, including the brain. Dysregulation of insulin signaling in neurons and astrocytes has been implicated in altered mood, cognition, and the pathogenesis of Alzheimers disease (AD). To define the role of insulin signaling in microglia, the primary phagocytes in brain critical for maintenance and damage repair, we created mice with an inducible microglia-specific insulin receptor knockout (MG-IRKO). RiboTag profiling of microglial mRNAs revealed that loss of insulin signaling results in alterations of gene expression in pathways related to innate immunity and cellular metabolism. In vitro, loss of insulin signaling in microglia results in metabolic reprograming with an increase in glycolysis and impaired uptake of Aβ. In vivo, MG-IRKO mice exhibit alterations in mood and social behavior, and when crossed with the 5xFAD mouse model of AD, the resultant mice exhibit increased levels of Aβ; plaque and elevated neuroinflammation. Thus, insulin signaling in microglia plays a key role in microglial cellular metabolism, neuroinflammation and the ability of the cells to take up Aβ; such that reduced insulin signaling in microglia alters mood and social behavior and accelerates AD pathogenesis. Together these data indicate key roles of insulin action in microglia and the potential of targeting insulin signaling in microglia in treatment of AD.

GLP-1 mimetics and diabetic ketoacidosis: possible interactions and clinical consequences.

Diabetic ketoacidosis is a serious diabetes-related consequence that occurs in type 1 diabetes and less commonly in type 2 diabetes and is a major cause of death. It results from the metabolic consequences due to a lack of insulin secretion or impaired insulin activity in diabetes leading to dysregulated pathophysiologic pathways resulting in excessive ketone body formation. While ketone bodies are physiologic molecules, their high levels reduce the physiological pH of the blood and induce ketoacidosis, leading to increasing metabolic dysfunction. Glucagon-like peptide-1 (GLP-1) mimetics are a class of recently developed diabetes therapy that do not lead to hypoglycemic, but some reports have suggested a relationship between GLP-1 mimetics and ketogenesis. To clarify the possible interactions between GLP-1 mimetics and ketogenesis in diabetes, this review was undertaken to collate and interpret the literature.

The influence of insulin and incretin-based therapies on renal tubular transport.

The tubular function of the kidney is very complex and is finely regulated by many factors. These include a variety of hormonal signaling pathways which are involved in the expression, activation and regulation of renal transporters responsible for the handling of electrolytes. Glucose-lowering drugs such as insulin and incretin-based therapies, exert a well-known renal protective role in diabetic kidney disease, mainly acting at the glomerular level. In the literature, several studies have described the effect of insulin and the incretin hormones on tubular transport. Most of these studies focused on the variations in excretion and clearance of sodium but did not extensively and systematically investigate the possible variations that these hormones may induce in the tubular regulation of all the other electrolytes, urea metabolism, acid-base balance and urinary pH. While insulin action on the kidney is very well-described, the renal tubular impact of incretin-based therapies is less consistent and the results available are scarce. To our knowledge, this is the first review summarizing the effects induced on renal tubules by insulin, glucagon-like peptide-1 (GLP-1) receptor agonists and serine protease dipeptidyl peptidase-4 (DPP4) inhibitors in both healthy and diabetic human subjects. This is significant because it highlights the existence of a renal-gut and pancreas axis which also has a direct tubular effect and enables a deeper understanding of renal physiology.

Caffeine Inhibits Both Basal and Insulin-Activated Urate Transport.

Caffeine, an adenosine receptor antagonist, is a potent central nervous system stimulant that also impairs insulin signaling. Recent studies have suggested that coffee consumption lowers serum urate (SU) and protects against gout by unknown mechanisms. We hypothesized that caffeine lowers SU by affecting activity of urate transporters. We examined the effect of caffeine and adenosine on basal and insulin stimulation of net 14C-urate uptake in the human renal proximal tubule cell line PTC-05 and on individual urate transporters expressed in Xenopus laevis oocytes. We found that caffeine and adenosine efficiently inhibited both basal and insulin stimulation of net 14C-urate uptake mediated by endogenous urate transporters in PTC-05 cells. In oocytes expressing individual urate transporters, caffeine (>0.2 mM) more efficiently inhibited the basal urate transport activity of GLUT9 isoforms, OAT4, OAT1, OAT3, NPT1, ABCG2, and ABCC4 than did adenosine without significantly affecting URAT1 and OAT10. However, unlike adenosine, caffeine at lower concentrations (<0.2 mM) very effectively inhibited insulin activation of urate transport activity of GLUT9, OAT10, OAT1, OAT3, NPT1, ABCG2, and ABCC4 by blocking activation of Akt and extracellular signal-regulated kinase. We postulate that inhibition of urate transport activity of the re-absorptive transporters GLUT9, OAT10, and OAT4 by caffeine is a key mechanism in its urate-lowering effects. Additionally, the ability of caffeine to block insulin-activated urate transport by GLUT9a and OAT10 suggests greater relative inhibition of these transporters in hyperinsulinemia.

Acute Sympathetic Blockade Improves Insulin-Mediated Microvascular Blood Flow in the Forearm of Adult Human Subjects With Obesity.

Obesity is associated with resistance to the metabolic (glucose uptake) and vascular (nitric-oxide mediated dilation and microvascular recruitment) actions of insulin. These vascular effects contribute to insulin sensitivity by increasing tissue delivery of glucose. Studies by us and others suggest that sympathetic activation contributes to insulin resistance to glucose uptake. Here we tested the hypothesis that sympathetic activation contributes to impaired insulin-mediated vasodilation in adult subjects with obesity. In a randomized crossover study, we used a euglycemic hyperinsulinemic clamp in 12 subjects with obesity to induce forearm arterial vasodilation (forearm blood flow) and microvascular recruitment (contrast-enhanced ultrasonography) during an intrabrachial infusion of saline (control) or phentolamine (sympathetic blockade). Insulin increased forearm blood flow on both study days (from 2.21±1.22 to 4.89±4.21 mL/100 mL per min, P=0.003 and from 2.42±0.89 to 7.19±3.35 mL/100 mL per min, P=0.002 for the intact and blocked day, respectively). Sympathetic blockade with phentolamine resulted in a significantly greater increase in microvascular flow velocity (∆microvascular flow velocity: 0.23±0.65 versus 2.51±3.01 arbitrary intensity units (AIU/s) for saline and phentolamine respectively, P=0.005), microvascular blood volume (∆microvascular blood volume: 1.69±2.45 versus 3.76±2.93 AIU, respectively, P=0.05), and microvascular blood flow (∆microvascular blood flow: 0.28±0.653 versus 2.51±3.01 AIU2/s, respectively, P=0.0161). To evaluate if this effect was not due to nonspecific vasodilation, we replicated the study in 6 subjects with obesity comparing intrabrachial infusion of phentolamine to sodium nitroprusside. At doses that produced similar increases in forearm blood flow, insulin-induced changes in microvascular flow velocity were greater during phentolamine than sodium nitroprusside (%microvascular flow velocity=58% versus 29%, respectively, P=0.031). We conclude that sympathetic activation impairs insulin-mediated microvascular recruitment in adult subjects with obesity.