Effect of insulin on proximal tubules handling of glucose: a systematic review

Renal proximal tubules reabsorb glucose from the glomerular filtrate and release it back into the circulation. Modulation of glomerular filtration and renal glucose disposal are some of the insulin actions, but little is known about a possible insulin effect on tubular glucose reabsorption. This review is aimed at synthesizing the current knowledge about insulin action on glucose handling by proximal tubules. Method. A systematic article selection from Medline (PubMed) and Embase between 2008 and 2019. 180 selected articles were clustered into topics (renal insulin handling, proximal tubule glucose transport, renal gluconeogenesis, and renal insulin resistance). Summary of Results. Insulin upregulates its renal uptake and degradation, and there is probably a renal site-specific insulin action and resistance; studies in diabetic animal models suggest that insulin increases renal SGLT2 protein content; in vivo human studies on glucose transport are few, and results of glucose transporter protein and mRNA contents are conflicting in human kidney biopsies; maximum renal glucose reabsorptive capacity is higher in diabetic patients than in healthy subjects; glucose stimulates SGLT1, SGLT2, and GLUT2 in renal cell cultures while insulin raises SGLT2 protein availability and activity and seems to directly inhibit the SGLT1 activity despite it activating this transporter indirectly. Besides, insulin regulates SGLT2 inhibitor bioavailability, inhibits renal gluconeogenesis, and interferes with Na(+)K(+)ATPase activity impacting on glucose transport. Conclusion. Available data points to an important insulin participation in renal glucose handling, including tubular glucose transport, but human studies with reproducible and comparable method are still needed202

Mechanisms of sodium-glucose cotransporter-2 inhibition: insights from large-scale proteomics

OBJECTIVE To assess the effects of empagliflozin, a selective sodium–glucose cotransporter 2 (SGLT2) inhibitor, on broad biological systems through proteomics. RESEARCH DESIGN AND METHODS Aptamer-based proteomics was used to quantify 3,713 proteins in 144 paired plasma samples obtained from 72 participants across the spectrum of glucose tolerance before and after 4 weeks of empagliflozin 25 mg/day. The biology of the plasma proteins significantly changed by empagliflozin (at false discovery rate–corrected P < 0.05) was discerned through Ingenuity Pathway Analysis. RESULTS Empagliflozin significantly affected levels of 43 proteins, 6 related to cardiomyocyte function (fatty acid–binding protein 3 and 4 [FABPA], neurotrophic receptor tyrosine kinase, renin, thrombospondin 4, and leptin receptor), 5 to iron handling (ferritin heavy chain 1, transferrin receptor protein 1, neogenin, growth differentiation factor 2 [GDF2], and β2-microglobulin), and 1 to sphingosine/ceramide metabolism (neutral ceramidase), a known pathway of cardiovascular disease. Among the protein changes achieving the strongest statistical significance, insulin-like binding factor protein-1 (IGFBP-1), transgelin-2, FABPA, GDF15, and sulphydryl oxidase 2 precursor were increased, while ferritin, thrombospondin 3, and Rearranged during Transfection (RET) were decreased by empagliflozin administration. CONCLUSIONS SGLT2 inhibition is associated, directly or indirectly, with multiple biological effects, including changes in markers of cardiomyocyte contraction/relaxation, iron handling, and other metabolic and renal targets. The most significant differences were detected in protein species (GDF15, ferritin, IGFBP-1, and FABP) potentially related to the clinical and metabolic changes that were actually measured in the same patients. These novel results may inform further studies using targeted proteomics and a prospective design

Early Hypertension Is Associated With Reduced Regional Cardiac Function, Insulin Resistance, Epicardial, and Visceral Fat

Mild-to-moderate hypertension is often associated with insulin resistance and visceral adiposity. Whether these metabolic abnormalities have an independent impact on regional cardiac function is not known. The goal of this study was to investigate the effects of increased blood pressure, insulin resistance, and ectopic fat accumulation on the changes in peak systolic circumferential strain. Thirty-five male subjects (age: 47±1 years; body mass index: 28.4±0.6 kg . m −2 ; mean±SEM) included 13 with normal blood pressure (BP: 113±5/67±2 mm Hg), 13 with prehypertension (BP: 130±1/76±2 mm Hg), and 9 newly diagnosed with essential hypertension (BP: 150±2/94±2 mm Hg) who underwent cardiac magnetic resonance tissue tagging (MRI) and MRI quantitation of abdominal visceral and epicardial fat. Glucose tolerance, on oral glucose tolerance test, and insulin resistance were assessed along with the serum lipid profile. All of the subjects had normal glucose tolerance, left- and right-ventricular volumes, and ejection fraction. Across the BP groups, left ventricular mass tended to increase, and circumferential shortening was progressively reduced at basal, midheart, and apical segments (on average, from −17.0±0.5% in normal blood pressure to −15.2±0.7% in prehypertension to −13.6±0.8% in those newly diagnosed with essential hypertension; P =0.004). Reduced circumferential strain was significantly associated with raised BP independent of age ( r =0.41; P =0.01) and with epicardial and visceral fat, serum triglycerides, and insulin resistance independent of age and BP. In conclusion, regional left ventricular function is already reduced at the early stages of hypertension despite the normal global cardiac function. Insulin resistance, dyslipidemia, and ectopic fat accumulation are associated with reduced regional systolic function

Resposta insulinemica e pressorica a ingestão oral de glicose em pacientes com hipertensão arterial essencial

Orientador: Jose Francisco FigueiredoDissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências MédicasResumo: Não informadoAbstract: Not informedMestradoMestre em Medicin

Efeitos da ingestão oral de glicose sobre a excreção urinaria de eletrolitos e acidos em pacientes com hipertensão arterial essencial

Orientador : Jose Antonio Rocha GontijoTese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciencias MedicasResumo: Indivíduos normotensos (n = 18) e pacientes portadores de hipertensão arterial essencial (n = 1 7), sem doenças intercorrentes ou complicações crônicas da hipertensão arterial, tolerantes à sobrecarga oral de glicose pelos critérios da NDDG, com peso corporal Igual a ± 20% do Ideal, foram submetidos à ingestão de glicose elou água (20 ml/kg). O ensaio controle (hídrico) realizado após 12 h de jejum correspondeu à ingestão hídrica com reposição via oral horária de um volume de água, semelhante ao fluxo miccional durante o mesmo período. O estudo se estendeu por 6 h, nas quais foram medidas a pressão arterial e coletados sangue e urina para avaliar alguns parâmetros funcionais do nefro. Utilizando-se de protocolo experimental similar, foi realizado o ensaio glicose, com Ingestão oral de glicose (100g em solução a 22%). após período controle de 2 h. Durante os experimentos hídricos, em normotensos (NT) e em hipertensos (HT). permaneceram estáveis as concentrações de sódio, creatinina, glicose e Insulina plasmáticas, assim como a filtração glomerular (clearance de creatinina endógena). as cargas filtradas de sódio e potássio e a PAM. Foi promovida uma diurese aquosa com volumes similares nos dois grupos. Nos HT observou-se uma maior excreção de sódio no período controle (natriurese exacerbada), que diminuiu progressivamente nos períodos subseqüentes. A excreção urinária de ácidos (monofosfato ácido e amônia) aumentou discreta e continuamente. até o final do experimento. Após a Ingestão oral de glicose. o decréscimo da PAM foi significativamente maior nos HT, sem, entretanto, apresentar modificações significativas da filtração glomerular nos dois grupos estudados. As concentrações plasmáticas de creatinina, sódio, potássio. e as cargas filtradas de sódio e potássio não se modificaram no decorrer deste ensaio. Em 5 dos HT verificou-se a presença de elevados níveis insulinêmicos (HHI) durante todo o experimento, acompanhados por um aumento da glicemia aos 60 min após IOG. sugerindo resistência à Insulina neste subgrupo. Após IOG. ocorreu um a acentuada antinatriurese, com variações percentuais da FENa ao redor de -30% nos NT e HT, mantida durante todo o experimento neste último grupo. Concomitantemente observou-se uma maior excreção de acidez titulável e ácidos urinários não voláteis, mantida apenas por 120 minutos. A potassemia não apresentou qualquer modificação nos normotensos-hidricos, decrescendo nos hipertensos-hidricos e em NT e HT após glicose. A FEK diminuiu nos grupos que ingeriram glicose, sugerindo que a insulina e/ou glicose têm efeitos diretos ou indiretos sobre a secreção tubular distal de potássio. Os pacientes hiperinsulinêmicos apresentaram uma diminuição do CCr aos 60 min após 10G. sugerindo uma modificação hemodinâmica intra renal. A menor excreção urinária de potássio observada nestes pacientes pode ser indicativa de uma sensibilidade normal à ação Insulínica no manuseio renal do potássio. Os resultados deste trabalho apresentam um efeito da 10G sobre a reabsorção tubular de sódio. similar em NT e HT. embora neste último grupo tenha sido documentada hiperinsulinemia. Estes sugerem uma resistência tissular renal à ação antinatriurética da Insulina nos pacientes estudados. o que poderia contribuir para o desenvolvimento ou manutenção de elevados níveis pressóricos, através da retenção crônica de sódio. Os possíveis mecanismos envolvidos na antinatriurese, na anticarfurese e os sítios tubulares de ação da insulina, após glicose, são discutidos, assim como os mecanismos da natriurese exacerbada nos hipertensos após ingestão de águaAbstract: This study was conducted on 18 normotesive healthy subjetcs (NT) and on 17 essentlally hypertenslve (HT) patlents wlth dlastolic blood pressure above 95 mmHg, aged between twenty and forty five years old. Additional criteria for Inclusion In the study were 90 to 110% o, Ideal body welght according to the Metropolltan Llfe Insurance Tables, and a normal gfucose tolerance test. No patient or control was recelving any medicatlon. The studies wer.e performed in the morning, starting at 7:00 AM, after a overnlght fast, until 1 :00 PM. Imedlately after to empty his bladder, each subject ingested 20 ml of tap water/kg body weight and hourly volume similar to the diuresis. After a 2 h control period, an oral glucose tolerance test wlth a 100g glucose load was performed (GTT) on 15 normotensive (NG)- and on 15 hypertensive (HG). The control groups, 15 normotensive (NH) and 12 hypertensive (HH), received only tap water. Blood pressure was measured at 30 min Intervals. Urine aliquots were pooled at 1 hour Intervals and bfood samples were collected at 8:00, 9:30; 10:00; 10:30; 11 :00; 12:00 AM and 1 :00 PM. After oral gfucose ingestion (IOG), Insulin levels were signiflcantly higher In five of the 15 patients (hyperlnsullnemic hypertensive HHI) than in normotensive and in normoinsulinemic hypertensive (HNI). The maximum plasma glucose. at 60 min after IOG were slgnlflcantly hlgher In the HNI subgroup. There is no significant dirrerence between groups or significant changes in plasma levels of Na+. K+ and creatinine; In creatinine clearances and glomerular fIItratlon rate of Na + and K+. except In HHI. In this subgroup. a translent but significant decrease In creatlnlne clearance occurred at 60 min after 10G. followed by a significant fali of the glomerular filtration rate of K+ and Na+. After water load. it was observed a significant hlgher urinary sodium excretion (UNaV) In both hypertenslve groups. HH and HG, than in normotensives. On the other hand, a glucose ingestion induced a significant fall In UNaV and In fractlonal sodium excretion. similar in NG and HG. and In HHI and HNI. Also, a similar decrease In plasma K+ levels, and a similar antlkalluresis were observed in NG and HG groups, but a higher antlkalluresls was obtained In HHI subgroups. No significant differences were found between groups, neither between control and experimental periods for NH4 + urinaryexcretion. The urinary aeidity tritrable exeretion decreased slow and eon tinously in the control groups (NH and HH) and increased more in NG 1han In HG groups a1 60 min after glucose loading Ingestion. No significant correlations were found between plasma Insulin or glucose and frational sodium or potassium excretion. Since the oral glucose load has no effect on glomerular filtration rate, except in HHI. the antinatriuresis seem to be due an increase in tubular lon reabsorptlon. The tubular sltes involved In thls insulln actlons m ay be the proxlmal nephron segments and the tlck ascend Ing 11mb of Henle. The results of thls protocol may suggest a resistance in renal tissues to insulin actlon on natriuresis, but not to the effects on kalluresisDoutoradoDoutor em Medicin

Loss of the incretin effect in type 2 diabetes: a systematic review and meta-analysis

Context: Loss of the incretin effect (IE) in type 2 diabetes (T2D) contributes to hyperglycemia and the mechanisms underlying this impairment are unclear. Objective: To quantify the IE impairment in T2D and to investigate the factors associated with it using a meta-analytic approach. Data sources: PubMed, Scopus and Web-of-Science. Study selection: Studies measuring IE by the gold-standard protocol employing an OGTT and an intravenous glucose infusion at matched glucose levels. Data extraction: We extracted IE, sex, age, BMI, HbA1c, fasting values and areas-under-curve (AUC) of glucose, insulin, C-peptide, GIP and GLP-1. In T2D subjects, we also recorded T2D duration, age at diagnosis, and the percentage of subjects taking antidiabetic medications. Data synthesis: The IE weighted mean difference between T2D and NGT subjects was -27.3% (CI [-36.5 -18.1]%; p<0.001; I 2 = 86.6%) and was affected by age (p<0.005). By meta-regression of combined NGT and T2D data, IE was inversely associated with glucose tolerance (lower IE in T2D), BMI, and fasting GIP (p<0.05). By meta-regression of T2D studies only, IE was associated with the OGTT glucose dose (p<0.0001). IE from insulin was larger than IE from C-peptide (weighted mean difference 11.2%, CI [9.2-13.2]%; p<0.0001; I 2=28.1%); the IE difference was inversely associated with glucose tolerance and fasting glucose. Conclusions: The IE impairment in T2D vs NGT is consistent though considerably variable, age being a possible factor affecting the IE difference. Glucose tolerance, BMI, and fasting GIP are independently associated with IE; in T2D subjects only, the OGTT dose is a significant covariate

Chronotopic and blood pressure response to oral glucose load in chagas' disease

Cardiac chronotropic and pressor responses after an oral load of glucose were assessed in sixteen Chagasic subjects and 28 controls by means of blood pressure and pulse rate measurements. Cardiovascular response was correlated with serum insulin and glucose levels. The experiment identified a subgroup of Chagasic subjects (n=8) with a hypoinsulinemic behavior presenting less chronotropic and pressor responses than controls. This may indicate a lower insulin activity and/or an early Autonomic Nervous System dysfunction in this subgroup