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

Retinol-Binding Protein-4 in Women With Untreated Essential Hypertension

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Complete Genome Sequences of Mycobacterium smegmatis Phages Chewbacca, Reptar3000, and Riparian, Isolated in Las Vegas, Nevada

Here, we present the complete genome sequences of Mycobacterium smegmatis phages Chewbacca, Reptar3000, and Riparian, isolated from soil in Las Vegas, NV. The phages were isolated and annotated by undergraduate students enrolled in the Phage Discovery course offered by the School of Life Sciences at the University of Nevada, Las Vega

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

Long-term effects of bariatric surgery on meal disposal and beta-cell function in diabetic and nondiabetic patients.

Gastric bypass surgery leads to marked improvements in glucose tolerance and insulin sensitivity in obese type 2 diabetes; the impact on glucose fluxes in response to a physiological stimulus - such as a mixed meal (MTT) - has not been determined. We administered an MTT to 12 obese type 2 diabetic patients (T2D) and 15 obese nondiabetic subjects (ND) before and one year after surgery (10 T2D and 11 ND) using the double-tracer technique and modeling of ß-cell function. In both groups postsurgery, tracer-derived appearance of oral glucose was biphasic, a rapid increase followed by a sharp drop, a pattern that was mirrored by postprandial glucose levels and insulin secretion. In diabetic patients, surgery lowered fasting and postprandial glucose levels; peripheral insulin sensitivity increased in proportion to weight loss (∼30%), ß-cell glucose sensitivity doubled but did not normalize (viz. 21 nonsurgical obese and lean controls). Endogenous glucose production, however, was less suppressed during the MMT as the combined result of a relative hyperglucagonemia and the rapid fall in plasma glucose and insulin levels.We conclude that, in type 2 diabetes bypass surgery changes the postprandial response to a dumping-like pattern, improves glucose tolerance, ß-cell function, and peripheral insulin sensitivity but worsens endogenous glucose output in response to a physiological stimulus

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

Early and longer term effects of gastric bypass surgery on tissue-specific insulin sensitivity and beta cell function in morbidly obese patients with and without type 2 diabetes

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Body Mass Index, abdominal adiposity, obesity, and cardiovascular reactions to psychological stress in a large community sample

OBJECTIVE: To examine the association between adiposity and the magnitude of cardiovascular reactions to acute psychological stress cross-sectionally and prospectively in a large community sample.\ud \ud METHODS: Blood pressure and heart rate (HR) were measured at rest and in response to a brief time-pressured mental arithmetic stress in 1647 adults. At the same session and 5 years later, height, weight, waist and hip circumference were measured and body mass index (BMI) and waist-hip ratio were computed. Obesity was defined as a body mass index of > or = 30 kg/m(2).\ud \ud RESULTS: Contrary to expectations, the most robust and consistent results to emerge from cross-sectional analyses were negative associations between all three measures of adiposity and HR reactivity; those with greater BMI and waist-hip ratios and those categorized as obese displayed smaller HR reactions to stress. In prospective analyses, high HR reactivity was associated with a reduced likelihood of becoming obese in the subsequent 5 years.\ud \ud CONCLUSIONS: Our analyses suggest that it is low, not high, HR reactivity that is related to adiposity. Low HR reactivity, probably by reflecting generally blunted sympathetic nervous system reactions to challenge, may be a risk marker for developing obesity.\ud \u

First-Phase Insulin Secretion Restoration and Differential Response to Glucose Load Depending on the Route of Administration in Type 2 Diabetic Subjects After Bariatric Surgery

OBJECTIVE—The purpose of this study was to elucidate the mechanisms of diabetes reversibility after malabsorptive bariatric surgery

RD Lawrence Lecture 2008 Targeting GLP-1 release as a potential strategy for the therapy of Type 2 diabetes

Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are gastrointestinal hormones that play an important role in stimulating postprandial insulin release from pancreatic β-cells. Agents that either mimic GLP-1 or prevent its degradation are now available for the treatment of Type 2 diabetes, and strategies to enhance endogenous GLP-1 release are under assessment. As intestinal peptides have a range of actions, including appetite regulation and coordination of fat metabolism, harnessing the enteric endocrine system is a promising new field for drug development