Renal and vascular benefits of C-peptide: Molecular mechanisms of C-peptide action

C-peptide has long been thought to be an inert byproduct of insulin production, but it has become apparent, and accepted, that C-peptide has important biological properties. C-peptide displays beneficial effects in many tissues affected by diabetic complications, such as increased peripheral blood flow and protection from renal damage. However, the mechanisms mediating these effects remain unclear. C-peptide interacts with cellular membranes at unidentified sites distinctive of the insulin family of receptors, and signals to multiple targets known to play a role in diabetes and diabetic complications, such as Na+/K+-ATPase and NOS. In general, the physiological and molecular effects of C-peptide resemble insulin, but C-peptide also possesses traits separate from those of insulin. These basic studies have been confirmed in human studies, suggesting that C-peptide may lend itself to clinical applications. However, the molecular and physiological properties of C-peptide are not completely elucidated, and large clinical studies have not begun. In order to further these goals, we critically summarize the current state of knowledge regarding C-peptide’s renal and vascular effects and the molecular signaling of C-peptide

Grön offentlig upphandling i transportsektorn

Många kommuner i Sverige ställer krav på miljöbilar i upphandlingen av kommunala tjänstebilar, och en del ställer även specifika krav på elbilar. Detta projekt har utvärderat offentlig upphandling för att svara på frågor om vilken potential upphandling har för att främja förnybara drivmedel, vilka de praktiska erfarenheterna är, huruvida offentlig upphandling används strategiskt och hur styrmedlet kan vidareutvecklas.Metoden som använts är komparativa fallstudier av kommunerna Malmö och Östersund, samt regionerna Skåne och Jämtland. Det empiriska underlaget för studierna består av en kombination av dokumentstudier och semistrukturerade kvalitativa intervjuer som genomförts med upphandlare, miljöstrateger, kollektivtrafikstrateger, politiker och representanter från privata trans­portoperatörer.Det övergripande syftet är att öka förståelsen för utmaningarna med grön offentlig upphandling och hur dessa bemötts i några utvalda fall. Även om det råder skillnader i de olika orternas och regionernas politiska, geografiska och infrastrukturella förutsättningar samt i sättet på vilket kraven i upphandling utformats som följd av detta, så har studien kunnat peka på några generella policyimplikationer som rör lagstiftning och reglering, kostnader, politiska mål och samverkan mellan aktörer. Resultaten från projektet bidrar därmed till kunskapen om hur användningen av offentlig upphandling kan förbättras och utvecklas

Metabolic changes in summer active and anuric hibernating free-ranging brown bears (ursus arctos)

The brown bear (Ursus arctos) hibernates for 5 to 6 months each winter and during this time ingests no food or water and remains anuric and inactive. Despite these extreme conditions, bears do not develop azotemia and preserve their muscle and bone strength. To date most renal studies have been limited to small numbers of bears, often in captive environments. Sixteen free-ranging bears were darted and had blood drawn both during hibernation in winter and summer. Samples were collected for measurement of creatinine and urea, markers of inflammation, the calcium-phosphate axis, and nutritional parameters including amino acids. In winter the bear serum creatinine increased 2.5 fold despite a 2-fold decrease in urea, indicating a remarkable ability to recycle urea nitrogen during hibernation. During hibernation serum calcium remained constant despite a decrease in serum phosphate and a rise in FGF23 levels. Despite prolonged inactivity and reduced renal function, inflammation does not ensue and bears seem to have enhanced antioxidant defense mechanisms during hibernation. Nutrition parameters showed high fat stores, preserved amino acids and mild hyperglycemia during hibernation. While total, essential, non-essential and branched chain amino acids concentrations do not change during hibernation anorexia, changes in individual amino acids ornithine, citrulline and arginine indicate an active, although reduced urea cycle and nitrogen recycling to proteins. Serum uric acid and serum fructose levels were elevated in summer and changes between seasons were positively correlated. Further studies to understand how bears can prevent the development of uremia despite minimal renal function during hibernation could provide new therapeutic avenues for the treatment of human kidney disease

Insufficient insulin administration to diabetic rats increases substrate utilization and maintains lactate production in the kidney

Good glycemic control is crucial to prevent the onset and progression of late diabetic complications, but insulin treatment often fails to achieve normalization of glycemic control to the level seen in healthy controls. In fact, recent experimental studies indicate that insufficient treatment with insulin, resulting in poor glycemic control, has an additional effect on progression of late diabetic complications, than poor glycemic control on its own. We therefore compared renal metabolic alterations during conditions of poor glycemic control with and without suboptimal insulin administration, which did not restore glycemic control, to streptozotocin (STZ)‐diabetic rats using noninvasive hyperpolarized (13)C‐pyruvate magnetic resonance imaging (MRI) and blood oxygenation level–dependent (BOLD) (1)H‐MRI to determine renal metabolic flux and oxygen availability, respectively. Suboptimal insulin administration increased pyruvate utilization and metabolic flux via both anaerobic and aerobic pathways in diabetic rats even though insulin did not affect kidney oxygen availability, HbA(1c), or oxidative stress. These results imply direct effects of insulin in the regulation of cellular substrate utilization and metabolic fluxes during conditions of poor glycemic control. The study demonstrates that poor glycemic control in combination with suboptimal insulin administration accelerates metabolic alterations by increasing both anaerobic and aerobic metabolism resulting in increased utilization of energy substrates. The results demonstrate the importance of tight glycemic control in insulinopenic diabetes, and that insulin, when administered insufficiently, adds an additional burden on top of poor glycemic control

Circadian variation in renal blood flow and kidney function in healthy volunteers monitored using non-invasive magnetic resonance imaging

Circadian regulation of kidney function is involved in maintaining whole-body homeostasis and dysfunctional circadian rhythm can potentially be involved in disease development. Magnetic Resonance Imaging (MRI)provides reliable and reproducible repetitive estimates of kidney function non-invasively without the risk of adverse events associated with contrast agents and ionizing radiation. The purpose of this study was to estimate circadian variations in kidney function in healthy human subjects using MRI, and relate the findings with urinary excretions of electrolytes and markers of kidney function.Phase Contrast imaging, Arterial Spin Labeling and Blood Oxygen Level DependentR2*-mapping were used to assess the total renal blood flow and regional perfusion,and intrarenal oxygenation in eight female and eight male healthy volunteers every fourth hour during a 24hperiod. Parallel with MRI scans, standard urinary and plasma parameters were quantified. Significant circadian variations of total renal blood flow were found over 24hwith increasing flow from noon to midnight and decreasing flow during the night. In contrast, no circadian variation in intrarenal oxygenation was detected.Urinary excretions of electrolytes, osmotically active particles, creatinine and urea all displayed circadian variations, peaking during the afternoon and evening hours.In conclusion, total renal blood flow and kidney function, as estimated from excretion of electrolytes and waste products, display profound circadian variations, whereas intrarenal oxygenation displays significantly less circadian variation

Decreased renal perfusion during acute kidney injury in critical COVID-19 assessed by magnetic resonance imaging: a prospective case control study

Abstract: Background: Renal hypoperfusion has been suggested to contribute to the development of acute kidney injury (AKI) in critical COVID-19. However, limited data exist to support this. We aim to investigate the differences in renal perfusion, oxygenation and water diffusion using multiparametric magnetic resonance imaging in critically ill COVID-19 patients with and without AKI. Methods: A prospective case–control study where patients without prior kidney disease treated in intensive care for respiratory failure due to COVID-19 were examined. Kidney Disease: Improving Global Outcomes Creatinine criteria were used for group allocation. Main comparisons were tested using Mann–Whitney U test. Results: Nineteen patients were examined, ten with AKI and nine without AKI. Patients with AKI were examined in median 1 [0–2] day after criteria fulfillment. Age and baseline Plasma-Creatinine were similar in both groups. Total renal blood flow was lower in patients with AKI compared with patients without (median 645 quartile range [423–753] vs. 859 [746–920] ml/min, p = 0.037). Regional perfusion was reduced in both cortex (76 [51–112] vs. 146 [123–169] ml/100 g/min, p = 0.015) and medulla (28 [18–47] vs. 47 [38–73] ml/100 g/min, p = 0.03). Renal venous saturation was similar in both groups (72% [64–75] vs. 72% [63–84], ns.), as was regional oxygenation (R2*) in cortex (17 [16–19] vs. 17 [16–18] 1/s, ns.) and medulla (29 [24–39] vs. 27 [23–29] 1/s, ns.). Conclusions: In critically ill COVID-19 patients with AKI, the total, cortical and medullary renal blood flows were reduced compared with similar patients without AKI, whereas no differences in renal oxygenation were demonstrable in this setting. Trial registration ClinicalTrials ID: NCT02765191, registered May 6 2014 and updated May 7 2020. Graphic Abstract

Repression of hypoxia-inducible factor-1 contributes to increased mitochondrial reactive oxygen species production in diabetes

Background: Excessive production of mitochondrial reactive oxygen species (ROS) is a central mechanism for the development of diabetes complications. Recently, hypoxia has been identified to play an additional pathogenic role in diabetes. In this study, we hypothesized that ROS overproduction was secondary to the impaired responses to hypoxia due to the inhibition of hypoxia-inducible factor-1 (HIF-1) by hyperglycemia. Methods: The ROS levels were analyzed in the blood of healthy subjects and individuals with type 1 diabetes after exposure to hypoxia. The relation between HIF-1, glucose levels, ROS production and its functional consequences were analyzed in renal mIMCD-3 cells and in kidneys of mouse models of diabetes. Results: Exposure to hypoxia increased circulating ROS in subjects with diabetes, but not in subjects without diabetes. High glucose concentrations repressed HIF-1 both in hypoxic cells and in kidneys of animals with diabetes, through a HIF prolyl-hydroxylase (PHD)-dependent mechanism. The impaired HIF-1 signaling contributed to excess production of mitochondrial ROS through increased mitochondrial respiration that was mediated by Pyruvate dehydrogenase kinase 1 (PDK1). The restoration of HIF-1 function attenuated ROS overproduction despite persistent hyperglycemia, and conferred protection against apoptosis and renal injury in diabetes. Conclusions: We conclude that the repression of HIF-1 plays a central role in mitochondrial ROS overproduction in diabetes and is a potential therapeutic target for diabetic complications. These findings are timely since the first PHD inhibitor that can activate HIF-1 has been newly approved for clinical use. Funding: This work was supported by grants from the Swedish Research Council, Stockholm County Research Council, Stockholm Regional Research Foundation, Bert von Kantzows Foundation, Swedish Society of Medicine, Kung Gustaf V:s och Drottning Victorias Frimurarestifelse, Karolinska Institute's Research Foundations, Strategic Research Programme in Diabetes, and Erling-Persson Family Foundation for S-B.C.; grants from the Swedish Research Council and Swedish Heart and Lung Foundation for T.A.S.; and ERC consolidator grant for M.M.Peer reviewe

Low Postseroconversion CD4+ T-cell Level Is Associated with Faster Disease Progression and Higher Viral Evolutionary Rate in HIV-2 Infection

L