Intermittent fasting (IF) protects against the development of metabolic diseases and cancer, but whether it can prevent diabetic microvascular complications is not known. In mice, we examined the impact of long-term IF on diabetic retinopathy (DR). Despite no change in glycated hemoglobin, mice on the IF regimen displayed significantly longer survival and a reduction in DR end points, including acellular capillaries and leukocyte infiltration. We hypothesized that IF-mediated changes in the gut microbiota would produce beneficial metabolites and prevent the development of DR. Microbiome analysis revealed increased levels of Firmicutes and decreased Bacteroidetes and Verrucomicrobia. Compared with mice on ad libitum feeding, changes in the microbiome of the mice on IF were associated with increases in gut mucin, goblet cell number, villi length, and reductions in plasma peptidoglycan. Consistent with the known modulatory effects of Firmicutes on bile acid (BA) metabolism, measurement of BAs demonstrated a significant increase of tauroursodeoxycholate (TUDCA), a neuroprotective BA, in on IF but not in on AL feeding. TGR5, the TUDCA receptor, was found in the retinal primary ganglion cells. Expression of TGR5 did not change with IF or diabetes. However, IF reduced retinal TNF-α mRNA, which is a downstream target of TGR5 activation. Pharmacological activation of TGR5 using INT-767 prevented DR in a second diabetic mouse model. These findings support the concept that IF prevents DR by restructuring the microbiota toward species producing TUDCA and subsequent retinal protection by TGR5 activation.
Over the past 25 years, successive cloning of SLC34A1, SLC34A2 and SLC34A3, which encode the sodium-dependent inorganic phosphate (P i ) cotransport proteins 2a-2c, has facilitated the identification of molecular mechanisms that underlie the regulation of renal and intestinal P i transport. P i and various hormones, including parathyroid hormone and phosphatonins, such as fibroblast growth factor 23, regulate the activity of these P i transporters through transcriptional, translational and post-translational mechanisms involving interactions with PDZ domain-containing proteins, lipid microdomains and acute trafficking of the transporters via endocytosis and exocytosis. In humans and rodents, mutations in any of the three transporters lead to dysregulation of epithelial P i transport with effects on serum P i levels and can cause cardiovascular and musculoskeletal damage, illustrating the importance of these transporters in the maintenance of local and systemic P i homeostasis. Functional and structural studies have provided insights into the mechanism by which these proteins transport P i , whereas in vivo and ex vivo cell culture studies have identified several small molecules that can modify their transport function. These small molecules represent potential new drugs to help maintain P i homeostasis in patients with chronic kidney disease -a condition that is associated with hyperphosphataemia and severe cardiovascular and skeletal consequences.
The inhibitory action of parathyroid hormone (PTH) on Pi reabsorption in the renal proximal tubule is accompanied by a specific decrease in Na-Pi cotransport at the apical brush-border membrane (BBM). It is not known whether this decrease represents decreased activity of Na-Pi cotransporters already present in the BBM or whether the number of cotransporters is decreased. The present study of the molecular mechanism of PTH action made use of a specific cDNA probe and antiserum to a rat renal Na-Pi cotransporter (NaPi-2). Three groups of rats were used: intact controls, chronically parathyroidectomized (PTX), and PTX rats treated acutely (2 h) with bovine PTH-(1--34). Na-Pi cotransport by isolated renal BBM vesicles was increased to 1,315 +/- 44 in PTX rats, compared with 721 +/- 94 pmol.mg-1.10 s-1 in controls (P < 0.002), and was returned to control levels by PTH. Western blots of these BBM showed that PTX caused a 2.8-fold increase in NaPi-2 protein content, which was reduced to control levels by PTH. Immunohistochemistry of perfusion-fixed kidneys showed NaPi-2-specific immunofluorescence exclusively in apical BBM of proximal tubules. Expression of NaPi-2 protein at these sites was increased in PTX rats and decreased after PTH treatment. Northern analysis of total RNA showed that the abundance of NaPi-2-specific mRNA was not changed by PTX but there was a small decrease in response to PTH. The data indicate that PTH regulation of renal Na-Pi cotransport is determined by changes in expression of NaPi-2 protein in the renal BBM.(ABSTRACT TRUNCATED AT 250 WORDS)
Heart failure (HF) has been recognized as a common complication of diabetes, with a prevalence of up to 22% in individuals with diabetes and increasing incidence rates. Data also suggest that HF may develop in individuals with diabetes even in the absence of hypertension, coronary heart disease, or valvular heart disease and, as such, represents a major cardiovascular complication in this vulnerable population; HF may also be the first presentation of cardiovascular disease in many individuals with diabetes. Given that during the past decade, the prevalence of diabetes (particularly type 2 diabetes) has risen by 30% globally (with prevalence expected to increase further), the burden of HF on the health care system will continue to rise. The scope of this American Diabetes Association consensus report with designated representation from the American College of Cardiology is to provide clear guidance to practitioners on the best approaches for screening and diagnosing HF in individuals with diabetes or prediabetes, with the goal to ensure access to optimal, evidence-based management for all and to mitigate the risks of serious complications, leveraging prior policy statements by the American College of Cardiology and American Heart Association.
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