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The primary cilium is a narrow organelle located at the surface of the cell in contact with the extracellular environment. Once underappreciated, now is thought to efficiently sense external environmental cues and mediate cell-to-cell communication, because many receptors, ion channels, and signaling molecules are highly or differentially expressed in primary cilium. Rare genetic disorders that affect cilia integrity and function, such as Bardet-Biedl syndrome and Alström syndrome, have awoken interest in studying the biology of cilium. In this review, we discuss recent evidence suggesting emerging roles of primary cilium and cilia-mediated signaling pathways in the regulation of pancreatic β- and α-cell functions, and its implications in regulating glucose homeostasis.

Antiangiogenic factors are currently used for the prediction of preeclampsia. The present study aimed to evaluate the relationship between antiangiogenic factors and lipid and carbohydrate metabolism in maternal plasma and placenta. We analyzed 56 pregnant women, 30 healthy and 26 with preeclampsia (including early and late onset). We compared antiangiogenic factors soluble Fms-like Tyrosine Kinase-1 (sfLt-1), placental growth factor (PlGF), and soluble endoglin (sEng)), lipid and carbohydrate metabolism in maternal plasma, and lipid metabolism in the placenta from assays of fatty acid oxidation, fatty acid esterification, and triglyceride levels in all groups. Antiangiogenic factors sFlt-1, sFlt-1/PlGF ratio, and sEng showed a positive correlation with triglyceride, free fatty acid, and C-peptide maternal serum levels. However, there was no relationship between angiogenic factors and placental lipid metabolism parameters. Free fatty acids were predictive of elevated sFlt-1 and sEng, while C-peptide was predictive of an elevated sFlt1/PlGF ratio. The findings in this study generate a model to predict elevated antiangiogenic factor values and the relationship between them with different products of lipid and carbohydrate metabolism in maternal serum and placenta in preeclampsia.

Insulin-degrading enzyme (IDE) is a highly conserved and ubiquitously expressed Zn2+-metallopeptidase that regulates hepatic insulin sensitivity, albeit its regulation in response to the fasting-to-postprandial transition is poorly understood. In this work, we studied the regulation of IDE mRNA and protein levels as well as its proteolytic activity in the liver, skeletal muscle, and kidneys under fasting (18 h) and refeeding (30 min and 3 h) conditions, in mice fed a standard (SD) or high-fat (HFD) diets. In the liver of mice fed an HFD, fasting reduced IDE protein levels (~30%); whereas refeeding increased its activity (~45%) in both mice fed an SD and HFD. Likewise, IDE protein levels were reduced in the skeletal muscle (~30%) of mice fed an HFD during the fasting state. Circulating lactate concentrations directly correlated with hepatic IDE activity and protein levels. Of note, L-lactate in liver lysates augmented IDE activity in a dose-dependent manner. Additionally, IDE protein levels in liver and muscle tissues, but not its activity, inversely correlated (R2 = 0.3734 and 0.2951, respectively; p < 0.01) with a surrogate marker of insulin resistance (HOMA index). Finally, a multivariate analysis suggests that circulating insulin, glucose, non-esterified fatty acids, and lactate levels might be important in regulating IDE in liver and muscle tissues. Our results highlight that the nutritional regulation of IDE in liver and skeletal muscle is more complex than previously expected in mice, and that fasting/refeeding does not strongly influence the regulation of renal IDE.

Hepatic insulin clearance, a physiological process that in response to nutritional cues clears ~50–80% of circulating insulin, is emerging as an important factor in our understanding of the pathogenesis of type 2 diabetes mellitus (T2DM). Insulin-degrading enzyme (IDE) is a highly conserved Zn2+-metalloprotease that degrades insulin and several other intermediate-size peptides. Both, insulin clearance and IDE activity are reduced in diabetic patients, albeit the cause-effect relationship in humans remains unproven. Because historically IDE has been proposed as the main enzyme involved in insulin degradation, efforts in the development of IDE inhibitors as therapeutics in diabetic patients has attracted attention during the last decades. In this review, we retrace the path from Mirsky’s seminal discovery of IDE to the present, highlighting the pros and cons of the development of IDE inhibitors as a pharmacological approach to treating diabetic patients.

Insulin-degrading enzyme (IDE) is a highly conserved and ubiquitously expressed metalloprotease that degrades insulin and several other intermediate-size peptides. For many decades, IDE had been assumed to be involved primarily in hepatic insulin clearance, a key process that regulates availability of circulating insulin levels for peripheral tissues. Emerging evidence, however, suggests that IDE has several other important physiological functions relevant to glucose and insulin homeostasis, including the regulation of insulin secretion from pancreatic β-cells. Investigation of mice with tissue-specific genetic deletion of Ide in the liver and pancreatic β-cells (L-IDE-KO and B-IDE-KO mice, respectively) has revealed additional roles for IDE in the regulation of hepatic insulin action and sensitivity. In this review, we discuss current knowledge about IDE’s function as a regulator of insulin secretion and hepatic insulin sensitivity, both evaluating the classical view of IDE as an insulin protease and also exploring evidence for several non-proteolytic functions. Insulin proteostasis and insulin sensitivity have both been highlighted as targets controlling blood sugar levels in type 2 diabetes, so a clearer understanding the physiological functions of IDE in pancreas and liver could led to the development of novel therapeutics for the treatment of this disease.

Two new chloro-furanocembranolides (1, 2) and two new 1,4-diketo cembranolides (3, 4) were isolated from the crude extract of Leptogorgia sp. together with a new seco-furanocembranolide (5) and the known Z-deoxypukalide (6), rubifolide (7), scabrolide D (8) and epoxylophodione (9). Their structures were determined based on spectroscopic evidence. Four compounds: 1, 2, 7 and 8 were found to activate the proliferation of pancreatic insulin-producing (beta) cells.

Type 2 diabetes (T2DM) is a complex disease linked to pancreatic beta-cell failure and insulin resistance. Current antidiabetic treatment regimens for T2DM include insulin sensitizers and insulin secretagogues. We have previously demonstrated that leptolide, a member of the furanocembranolides family, promotes pancreatic beta-cell proliferation in mice. Considering the beneficial effects of leptolide in diabetic mice, in this study, we aimed to address the capability of leptolide to improve insulin resistance associated with the pathology of obesity. To this end, we tested the hypothesis that leptolide should protect against fatty acid-induced insulin resistance in hepatocytes. In a time-dependent manner, leptolide (0.1 µM) augmented insulin-stimulated phosphorylation of protein kinase B (PKB) by two-fold above vehicle-treated HepG2 cells. In addition, leptolide (0.1 µM) counteracted palmitate-induced insulin resistance by augmenting by four-fold insulin-stimulated phosphorylation of PKB in HepG2 cells. In vivo, acute intraperitoneal administration of leptolide (0.1 mg/kg and 1 mg/kg) improved glucose tolerance and insulin sensitivity in lean mice. Likewise, prolonged leptolide treatment (0.1 mg/kg) in diet-induced obese mice improved insulin sensitivity. These effects were paralleled with an ~50% increased of insulin-stimulated phosphorylation of PKB in liver and skeletal muscle and reduced circulating pro-inflammatory cytokines in obese mice. We concluded that leptolide significantly improves insulin sensitivity in vitro and in obese mice, suggesting that leptolide may be another potential treatment for T2DM.

There is an urgency to find new treatments for the devastating epidemic of diabetes. Pancreatic β-cells viability and function are impaired in the two most common forms of diabetes, type 1 and type 2. Regeneration of pancreatic β-cells has been proposed as a potential therapy for diabetes. In a preliminary study, we screened a collection of marine products for β-cell proliferation. One unique compound (epoxypukalide) showed capability to induce β-cell replication in the cell line INS1 832/13 and in primary rat cell cultures. Epoxypukalide was used to study β-cell proliferation by [(3)H]thymidine incorporation and BrdU incorporation followed by BrdU/insulin staining in primary cultures of rat islets. AKT and ERK1/2 signalling pathways were analyzed. Cell cycle activators, cyclin D2 and cyclin E, were detected by western-blot. Apoptosis was studied by TUNEL and cleaved caspase 3. β-cell function was measured by glucose-stimulated insulin secretion. Epoxypukalide induced 2.5-fold increase in β-cell proliferation; this effect was mediated by activation of ERK1/2 signalling pathway and upregulation of the cell cycle activators, cyclin D2 and cyclin E. Interestingly, epoxypukalide showed protection from basal (40% lower versus control) and cytokine-induced apoptosis (80% lower versus control). Finally, epoxypukalide did not impair β-cell function when measured by glucose-stimulated insulin secretion. In conclusion, epoxypukalide induces β-cell proliferation and protects against basal and cytokine-mediated β-cell death in primary cultures of rat islets. These findings may be translated into new treatments for diabetes.

Multiple myeloma is a haematological malignancy characterized by the clonal proliferation of plasma cells. It has been proposed that targeting cancer cell metabolism would provide a new selective anticancer therapeutic strategy. In this work, we tested the hypothesis that inhibition of β-oxidation and de novo fatty acid synthesis would reduce cell proliferation in human myeloma cells. We evaluated the effect of etomoxir and orlistat on fatty acid metabolism, glucose metabolism, cell cycle distribution, proliferation, cell death and expression of G1/S phase regulatory proteins in myeloma cells. Etomoxir and orlistat inhibited β-oxidation and de novo fatty acid synthesis respectively in myeloma cells, without altering significantly glucose metabolism. These effects were associated with reduced cell viability and cell cycle arrest in G0/G1. Specifically, etomoxir and orlistat reduced by 40-70% myeloma cells proliferation. The combination of etomoxir and orlistat resulted in an additive inhibitory effect on cell proliferation. Orlistat induced apoptosis and sensitized RPMI-8226 cells to apoptosis induction by bortezomib, whereas apoptosis was not altered by etomoxir. Finally, the inhibitory effect of both drugs on cell proliferation was associated with reduced p21 protein levels and phosphorylation levels of retinoblastoma protein. In conclusion, inhibition of fatty acid metabolism represents a potential therapeutic approach to treat human multiple myeloma.

Although the COVID-19 disease has developed into a worldwide pandemic, its pathophysiology remains to be fully understood. Insulin-degrading enzyme (IDE), a zinc-metalloprotease with a high affinity for insulin, has been found in the interactomes of multiple SARS-CoV-2 proteins. However, the relevance of IDE in the innate and adaptative immune responses elicited by circulating peripheral blood mononuclear cells is unknown. Here, we show that IDE is highly expressed on the surface of circulating monocytes, T-cells (both CD4+ and CD4−), and, to a lower extent, in B-cells from healthy controls. Notably, IDE’s surface expression was upregulated on monocytes from COVID-19 patients at diagnosis, and it was increased in more severe patients. However, IDE’s surface expression was downregulated (relative to healthy controls) 3 months after hospital discharge in all the studied immune subsets, with this effect being more pronounced in males than in females, and thus it was sex-dependent. Additionally, IDE levels in monocytes, CD4+ T-cells, and CD4− T-cells were inversely correlated with circulating insulin levels in COVID-19 patients (both at diagnosis and after hospital discharge). Of note, high glucose and insulin levels downregulated IDE surface expression by ~30% in the monocytes isolated from healthy donors, without affecting its expression in CD4+ T-cells and CD4− T-cells. In conclusion, our studies reveal the sex- and metabolism-dependent regulation of IDE in monocytes, suggesting that its regulation might be important for the recruitment of immune cells to the site of infection, as well as for glucometabolic control, in COVID-19 patients.

Type 1 diabetes mellitus (T1DM) is characterized by beta cell loss because of an autoimmune attack. Here the authors show that an agonist for LRH-1/NR5A2, a nuclear receptor known to be protective against beta cell apoptosis, inhibits immune-mediated inflammation and hyperglycemia in T1DM mouse models.

The worldwide epidemics of obesity and diabetes have been linked to increased sugar consumption in humans. Here, we review fructose and glucose metabolism, as well as potential molecular mechanisms by which excessive sugar consumption is associated to metabolic diseases and insulin resistance in humans. To this end, we focus on understanding molecular and cellular mechanisms of fructose and glucose transport and sensing in the intestine, the intracellular signaling effects of dietary sugar metabolism, and its impact on glucose homeostasis in health and disease. Finally, the peripheral and central effects of dietary sugars on the gut−brain axis will be reviewed.

Apolipoproteins (apo) are constituents of lipoproteins crucial for lipid homeostasis. Aberrant expression of apolipoproteins is associated with metabolic abnormalities. Here we characterized apolipoprotein D (apoD) in triglyceride metabolism. Unlike canonical apolipoproteins that are mainly produced in the liver, apoD is an atypical apolipoprotein with broad tissue distribution. We show that circulating apoD is present mainly in HDL and, to a lesser extent, in LDL and VLDL and that its plasma levels were reduced in db/db mice with visceral obesity and altered lipid metabolism. Elevated apoD production, derived from adenovirus-mediated gene transfer, resulted in significant reduction in plasma triglyceride levels in mice. This effect was attributable to en­hanced LPL activity and improved catabolism of triglyceride-rich particles. In contrast, VLDL triglyceride production remained unchanged in response to elevated apoD production. These findings were recapitulated in high-fat–induced obese mice. Obese mice with elevated apoD production exhibited significantly improved triglyceride profiles, correlating with increased plasma LPL activity and enhanced postprandial fat tolerance. ApoD was shown to promote LPL-mediated hydrolysis of VLDL in vitro, correlating with its TG-lowering action in vivo. Apolipoprotein D plays a significant role in lipid metabolism. These data provide important clues to clinical observations that genetic variants of apoD are associated with abnormal lipid metabolism and increased risk of metabolic syndrome.

Apolipoprotein A-V (apoA-V) and apoC-III are exchangeable constituents of VLDL and HDL. ApoA-V counteracts the effect of apoC-III on triglyceride (TG) metabolism with poorly defined mechanisms. To better understand the effects of apoA-V on TG and cholesterol metabolism, we delivered apoA-V cDNA into livers of hypertriglyceridemic APOC3 transgenic mice by adenovirus-mediated gene transfer. In response to hepatic apoA-V production, plasma TG levels were reduced significantly as a result of enhanced VLDL catabolism without alternations in VLDL production. This effect was associated with reduced apoC-III content in VLDL. Increased apoA-V production also resulted in decreased apoC-III and increased apoA-I content in HDL. Furthermore, apoA-V-enriched HDL was associated with enhanced LCAT activity and increased cholesterol efflux. This effect, along with apoE enrichment in HDL, contributed to HDL core expansion and α-HDL formation, accounting for significant increases in both the number and size of HDL particles. As a result, apoA-V-treated APOC3 transgenic mice exhibited decreased VLDL-cholesterol and increased HDL-cholesterol levels. ApoA-V-mediated reduction of apoC-III content in VLDL represents an important mechanism by which apoA-V acts to ameliorate hypertriglyceridemia in adult APOC3 transgenic mice. In addition, increased apoA-V levels accounted for cholesterol redistribution from VLDL to larger HDL particles. These data suggest that in addition to its TG-lowering effect, apoA-V plays a significant role in modulating HDL maturation and cholesterol metabolism.

Type 2 diabetes (T2D) is an important risk factor to suffer dementia, including Alzheimer's disease (AD), and some neuropathological features observed in dementia could be mediated by T2D metabolic alterations. Since brain atrophy and impaired neurogenesis have been observed both T2D and AD we analyzed central nervous system (CNS) morphological alterations in the db/db mice (leptin receptor KO mice), as a model of long-term insulin resistance and T2D, and in C57Bl6 mice fed with high fat diet (HFD), as a model of diet induced insulin resistance and prediabetes. Db/db mice showed an age-dependent cortical and hippocampal atrophy, whereas in HFD mice cortex and hippocampus were preserved. We also detected increased neurogenesis and cell proliferation rates in young db/db mice when compared with control littermates. Our study shows that metabolic parameters serve as predictors of both atrophy and altered proliferation and neurogenesis in the CNS. Moreover in the cortex, atrophy, cell proliferation and neurogenesis were significantly correlated. Our data suggest that T2D may underline some of the pathological features observed in the dementia process. They also support that blood glucose control in elderly patients could help to slow down dementia evolution and maybe, improve its prognosis.