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Elevated lipoprotein (a) [Lp(a)] levels increase the risk for CVD. Novel treatments that decrease LDL cholesterol (LDL-C) have also shown promise for reducing Lp(a) levels. Mipomersen, an antisense oligonucleotide that inhibits apoB synthesis, is approved for the treatment of homozygous familial hypercholesterolemia. It decreases plasma levels of LDL-C by 25% to 39% and lowers levels of Lp(a) by 21% to 39%. We examined the mechanisms for Lp(a) lowering during mipomersen treatment. We enrolled 14 healthy volunteers who received weekly placebo injections for 3 weeks followed by weekly injections of mipomersen for 7 weeks. Stable isotope kinetic studies were performed using deuterated leucine at the end of the placebo and mipomersen treatment periods. The fractional catabolic rate (FCR) of Lp(a) was determined from the enrichment of a leucine-containing peptide specific to apo(a) by LC/MS. The production rate (PR) of Lp(a) was calculated from the product of Lp(a) FCR and Lp(a) concentration (converted to pool size). In a diverse population, mipomersen reduced plasma Lp(a) levels by 21%. In the overall study group, mipomersen treatment resulted in a 27% increase in the FCR of Lp(a) with no significant change in PR. However, there was heterogeneity in the response to mipomersen therapy, and changes in both FCRs and PRs affected the degree of change in Lp(a) concentrations. Mipomersen treatment decreases Lp(a) plasma levels mainly by increasing the FCR of Lp(a), although changes in Lp(a) PR were significant predictors of reductions in Lp(a) levels in some subjects.

Circadian disruption and obesity synergize to predispose to development of type 2 diabetes mellitus (T2DM), signifying that therapeutic targeting of both circadian and metabolic dysfunctions should be considered as a potential treatment approach. To address this hypothesis, we studied rats concomitantly exposed to circadian disruption and diet-induced obesity (CDO), a rat model recently shown to recapitulate phenotypical aspects of obese T2DM (eg, circadian disruption, obesity, insulin resistance, and islet failure). CDO rats were subsequently treated daily (for 12 wk) by timed oral gavage with vehicle, melatonin (a known chronobiotic), metformin, or combination treatment of both therapeutics. Melatonin treatment alone improved circadian activity rhythms, attenuated induction of β-cell failure, and enhanced glucose tolerance. Metformin alone did not modify circadian activity but enhanced insulin sensitivity and glucose tolerance. Importantly, the combination of melatonin and metformin had synergistic actions to modify progression of metabolic dysfunction in CDO rats through improved adiposity, circadian activity, insulin sensitivity, and islet cell failure. This study suggests that management of both circadian and metabolic dysfunctions should be considered as a potential preventative and therapeutic option for treatment of obesity and T2DM.

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Laser capture microdissection (LCM) is a powerful method to isolate specific populations of cells for subsequent analysis such as gene expression profiling, for example, microarrays or ribonucleic (RNA)-Seq. This technique has been applied to frozen as well as formalin-fixed, paraffin-embedded (FFPE) specimens with variable outcomes regarding quality and quantity of extracted RNA. The goal of the study was to develop the methods to isolate high-quality RNA from islets of Langerhans and pancreatic duct glands (PDG) isolated by LCM. We report an optimized protocol for frozen sections to minimize RNA degradation and maximize recovery of expected transcripts from the samples using quantitative real-time polymerase chain reaction (RT-PCR) by adding RNase inhibitors at multiple steps during the experiment. This technique reproducibly delivered intact RNA (RIN values 6–7). Using quantitative RT-PCR, the expected profiles of insulin, glucagon, mucin6 (Muc6), and cytokeratin-19 (CK-19) mRNA in PDGs and pancreatic islets were detected. The described experimental protocol for frozen pancreas tissue might also be useful for other tissues with moderate to high levels of intrinsic ribonuclease (RNase) activity.

There are clear epidemiological associations between circadian disruption, obesity, and pathogenesis of type 2 diabetes. The mechanisms driving these associations are unclear. In the current study, we hypothesized that continuous exposure to constant light (LL) compromises pancreatic β-cell functional and morphological adaption to diet-induced obesity leading to development of type 2 diabetes. To address this hypothesis, we studied wild type Sprague Dawley as well as Period-1luciferase reporter transgenic rats (Per1-Luc) for 10 weeks under standard light-dark cycle (LD) or LL with concomitant ad libitum access to either standard chow or 60% high-fat diet (HFD). Exposure to HFD led to a comparable increase in food intake, body weight, and adiposity in both LD- and LL-treated rats. However, LL rats displayed profound loss of behavioral circadian rhythms as well as disrupted pancreatic islet clock function characterized by the impairment in the amplitude and the phase islet clock oscillations. Under LD cycle, HFD did not adversely alter diurnal glycemia, diurnal insulinemia, β-cell secretory function as well as β-cell survival, indicating successful adaptation to increased metabolic demand. In contrast, concomitant exposure to LL and HFD resulted in development of hyperglycemia characterized by loss of diurnal changes in insulin secretion, compromised β-cell function, and induction of β-cell apoptosis. This study suggests that circadian disruption and diet-induced obesity synergize to promote development of β-cell failure, likely mediated as a consequence of impaired islet clock function.

Type 2 diabetes mellitus (T2DM) is characterized by pancreatic islet failure due to loss of β-cell secretory function and mass. Studies have identified a link between a variance in the gene encoding melatonin (MT) receptor 2, T2DM, and impaired insulin secretion. This genetic linkage raises the question whether MT signaling plays a role in regulation of β-cell function and survival in T2DM. To address this postulate, we used INS 832/13 cells to test whether activation of MT signaling attenuates proteotoxicity-induced β-cell apoptosis and through which molecular mechanism. We also used nondiabetic and T2DM human islets to test the potential of MT signaling to attenuate deleterious effects of glucotoxicity and T2DM on β-cell function. MT signaling in β-cells (with duration designed to mimic typical nightly exposure) significantly enhanced activation of the cAMP-dependent signal transduction pathway and attenuated proteotoxicity-induced β-cell apoptosis evidenced by reduced caspase-3 cleavage (∼40%), decreased activation of stress-activated protein kinase/Jun-amino-terminal kinase (∼50%) and diminished oxidative stress response. Activation of MT signaling in human islets was shown to restore glucose-stimulated insulin secretion in islets exposed to chronic hyperglycemia as well as in T2DM islets. Our data suggest that β-cell MT signaling is important for the regulation of β-cell survival and function and implies a preventative and therapeutic potential for preservation of β-cell mass and function in T2DM.

Diabetes is a common multisystem disease that results in hyperglycemia due to a relative or absolute insulin deficiency. Improved glycemic control decreases the risk of development and progression of microvascular and, to a lesser extent, macrovascular complications and prevents symptomatic hyperglycemia. However, complex treatment regimens aimed at improving glycemic control are associated with an increased incidence of hypoglycemia. On paper at least, cellular therapies arising from reprogramed stem cells or other somatic cell types would provide ideal therapy for diabetes and the prevention of its complications. This hypothesis has led to intensive efforts to grow β cells from various sources. In this review, we provide an overview of β-cell development as well as the efforts reported to date in terms of cellular therapy for diabetes. Engineering β-cell replacement therapy requires an understanding of how β cells respond to other metabolites such as amino acids, free fatty acids, and ketones. Indeed, efforts thus far have been characterized by an inability of cellular replacement products to adequately respond to metabolites that normally couple the metabolic state to β-cell function and insulin secretion. Efforts to date intended to capitalize on current knowledge of islet cell development and stimulus-secretion coupling of the β cell are encouraging but as yet of little clinical relevance.

Abstract: Background: The impact of chronic alcohol consumption on hepatic gluconeogenesis (HGN) between males and females is unknown. To determine the effects of chronic alcohol consumption (8 weeks) on HGN, the isolated liver perfusion technique was used on 24‐hr‐fasted male and female Wistar rats.

Introduction:ApoliproteinC3 (apoC3) is a small (~8.8kDa) protein, made in the liver. It is an inhibitor of lipoprotein lipase as well as the uptake of triglyceride (TG) rich lipoproteins and remnants by the liver. Overexpression contributes to atherosclerosis by increasing plasma concentration of TG-rich lipoproteins. A recent study reported the presence of apoC3 on lipoprotein(a) [Lp(a)] particles in subjects with mild to moderate aortic stenosis. Lp(a) is an apoB100 containing lipoprotein with apo(a) covalently bound and is a causal factor of ASCVD. Our goal was to investigate relationships between apoC3 and Lp(a) in a healthy population.Methods:We analyzed data from 39 healthy subjects who completed studies of lipoprotein metabolism at the Columbia University Irving Medical Center. Subjects were 18 - 75 years old, and 44% were female. Twenty were Black, 9 Hispanic, 8 White, and 2 mixed race. Lipids (total Cholesterol (C), TG, HDLC, LDLC) were measured by an automatic analyzer. Plasma apoC3, apoB100 and Lp(a) levels were measured via validated ELISA assays. Lp(a) particles were isolated from plasma by immunoprecipitation (IP) with a monoclonal antibody and Western blots were performed.Results:We did not find an association between plasma Lp(a) and apoC3 levels. In a sub-group analysis of participants (N=15), with Lp(a) levels >100nmol/L, we found a significant negative association between apoC3 and Lp(a) plasma concentrations (R = -0.58, p=0.018). Based on the Western blots and ELISA analysis, we see an interaction between Lp(a) (apo(a) and apoB100 intact) and apoC3. There seem to be some differences in the Lp(a) and apoC3 interaction based on Lp(a) plasma concentration.Conclusion and Future Direction:In healthy subjects, there is no association of apoC3 with Lp(a) plasma levels. In a subset of subjects (high Lp(a)), we observed an association with apoC3 plasma levels. Our small data set suggests possible distinct roles for apoC3 in healthy individuals with high Lp(a) level. ApoC3 may be associated with specific circulating isoform sizes of Lp(a). Future studies will focus on analysis of larger cohorts and examining lipid composition in the isolated particles.

Coordinated communication among pancreatic islet cells is necessary for maintenance of glucose homeostasis. In diabetes, chronic exposure to pro-inflammatory cytokines has been shown to perturb β cell communication and function. Compelling evidence has implicated extracellular vesicles (EVs) in modulating physiological and pathological responses to β cell stress. We report that pro-inflammatory β cell small EVs (cytokine-exposed EVs [cytoEVs]) induce β cell dysfunction, promote a pro-inflammatory islet transcriptome, and enhance recruitment of CD8+T cells and macrophages. Proteomic analysis of cytoEVs shows enrichment of the chemokine CXCL10, with surface topological analysis depicting CXCL10 as membrane bound on cytoEVs to facilitate direct binding to CXCR3 receptors on the surface of β cells. CXCR3 receptor inhibition reduced CXCL10-cytoEV binding and attenuated β cell dysfunction, inflammatory gene expression, and leukocyte recruitment to islets. This work implies a significant role of pro-inflammatory β cell-derived small EVs in modulating β cell function, global gene expression, and antigen presentation through activation of the CXCL10/CXCR3 axis.

There is debate on whether the reported increase in the number of cases of childhood thyroid cancer in Belarus is real and attributable to radiation released following the Chernobyl nuclear accident, or rather an artefact due to incorrect histological diagnosis, more complete case reporting and mass screening of children after the accident. We have scrutinised the histological slides of 120 (75%) of the 160 cases reported among children aged up to 15 years to the Belarus tumour registry from 1986 to 1992 and examined time trends and geographical patterns in incidence and tumour characteristics. Incidence based on reported cases increased from 0.041 per 100.000 in 1986 to 2.548 in 1992. Carcinoma was confirmed in 94% of reviewed tumours. Except for one medullary carcinoma all histologies were of the papillary type. Most of the tumours had spread beyond the organ capsule and measured over 10 mm in diameter. There was a weak and statistically non-significant trend (p=0.19) towards smaller tumours in the later years. The proportion of cases with lymphnode or distant metastasis remained unchanged. Incidence based on histologically confirmed cases was highest adjacent and to the west and north of Chernobyl, matching best estimates of iodine-131 contamination. Our data thus strongly suggest that the observed increase is real but more data are needed in order to assess the impact of mass screening and to clarify the possible association with radiation released at Chernobyl in 1986. Es wird diskutiert, ob die berichtete Zunahme von Fällen kindlichen Schilddrüsenkarzinoms in Belarus echt und der Strahlung in der Folge des Nuklearunfalls von Tschernobyl zuzuschreiben ist, oder obes sich um einen Artefakt handelt, indem nach dem Unfall falsche histologische Diagnosen gestellt wurden, die Berichterstattung über die Fälle vollständiger wurde oder Massenfrüherfassungsaktivitäten bei Kindern durchgeführt wurden. Wir haben die histologischen Präparate von 120 (75%) der 160 Fälle von Schilddrüsenkarzinom bei Kindern bis zu 15 Jahren überprüft, die zwischen 1986 und 1992 dem Krebsregister von Belarus gemeldet worden sind, sowie die zeitliche Entwicklung und geographische Verteilung der aufgetretenen Fälle und deren Merkmale analysiert. Gestützt auf die gemeldeten Fälle nahm die inzidenzrate von 0,041 pro 100000 im Jahre 1986 auf 2,548 im Jahre 1992 zu. In 94% der überprüften Fälle wurde Krebs als Diagnose bestätigt. Mit einer Ausnahme von medullärem Karzinom wurden nur papilläre Karzinome gefunden. Die Mehrzahl der Tumoren hatte die Organkapsel durchbrochen und massen über 10 mm im Durchmesser. Im Laufe der Zeit fand sich ein schwacher und statistisch nicht signifikanter Trend (p+0,19) in Richtung kleinerer Tumoren. Der Anteil von Tumoren mit Lymphknoten- und entfernten Metastasen blieb unverändert. Gestützt auf die histologisch bestätigten Fälle war die inzidenz angrenzend an Tschernobyl und in westlicher und nördlicher Richtung am höchsten, was auch der Kontamination mit Jod-131 entspricht. Unsere Daten weisen damit deutlich darauf hin, dass die beobachtete zunahme echt ist, doch werden noch weitere Daten benötigt, um das Ausmass des Einflusses des Massenscreening abzuschätzen und die mögliche Beziehung mit der im Jahre 1986 in Tschernobyl freigesetzten radioaktiven Strahlung abzuklären. La question est posée de savoir si l'augmentation du nombre de cas de cancer de la thyroide observée chez les enfants en Belarus est réelle et à attribuer à l'irradiation relâchée suivant l'accident nucléaire de Tchernobyl, ou si elle reflète un phénomène artificiel dû à un diagnostique histologique erroné, une déclaration de cas plus complète ou le résultat des campagnes de dépistage qui ont suivi l'accident. Nous avons examiné les préparations histologiques de 120 (75%) des 160 cas survenus chez les enfants de moins de 15 ans rapportés entre 1986 et 1992 au registre des tumeurs de la république de Belarus, et analysé les chronologiques et les distributions géographiques de l'incidence et des caractéristiques des tumeurs. L'incidence des cas déclarés a augmenté de 0,041 par 100 000 en 1986 à 2,548 en 1992. Le diagnostique de carcinome a été confirmé dans 94% des tumeurs re-examinées. A l'exeption d'un seul cas de carcinome médullaire, toutes les histologies étaient du type papillaire. La plupart des tumeurs s'étandaient au delà de la capsule de l'organe, et avaient un diamètre supérieur à 10 mm. Pour les années les plus récentes, les tumeurs mesurées au moment du diagnostique sont devenues légerement et non-significativement (p=0,19) plus petites. La proportion des tumeurs ayant développé des métastases lymphatiques ou pulmonaires n'a pas changé. L'augmentation de l'incidence des cas confirmés à été parficulièrement importante dans le voisinage, ainsi que dans l'ouest et le nord de Tchernobyl, ce qui correspond assez bjen à la distribution de la contamination par l'iode-131. Nos données suggèrent donc fortement que l'augmentation observée et réelle. Néanmoins, d'avantage de données sur le dépistage en masse sont nécessaires pour clarifier l'association possible avec l'irradiation consécutive à Tchernobyl en 1986.

The effect of surface active substances on plastic flow of naphthalene single crystals is considered. The role of normal and shear stresses is revealed. Rates of single crystals flow in different glide systems under constant stress are compared. The stress of plastic flow in single crystals can be decreased in active media by as much as 50%.

The Pacific Mobile belt is differentiated into an outer (continental) zone of predominantly Mesozoic folding (Verkhoyansk -Chukotka, Mongolo-Okhotsk, and Sikhote-Alin folded provinces) and an inner oceanic zone of Cenozoic folding, adjacent to mobile provinces of the "island arc" type (Sakhalin, the Kuriles, Kamchatka). These zones are separated by the East-Asian volcanic belt associated with a fault system which cuts off the older Mesozoic Verkhoyansk-Chukotka and Sikhote- Alin structures. Two important mineralization epochs are evident - Sino-Cambrian and late Mesozoic- Cenozoic. The Mesozoic-Cenozoic mineralization epoch exhibits a definite tendency for “rejuvenation” of the mineralization processes, going away from the continent and toward the Pacific trough, from late Jurassic in the eastern Trans-Baykal region and parts of the northeast to Neogene in the province of the Okhotsk geosynclines. An outstanding feature of endogeneous mineralization in this region is the linear arrangement of the ore zones determined by a system of major magma-controlling and other faults.—C. E. Sears

This paper demonstrates the close causal relationship of magmatic bodies and mineralization with tectonic structures, mainly with fractures which were very well developed in the Soviet Northeast. Its purpose is to draw attention to a deeper analysis of the interdependence of magmatic and mineralizing processes with tectonic processes. It may be of interest also to those studying the relationship between tectonics, magmatism and mineralization in other regions of the Soviet Union.The complicated geological structure of the Soviet Northeast is the result of intensive Mesozoic and Cenozoic folding, forming two interrelated folded regions - the Verkhoyansk-Chulcot of Mesozoic age, and the Koryak-Kamchatka of Cenozoic age. The principal tectonic elements of the Verkhoyansk- Chukot folded region are the Yana-Kolyma and Chukot orogenic zones, which consist of Verkhoyansk complex deposits and the median massif of Kolyma. Intensive extrusive and intrusive magmatic activity is characteristic of the Mesozoic and Cenozoic folded regions. Fractures as well as folds are of great importance in the tectonic structure of the Soviet Northeast, which fractures differ from each other by the depth of formation, magnitude, and duration of activity. Endogenetic mineralization of the Soviet Northeast is of Precambrian, middle Paleozoic, Mesozoic and Cenozoic ages, although the principal deposits are Mesozoic and Cenozoic. V. I. Smirnov divided ore-bearing belts into three types: 1) belts extending along major faults, 2) belts, located along the junctions between geological regions of varying mobility, and 3) belts extending along the presumed large fractures in the consolidated basement of folded regions. All three types of ore-bearing belts are present in the Soviet Northeast. The antimony-mercury belts (zones) of the Koryak highlands belong primarily to belts extending along the major fractures - structural junctions. However, the gold belt of Yana-Indigirka-Kolyma, the Northern and Main rare-metal belts, as well as the Allakh-Yun gold zone may be classified as belts located along the junction between zones of varying mobility. The regularities in distribution of endogenetic mineral deposits in the Soviet Northeast Mesozoic and Cenozoic folded regions lead to specific inferences in future prospecting for gold, tin, tungsten, molybdenum, cobalt, lead, zinc, copper, and mercury. A primary problem in the study of mineral resources in the Northeast is further elucidation of regularities in distribution of mineral deposits based on regional metallogenetic mapping and analysis.- -M. Russell.

Intrinsic β-cell circadian clocks are important regulators of insulin secretion and overall glucose homeostasis. Whether the circadian clock in β-cells is perturbed following exposure to prodiabetogenic stressors such as proinflammatory cytokines, and whether these perturbations are featured during the development of diabetes, remains unknown. To address this, we examined the effects of cytokine-mediated inflammation common to the pathophysiology of diabetes, on the physiological and molecular regulation of the β-cell circadian clock. Specifically, we provide evidence that the key diabetogenic cytokine IL-1β disrupts functionality of the β-cell circadian clock and impairs circadian regulation of glucose-stimulated insulin secretion. The deleterious effects of IL-1β on the circadian clock were attributed to impaired expression of key circadian transcription factor Bmal1, and its regulator, the NAD-dependent deacetylase, Sirtuin 1 (SIRT1). Moreover, we also identified that Type 2 diabetes in humans is associated with reduced immunoreactivity of β-cell BMAL1 and SIRT1, suggestive of a potential causative link between islet inflammation, circadian clock disruption, and β-cell failure. These data suggest that the circadian clock in β-cells is perturbed following exposure to proinflammatory stressors and highlights the potential for therapeutic targeting of the circadian system for treatment for β-cell failure in diabetes.

High-fat diet (HFD)-fed mouse models have been widely used to study early type 2 diabetes. Decreased β-cell glucokinase (GCK) expression has been observed in HFD-induced diabetes. However, owing to its crucial roles in glucose metabolism in the liver and in islet β-cells, the contribution of decreased GCK expression to the development of HFD-induced diabetes is unclear. Here, we employed a β-cell-targeted gene transfer vector and determined the impact of β-cell-specific increase in GCK expression on β-cell function and glucose handling in vitro and in vivo. Overexpression of GCK enhanced glycolytic flux, ATP-sensitive potassium channel activation and membrane depolarization, and increased proliferation in Min6 cells. β-cell-targeted GCK transduction did not change glucose handling in chow-fed C57BL/6 mice. Although adult mice fed a HFD showed reduced islet GCK expression, impaired glucose tolerance and decreased glucose-stimulated insulin secretion (GSIS), β-cell-targeted GCK transduction improved glucose tolerance and restored GSIS. Islet perifusion experiments verified restored GSIS in isolated HFD islets by GCK transduction. Thus, our data identify impaired β-cell GCK expression as an underlying mechanism for dysregulated β-cell function and glycemic control in HFD-induced diabetes. Our data also imply an etiological role of GCK in diet-induced diabetes. This article has an associated First Person interview with the first author of the paper.

Blood glucose concentrations are maintained by insulin secreted from ß-cells located in the islets of Langerhans. There are ~2000 ß-cells per islet, and ~one million islets of Langerhans scattered throughout the pancreas. The islet in type 2 diabetes mellitus (T2D) has deficient ß-cell mass due to increased ß-cell apoptosis and islet amyloid derived from islet amyloid polypeptide (IAPP). Accumulating evidence implicates toxic IAPP oligomers in the mediation of ß-cell apoptosis in T2D. Humans, monkeys, and cats express an amyloidogenic toxic form of IAPP and spontaneously develop diabetes characterized by islet amyloid deposits. However, longitudinal studies of islet pathology in humans are impossible, and studies in nonhuman primates and cats are costly and impractical. Rodent IAPP is not amyloidogenic, thus commonly used rodent models of diabetes do not recapitulate islet pathology in humans. To investigate the diabetogenic role of human IAPP (h-IAPP), several mouse models and, more recently, a rat model transgenic for h-IAPP have been developed. Studies in these models have revealed that the toxic effect of h-IAPP on ß-cell apoptosis demonstrates a threshold-dependent effect. Specifically, increasing h-IAPP transgene expression by breeding or induction of insulin resistance leads to increased ß-cell apoptosis and diabetes. These transgenic rodent models for h-IAPP provide an opportunity to elucidate the mechanisms responsible for h-IAPP-induced ß-cell apoptosis further and to test novel approaches to the prevention and treatment of T2D.