Pancreatic β-cell imaging in humans: Fiction or option?

Diabetes mellitus is a growing worldwide epidemic disease, currently affecting 1 in 12 adults. Treatment of disease complications typically consumes ∼10% of healthcare budgets in developed societies. Whilst immune‐mediated destruction of insulin‐secreting pancreatic β cells is responsible for Type 1 diabetes, both the loss and dysfunction of these cells underly the more prevalent Type 2 diabetes. The establishment of robust drug development programmes aimed at β‐cell restoration is still hampered by the absence of means to measure β‐cell mass prospectively in vivo, an approach which would provide new opportunities for understanding disease mechanisms and ultimately assigning personalized treatments. In the present review, we describe the progress towards this goal achieved by the Innovative Medicines Initiative in Diabetes, a collaborative public–private consortium supported by the European Commission and by dedicated resources of pharmaceutical companies. We compare several of the available imaging methods and molecular targets and provide suggestions as to the likeliest to lead to tractable approaches. Furthermore, we discuss the simultaneous development of animal models that can be used to measure subtle changes in β‐cell mass, a prerequisite for validating the clinical potential of the different imaging tracers

Role of AMP-activated protein kinase in adipose tissue metabolism and inflammation

AMPK (AMP-activated protein kinase) is a key regulator of cellular and whole-body energy balance. AMPK phosphorylates and regulates many proteins concerned with nutrient metabolism, largely acting to suppress anabolic ATP-consuming pathways while stimulating catabolic ATP-generating pathways. This has led to considerable interest in AMPK as a therapeutic target for the metabolic dysfunction observed in obesity and insulin resistance. The role of AMPK in skeletal muscle and the liver has been extensively studied, such that AMPK has been demonstrated to inhibit synthesis of fatty acids, cholesterol and isoprenoids, hepatic gluconeogenesis and translation while increasing fatty acid oxidation, muscle glucose transport, mitochondrial biogenesis and caloric intake. The role of AMPK in the other principal metabolic and insulin-sensitive tissue, adipose, remains poorly characterized in comparison, yet increasing evidence supports an important role for AMPK in adipose tissue function. Obesity is characterized by hypertrophy of adipocytes and the development of a chronic sub-clinical pro-inflammatory environment in adipose tissue, leading to increased infiltration of immune cells. This combination of dysfunctional hypertrophic adipocytes and a pro-inflammatory environment contributes to insulin resistance and the development of Type 2 diabetes. Exciting recent studies indicate that AMPK may not only influence metabolism in adipocytes, but also act to suppress this pro-inflammatory environment, such that targeting AMPK in adipose tissue may be desirable to normalize adipose dysfunction and inflammation. In the present review, we discuss the role of AMPK in adipose tissue, focussing on the regulation of carbohydrate and lipid metabolism, adipogenesis and pro-inflammatory pathways in physiological and pathophysiological conditions

AMPK is essential for energy homeostasis regulation and glucose sensing by POMC and AgRP neurons

Hypothalamic AMP-activated protein kinase (AMPK) has been suggested to act as a key sensing mechanism, responding to hormones and nutrients in the regulation of energy homeostasis. However, the precise neuronal populations and cellular mechanisms involved are unclear. The effects of long-term manipulation of hypothalamic AMPK on energy balance are also unknown. To directly address such issues, we generated POMC alpha 2KO and AgRP alpha 2KO mice lacking AMPK alpha 2 in proopiomelanocortin- (POMC-) and agouti-related protein-expressing (AgRP-expressing) neurons, key regulators of energy homeostasis. POMC alpha 2KO mice developed obesity due to reduced energy expenditure and dysregulated food intake but remained sensitive to leptin. in contrast, AgRPa2KO mice developed an age-dependent lean phenotype with increased sensitivity to a melanocortin agonist. Electrophysiological studies in AMPK alpha 2-deficient POMC or AgRP neurons revealed normal leptin or insulin action but absent responses to alterations in extracellular glucose levels, showing that glucose-sensing signaling mechanisms in these neurons are distinct from those pathways utilized by leptin or insulin. Taken together with the divergent phenotypes of POMC alpha 2KO and AgRP alpha 2KO mice, our findings suggest that while AMPK plays a key role in hypothalamic function, it does not act as a general sensor and integrator of energy homeostasis in the mediobasal hypothalamus

GaMin’11 – an International Inter-laboratory Comparison for Geochemical CO2 - Saline Fluid - Mineral Interaction Experiments

Due to the strong interest in geochemical CO2-fluid-rock interaction in the context of geological storage of CO2 a growing number of research groups have used a variety of different experimental ways to identify important geochemical dissolution or precipitation reactions and – if possible – quantify the rates and extent of mineral or rock alteration. In this inter-laboratory comparison the gas-fluid-mineral reactions of three samples of rock-forming minerals have been investigated by 11 experimental labs. The reported results point to robust identification of the major processes in the experiments by most groups. The dissolution rates derived from the changes in composition of the aqueous phase are consistent overall, but the variation could be reduced by using similar corrections for changing parameters in the reaction cells over time. The comparison of experimental setups and procedures as well as of data corrections identified potential improvements for future gas-fluid-rock studies

Cyclin-Dependent Kinase 5 Promotes Pancreatic β-Cell Survival via Fak-Akt Signaling Pathways

ObjectiveCyclin-dependent kinase 5 (CDK5) regulatory subunit-associated protein 1-like 1 has recently been linked to type 2 diabetes by genome-wide association studies. While CDK5 and its regulatory protein p35 are both expressed and display enzymatic activity in pancreatic β-cells, their precise role in the β-cell remains unknown. Because type 2 diabetes is characterized by a deficit in β-cell mass and increased β-cell apoptosis, we investigated the role of CDK5 in β-cell survival.Research design and methodsWe used INS 832/13 cells, rat islets isolated from wild-type or human islet amyloid polypeptide (h-IAPP) transgenic rats, and pancreatic tissue from rats and humans with and without type 2 diabetes and investigated the effect of CDK5/p35 inhibition (by small interfering RNA or by chemical inhibition) as well as CDK5/p35 overexpression on β-cell vulnerability to apoptosis.ResultsCDK5 inhibition led to increased β-cell apoptosis. To identify the mechanisms involved, we examined the phosphorylation state of focal adhesion kinase (Fak)(Ser732), a known target of CDK5. Following CDK5 inhibition, the phosphorylation of Fak(Ser732) decreased with resulting attenuation of phosphatidylinositol 3-kinase (PI3K)/Akt survival pathway. Conversely, CDK5 overexpression increased Fak(Ser732) phosphorylation and protected β-cells against apoptosis induced by the inhibition of the β-1 integrin signaling pathway. Also, Fak(Ser732) phosphorylation was less abundant in β-cells in both h-IAPP transgenic rats and humans with type 2 diabetes.ConclusionsThis study shows that by regulating Fak phosphorylation and subsequently PI3K/Akt survival pathway, CDK5 plays a previously unrecognized role in promoting β-cell survival

Methyl donor deficiency impairs fatty acid oxidation through PGC-1α hypomethylation and decreased ER-α, ERR-α, and HNF-4α in the rat liver

BACKGROUND & AIMS: Folate and cobalamin are methyl donors needed for the synthesis of methionine, which is the precursor of S-adenosylmethionine, the substrate of methylation in epigenetic, and epigenomic pathways. Methyl donor deficiency produces liver steatosis and predisposes to metabolic syndrome. Whether impaired fatty acid oxidation contributes to this steatosis remains unknown.METHODS: We evaluated the consequences of methyl donor deficient diet in liver of pups from dams subjected to deficiency during gestation and lactation. RESULTS: The deprived rats had microvesicular steatosis, with increased triglycerides, decreased methionine synthase activity, S-adenosylmethionine, and S-adenosylmethionine/S-adenosylhomocysteine ratio. We observed no change in apoptosis markers, oxidant and reticulum stresses, and carnityl-palmitoyl transferase 1 activity, and a decreased expression of SREBP-1c. Impaired beta-oxidation of fatty acids and carnitine deficit were the predominant changes, with decreased free and total carnitines, increased C14:1/C16 acylcarnitine ratio, decrease of oxidation rate of palmitoyl-CoA and palmitoyl-L-carnitine and decrease of expression of novel organic cation transporter 1, acylCoA-dehydrogenase and trifunctional enzyme subunit alpha and decreased activity of complexes I and II. These changes were related to lower protein expression of ER-α, ERR-α and HNF-4α, and hypomethylation of PGC-1α co-activator that reduced its binding with PPAR-α, ERR-α, and HNF-4α. CONCLUSIONS: The liver steatosis resulted predominantly from hypomethylation of PGC1-α, decreased binding with its partners and subsequent impaired mitochondrial fatty acid oxidation. This link between methyl donor deficiency and epigenomic deregulations of energy metabolism opens new insights into the pathogenesis of fatty liver disease, in particular, in relation to the fetal programming hypothesis

Planet Hunters TESS. V. A Planetary System Around a Binary Star, Including a Mini-Neptune in the Habitable Zone

We report on the discovery and validation of a transiting long-period mini-Neptune orbiting a bright (V = 9.0 mag) G dwarf (TOI 4633; R = 1.05 R ⊙, M = 1.10 M ⊙). The planet was identified in data from the Transiting Exoplanet Survey Satellite by citizen scientists taking part in the Planet Hunters TESS project. Modelling of the transit events yields an orbital period of 271.9445 ± 0.0040 days and radius of 3.2 ± 0.20 R ⊕. The Earth-like orbital period and an incident flux of 1.56−0.16+0.20 F ⊕ places it in the optimistic habitable zone around the star. Doppler spectroscopy of the system allowed us to place an upper mass limit on the transiting planet and revealed a non-transiting planet candidate in the system with a period of 34.15 ± 0.15 days. Furthermore, the combination of archival data dating back to 1905 with new high angular resolution imaging revealed a stellar companion orbiting the primary star with an orbital period of around 230 yr and an eccentricity of about 0.9. The long period of the transiting planet, combined with the high eccentricity and close approach of the companion star makes this a valuable system for testing the formation and stability of planets in binary systems

Memantine increases NMDA receptor level in the prefrontal cortex but fails to reverse apomorphine-induced conditioned place preference in rats

Studies have shown that inflammation and neurodegeneration may accompany the development of addiction to apomorphine and that the glutamate NMDA receptor antagonist, memantine, may be neuroprotective. The similarity between apomorphine and dopamine with regard to their chemical, pharmacological and toxicological properties provided a basis for investigating the mechanism of action of the former agent. In this study, we investigated whether memantine would suppress apomorphine-seeking behavior in rats subjected to apomorphine-induced place preference conditioning, through modulation of NMDA receptors in the prefrontal cortex. Repeated apomorphine (1 mg/kg) treatment induced conditioned place preference (CPP) and had no significant effect on NMDA receptor levels in the prefrontal cortex. Prior treatment with memantine (5 mg/kg or 10 mg/kg) increased the levels of NMDA receptors in the prefrontal cortex but did not suppress CPP induced by apomorphine. These data give further support to the addictive effect of apomorphine and demonstrate that blockade of NMDA receptors by memantine is unable to suppress apomorphine-seeking behavior