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  • Inhibition of recombinant K(ATP) channels by the antidiabetic agents midaglizole, LY397364 and LY389382.

    17 October 2018

    Most imidazolines inhibit ATP-sensitive K(+) (K(ATP)) channels. Since these drugs are potentially clinically relevant insulin secretagogues, it is important to know whether extrapancreatic K(ATP) channels are targeted. We examined the effects of three imidazoline-derived antidiabetic drugs on the cloned K(ATP) channel, expressed in Xenopus laevis oocytes, and their specificity for interaction with the pore-forming Kir6.2 or the sulphonylurea receptor (SUR) 1 subunit. Midaglizole, LY397364 and LY389382 blocked Kir6.2deltaC currents with IC(50) of 3.8, 6.1 and 0.7 microM, respectively. The block of Kir6.2/SUR1 currents by LY397364 and LY389382 was best fit by a two-site model, suggesting that these drugs also interact with SUR1. However, since all three drugs interact with the Kir6.2 subunit, and Kir6.2 forms the pore of extrapancreatic K(ATP) channels, these drugs are unlikely to be specific for the beta-cell.

  • Development of postpartum Graves' disease and type 1 diabetes after delivery in a patient with gestational diabetes.

    17 October 2018

    Pregnancy and the postpartum period are associated with changes of the immune system. These changes might eventually result in autoimmune diseases, such as Graves' disease and type 1 diabetes mellitus, in the postpartum period. We describe a case of a patient with gestational diabetes who developed both Graves' disease and type 1 diabetes mellitus in the postpartum period. The pathology of gestational diabetes (GDM) is close to that of type 2 diabetes mellitus. However, the present case emphasizes the importance of screening and monitoring high-risk GDM patients for all available autoimmune antibodies throughout pregnancy and the postpartum period, as GDM has a risk of developing into type 1 diabetes and multiple autoimmune diseases. In addition, only Graves' disease was transient, whereas type 1 diabetes mellitus remained permanent in the present case. Thus, the present case shows etiological differences between these two autoimmune diseases. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2010.00089.x,2011).

  • The value of in vitro studies in a case of neonatal diabetes with a novel Kir6.2-W68G mutation.

    17 October 2018

    In infants, especially with novel previously undescribed mutations of the KATP channel causing neonatal diabetes, in vitro studies can be used to both predict the response to sulphonylurea treatment and support a second trial of glibenclamide at higher than standard doses if the expected response is not observed.

  • Fetal programming of adipose tissue function: an evolutionary perspective.

    17 October 2018

    Obesity is an escalating threat of pandemic proportions and has risen to such unrivaled prominence in such a short period of time that it has come to define a whole generation in many countries around the globe. The burden of obesity, however, is not equally shared among the population, with certain ethnicities being more prone to obesity than others, while some appear to be resistant to obesity altogether. The reasons behind this ethnic basis for obesity resistance and susceptibility, however, have remained largely elusive. In recent years, much evidence has shown that the level of brown adipose tissue thermogenesis, which augments energy expenditure and is negatively associated with obesity in both rodents and humans, varies greatly between ethnicities. Interestingly, the incidence of low birth weight, which is associated with an increased propensity for obesity and cardiovascular disease in later life, has also been shown to vary by ethnic background. This review serves to reconcile ethnic variations in BAT development and function with ethnic differences in birth weight outcomes to argue that the variation in obesity susceptibility between ethnic groups may have its origins in the in utero programming of BAT development and function as a result of evolutionary adaptation to cold environments.

  • Food cues and ghrelin recruit the same neuronal circuitry.

    17 October 2018

    BACKGROUND: Cues that are associated with the availability of food are known to trigger food anticipatory activity (FAA). This activity is expressed as increased locomotor activity and enables an animal to prepare for maximal utilization of nutritional resources. Although the exact neural network that mediates FAA is still unknown, several studies have revealed that the medial hypothalamus is involved. Interestingly, this area is responsive to the anorexigenic hormone leptin and the orexigenic hormone ghrelin that have been shown to modulate FAA. However, how FAA is regulated by neuronal activity and how leptin and ghrelin modulate this activity is still poorly understood. OBJECTIVE: We aimed to examine how the total neuronal population and individual neurons in the medial hypothalamus respond to cue-signaled food availability in awake, behaving rats. In addition, ghrelin and leptin were injected to investigate whether these hormones could have a modulatory role in the regulation of FAA. DESIGN: Using in vivo electrophysiology, neuronal activity was recorded in the medial hypothalamus in freely moving rats kept on a random feeding schedule, in which a light cue signaled upcoming food delivery. Ghrelin and leptin were administered systemically following the behavioral paradigm. RESULTS: The food-predictive cue induced FAA as well as a significant increase in neural activity on a population level. More importantly, a sub-population of medial hypothalamic neurons displayed highly correlated identical responses to both ghrelin and FAA, suggesting that these neurons are part of the network that regulates FAA. CONCLUSION: This study reveals a role for ghrelin, but not leptin, signaling within medial hypothalamus in FAA on both a population level and in single cells, identifying a subset of neurons onto which cue information and ghrelin signaling converge, possibly to drive FAA.

  • Ghrelin mediates anticipation to a palatable meal in rats.

    17 October 2018

    Food anticipatory activity (FAA) is displayed in rats when access to food is restricted to a specific time frame of their circadian phase, a behavior thought to reflect both hunger and the motivation to eat. Rats also display FAA in a feeding schedule with ad libitum access to normal chow, but limited availability of a palatable meal, which is thought to involve mainly motivational aspects. The orexigenic hormone ghrelin has been implicated in FAA in rodents with restricted access to chow. Because ghrelin plays an important role not only in the control of food intake, but also in reward, we sought to determine the role of ghrelin in anticipation to a palatable meal. Plasma ghrelin levels of non-restricted rats that anticipated chocolate correlated positively with FAA and were increased compared with chow-fed control rats. Furthermore, centrally injected ghrelin increased, whereas an antagonist of the ghrelin receptor decreased, the anticipation to chocolate. Therefore, we hypothesize that central ghrelin signaling is able to mediate the motivational drive to eat.

  • Melanocortin receptor-mediated effects on obesity are distributed over specific hypothalamic regions.

    17 October 2018

    OBJECTIVE: Reduction of melanocortin signaling in the brain results in obesity. However, where in the brain reduced melanocortin signaling mediates this effect is poorly understood. DESIGN: We determined the effects of long-term inhibition of melanocortin receptor activity in specific brain regions of the rat brain. Melanocortin signaling was inhibited by injection of a recombinant adeno-associated viral (rAAV) vector that overexpressed Agouti-related peptide (AgRP) into the paraventricular nucleus (PVN), the ventromedial hypothalamus (VMH), the lateral hypothalamus (LH) or the accumbens shell (Acc). RESULTS: Overexpression of AgRP in the rat PVN, VMH or LH increased bodyweight, the percentage of white adipose tissue, plasma leptin and insulin concentrations and food intake. Food intake was mainly increased because of an increase in meal size in the light and dark phases, after overexpression of AgRP in the PVN, LH or VMH. Overexpression of AgRP in the PVN or VMH reduced average body core temperature in the dark on day 40 post injection, whereas AgRP overexpression in the LH did not affect temperature. In addition, overexpression of AgRP in the PVN, LH or VMH did not significantly alter mRNA expression of AgRP, neuropeptide Y (NPY), pro-opiomelanocortin (POMC) or suppressor of cytokine signaling 3 (SOCS3) in the arcuate. Overexpression of AgRP in the Acc did not have any effect on the measured parameters. CONCLUSIONS: Reduction of melanocortin signaling in several hypothalamic regions increased meal size. However, there were brain area-specific effects on other parameters such as core temperature and plasma leptin concentrations. In a previous study, where NPY was overexpressed with an rAAV vector in the PVN and LH, meal frequency and meal size were increased respectively, whereas locomotor activity was reduced by NPY overexpression at both nuclei. Taken together, AgRP and NPY have complementary roles in energy balance.