Frank Reimann

Uppsala University, Uppsala, Uppsala, Sweden

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Publications (108)981.08 Total impact

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    ABSTRACT: Objective Larger portion sizes (PS) are associated with greater energy intake (EI), but little evidence exists on the appetitive effects of PS reduction. This study investigated the impact of reducing breakfast PS on subsequent EI, postprandial gastrointestinal hormone responses, and appetite ratings.Methods In a randomized crossover design (n = 33 adults; mean BMI 29 kg/m2), a compulsory breakfast was based on 25% of gender-specific estimated daily energy requirements; PS was reduced by 20% and 40%. EI was measured at an ad libitum lunch (240 min) and snack (360 min) and by weighed diet diaries until bed. Blood was sampled until lunch in 20 participants. Appetite ratings were measured using visual analogue scales.ResultsEI at lunch (control: 2,930 ± 203; 20% reduction: 2,853 ± 198; 40% reduction: 2,911 ± 179 kJ) and over the whole day except breakfast (control: 7,374 ± 361; 20% reduction: 7,566 ± 468; 40% reduction: 7,413 ± 417 kJ) did not differ. Postprandial PYY, GLP-1, GIP, insulin, and fullness profiles were lower and hunger, desire to eat, and prospective consumption higher following 40% reduction compared to control. Appetite ratings profiles, but not hormone concentrations, were associated with subsequent EI.Conclusions Smaller portions at breakfast led to reductions in gastrointestinal hormone secretion but did not affect subsequent energy intake, suggesting small reductions in portion size may be a useful strategy to constrain EI.
    Obesity 06/2015; DOI:10.1002/oby.21105 · 4.39 Impact Factor
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    ABSTRACT: Pain perception has evolved as a warning mechanism to alert organisms to tissue damage and dangerous environments. In humans, however, undesirable, excessive or chronic pain is a common and major societal burden for which available medical treatments are currently suboptimal. New therapeutic options have recently been derived from studies of individuals with congenital insensitivity to pain (CIP). Here we identified 10 different homozygous mutations in PRDM12 (encoding PRDI-BF1 and RIZ homology domain-containing protein 12) in subjects with CIP from 11 families. Prdm proteins are a family of epigenetic regulators that control neural specification and neurogenesis. We determined that Prdm12 is expressed in nociceptors and their progenitors and participates in the development of sensory neurons in Xenopus embryos. Moreover, CIP-associated mutants abrogate the histone-modifying potential associated with wild-type Prdm12. Prdm12 emerges as a key factor in the orchestration of sensory neurogenesis and may hold promise as a target for new pain therapeutics.
    Nature Genetics 05/2015; DOI:10.1038/ng.3308 · 29.65 Impact Factor
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    ABSTRACT: The importance of NaV1.7 (encoded by SCN9A) in the regulation of pain sensing is exemplified by the heterogeneity of clinical phenotypes associated with its mutation. Gain-of-function mutations are typically pain-causing and have been associated with inherited erythromelalgia (IEM) and paroxysmal extreme pain disorder (PEPD). IEM is usually caused by enhanced NaV1.7 channel activation, whereas mutations that alter steady-state fast inactivation often lead to PEPD. In contrast, nonfunctional mutations in SCN9A are known to underlie congenital insensitivity to pain (CIP). Although well documented, the correlation between SCN9A genotypes and clinical phenotypes is still unclear. Here we report three families with novel SCN9A mutations. In a multiaffected dominant family with IEM, we found the heterozygous change L245 V. Electrophysiological characterization showed that this mutation did not affect channel activation but instead resulted in incomplete fast inactivation and a small hyperpolarizing shift in steady-state slow inactivation, characteristics more commonly associated with PEPD. In two compound heterozygous CIP patients, we found mutations that still retained functionality of the channels, with two C-terminal mutations (W1775R and L1831X) exhibiting a depolarizing shift in channel activation. Two mutations (A1236E and L1831X) resulted in a hyperpolarizing shift in steady-state fast inactivation. To our knowledge, these are the first descriptions of mutations with some retained channel function causing CIP. This study emphasizes the complex genotype–phenotype correlations that exist for SCN9A and highlights the C-terminal cytoplasmic region of NaV1.7 as a critical region for channel function, potentially facilitating analgesic drug development studies.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 05/2015; 35(20):7674-7681. DOI:10.1523/JNEUROSCI.3935-14.2015 · 6.75 Impact Factor
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    ABSTRACT: Cytoplasmic ATP and Ca(2+) are implicated in current models of glucose's control of glucagon and insulin secretion from pancreatic α- and β-cells, respectively, but little is known about ATP and its relation to Ca(2+) in α-cells. We therefore expressed the fluorescent ATP biosensor Perceval in mouse pancreatic islets and loaded them with a Ca(2+) indicator. With total internal reflection fluorescence microscopy, we recorded subplasma membrane concentrations of Ca(2+) and ATP ([Ca(2+)]pm; [ATP]pm) in superficial α- and β-cells of intact islets and related signaling to glucagon and insulin secretion by immunoassay. Consistent with ATP's controlling glucagon and insulin secretion during hypo- and hyperglycemia, respectively, the dose-response relationship for glucose-induced [ATP]pm generation was left shifted in α-cells compared to β-cells. Both cell types showed [Ca(2+)]pm and [ATP]pm oscillations in opposite phase, probably reflecting energy-consuming Ca(2+) transport. Although pulsatile insulin and glucagon release are in opposite phase, [Ca(2+)]pm synchronized in the same phase between α- and β-cells. This paradox can be explained by the overriding of Ca(2+) stimulation by paracrine inhibition, because somatostatin receptor blockade potently stimulated glucagon release with little effect on Ca(2+). The data indicate that an α-cell-intrinsic mechanism controls glucagon in hypoglycemia and that paracrine factors shape pulsatile secretion in hyperglycemia.-Li, J., Yu, Q., Ahooghalandari, P., Gribble, F. M., Reimann, F., Tengholm, A., Gylfe, E. Submembrane ATP and Ca(2+) kinetics in α-cells: unexpected signaling for glucagon secretion. © FASEB.
    The FASEB Journal 04/2015; DOI:10.1096/fj.14-265918 · 5.48 Impact Factor
  • PLoS ONE 03/2015; 10(3):e0119034. DOI:10.1371/journal.pone.0119034 · 3.53 Impact Factor
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    ABSTRACT: Altered secretion of insulin as well as glucagon has been implicated in the pathogenesis of Type 2 Diabetes, but the mechanisms controlling glucagon secretion from α-cells largely remain unresolved. Therefore, we studied the regulation of glucagon secretion from αTC1-6 cells and compared it to insulin release from INS-1 832/13 cells. We found that INS-1 832/13 and αTC1-6 cells, respectively, secreted insulin and glucagon concentration-dependently in response to glucose. In contrast, tight coupling of glycolytic and mitochondrial metabolism was observed only in INS-1 832/13 cells. While glycolytic metabolism was similar in the two cell-lines, Krebs-cycle metabolism, respiration and ATP-levels were less glucose-responsive in αTC1-6 cells. Inhibition of the malate-aspartate shuttle, using phenyl succinate, abolished glucose-provoked ATP production and hormone secretion from αTC1-6, but not INS-1 832/13 cells. Blocking the malate-aspartate shuttle increased levels of glycerol-3-phosphate only in INS-1 832/13 cells. Accordingly, relative expression of constituents in the glycerolphosphate shuttle compared to malate-aspartate shuttle was lower in αTC1-6 cells. Our data suggest that the glycerolphosphate shuttle augments the malate-aspartate shuttle in the INS-1 832/13 but not in αTC1-6 cells. These results were confirmed in mouse islets, where phenyl succinate abrogated secretion of glucagon but not insulin. Furthermore, expression of the rate-limiting enzyme of the glycerolphosphate shuttle, was higher in sorted primary ß- than α-cells. Thus, suppressed glycerolphosphate shuttle activity in the α-cell may prevent a high rate of glycolysis and consequently glucagon secretion in response to glucose. Accordingly, pyruvate- and lactate-elicited glucagon secretion remains unaffected since their signaling is independent on mitochondrial shuttles.
    Biochemical Journal 03/2015; DOI:10.1042/BJ20140697 · 4.78 Impact Factor
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    ABSTRACT: The enteroendocrine system is the primary sensor of ingested nutrients and is responsible for secreting an array of gut hormones, which modulate multiple physiological responses including gastrointestinal motility and secretion, glucose homeostasis, and appetite. This Review provides an up-to-date synopsis of the molecular mechanisms underlying enteroendocrine nutrient sensing and highlights our current understanding of the neuro-hormonal regulation of gut hormone secretion, including the interaction between the enteroendocrine system and the enteric nervous system. It is hoped that a deeper understanding of how these systems collectively regulate postprandial physiology will further facilitate the development of novel therapeutic strategies.
    Journal of Clinical Investigation 02/2015; 125(3). DOI:10.1172/JCI76309 · 13.77 Impact Factor
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    ABSTRACT: Obesity is a global concern and can be effectively treated with bariatric surgery, which is expensive and invasive. Weight loss after surgery has been attributed to increased nutrient delivery to the lower small intestine with release of satiety-promoting gut hormones such as glucagon-like peptide 1 (GLP-1). We aimed to assess whether glutamine, a potent secretagogue of GLP-1 in vivo, increases GLP-1 release, improves glucose tolerance, or reduces meal size in volunteers.
    The Lancet 02/2015; 385:S68. DOI:10.1016/S0140-6736(15)60383-X · 45.22 Impact Factor
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    ABSTRACT: Glucagon release from pancreatic alpha cells is required for normal glucose homoeostasis and is dysregulated in both Type 1 and Type 2 diabetes. The tumour suppressor LKB1 (STK11) and the downstream kinase AMP-activated protein kinase (AMPK), modulate cellular metabolism and growth, and AMPK is an important target of the anti-hyperglycaemic agent metformin. While LKB1 and AMPK have emerged recently as regulators of beta cell mass and insulin secretion, the role of these enzymes in the control of glucagon production in vivo is unclear. Here, we ablated LKB1 (αLKB1KO), or the catalytic alpha subunits of AMPK (αAMPKdKO, -α1KO, -α2KO), selectively in ∼45% of alpha cells in mice by deleting the corresponding flox'd alleles with a preproglucagon promoter (PPG) Cre. Blood glucose levels in male αLKB1KO mice were lower during intraperitoneal glucose, aminoimidazole carboxamide ribonucleotide (AICAR) or arginine tolerance tests, and glucose infusion rates were increased in hypoglycemic clamps (p < 0.01). αLKB1KO mice also displayed impaired hypoglycemia-induced glucagon release. Glucose infusion rates were also elevated (p < 0.001) in αAMPKα1 null mice, and hypoglycemia-induced plasma glucagon increases tended to be lower (p = 0.06). Glucagon secretion from isolated islets was sensitized to the inhibitory action of glucose in αLKB1KO, αAMPKdKO, and -α1KO, but not -α2KO islets. An LKB1-dependent signalling cassette, involving but not restricted to AMPKα1, is required in pancreatic alpha cells for the control of glucagon release by glucose.
    01/2015; 4(4). DOI:10.1016/j.molmet.2015.01.006
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    ABSTRACT: Glucagon-like peptide-1-based (GLP-1-based) therapies improve glycemic control in patients with type 2 diabetes. While these agents augment insulin secretion, they do not mimic the physiological meal-related rise and fall of GLP-1 concentrations. Here, we tested the hypothesis that increasing the number of intestinal L cells, which produce GLP-1, is an alternative strategy to augment insulin responses and improve glucose tolerance. Blocking the NOTCH signaling pathway with the γ-secretase inhibitor dibenzazepine increased the number of L cells in intestinal organoid-based mouse and human culture systems and augmented glucose-stimulated GLP-1 secretion. In a high-fat diet-fed mouse model of impaired glucose tolerance and type 2 diabetes, dibenzazepine administration increased L cell numbers in the intestine, improved the early insulin response to glucose, and restored glucose tolerance. Dibenzazepine also increased K cell numbers, resulting in increased gastric inhibitory polypeptide (GIP) secretion. Using a GLP-1 receptor antagonist, we determined that the insulinotropic effect of dibenzazepine was mediated through an increase in GLP-1 signaling. Together, our data indicate that modulation of the development of incretin-producing cells in the intestine has potential as a therapeutic strategy to improve glycemic control.
    The Journal of clinical investigation 12/2014; 125(1). DOI:10.1172/JCI75838 · 13.77 Impact Factor
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    ABSTRACT: The melanocortin-4 receptor (MC4R) is expressed in the brainstem and vagal afferent nerves and regulates a number of aspects of gastrointestinal function. Here we show that the receptor is also diffusely expressed in cells of the gastrointestinal system, from stomach to descending colon. Furthermore, MC4R is the second most highly enriched GPCR in peptide YY (PYY) and glucagon-like peptide 1 (GLP-1) expressing enteroendocrine L cells. When vectorial ion transport is measured across mouse or human intestinal mucosa, administration of α-MSH induces a MC4R-specific PYY-dependent antisecretory response consistent with a role for the MC4R in paracrine inhibition of electrolyte secretion. Finally, MC4R-dependent acute PYY and GLP-1 release from L cells can be stimulated in vivo by intraperitoneal (i.p.) administration of melanocortin peptides to mice. This suggests physiological significance for MC4R in L cells and indicates a previously unrecognized peripheral role for the MC4R, complementing vagal and central receptor functions. Copyright © 2014 Elsevier Inc. All rights reserved.
    Cell Metabolism 12/2014; 20(6):1018-29. DOI:10.1016/j.cmet.2014.10.004 · 16.75 Impact Factor
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    ABSTRACT: It has long been speculated that metabolites, produced by gut microbiota, influence host metabolism in health and diseases. Here, we reveal that indole, a metabolite produced from the dissimilation of tryptophan, is able to modulate the secretion of glucagon-like peptide-1 (GLP-1) from immortalized and primary mouse colonic L cells. Indole increased GLP-1 release during short exposures, but it reduced secretion over longer periods. These effects were attributed to the ability of indole to affect two key molecular mechanisms in L cells. On the one hand, indole inhibited voltage-gated K+ channels, increased the temporal width of action potentials fired by L cells, and led to enhanced Ca2+ entry, thereby acutely stimulating GLP-1 secretion. On the other hand, indole slowed ATP production by blocking NADH dehydrogenase, thus leading to a prolonged reduction of GLP-1 secretion. Our results identify indole as a signaling molecule by which gut microbiota communicate with L cells and influence host metabolism
    Cell Reports 11/2014; 9(4). DOI:10.1016/j.celrep.2014.10.032 · 7.21 Impact Factor
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    ABSTRACT: Glucagon-like peptide-1 (GLP-1) affects central autonomic neurons, including those controlling the cardiovascular system, thermogenesis, and energy balance. Preproglucagon (PPG) neurons, located mainly in the nucleus tractus solitarius (NTS) and medullary reticular formation, produce GLP-1. In transgenic mice expressing glucagon promoter-driven yellow fluorescent protein (YFP), these brainstem PPG neurons project to many central autonomic regions where GLP-1 receptors are expressed. The spinal cord also contains GLP-1 receptor mRNA but the distribution of spinal PPG axons is unknown. Here, we used two-color immunoperoxidase labeling to examine PPG innervation of spinal segments T1–S4 in YFP-PPG mice. Immunoreactivity for YFP identified spinal PPG axons and perikarya. We classified spinal neurons receiving PPG input by immunoreactivity for choline acetyltransferase (ChAT), nitric oxide synthase (NOS) and/or Fluorogold (FG) retrogradely transported from the peritoneal cavity. FG microinjected at T9 defined cell bodies that supplied spinal PPG innervation. The deep dorsal horn of lower lumbar cord contained YFP-immunoreactive neurons. Non-varicose, YFP-immunoreactive axons were prominent in the lateral funiculus, ventral white commissure and around the ventral median fissure. In T1–L2, varicose, YFP-containing axons closely apposed many ChAT-immunoreactive sympathetic preganglionic neurons (SPN) in the intermediolateral cell column (IML) and dorsal lamina X. In the sacral parasympathetic nucleus, about 10% of ChAT-immunoreactive preganglionic neurons received YFP appositions, as did occasional ChAT-positive motor neurons throughout the rostrocaudal extent of the ventral horn. YFP appositions also occurred on NOS-immunoreactive spinal interneurons and on spinal YFP-immunoreactive neurons. Injecting FG at T9 retrogradely labeled many YFP-PPG cell bodies in the medulla but none of the spinal YFP-immunoreactive neurons. These results show that brainstem PPG neurons innervate spinal autonomic and somatic motor neurons. The distributions of spinal PPG axons and spinal GLP-1 receptors correlate well. SPN receive the densest PPG innervation. Brainstem PPG neurons could directly modulate sympathetic outflow through their spinal inputs to SPN or interneurons.
    Neuroscience 11/2014; 284. DOI:10.1016/j.neuroscience.2014.10.043 · 3.33 Impact Factor
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    ABSTRACT: Stimulus-coupled incretin secretion from enteroendocrine cells plays a fundamental role in glucose homeostasis, and could be targeted for the treatment of type-2 diabetes. Here, we investigated the expression and function of transient receptor potential (TRP) ion channels in enteroendocrine L-cells producing glucagon-like peptide-1 (GLP-1). By microarray and qPCR analysis we identified trpa1 as an L-cell enriched transcript in the small intestine. Calcium imaging of primary L-cells and the model cell line GLUTag revealed responses triggered by the TRPA1 agonists allyl-isothiocyanate (AITC, mustard oil), carvacrol and polyunsaturated fatty acids, that were blocked by TRPA1 antagonists. Electrophysiology in GLUTag cells showed that carvacrol induced a current with characteristics typical of TRPA1 and triggered the firing of action potentials. TRPA1 activation caused an increase in GLP-1 secretion from primary murine intestinal cultures and GLUTag cells; an effect that was abolished in cultures from trpa1(-/-) mice or by pharmacological TRPA1 inhibition. These findings present TRPA1 as a novel sensory mechanism in enteroendocrine L-cells, coupled to the facilitation of GLP-1 release, which may be exploitable as a target for treating diabetes.
    Diabetes 10/2014; 64(4). DOI:10.2337/db14-0737 · 8.47 Impact Factor
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    ABSTRACT: Liver kinase B1 (LKB1/STK11) is a serine/threonine kinase and tumour suppressor mutated in Peutz-Jeghers Syndrome (PJS), a premalignant syndrome associated with the development of gastrointestinal polyps. Proglucagon expressing entero-endocrine cells are involved in the control of glucose homeostasis and the regulation of appetite through the secretion of gut hormones including glucagon-like peptide-1 (GLP-1) and peptide tyrosine tyrosine (PYY). To determine the role of LKB1 in these cells, we bred mice bearing flox'd alleles of Lkb1 against animals carrying Cre recombinase under proglucagon promoter control. These mice (GluLKB1KO) were viable and displayed near normal growth rates and glucose homeostasis. However, they developed large polyps at the gastro-duodenal junction, and displayed premature mortality, from 120 days of age. Histological analysis of these polyps demonstrated that they had a PJS-like appearance with an arborizing smooth muscle core. Circulating GLP-1 levels were normal in GluLKB1KO mice and the polyps expressed low levels of the peptide, similar to those in the neighbouring duodenum. Lineage tracing using a Rosa26tdRFP transgene revealed, unexpectedly, that enterocytes within the polyps were derived from non-proglucagon expressing precursors whereas connective tissue was largely derived from proglucagon expressing precursors. Developmental studies in wild type mice suggest that a subpopulation of proglucagon expressing cells undergo epithelial mesenchymal transition (EMT) to become smooth muscle like cells. Thus it is likely that polyps in the GluLKB1KO mice are derived from a unique population of smooth muscle like cells previously derived from a proglucagon expressing precursor. The loss of LKB1 within this subpopulation appears sufficient to drive tumorigenesis.
    Disease Models and Mechanisms 09/2014; DOI:10.1242/dmm.014720 · 5.54 Impact Factor
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    ABSTRACT: New FindingsWhat is the topic of this review? Gut hormones, especially glucagon-like peptide-1 (GLP-1), have beneficial effects in diabetes and obesity. Recent research addresses the underlying mechanisms of the secretion and action of GLP-1.What advances does it highlight? The development of transgenic reporter mice with fluorescently tagged GLP-1-secreting cells has helped to characterize the molecular mechanisms underlying hormone secretion and has challenged the traditional classification of enteroendocrine cells by hormone expression alone. Recent adoption of this strategy to label GLP-1-receptor-positive cells has highlighted that peripheral and centrally released GLP-1 acts on a number of different targets, including a variety of neurons. Evidence for their role in glucose homeostasis and appetite control is discussed.After food is ingested, nutrients pass through the gastrointestinal tract, stimulating the release of a range of peptide hormones. Among their many local, central and peripheral actions, these hormones act to mediate glucose metabolism and satiety. Indeed, it is the modification of gut hormone secretion that is considered partly responsible for the normalization of glycaemic control and the reduction in appetite seen in many patients after certain forms of bariatric surgery. This review describes recent developments in our understanding of the secretion and action of anorexigenic gut hormones, primarily concentrating on glucagon-like peptide-1 (GLP-1).
    Experimental physiology 09/2014; 99(9). DOI:10.1113/expphysiol.2014.079764 · 2.87 Impact Factor
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    ABSTRACT: Diabetes is characterized by hyperglycaemia due to impaired insulin secretion and aberrant glucagon secretion resulting from changes in pancreatic islet cell function and/or mass. The extent to which hyperglycaemia per se underlies these alterations remains poorly understood. Here we show that β-cell-specific expression of a human activating KATP channel mutation in adult mice leads to rapid diabetes and marked alterations in islet morphology, ultrastructure and gene expression. Chronic hyperglycaemia is associated with a dramatic reduction in insulin-positive cells and an increase in glucagon-positive cells in islets, without alterations in cell turnover. Furthermore, some β-cells begin expressing glucagon, whilst retaining many β-cell characteristics. Hyperglycaemia, rather than KATP channel activation, underlies these changes, as they are prevented by insulin therapy and fully reversed by sulphonylureas. Our data suggest that many changes in islet structure and function associated with diabetes are attributable to hyperglycaemia alone and are reversed when blood glucose is normalized.
    Nature Communications 08/2014; 5:4639. DOI:10.1038/ncomms5639 · 10.74 Impact Factor
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    ABSTRACT: Total or near-total loss of insulin-producing β-cells occurs in type 1 diabetes. Restoration of insulin production in type 1 diabetes is thus a major medical challenge. We previously observed in mice in which β-cells are completely ablated that the pancreas reconstitutes new insulin-producing cells in the absence of autoimmunity. The process involves the contribution of islet non-β-cells; specifically, glucagon-producing α-cells begin producing insulin by a process of reprogramming (transdifferentiation) without proliferation. Here we show the influence of age on β-cell reconstitution from heterologous islet cells after near-total β-cell loss in mice. We found that senescence does not alter α-cell plasticity: α-cells can reprogram to produce insulin from puberty through to adulthood, and also in aged individuals, even a long time after β-cell loss. In contrast, before puberty there is no detectable α-cell conversion, although β-cell reconstitution after injury is more efficient, always leading to diabetes recovery. This process occurs through a newly discovered mechanism: the spontaneous en masse reprogramming of somatostatin-producing δ-cells. The juveniles display 'somatostatin-to-insulin' δ-cell conversion, involving dedifferentiation, proliferation and re-expression of islet developmental regulators. This juvenile adaptability relies, at least in part, upon the combined action of FoxO1 and downstream effectors. Restoration of insulin producing-cells from non-β-cell origins is thus enabled throughout life via δ- or α-cell spontaneous reprogramming. A landscape with multiple intra-islet cell interconversion events is emerging, offering new perspectives for therapy.
    Nature 08/2014; 514(7523). DOI:10.1038/nature13633 · 42.35 Impact Factor
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    ABSTRACT: The parabrachial nucleus (PBN) is a key nucleus for the regulation of feeding behavior. Inhibitory inputs from the hypothalamus to the PBN play a crucial role in the normal maintenance of feeding behavior, as their loss leads to starvation. Viscerosensory stimuli result in neuronal activation of the PBN, however the origin and neurochemical identity of the excitatory neuronal input to the PBN remain largely unexplored. Here we hypothesize that hindbrain glucagon-like peptide 1 (GLP-1) neurons provide excitatory inputs to the PBN, activation of which may lead to a reduction in feeding behavior. Our data, obtained from mice expressing the yellow fluorescent protein in GLP-1-producing neurons, revealed that hindbrain GLP-1-producing neurons project to the lateral PBN (lPBN). Stimulation of lPBN GLP-1 receptors (GLP-1R) reduced the intake of chow and palatable food and decreased body weight in rats. It also activated lPBN neurons, reflected by an increase in the number of c-Fos-positive cells in this region. Further support for an excitatory role of GLP-1 in the PBN is provided by electrophysiological studies showing a remarkable increase in firing of lPBN neurons after exendin-4 application. We show that within the PBN, GLP-1R activation increased gene expression of two energy balance regulating peptides, calcitonin gene related peptide (CGRP) and interleukin-6. Moreover, nearly seventy percent of the lPBN GLP-1 fibers innervated lPBN CGRP neurons. Direct intra-lPBN CGRP application resulted in anorexia. Collectively, our molecular, anatomical, electrophysiological, pharmacological and behavioral data provide evidence for a functional role of the GLP-1R for feeding control in the PBN.
    Endocrinology 08/2014; 155(11):en20141248. DOI:10.1210/en.2014-1248 · 4.64 Impact Factor
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    ABSTRACT: Mouse pancreatic β- and α-cells are equipped with voltage-gated Na+ currents that inactivate over widely different membrane potentials (half-maximal inactivation [V0.5] at -100 mV and -50 mV in β- and α-cells, respectively). Single-cell PCR analyses show that both α- and β-cells have Nav1.3 (Scn3) and Nav1.7 (Scn9a) α-subunits, but their relative proportions differ: β-cells principally express Nav1.7 and α-cells Nav1.3. In α-cells, genetically ablating Scn3a reduces the Na+ current by 80%. In β-cells, knockout of Scn9a lowers the Na+ current by >85%, unveiling a small Scn3a-dependent component. Glucagon and insulin secretion are inhibited in Scn3a−/− islets but unaffected in Scn9a-deficient islets. Thus Nav1.3 is the functionally important Na+ channel α-subunit in both α- and β-cells because Nav1.7 is largely inactive at physiological membrane potentials due to its unusually negative voltage dependence of inactivation. Interestingly, the Nav1.7 sequence in brain and islets is identical and yet the V0.5 for inactivation is >30mV more negative in β-cells. This may indicate the presence of an intracellular factor that modulates the voltage dependence of inactivation.This article is protected by copyright. All rights reserved
    The Journal of Physiology 08/2014; 592(21). DOI:10.1113/jphysiol.2014.274209 · 4.54 Impact Factor

Publication Stats

5k Citations
981.08 Total Impact Points

Institutions

  • 2015
    • Uppsala University
      • Department of Medical Cell Biology
      Uppsala, Uppsala, Sweden
  • 2002–2015
    • University of Cambridge
      • • Department of Clinical Biochemistry
      • • Cambridge Institute for Medical Research
      • • Department of Biochemistry
      Cambridge, England, United Kingdom
  • 2004–2014
    • Cambridge Institute for Medical Research
      Cambridge, England, United Kingdom