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  • Fetal macrosomia and neonatal hyperinsulinemic hypoglycemia associated with transplacental transfer of sulfonylurea in a mother with KCNJ11-related neonatal diabetes.

    17 October 2018

    OBJECTIVE: Sulfonylureas (SUs) are effective at controlling glycemia in permanent neonatal diabetes mellitus (PNDM) caused by KCNJ11 (Kir6.2) mutations. RESEARCH DESIGN AND METHODS: We report the case of a woman with PNDM who continued high doses of glibenclamide (85 mg/day) during her pregnancy. The baby was born preterm, and presented with macrosomia and severe hyperinsulinemic hypoglycemia requiring high-rate intravenous glucose infusion. RESULTS: Postnatal genetic testing excluded a KCNJ11 mutation in the baby. Glibenclamide was detected in both the baby's blood and the maternal milk. CONCLUSIONS: We hypothesize that high doses of glibenclamide in the mother led to transplacental passage of the drug and overstimulation of fetal β-cells, which resulted in severe hyperinsulinemic hypoglycemia in the neonate (who did not carry the mutation) and contributed to fetal macrosomia. We suggest that glibenclamide (and other SUs) should be avoided in mothers with PNDM if the baby does not carry the mutation or if prenatal screening has not been performed, while glibenclamide may be beneficial when the fetus is a PNDM carrier.

  • A mutation causing increased KATP channel activity leads to reduced anxiety in mice.

    17 October 2018

    Activating mutations in the Kir6.2 (KCNJ11) subunit of the ATP-sensitive potassium channel cause neonatal diabetes. Many patients also suffer from neurological complications. By using mice carrying a human Kir6.2 mutation (Val(59) to Met(59); nV59M mice) targeted to neurones, we show that these mutations also result in altered anxiety behaviour. The light/dark box, successive alleys and elevated plus maze tasks revealed that nV59M mice have reduced anxiety related responses. Additionally, nV59M mice displayed enhanced basal locomotor activity and exploratory behaviour, as assessed by the low anxiety open-field test. These findings, in combination with previously reported hyperactivity of nV59M mice, appear to correlate with the increased impulsivity and inattentiveness reported in iDEND/DEND patients.

  • Type 2 diabetes and congenital hyperinsulinism cause DNA double-strand breaks and p53 activity in β cells.

    17 October 2018

    β cell failure in type 2 diabetes (T2D) is associated with hyperglycemia, but the mechanisms are not fully understood. Congenital hyperinsulinism caused by glucokinase mutations (GCK-CHI) is associated with β cell replication and apoptosis. Here, we show that genetic activation of β cell glucokinase, initially triggering replication, causes apoptosis associated with DNA double-strand breaks and activation of the tumor suppressor p53. ATP-sensitive potassium channels (KATP channels) and calcineurin mediate this toxic effect. Toxicity of long-term glucokinase overactivity was confirmed by finding late-onset diabetes in older members of a GCK-CHI family. Glucagon-like peptide-1 (GLP-1) mimetic treatment or p53 deletion rescues β cells from glucokinase-induced death, but only GLP-1 analog rescues β cell function. DNA damage and p53 activity in T2D suggest shared mechanisms of β cell failure in hyperglycemia and CHI. Our results reveal membrane depolarization via KATP channels, calcineurin signaling, DNA breaks, and p53 as determinants of β cell glucotoxicity and suggest pharmacological approaches to enhance β cell survival in diabetes.

  • ATP-sensitive potassium channels in health and disease

    17 October 2018

    Since their discovery over 20 years ago, it has been recognized that adenosine triphosphate-sensitive potassium (KATP) channels play a critical role in insulin secretion. When these channels are open, insulin secretion is inhibited, and when they are shut, secretion is initiated. Consequently drugs, mutations, or changes in beta-cell metabolism that open KATP channels decrease insulin secretion and may cause diabetes, whereas those manipulations that close KATP channels have the opposite effect, increasing insulin secretion and hypoglycemia. This chapter reviews our current knowledge of the pancreatic beta-cell KATP channel, and discusses new data on its structure, structure-function relationships, and role in disease. © 2008 Springer.

  • Na+ current properties in islet α- and β-cells reflect cell-specific Scn3a and Scn9a expression.

    17 October 2018

    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 >30 mV more negative in β-cells. This may indicate the presence of an intracellular factor that modulates the voltage dependence of inactivation.

  • Functional Microarchitecture of the Mouse Dorsal Inferior Colliculus Revealed through In Vivo Two-Photon Calcium Imaging.

    17 October 2018

    UNLABELLED: The inferior colliculus (IC) is an obligatory relay for ascending auditory inputs from the brainstem and receives descending input from the auditory cortex. The IC comprises a central nucleus (CNIC), surrounded by several shell regions, but the internal organization of this midbrain nucleus remains incompletely understood. We used two-photon calcium imaging to study the functional microarchitecture of both neurons in the mouse dorsal IC and corticocollicular axons that terminate there. In contrast to previous electrophysiological studies, our approach revealed a clear functional distinction between the CNIC and the dorsal cortex of the IC (DCIC), suggesting that the mouse midbrain is more similar to that of other mammals than previously thought. We found that the DCIC comprises a thin sheet of neurons, sometimes extending barely 100 μm below the pial surface. The sound frequency representation in the DCIC approximated the mouse's full hearing range, whereas dorsal CNIC neurons almost exclusively preferred low frequencies. The response properties of neurons in these two regions were otherwise surprisingly similar, and the frequency tuning of DCIC neurons was only slightly broader than that of CNIC neurons. In several animals, frequency gradients were observed in the DCIC, and a comparable tonotopic arrangement was observed across the boutons of the corticocollicular axons, which form a dense mesh beneath the dorsal surface of the IC. Nevertheless, acoustically responsive corticocollicular boutons were sparse, produced unreliable responses, and were more broadly tuned than DCIC neurons, suggesting that they have a largely modulatory rather than driving influence on auditory midbrain neurons. SIGNIFICANCE STATEMENT: Due to its genetic tractability, the mouse is fast becoming the most popular animal model for sensory neuroscience. Nevertheless, many aspects of its neural architecture are still poorly understood. Here, we image the dorsal auditory midbrain and its inputs from the cortex, revealing a hitherto hidden level of organization and paving the way for the direct observation of corticocollicular interactions. We show that a precise functional organization exists in the mouse auditory midbrain, which has been missed by previous, more macroscopic approaches. The fine-scale distribution of sound-frequency tuning suggests that the mouse midbrain is more similar to that of other mammals than previously thought and contrasts with the more heterogeneous organization reported in imaging studies of auditory cortex.

  • Cardiac perfusion imaging using hyperpolarized (13)C urea using flow sensitizing gradients.

    17 October 2018

    PURPOSE: To demonstrate the feasibility of imaging the first passage of a bolus of hyperpolarized (13)C urea through the rodent heart using flow-sensitizing gradients to reduce signal from the blood pool. METHODS: A flow-sensitizing bipolar gradient was optimized to reduce the bright signal within the cardiac chambers, enabling improved contrast of the agent within the tissue capillary bed. The gradient was incorporated into a dynamic golden angle spiral (13)C imaging sequence. Healthy rats were scanned during rest (n = 3) and under adenosine stress-induced hyperemia (n = 3). RESULTS: A two-fold increase in myocardial perfusion relative to rest was detected during adenosine stress-induced hyperemia, consistent with a myocardial perfusion reserve of two in rodents. CONCLUSION: The new pulse sequence was used to obtain dynamic images of the first passage of hyperpolarized (13)C urea in the rodent heart, without contamination from bright signal within the neighboring cardiac lumen. This probe of myocardial perfusion is expected to enable new hyperpolarized (13)C studies in which the cardiac metabolism/perfusion mismatch can be identified. Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance.

  • Robust and high resolution hyperpolarized metabolic imaging of the rat heart at 7 T with 3D spectral-spatial EPI.

    17 October 2018

    PURPOSE: Hyperpolarized metabolic imaging has the potential to revolutionize the diagnosis and management of diseases where metabolism is dysregulated, such as heart disease. We investigated the feasibility of imaging rodent myocardial metabolism at high resolution at 7 T. METHODS: We present here a fly-back spectral-spatial radiofrequency pulse that sidestepped maximum gradient strength requirements and enabled high resolution metabolic imaging of the rodent myocardium. A 3D echo-planar imaging readout followed, with centric ordered z-phase encoding. The cardiac gated sequence was used to image metabolism in rodents whose metabolic state had been manipulated by being fasted, fed, or fed and given the pyruvate dehydrogenase kinase inhibitor dichloroacetate. RESULTS: We imaged hyperpolarized metabolites with a spatial resolution of 2×2×3.8 mm(3) and a temporal resolution of 1.8 s in the rat heart at 7 T. Significant differences in myocardial pyruvate dehydrogenase flux were observed between the three groups of animals, concomitant with the known biochemistry. CONCLUSION: The proposed sequence was able to image in vivo metabolism with excellent spatial resolution in the rat heart. The field of view enabled the simultaneous multi-organ acquisition of metabolic information from the rat, which is of great utility for preclinical research in cardiovascular disease. Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance.