Uniwersytet Medyczny w Łodzi Medical University of Lodz https://publicum.umed.lodz.pl Higher Blood Glucose Variability is Associated with Increased Risk of Hypoglycemia Publikacja / Publication in Well or Poorly Controlled Type 1 or Type 2 Diabetes, Czupryniak Leszek, Borkowska Anna, Szymańska-Garbacz Elektra DOI wersji wydawcy / Published http://dx.doi.org/10.2337/db17-381-663 version DOI Adres publikacji w Repozytorium URL / Publication address in https://publicum.umed.lodz.pl/info/article/AML063ddbabfba14480a6e45b1d944e1ccd/ Repository Data opublikowania w Repozytorium 2020-08-31 / Deposited in Repository on Rodzaj licencji / Type of licence Other open licence Czupryniak Leszek, Borkowska Anna, Szymańska-Garbacz Elektra : Higher Blood Glucose Variability is Associated with Increased Risk of Hypoglycemia in Well or Cytuj tę wersję / Cite this version Poorly Controlled Type 1 or Type 2 Diabetes, Diabetes, vol. 66, no. Suppl. 1, 2017, pp. 103-104, DOI:10.2337/db17-381-663 COMPLICATIONS—HYPOGLYCEMIA COMPLICATIONS—HYPOGLYCEMIA an activating role of SAMSN1, L-triiodothyronine, IFNA4, JAK1 and mTORC1, and an inhibitory action of BDNF, POR, ESR1, CTNNB1 and ERG on the gene networks identified in our samples. Moderated Poster Discussion: Hypoglycemia—Novel Concepts Our study for the first time characterizes the transcriptional responses (Posters: 381-P to 386-P), see page 19. of the BBB compartment to recurrent hypoglycemia exposure and may help identify novel therapeutic targets to restore the impaired responses against 381‑P hypoglycemia in patients with type 1 diabetes. & Supported By: National Institutes of Health; JDRF Hypoglycemia‑Associated Autonomic Failure Is Associated with POSTERS Complications Coordinated miRNA‑mRNA Network Changes in the Ventromedial Acute and Chronic Hypothalamus & 383‑P RAHUL AGRAWAL, CASEY TAYLOR, ADRIANA VIEIRA-DE-ABREU, SIMON J. KATP Channel Opening Increases Severe Hypoglycemia‑Induced FISHER, Salt Lake City, UT Cardiac Arrhythmias We tested the hypothesis that the maladaptive response to recurrent CANDACE M. RENO, JUSTIN BAYLES, ALLIE SKINNER, SIMON J. FISHER, Salt hypoglycemia (RH; i.e., HAAF) is mediated by the coordinated changes in Lake City, UT microRNA-mRNA expression in ventromedial hypothalamus (VMH). Insulin The mechanisms of how severe hypoglycemia leads to fatal cardiac induced (2-1.2 U/kg, sc) RH (30-50 mg/dl x 3 days, n=10) or recurrent saline arrhythmias are unknown. It is hypothesized that ATP sensitive potassium (RS, n=10) Sprague-Dawley rats were subjected to either, 1) hyperinsulinemic (KATP) channels regulate arrhythmias during severe hypoglycemia. To test (20 mU/kg/min) hypoglycemic (40-50 mg/dl) clamps, or 2) were euthanized to the role of KATP channels in severe hypoglycemia-induced arrhythmias, obtain RNA from the VMH for genome-wide microRNAome and transcrip- nondiabetic Sprague Dawley rats were infused with either vehicle (VEH, tome profiling. As expected, the epinephrine response to hypoglycemia was 18% ethanol, n=6), KATP blocker (glibenclamide, GLIB, 5 mg/kg/hr n=5), or blunted by 55% in RH rats. A total of 205 miRNAs and 1013 mRNAs were KATP opener (diazoxide, DIAZ, 5 mg/kg/hr, n=4) during a hyperinsulinemic differentially expressed (false discovery rate; FDR<0.05) between groups. A (0.2 U/kg/min) severe hypoglycemic (10-15 mg/dl) clamp with electrocardio- miRNA target filtering analysis using Ingenuity Pathway Analysis (IPA) soft- gram recordings for 3 hours. The glucose infusion rates to maintain severe ware demonstrated coordinated changes in miRNA-mRNA with 82 miRNA hypoglycemia were not different among the groups indicating the drugs did pairing to 402 mRNA (FDR <0.05). miRNA-mRNA network analysis of RH not affect hypoglycemic counterregulation. Various types of cardiac arrhyth- induced genomic changes identified miR-23a-3p and miR-7a-5p based on mias were noted. Compared to VEH, 2nd degree heart block was not differ- their large predicted network and association with mRNA target changes, ent in GLIB, but DIAZ significantly increased 2nd degree heart block 10-fold specifically Clcn3 and Mknk2 (gene products involved in GABAergic synaptic (p<0.05; Figure). Third degree heart block was reduced by 22% in GLIB and vesicles release and pancreatic β-cells function, respectively). increased 19% in DIAZ compared to VEH. However, severe hypoglycemia- In conclusion, RH induced changes in VMH levels of miR-23a-3p and miR- induced mortality was not different among the groups. 7a-5p might be potential mediators or regulators of HAAF. In summary, during severe hypoglycemia, KATP blockade tended to reduce arrhythmias whereas KATP opening increased cardiac arrhythmias. Figure. In conclusion, acute modulation of KATP channel activity during severe hypoglycemia can affect the incidence of potentially fatal cardiac arrhythmias. Figure. Supported By: JDRF & 382‑P Blood‑Brain‑Barrier Transcriptome Response to Recurrent Hypo‑ glycemia Exposure in a Rodent Model of Hypoglycemia Unaware‑ ness ZEJIAN LIU, YUYAN DING, RAIMUND I. HERZOG, New Haven, CT Recurrent hypoglycemia (RH) results in hypoglycemia unawareness, which substantially increases the risk of severe hypoglycemic episodes. Pre- Supported By: National Institutes of Health vious studies suggested that changes of energy substrate transporters and other regulators at the level of the Blood-Brain-Barrier (BBB) may contribute to this problem. To understand response of the BBB to antecedent RH, we & 384‑P isolated cortical brain microvessels (MVs), immediately after an episode Hypoglycemia Effects on Neurocognitive Function in Type 1 Diabe‑ of acute hypoglycemia, from our rodent model, in which rats were either tes Mellitus Measured by Neuroimaging pretreated with 3 consecutive days of recurrent hypoglycemia (3dRH) or KAITLIN G. BRAU, ALEX I. WIESMAN, TIMOTHY J. MCDERMOTT, ANDJELA T. left untreated (n=15 per group). We then analyzed extracted RNA by whole DRINCIC, TONY W. WILSON, CYRUS V. DESOUZA, Omaha, NE exome sequencing to identify transcriptional differences. Hypoglycemia has been associated with diabetes-related cognitive dys- Verification of MVs purity confirmed a 50-fold enrichment of the endothe- function. We aimed to better understand neuronal changes that precipitate lial compartment in comparison to whole brain cortical tissue. Out of 13,951 the development and progression of this cognitive dysfunction in type 1 genes detected, we identified a signature of 50 genes that were character- diabetes mellitus (T1DM) by using a noninvasive functional neuroimaging istic for exposure to 3dRH, with 19 being upregulated and 31 being down- tool that directly evaluates neural activity, known as magnetoencephalogra- regulated. Manual annotation of the 50 genes suggests that RH attenuates phy (MEG). We hypothesized that MEG brain function parameters would be inflammatory responses, ameliorates vascular permeability and inhibits cell abnormal in patients with T1DM with more frequent hypoglycemia. Thirty- cycle progression. Ingenuity Pathway Analysis (IPA) revealed key signaling three patients with T1DM completed a somatosensory task during MEG. cascades affected by RH, including circadian rhythm, ER stress/unfolded During this task, electrical paired pulse stimulation was applied to a par- protein response (UPR), NF-κB, STAT3 and LXR/RXR signaling. Candidate ticipant’s right median nerve. All MEG data was processed following stan- pathways were validated by qPCR and/or Western blot in independently dard protocols, and the resulting images of functional brain activity were generated confirmatory MV samples. Upstream regulator analysis predicted averaged across all patients. The time series of activation in the peak voxel (cube of tissue) was then evaluated statistically for group differences. Data ADA-Supported Research & Moderated Poster Discussion For author disclosure information, see page A751. A101 Pobrano z https://publicum.umed.lodz.pl / Downloaded from Repository of Medical University of Lodz 2021-10-04 COMPLICATIONS—HYPOGLYCEMIA regarding outpatient frequency of hypoglycemia was collected. Patients & 386‑P were divided into two groups, 1-or-less and 3-or-more episodes of blood An Aptamer‑Based Platform for Platelet Proteomics following glucose < 70 mg/dL per week. Patients with more frequent hypoglycemia Induced Hypoglycaemia in Diabetes and Control Subjects had significantly stronger neural activity during the baseline period (before HASSAN KAHAL, ERIC S. KILPATRICK, THOZHUKAT SATHYAPALAN, ADITYA M. stimulation onset) relative to peers with less frequent episodes (p < 0.05). BHAGWAT, JOHANNES GRAUMANN, STEPHEN L. ATKIN, Coventry, United King- Patients with more episodes also had stronger absolute responses to the dom, Doha, Qatar, Hull, United Kingdom paired stimulations (p < 0.05), along with significantly reduced somatosen- Aims and Hypothesis: Strict glycaemic control has been associated with sory gating (i.e., equal responses to both stimulations; p < 0.05). Patients POSTERS an increased mortality rate in subjects with type 2 diabetes (T2DM), the Complications with more frequent hypoglycemic episodes had substantially elevated cause of which is unclear. Acute and Chronic spontaneous neural activity in somatosensory regions (i.e., brain “noise”) Methods: Using hyperinsulinaemic clamps, blood glucose levels were stabi- and abnormal responses to the stimulation. Such brain noise has been asso- lised at 90mg/dl for 1 hour (1 h), then reduced over 1 h to 50mg/dl for 1 h. Blood ciated with advancing age, which may suggest