bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prokineticin Receptor 1 Activation Induces Myogenesis and Ameliorates Insulin Resistance in Mouse Skeletal Muscle Cells
Authors: JONGSOO MOK , PARK JOONGHOON 
Published: June 2018

Type 2 diabetes is manifested by progressive metabolic impairments especially in skeletal muscle which becomes resistant to insulin. From KO mouse phenotype analyses (http://www.mousephenotype.org), we identified that loss of function of Melanocortin 2 Receptor Accessory Protein 2 (Mrap2) could induce metabolic disorders through Prokineticin receptor 1 (Prokr1/Gpr73). In this study, we investigated the possible role of Prokr1 in myogenesis and insulin resistance using murine myoblast cell line (C2C12) and primary mouse muscular satellite cells. We examined the expression levels of Prokr1 in C2C12 and muscular satellite cells during myogenic differentiation, and Prokr1 was upregulated during myogenic differentiation at mRNA and protein levels. Prokineticin 2 (Pk2), a natural ligand of Prokr1, induced intracellular calcium mobilization and cAMP generation in dose-dependent manner. Activation of Prokr1 using Pk2 led to increase the number of myoblast and myotube formation. It also induced Akt1 phosphorylation throughout the myogenesis without insulin stimulation. In myotube, Prokr1 activation increased Slc2a4/Glut4 expression, resulted in 2-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)-2-deoxyglucose uptake as well. Prokr1-mediated insulin resistance was attenuated in palmitate-induced insulin resistant myotube. These effects had been abolished in Prokr1 KO C2C12 cells. These results suggest that Prokr1 could be a crucial player in myogenesis and insulin resistance. Our data support the emerging concept that Prokr1 is a potential target for treatment of insulin resistance in type 2 diabetes mellitus.

Disclosure
M. Jongsoo: None. J. Park: None.
Mechanism Underlying the Biphasic Effect of ADP on Succinate-Energized Muscle Mitochondrial Respiration
Authors: FINK BRIAN , YU LIPING , SIVITZ WILLIAM 
Published: June 2018

Recently, we reported a novel phenomenon involving basic mitochondrial physiology. When ADP was sequentially added to mouse skeletal muscle mitochondria energized by succinate (in the absence of rotenone, commonly used to block complex I), we found a biphasic (increasing then decreasing) respiratory dose-response to clamped concentrations of ADP. Here we studied the mechanism. First, we confirmed observations that oxaloacetate (OAA) inhibits succinate dehydrogenase (SDH) by assessing the activity of the extracted complex. OAA is known to be difficult to measure by mass spectroscopy. Here we used a nuclear magnetic resonance method to assess OAA as well as malate and fumarate in mitochondria respiring on succinate. When isolated muscle mitochondria were incubated at varying clamped [ADP], we again observed the biphasic response to [ADP], but also found that the decrease in respiration was strongly associated with OAA accumulation. In addition, when a low (0.5 mM) concentration of pyruvate was added to metabolize OAA to citrate, the loss of succinate-supported respiration was reversed. Pyruvate (0.5 mM), added alone (without succinate), was essentially unable to support respiration. The effect of pyruvate to clear OAA and rescue succinate-supported respiration was blocked by inhibition of pyruvate uptake. Further, OAA accumulation with increasing [ADP] corresponded to a decrease in NADH consistent with utilization electrons by the transport system as malate was converted to OAA and consistent with OAA inhibition of SDH. We also found that the dynamic relationship of [ADP] to succinate-energized respiration varies according to muscle fiber type and specific body tissues in addition (as we reported in the past) to being affected in a rodent model of type 2 diabetes.
In summary, the biphasic respiratory response to succinate as respiration progresses from state 4 to 3 is initially triggered by [ADP]-dependent effects on membrane potential followed by inhibition of SDH by OAA.

Disclosure
B. Fink: None. L. Yu: None. W. Sivitz: None.
Real-World Distribution of Hematocrit Values in the Netherlands and the Czech Republic—A Cross-Sectional Study
Authors: ZIMA TOMAS , STORM HUIBERT , SPACEK MARTIN , WARDAT SAMI , HAUSS OLIVER , HINZMANN ROLF 
Published: June 2018

Many self-monitoring of blood glucose (SMBG)-systems demonstrate positive glucose bias at lower and negative bias at higher hematocrit (HCT) levels. Variations can thus lead to measurement errors and possibly to over- or underdosage of insulin. ISO 15197:2013 demands that manufacturers publish HCT-ranges within which BG-meters perform within certain tolerance limits. But how wide should these ranges be? In this cross-sectional study, we collect real-world data from hospital outpatients to assess the frequency of out-of-range HCT-values compared to healthy individuals.
Data from more than 1 million patients were collected from hospitals in Leeuwarden (NL) and Prague (CZ) and stratified by outpatient status, sex and age. Data were compared to common HCT labelled range limits and data from 1780 healthy Czech subjects to assess differences in distribution.
Compared to healthy subjects, outpatients from Prague were distributed with significantly higher dispersion of values. Independent of the location, low HCT-values are common in age groups known to also have high prevalence of diabetes.
Real-world data indicate that BG-meters labelled to perform only within the frequently used 30-55% range would leave thousands of patients at risk of falsely high or low results. Adequate SMBG-systems should be chosen carefully, particularly for patients with increased and decreased HCT-values.Age groupLocationTotal number Female / MaleNumber &lt;30% HCT  F / MPercentage &lt;30% HCT  F / MPrevalence of Diabetes (Eurostat)  F / M55-64NL27329 / 335461043 / 13243.8% / 3.9%6.2% / 10.3%55-64CZ22212 / 19035748 / 9703.4% / 5.1%10.9% / 11.6%65-74NL32004 / 441811958 / 28496.1% / 6.4%12.0% / 15.0%65-74CZ33598 / 313211987 / 19245.9% / 6.1%18.1% / 19.5%75+NL42435 / 450803431 / 45358.1% / 10.1%14.4% / 19.7%75+CZ26645 / 227061923 / 20417.2% / 9.0%27.3% / 25.3%

Disclosure
T. Zima: Research Support; Self; Roche Diabetes Care Health and Digital Solutions. H. Storm: None. M. Spacek: None. S. Wardat: Employee; Self; Roche Diagnostics Corporation. O. Hauss: Consultant; Self; Roche Diabetes Care GmbH. R. Hinzmann: Employee; Self; Roche Diagnostics Corporation.
Serum Creatinine Progressively Decreases with Obesity and Type 2 Diabetes in Nonhuman Primates
Authors: CHAUDHARI UDDHAV K. , NEWCOMB JENNIFER D. , HANSEN BARBARA C. 
Published: June 2018

Low muscle mass has been associated with insulin resistance and the development of type 2 diabetes (T2DM). Serum creatinine is a metabolite of creatine present in the skeletal muscle. The creatinine concentration is stable and directly proportional to skeletal muscle mass. Low levels of creatinine have been shown to be associated with the development of T2DM. The underlying mechanism of low creatinine and its risk for the development of diabetes is not known. Nonhuman primates (NHPs), maintained on a healthy diet, frequently develop spontaneous middle-aged obesity, metabolic syndrome (MetSyn), and T2DM similar to humans. In the present study, longitudinal evaluation of the associations between creatinine and the development of obesity, MetSyn, and T2DM in 125 male rhesus monkeys were studied. In addition, 7 male monkeys with long term calorie-restriction (CR) to maintain a healthy lean mass were used as a comparison group. Creatinine decreased as age (r=-0.39, p\0.001), body fat percent (r=-0.27, p\0.001), HbA1c% (r=-32, p\0.001) increased. Decrease in insulin sensitivity was significantly (r=0.07, p\0.001) associated with a decrease in percent fat free mass. Creatinine also declined with decreasing insulin sensitivity (r=0.23, p\0.05) and fat free mass (FFM) (r=0.26, p\001) indicating that monkeys with higher lean muscle mass exhibited better insulin sensitivity. Creatinine was significantly decreased in monkeys with T2DM compared to both MetSyn and metabolically normal monkeys (p\0.001). Longitudinal data analysis showed progressive decline of creatinine with MetSyn and the development of T2DM. CR monkeys showed no significant change in creatinine throughout the lifelong duration of calorie restriction. Also unchanged during CR were fasting plasma glucose, body fat, FFM, or body weight. This is the first longitudinal study showing the association of creatinine with the development of T2DM. Serum creatinine levels declined with decrease in fat free mass and insulin sensitivity.

Disclosure
U.K. Chaudhari: None. J.D. Newcomb: None. B.C. Hansen: None.
Metabolomic Signatures of Insulin Resistance in Human Skeletal Muscle Are Exacerbated with Insulin Stimulation
Authors: NEWSOM SEAN A. , PERREAULT LEIGH , KEREGE ANNA , HARRISON KATHLEEN A. , KAHN DARCY E. , NEMKOV TRAVIS , D’ALESSANDRO ANGELO , BERGMAN BRYAN 
Published: June 2018

Metabolomic profiling has identified signatures of insulin resistance in skeletal muscle; however, the direct effect of insulin stimulation on these metabolite signatures in humans remains largely unresolved. To address this, we investigated the effect of insulin stimulation on skeletal muscle metabolites in a well characterized cohort of humans spanning the spectrum of insulin sensitivity. Vastus lateralis muscle samples were obtained from endurance athletes, sedentary lean and obese adults, and individuals with type 2 diabetes (n=16,15,15,12, respectively) under basal conditions and 1-hour into a hyperinsulinemic-euglycemic clamp. Metabolomic analysis was performed using UPLC-MS/MS. Basal concentrations of TCA cycle intermediates, including citrate, alpha-ketoglutarate, succinate, fumarate, malate and oxaloacetate, were positively related to insulin sensitivity (steady-state clamp Rd glucose in mg/kg/min; all P&lt;0.01). Most of these relationships strengthened during insulin stimulation, with the strongest relationships observed for malate (r2 = 0.453, P&lt;0.01) and fumarate (r2 = 0.501, P&lt;0.01) that reflected a blunted increase in TCA intermediates during insulin stimulation with insulin resistance. Insulin stimulation lowered most medium- and long-chain acyl-carnitines compared with basal levels; however, this effect was also attenuated as a function of insulin resistance, signaling impaired metabolic flexibility. Notably, basal levels of several acyl-carnitines, including C12:0, C14:0, C16:0 and C18:1, were increased in endurance athletes compared with other groups (all P&lt;0.05). Several amino acids, including leucine, isoleucine and lysine, were negatively related to insulin sensitivity in the basal and insulin stimulated state (all P&lt;0.01). Together these findings indicate that physiologic insulin stimulation exacerbates metabolic signatures of skeletal muscle insulin resistance in humans.

Disclosure
S.A. Newsom: None. L. Perreault: Advisory Panel; Self; Novo Nordisk A/S. Speaker's Bureau; Self; Novo Nordisk A/S. Advisory Panel; Self; Merck & Co., Inc.. Speaker's Bureau; Self; Merck & Co., Inc., AstraZeneca, Janssen Pharmaceuticals, Inc., Boehringer Ingelheim Pharmaceuticals, Inc.. Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. Advisory Panel; Self; Sanofi. Speaker's Bureau; Self; Sanofi. A. Kerege: None. K.A. Harrison: None. D.E. Kahn: None. T. Nemkov: None. A. D’Alessandro: None. B. Bergman: Research Support; Self; Eli Lilly and Company. Advisory Panel; Spouse/Partner; Novo Nordisk Inc., Merck & Co., Inc., AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company.
Mitochondrial Function in High-Fat Fed and Exercise-Trained Mice Unable to Induce Autophagy
Authors: EHRLICHER SARAH E. , STIERWALT HARRISON D. , NEWSOM SEAN A. , ROBINSON MATTHEW M. 
Published: June 2018

Impaired mitochondrial lipid respiration is implicated in obesity-induced insulin resistance but can be enhanced with exercise training. Autophagy is involved in remodeling the mitochondrial proteome and may be required for mitochondrial and whole-body adaptations in lipid respiration. We used a diet-induced obesity model of C57BL/6J mice and investigated the requirement of autophagy for mitochondrial adaptations to 8 weeks of treadmill exercise training using transgenic mice that cannot induce autophagy with exercise (BCL) compared to wild type controls (WT, n=3-5). High fat (HF) fed mice had lower glucose tolerance at 4 weeks compared to low fat (LF, ∼35%, P&lt;0.01), regardless of genotype. After 8 weeks of exercise, LF-BCL mice had similar glucose tolerance to LF-WT mice. However, the HF-BCL mice had lower glucose tolerance compared to HF-WT mice (∼19%, P&lt;0.01) suggesting a blunted improvement in glucose tolerance following training in the absence of autophagy. At week 12, mitochondria were isolated from quadriceps for respirometry. Oxidative phosphorylation capacity was normalized to electron transport system capacity. Lipid supported respiration (octanoyl-carnitine) was higher in the HF mice compared to LF (∼17%, P&lt;0.01) and the lack of autophagy activation had no effect. Glutamate-malate-succinate supported respiration was lower in BCL mice compared to WT (∼11%, P&lt;0.05), but only on a LF diet suggesting the requirement of autophagy for improved mitochondrial function with exercise may vary between substrates. Whole body respiratory exchange ratio was measured during 24 hours of fasting and all mice shifted to lipid oxidation with no difference between diet or genotype (P = 0.11). Collectively, skeletal muscle mitochondrial lipid oxidation was greater with HF, despite glucose intolerance. The activation of autophagy with exercise was not required for mitochondrial lipid adaptations or whole body metabolic flexibility, but may be required for non-lipid substrates.

Disclosure
S.E. Ehrlicher: None. H.D. Stierwalt: None. S.A. Newsom: None. M.M. Robinson: None.
Mono- and Co-Activation of the GIP and GLP-1 Receptors Inhibits Bone Resorption
Authors: BERGMANN NATASHA C. , LUND ASGER B. , HEIMBÜRGER SEBASTIAN M. , JESSEN LENE , CHRISTENSEN MIKKEL B. , VILSBØLL TINA , KNOP FILIP K. 
Published: June 2018

We investigated the effect of mono- and co-administration of the incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) on bone resorption and formation. Seventeen overweight/obese men without diabetes were included in a randomized, double-blinded, placebo-controlled, cross-over study and subjected to a 50g oral glucose tolerance test (OGTT) and four isoglycemic intravenous glucose infusions (IIGI), mimicking the glucose excursions from the OGTT, with concomitant infusions of GIP (4 pmol/kg/min), GLP-1 (1 pmol/kg/min), GIP+GLP-1 (4 and 1 pmol/kg/min, respectively) or placebo. Bone resorption and formation were assessed by measurements of carboxy-terminal type 1 collagen crosslinks (CTX), and procollagen type 1 N-terminal propeptide (P1NP), respectively. Suppression of CTX is shown in Fig. 1. During OGTT the baseline subtracted area under the curve (bsAUC) was significantly lower than during IIGI+saline infusion (-9,117±566 (mean±SEM) vs. -4,333±583 %×min, P&lt;0.0001). Infusion of GLP-1 and GIP significantly potentiated CTX suppression to -10,751±799 %×min and 13,714±440 %×min, respectively. Co-administration of GIP+GLP-1 suppressed CTX to -15,466±268 %×min. P1NP levels were unaffected. Our data suggest that GLP-1, like GIP, may be involved in bone homeostasis and that co-administration of GIP+GLP-1 inhibits bone resorption more than each hormone alone.

Disclosure
N.C. Bergmann: Employee; Self; Zealand Pharma A/S. A.B. Lund: Other Relationship; Self; Novo Nordisk A/S. S.M. Heimbürger: Research Support; Self; Novo Nordisk A/S. L. Jessen: Employee; Self; Zealand Pharma A/S. Stock/Shareholder; Self; Zealand Pharma A/S, Novo Nordisk A/S. M.B. Christensen: None. T. Vilsbøll: Advisory Panel; Self; Amgen Inc., Boehringer Ingelheim GmbH, Eli Lilly and Company, AstraZeneca, MSD K.K., Sanofi, Novo Nordisk A/S. Consultant; Self; Amgen Inc., Boehringer Ingelheim GmbH, Eli Lilly and Company, AstraZeneca, MSD K.K., Sanofi, Novo Nordisk A/S. Speaker's Bureau; Self; Amgen Inc., Boehringer Ingelheim GmbH, Eli Lilly and Company, AstraZeneca, MSD K.K., Sanofi, Novo Nordisk A/S. Research Support; Self; Eli Lilly and Company, Novo Nordisk A/S. F.K. Knop: Advisory Panel; Self; AstraZeneca. Consultant; Self; AstraZeneca. Research Support; Self; AstraZeneca. Speaker's Bureau; Self; AstraZeneca. Advisory Panel; Self; Eli Lilly and Company. Speaker's Bureau; Self; Eli Lilly and Company. Advisory Panel; Self; Amgen Inc.. Speaker's Bureau; Self; Merck Sharp & Dohme Corp.. Advisory Panel; Self; Novo Nordisk A/S. Consultant; Self; Novo Nordisk A/S. Speaker's Bureau; Self; Novo Nordisk A/S. Consultant; Self; Amgen Inc.. Advisory Panel; Self; MedImmune, Sanofi. Consultant; Self; Sanofi. Research Support; Self; Sanofi. Speaker's Bureau; Self; Sanofi.
Hepatic Insulin Clearance Is Increased in the Patients with Poorly Controlled Type 2 Diabetes
Authors: OKURA TSUYOSHI , ANNO MARI , ITO YUICHI 
Published: June 2018

Aims: The hepatic insulin clearance (HIC) is an important pathophysiology of type 2 diabetes mellitus (T2DM). Some studies reported that HIC was decreased in the patients with T2DM. However, a basic research reported that hyperglycemia enhances HIC, and it is not well-known whether poorly controlled diabetes increases HIC in the patients with T2DM. We investigated whether HIC was increased in the patients with poorly controlled diabetes, and we also evaluated whether HIC associated with insulin resistance.
Methods: We performed meal tolerance test and hyperinsulinemic-euglycemic clamp for 23 patients with type 2 diabetes (mean HbA1c 7.5%). We calculated the postprandial C-peptide AUC/insulin AUC ratio as HIC.
Result: The HIC significantly correlated with HbA1c (R=0.60, P&lt;0.005). In the patients with high HIC above the median, the mean HbA1c was significantly higher than that of low HIC below the median (7.95% vs. 6.99%, P&lt;0.01). The HIC was not correlated with insulin resistance as evaluated by the glucose clamp method (R=0.29, P=0.16).
Conclusion: These results suggested that hepatic insulin clearance was increased in the patients with poorly controlled T2DM, especially in the patients with HbA1c&gt;8%.

Disclosure
T. Okura: None. M. Anno: None. Y. Ito: None.
Lower Risk of Dementia in Elderly Patients Initiated on Dipeptidyl Peptidase-4 Inhibitor vs. Sulfonylurea—A Population-Based Cohort Study
Authors: HAN SEUNG JIN , JEON JA YOUNG , LEE KWANWOO , KIM TAE HO , MOON HYUN UK 
Published: June 2018

Background: Type 2 diabetes is related with an increased risk of dementia. Dipeptidyl peptidase-4 inhibitors (DPP-4i) have shown promising results for its use in dementia in preclinical studies. Therefore, we investigated the risk of developing dementia in elderly patients initiated on DPP-4i vs. sulfonylurea (SU).
Methods: A population-based cohort study using claims database named the Korean National Health Insurance Service Senior cohort (ver. 3.0, 1 January 2002 to 31 December 2015) was performed. DPP-4i-treated patients and SU-treated patients were matched by 1:1 propensity score matching which was calculated with 49 confounding variables. Kaplan-Meier curves and Cox proportional hazards regression analysis were performed to estimate the risk of dementia among patients who were prescribed DPP-4i compared with patients who were prescribed SU.
Results: In total, 7,561 patients on each group were paired using propensity score matching. The risk of dementia was lower in the DPP-4i group compared to the DPP-4i group (hazard ratio [HR] 0.66; 95% confidence interval [CI] 0.56-0.79; P&lt;0.001). Also, HR of Alzheimer’s dementia, and vascular dementia were lower in DPP-4i-treated patients compared with SU-treated patients (HR 0.71; 95% CI 0.57-0.89); P=0.002 for Alzheimer’s dementia, HR 0.50; 95% CI 0.30-0.85); P=0.01 for vascular dementia).
Conclusions: Our findings suggest that DPP-4i use decrease the risk of dementia compared with SU.

Disclosure
S. Han: None. J. Jeon: None. K. Lee: None. T. Kim: None. H. Moon: None.
Deletion of OGlcNAc Transferase in Pancreatic Progenitors Causes Partial Pancreas Agenesis and Diabetes Independent of p53 in Mice
Authors: ALEJANDRO EMILYN , BAUMANN DANIEL , JO SEOKWON , AKHAPHONG BRIAN , LOCKRIDGE AMBER D. , MOHAN RAMKUMAR 
Published: June 2018

Deletion of the only nutrient-sensor enzyme, O-GlcNAc Transferase (OGT), catalyzing O-GlcNAc addition onto target proteins in pancreatic β-cells induces diabetes through β-cell failure. We hypothesized that OGT, expressed at a very high level in β-cells, has key developmental regulatory properties. In this study, we tested the hypothesis that OGT is required for pancreas and β-cell development by deleting OGT in pancreatic (Pdx1Cre, OGTKOPanc) or endocrine (Ngn3Cre, OGTKOEndo) progenitors. We show that mice lacking OGT in pancreatic progenitors (Pdx1+, OGTKOPanc) show near pancreas agenesis and loss of β-cell mass at birth. Few mice that grow into adulthood develop overt diabetes due to functional β-cell mass failure. OGT ablation in endocrine progenitors (Ngn3+, OGTKOEndo) resulted in normal pancreas mass but reduced β-cell mass and diabetes early in life, strongly revealing the temporal and importance of OGT for β-cell development. We observed loss of Pdx1 staining at birth and on embryonic (e) day 14.5 in OGTKOPanc. Transcriptome analysis of e14.5 progenitor single cells show distinct cell clustering populations in OGTKOPanc compared to littermate controls. Upstream regulator analysis of altered genes show enhanced activation of p53, also known as TP53 or tumor protein. Next we identified p53 to be O-GlcNAc-modified in β-cells. Concomitant deletion of p53 in the OGTKOPanc background (p53,OGTKOPanc) does not rescue pancreas agenesis in OGTKOPanc newborn, and adult p53,OGTKOPanc mice develop severe hyperglycemia and diabetes. These data highlight the novel role O-GlcNAc-modifications in pancreas and β-cell development and provide a new model to characterize the developmental defects associated with pancreatic agenesis.

Disclosure
E. Alejandro: None. D. Baumann: None. S. Jo: None. B. Akhaphong: None. A.D. Lockridge: None. R. Mohan: None.