A Single Bout of High-Intensity Interval Training Reduces Awareness of Subsequent Hypoglycemia in Patients With Type 1 Diabetes
High-intensity interval training (HIIT) has gained increasing popularity in patients with diabetes. HIIT acutely increases plasma lactate levels. This may be important, since the administration of lactate during hypoglycemia suppresses symptoms and counterregulation while preserving cognitive function. We tested the hypothesis that, in the short term, HIIT reduces awareness of hypoglycemia and attenuates hypoglycemia-induced cognitive dysfunction. In a randomized crossover trial, patients with type 1 diabetes and normal awareness of hypoglycemia (NAH), patients with impaired awareness of hypoglycemia (IAH), and healthy par...
Source: Diabetes - June 21, 2017 Category: Endocrinology Authors: Rooijackers, H. M.; Wiegers, E. C.; van der Graaf, M.; Thijssen, D. H.; Kessels, R. P. C.; Tack, C. J.; de Galan, B. E. Tags: Complications-Hypoglycemia Source Type: research
Impaired Glutamatergic Neurotransmission in the Ventromedial Hypothalamus May Contribute to Defective Counterregulation in Recurrently Hypoglycemic Rats
The objectives of this study were to understand the role of glutamatergic neurotransmission in the ventromedial hypothalamus (VMH) in response to hypoglycemia and to elucidate the effects of recurrent hypoglycemia (RH) on this neurotransmitter. We 1) measured changes in interstitial VMH glutamate levels by using microdialysis and biosensors, 2) identified the receptors that mediate glutamate’s stimulatory effects on the counterregulatory responses, 3) quantified glutamate metabolic enzyme levels in the VMH, 4) examined astrocytic glutamate reuptake mechanisms, and 5) used 1H-[13C]-nuclear magnetic resonance (NMR) spe...
Source: Diabetes - June 21, 2017 Category: Endocrinology Authors: Chowdhury, G. M. I.; Wang, P.; Ciardi, A.; Mamillapalli, R.; Johnson, J.; Zhu, W.; Eid, T.; Behar, K.; Chan, O. Tags: Complications-Hypoglycemia Source Type: research
Heterogeneous Nuclear Ribonucleoprotein F Stimulates Sirtuin-1 Gene Expression and Attenuates Nephropathy Progression in Diabetic Mice
We investigated the mechanism of heterogeneous nuclear ribonucleoprotein F (hnRNP F) renoprotective action in a type 2 diabetes (T2D) mouse model (db/db). Immortalized rat renal proximal tubular cells (IRPTCs) and kidneys from humans with T2D were also studied. The db/db mice developed hyperglycemia, oxidative stress, and nephropathy at age 20 weeks compared with their db/m littermates. These abnormalities, with the exception of hyperglycemia, were attenuated in db/db hnRNP F–transgenic (Tg) mice specifically overexpressing hnRNP F in their RPTCs. Sirtuin-1, Foxo3α, and catalase expression were significantly de...
Source: Diabetes - June 21, 2017 Category: Endocrinology Authors: Lo, C.-S.; Shi, Y.; Chenier, I.; Ghosh, A.; Wu, C.-H.; Cailhier, J.-F.; Ethier, J.; Lattouf, J.-B.; Filep, J. G.; Ingelfinger, J. R.; Zhang, S.-L.; Chan, J. S. D. Tags: Complications-Nephropathy-Basic and Experimental Science Source Type: research
Metabolic Syndrome, Insulin Resistance, and Cognitive Dysfunction: Does Your Metabolic Profile Affect Your Brain?
Dementia and type 2 diabetes are both characterized by long prodromal phases, challenging the study of potential risk factors and their temporal relation. The progressive relation among metabolic syndrome, insulin resistance (IR), and dementia has recently been questioned, wherefore the aim of this study was to assess the potential association among these precursors of type 2 diabetes and cognitive dysfunction. Using data from the Prospective Epidemiological Risk Factor (PERF) Study (n = 2,103), a prospective study of elderly women in Denmark, we found that impaired fasting plasma glucose concentration was associated with ...
Source: Diabetes - June 21, 2017 Category: Endocrinology Authors: Neergaard, J. S.; Dragsbaek, K.; Christiansen, C.; Nielsen, H. B.; Brix, S.; Karsdal, M. A.; Henriksen, K. Tags: Complications Source Type: research
Identification of RUNX1 as a Mediator of Aberrant Retinal Angiogenesis
Proliferative diabetic retinopathy (PDR) is a common cause of blindness in the developed world’s working adult population and affects those with type 1 and type 2 diabetes. We identified Runt-related transcription factor 1 (RUNX1) as a gene upregulated in CD31+ vascular endothelial cells obtained from human PDR fibrovascular membranes (FVMs) via transcriptomic analysis. In vitro studies using human retinal microvascular endothelial cells (HRMECs) showed increased RUNX1 RNA and protein expression in response to high glucose, whereas RUNX1 inhibition reduced HRMEC migration, proliferation, and tube formation. Immunohis...
Source: Diabetes - June 21, 2017 Category: Endocrinology Authors: Lam, J. D.; Oh, D. J.; Wong, L. L.; Amarnani, D.; Park-Windhol, C.; Sanchez, A. V.; Cardona-Velez, J.; McGuone, D.; Stemmer-Rachamimov, A. O.; Eliott, D.; Bielenberg, D. R.; van Zyl, T.; Shen, L.; Gai, X.; DAmore, P. A.; Kim, L. A.; Arboleda-Velasquez, J. Tags: Pathophysiology Source Type: research
Renal and Vascular Effects of Uric Acid Lowering in Normouricemic Patients With Uncomplicated Type 1 Diabetes
Higher plasma uric acid (PUA) levels are associated with lower glomerular filtration rate (GFR) and higher blood pressure (BP) in patients with type 1 diabetes (T1D). Our aim was to determine the impact of PUA lowering on renal and vascular function in patients with uncomplicated T1D. T1D patients (n = 49) were studied under euglycemic and hyperglycemic conditions at baseline and after PUA lowering with febuxostat (FBX) for 8 weeks. Healthy control subjects were studied under normoglycemic conditions (n = 24). PUA, GFR (inulin), effective renal plasma flow (para-aminohippurate), BP, and hemodynamic responses to an infusion...
Source: Diabetes - June 21, 2017 Category: Endocrinology Authors: Lytvyn, Y.; Har, R.; Locke, A.; Lai, V.; Fong, D.; Advani, A.; Perkins, B. A.; Cherney, D. Z. I. Tags: Complications-Nephropathy-Clinical and Translational Research Pathophysiology Source Type: research
Genetic Disruption of Adenosine Kinase in Mouse Pancreatic {beta}-Cells Protects Against High-Fat Diet-Induced Glucose Intolerance
Islet β-cells adapt to insulin resistance through increased insulin secretion and expansion. Type 2 diabetes typically occurs when prolonged insulin resistance exceeds the adaptive capacity of β-cells. Our prior screening efforts led to the discovery that adenosine kinase (ADK) inhibitors stimulate β-cell replication. Here, we evaluated whether ADK disruption in mouse β-cells affects β-cell mass and/or protects against high-fat diet (HFD)–induced glucose dysregulation. Mice targeted at the Adk locus were bred to Rip-Cre and Ins1-Cre/ERT1Lphi mice to enable constitutive (βADKO) and condit...
Source: Diabetes - June 21, 2017 Category: Endocrinology Authors: Navarro, G.; Abdolazami, Y.; Zhao, Z.; Xu, H.; Lee, S.; Armstrong, N. A.; Annes, J. P. Tags: Islet Biology-Beta Cell-Development and Postnatal Growth Islet Studies Source Type: research
GDF11 Attenuates Development of Type 2 Diabetes via Improvement of Islet {beta}-Cell Function and Survival
Growth differentiation factor 11 (GDF11) has been implicated in the regulation of islet development and a variety of aging conditions, but little is known about the physiological functions of GDF11 in adult pancreatic islets. Here, we showed that systematic replenishment of GDF11 not only preserved insulin secretion but also improved the survival and morphology of β-cells and improved glucose metabolism in both nongenetic and genetic mouse models of type 2 diabetes (T2D). Conversely, anti-GDF11 monoclonal antibody treatment caused β-cell failure and lethal T2D. In vitro treatment of isolated murine islets and MIN...
Source: Diabetes - June 21, 2017 Category: Endocrinology Authors: Li, H.; Li, Y.; Xiang, L.; Zhang, J.; Zhu, B.; Xiang, L.; Dong, J.; Liu, M.; Xiang, G. Tags: Islet Biology-Apoptosis Islet Studies Source Type: research
Functional and Metabolomic Consequences of KATP Channel Inactivation in Human Islets
Loss-of-function mutations of β-cell KATP channels cause the most severe form of congenital hyperinsulinism (KATPHI). KATPHI is characterized by fasting and protein-induced hypoglycemia that is unresponsive to medical therapy. For a better understanding of the pathophysiology of KATPHI, we examined cytosolic calcium ([Ca2+]i), insulin secretion, oxygen consumption, and [U-13C]glucose metabolism in islets isolated from the pancreases of children with KATPHI who required pancreatectomy. Basal [Ca2+]i and insulin secretion were higher in KATPHI islets compared with controls. Unlike controls, insulin secretion in KATPHI i...
Source: Diabetes - June 21, 2017 Category: Endocrinology Authors: Li, C.; Ackermann, A. M.; Boodhansingh, K. E.; Bhatti, T. R.; Liu, C.; Schug, J.; Doliba, N.; Han, B.; Cosgrove, K. E.; Banerjee, I.; Matschinsky, F. M.; Nissim, I.; Kaestner, K. H.; Naji, A.; Adzick, N. S.; Dunne, M. J.; Stanley, C. A.; De Leon, D. D. Tags: Islet Studies Source Type: research
Kv2.1 Clustering Contributes to Insulin Exocytosis and Rescues Human {beta}-Cell Dysfunction
In this study, we examine the mechanism by which the voltage-dependent K+ (Kv) channel Kv2.1 (KCNB1) facilitates depolarization-induced exocytosis in INS 832/13 cells and β-cells from human donors with and without type 2 diabetes (T2D). We find that Kv2.1, but not Kv2.2 (KCNB2), forms clusters of 6–12 tetrameric channels at the plasma membrane and facilitates insulin exocytosis. Knockdown of Kv2.1 expression reduces secretory granule targeting to the plasma membrane. Expression of the full-length channel (Kv2.1-wild-type) supports the glucose-dependent recruitment of secretory granules. However, a truncated chan...
Source: Diabetes - June 21, 2017 Category: Endocrinology Authors: Fu, J.; Dai, X.; Plummer, G.; Suzuki, K.; Bautista, A.; Githaka, J. M.; Senior, L.; Jensen, M.; Greitzer-Antes, D.; Manning Fox, J. E.; Gaisano, H. Y.; Newgard, C. B.; Touret, N.; MacDonald, P. E. Tags: Islet Studies Source Type: research
Prolonged Elimination of Negative Feedback Control Mechanisms Along the Insulin Signaling Pathway Impairs {beta}-Cell Function In Vivo
Cellular stress and proinflammatory cytokines induce phosphorylation of insulin receptor substrate (IRS) proteins at Ser sites that inhibit insulin and IGF-I signaling. We therefore examined the effects of mutation of five "inhibitory" Ser phosphorylation sites on IRS2 function in transgenic mice that overexpress, selectively in pancreatic β-cells, either wild-type (WT) or a mutated IRS2 protein (IRS25A). Islets size, number, and mRNA levels of catalase and superoxide dismutase were increased, whereas those of nitric oxide synthase were decreased, in 7- to 10-week-old IRS25A-β mice compared with IRS2WT-β mic...
Source: Diabetes - June 21, 2017 Category: Endocrinology Authors: Isaac, R.; Vinik, Y.; Boura-Halfon, S.; Farack, L.; Streim, S.; Elhanany, E.; Kam, Z.; Zick, Y. Tags: Islet Biology-Signal Transduction Islet Studies Source Type: research
Alterations in 3-Hydroxyisobutyrate and FGF21 Metabolism Are Associated With Protein Ingestion-Induced Insulin Resistance
Systemic hyperaminoacidemia, induced by either intravenous amino acid infusion or protein ingestion, reduces insulin-stimulated glucose disposal. Studies of mice suggest that the valine metabolite 3-hydroxyisobutyrate (3-HIB), fibroblast growth factor 21 (FGF21), adiponectin, and nonesterified fatty acids (NEFAs) may be involved in amino acid–mediated insulin resistance. We therefore measured in 30 women the rate of glucose disposal, and plasma 3-HIB, FGF21, adiponectin, and NEFA concentrations, under basal conditions and during a hyperinsulinemic-euglycemic clamp procedure (HECP), with and without concomitant ingest...
Source: Diabetes - June 21, 2017 Category: Endocrinology Authors: Harris, L.-A. L. S.; Smith, G. I.; Patterson, B. W.; Ramaswamy, R. S.; Okunade, A. L.; Kelly, S. C.; Porter, L. C.; Klein, S.; Yoshino, J.; Mittendorfer, B. Tags: Obesity-Human Obesity Studies Source Type: research
Tumor Necrosis Factor-{alpha} Promotes Phosphoinositide 3-Kinase Enhancer A and AMP-Activated Protein Kinase Interaction to Suppress Lipid Oxidation in Skeletal Muscle
We report in this study that phosphoinositide 3-kinase enhancer A (PIKE-A) is a novel effector of TNF-α to facilitate its metabolic modulation in the skeletal muscle. Depletion of PIKE-A in C2C12 myotubes diminished the inhibitory activities of TNF-α on mitochondrial respiration and lipid oxidation, whereas PIKE-A overexpression exacerbated these cellular responses. We also found that TNF-α promoted the interaction between PIKE-A and AMP-activated protein kinase (AMPK) to suppress its kinase activity in vitro and in vivo. As a result, animals with PIKE ablation in the skeletal muscle per se display an upr...
Source: Diabetes - June 21, 2017 Category: Endocrinology Authors: Tse, M. C. L.; Herlea-Pana, O.; Brobst, D.; Yang, X.; Wood, J.; Hu, X.; Liu, Z.; Lee, C. W.; Zaw, A. M.; Chow, B. K. C.; Ye, K.; Chan, C. B. Tags: Signal Transduction Source Type: research
Hypoglycemic Effect of Combined Ghrelin and Glucagon Receptor Blockade
Glucagon receptor (GcgR) blockade has been proposed as an alternative to insulin monotherapy for treating type 1 diabetes since deletion or inhibition of GcgRs corrects hyperglycemia in models of diabetes. The factors regulating glycemia in a setting devoid of insulin and glucagon function remain unclear but may include the hormone ghrelin. Not only is ghrelin release controlled by glucose but also ghrelin has many actions that can raise or reduce falls in blood glucose level. Here, we tested the hypothesis that ghrelin rises to prevent hypoglycemia in the absence of glucagon function. Both GcgR knockout (Gcgr–/&ndas...
Source: Diabetes - June 21, 2017 Category: Endocrinology Authors: Mani, B. K.; Uchida, A.; Lee, Y.; Osborne-Lawrence, S.; Charron, M. J.; Unger, R. H.; Berglund, E. D.; Zigman, J. M. Tags: Integrated Physiology-Other Hormones Metabolism Source Type: research
Elovl6 Deficiency Improves Glycemic Control in Diabetic db/db Mice by Expanding {beta}-Cell Mass and Increasing Insulin Secretory Capacity
Dysfunctional fatty acid (FA) metabolism plays an important role in the pathogenesis of β-cell dysfunction and loss of β-cell mass in type 2 diabetes (T2D). Elovl6 is a microsomal enzyme that is responsible for converting C16 saturated and monounsaturated FAs into C18 species. We previously showed that Elovl6 played a critical role in the development of obesity-induced insulin resistance by modifying FA composition. To further define its role in T2D development, we assessed the effects of Elovl6 deletion in leptin receptor–deficient C57BL/KsJ db/db mice, a model of T2D. The db/db;Elovl6–/– mice ...
Source: Diabetes - June 21, 2017 Category: Endocrinology Authors: Zhao, H.; Matsuzaka, T.; Nakano, Y.; Motomura, K.; Tang, N.; Yokoo, T.; Okajima, Y.; Han, S.-i.; Takeuchi, Y.; Aita, Y.; Iwasaki, H.; Yatoh, S.; Suzuki, H.; Sekiya, M.; Yahagi, N.; Nakagawa, Y.; Sone, H.; Yamada, N.; Shimano, H. Tags: Obesity-Animal Metabolism Source Type: research
