BACKGROUND. The duration and patterns of β cell dysfunction during type 1 diabetes (T1D) development have not been fully defined. METHODS. Metabolic measures derived from oral glucose tolerance tests (OGTTs) were compared between autoantibody-positive (aAb+) individuals followed in the TrialNet Pathway to Prevention study who developed diabetes after 5 or more years or less than 5 years of longitudinal follow-up (Progressors≥5, n = 75; Progressors<5, n = 474) and 144 aAb-negative (aAb–) relatives. RESULTS. Mean age at study entry was 15.0 ± 12.6 years for Progressors≥5; 12.0 ± 9.1 for Progressors<5; and 16.3 ± 10.4 for aAb– relatives. At baseline, Progressors≥5 already exhibited significantly lower fasting C-peptide (P < 0.01), C-peptide AUC (P < 0.001), and early C-peptide responses (30- to 0-minute C-peptide; P < 0.001) compared with aAb– relatives, while 2-hour glucose (P = 0.03), glucose AUC (<0.001), and Index60 (<0.001) were all higher. Despite significant baseline impairment, metabolic measures in Progressors≥5 were relatively stable until 2 years prior to T1D diagnosis, when there was accelerated C-peptide decline and rising glycemia from 2 years until diabetes diagnosis. Remarkably, patterns of progression within 3 years of diagnosis were nearly identical between Progressors≥5 and Progressors<5. CONCLUSION. These data provide insight into the chronicity of β cell dysfunction in T1D and indicate that β cell dysfunction may precede diabetes diagnosis by more than 5 years in a subset of aAb+ individuals. Even among individuals with varying lengths of aAb positivity, our findings indicate that patterns of metabolic decline are uniform within the last 3 years of progression to T1D. TRIAL REGISTRATION. Clinicaltrials.gov NCT00097292. FUNDING. The Type 1 Diabetes TrialNet Study Group is a clinical trials network currently funded by the NIH through the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Allergy and Infectious Diseases, and The Eunice Kennedy Shriver National Institute of Child Health and Human Development and the Juvenile Diabetes Research Foundation.
Carmella Evans-Molina, Emily K. Sims, Linda A. DiMeglio, Heba M. Ismail, Andrea K. Steck, Jerry P. Palmer, Jeffrey P. Krischer, Susan Geyer, Ping Xu, Jay M. Sosenko, the Type 1 Diabetes TrialNet Study Group
BACKGROUND. Exercise has profound pleiotropic health benefits, yet the underlying mechanisms remain incompletely understood. Endocrine FGF21, bile acids (BAs), and BA-induced FGF19 have emerged as metabolic signaling molecules. Here, we investigated if dissimilar modes of exercise, resistance exercise (RE) and endurance exercise (EE), regulate plasma BAs, FGF19, and FGF21 in humans. METHODS. Ten healthy, moderately trained males were enrolled in a randomized crossover study of 1 hour of bicycling at 70% of VO2peak (EE) and 1 hour of high-volume RE. Hormones and metabolites were measured in venous blood and sampled before and after exercise and at 15, 30, 60, 90, 120, and 180 minutes after exercise. RESULTS. We observed exercise mode–specific changes in plasma concentrations of FGF19 and FGF21. Whereas FGF19 decreased following RE (P < 0.001), FGF21 increased in response to EE (P < 0.001). Total plasma BAs decreased exclusively following RE (P < 0.05), but the composition of BAs changed in response to both types of exercise. Notably, circulating levels of the potent TGR5 receptor agonist, lithocholic acid, increased with both types of exercise (P < 0.001). CONCLUSION. This study reveals divergent effects of EE and RE on circulating concentrations of the BA species, FGF19, and FGF21. We identify temporal relationships between decreased BA and FGF19 following RE and a sharp disparity in FGF21 concentrations, with EE eliciting a clear increase parallel to that of glucagon. FUNDING. The Novo Nordisk Foundation (NNF17OC0026114) and the Lundbeck Foundation (R238-2016-2859).
Thomas Morville, Ronni E. Sahl, Samuel A.J. Trammell, Jens S. Svenningsen, Matthew P. Gillum, Jørn W. Helge, Christoffer Clemmensen
BACKGROUND. The induction of beige adipocytes in s.c. white adipose tissue (WAT) depots of humans is postulated to improve glucose and lipid metabolism in obesity. The ability of obese, insulin-resistant humans to induce beige adipose tissue is unknown. METHODS. We exposed lean and obese research participants to cold (30-minute ice pack application each day for 10 days of the upper thigh) or treated them with the β3 agonist mirabegron. We determined beige adipose marker expression by IHC and quantitative PCR, and we analyzed mitochondrial bioenergetics and UCP activity with an Oxytherm system. RESULTS. Cold significantly induced UCP1 and TMEM26 protein in both lean and obese subjects, and this response was not associated with age. Interestingly, these proteins increased to the same extent in s.c. WAT of the noniced contralateral leg, indicating a crossover effect. We further analyzed the bioenergetics of purified mitochondria from the abdominal s.c. WAT of cold-treated subjects and determined that repeat ice application significantly increased uncoupled respiration, consistent with the UCP1 protein induction and subsequent activation. Cold also increased State 3 and maximal respiration, and this effect on mitochondrial bioenergetics was stronger in summer than winter. Chronic treatment (10 weeks; 50 mg/day) with the β3 receptor agonist mirabegron induces UCP1, TMEM26, CIDEA, and phosphorylation of HSL on serine660 in obese subjects. CONCLUSION. Cold or β3 agonists cause the induction of beige adipose tissue in human s.c. WAT; this phenomenon may be exploited to increase beige adipose in older, insulin-resistant, obese individuals. TRIAL REGISTRATION. Clinicaltrials.gov NCT02596776, NCT02919176. FUNDING. NIH (DK107646, DK112282, P20GM103527, and by CTSA grant UL1TR001998).
Brian S. Finlin, Hasiyet Memetimin, Amy L. Confides, Ildiko Kasza, Beibei Zhu, Hemendra J. Vekaria, Brianna Harfmann, Kelly A. Jones, Zachary R. Johnson, Philip M. Westgate, Caroline M. Alexander, Patrick G. Sullivan, Esther E. Dupont-Versteegden, Philip A. Kern
Aldosterone synthase inhibitors (ASIs) should alleviate obesity-related cardiovascular and renal problems resulting partly from aldosterone excess, but their clinical use may have limitations. To improve knowledge for the use of ASIs, we investigated physiology in aldosterone synthase–knockout (ASKO) mice. On regular chow diet (CD), ASKO mice ate more and weighed less than WT mice, largely because they hyperventilated to eliminate acid as CO2. Replacing CD with high-fat diet (HFD) lessened the respiratory burden in ASKO mice, as did 12- to 15-hour fasting. The latter eliminated the genotype differences in respiratory workload and energy expenditure (EE). Thus, aldosterone deficiency burdened the organism more when the animals ate carbohydrate-rich chow than when they ate a HFD. Chronic HFD exposure further promoted hyperinsulinemia in ASKO mice that contributed to visceral fat accumulation accompanied by reduced lipolysis, thermogenic reprogramming, and the absence of weight-gain-related EE increases. Intracerebroventricular aldosterone supplementation in ASKO mice attenuated the HFD-induced hyperinsulinemia, but did not affect EE, suggesting that the presence of aldosterone increased the body’s energetic efficiency, thus counteracting the EE-increasing effect of low insulin. ASIs may therefore cause acid-overload-induced respiratory burden and promote obesity. Their use in patients with preexisting renal and cardiopulmonary diseases might be contraindicated.
Wan-Hui Liao, Claudia Suendermann, Andrea Eva Steuer, Gustavo Pacheco Lopez, Alex Odermatt, Nourdine Faresse, Maciej Henneberg, Wolfgang Langhans
The neuropathological effects of phenylketonuria (PKU) stem from the inability of the body to metabolize excess phenylalanine (Phe), resulting in accumulation of Phe in the blood and brain. Since the kidney normally reabsorbs circulating amino acids with high efficiency, we hypothesized that preventing the renal uptake of Phe might provide a disposal pathway that could lower systemic Phe levels. SLC6A19 is a neutral amino acid transporter responsible for absorption of the majority of free Phe in the small intestine and reuptake of Phe by renal proximal tubule cells. Transgenic KO mice lacking SLC6A19 have elevated levels of Phe and other amino acids in their urine but are otherwise healthy. Here, we crossed the Pahenu2 mouse model of PKU with the Slc6a19-KO mouse. These mutant/KO mice exhibited abundant excretion of Phe in the urine and an approximately 70% decrease in plasma Phe levels. Importantly, brain Phe levels were decreased by 50%, and the levels of key neurotransmitters were increased in the mutant/KO mice. In addition, a deficit in spatial working memory and markers of neuropathology were corrected. Finally, treatment of Pahenu2 mice with Slc6a19 antisense oligonucleotides lowered Phe levels. The results suggest that inhibition of SLC6A19 may represent a novel approach for the treatment of PKU and related aminoacidopathies.
Adam M. Belanger, Malgorzata Przybylska, Estelle Gefteas, Matthew Furgerson, Sarah Geller, Alla Kloss, Seng H. Cheng, Yunxiang Zhu, Nelson S. Yew
Cachexia syndrome consists of adipose and muscle loss, often despite normal food intake. We hypothesized that cachexia-associated adipose wasting is driven in part by tumor humoral factors that induce adipocyte lipolysis. We developed an assay to purify secreted factors from a cachexia-inducing colon cancer line that increases lipolysis in adipocytes and identified leukemia inhibitory factor (LIF) by mass spectrometry. Recombinant LIF induced lipolysis in vitro. Peripheral LIF administered to mice caused >50% loss of adipose tissue and >10% reduction in body weight despite only transient hypophagia due to decreasing leptin. LIF-injected mice lacking leptin (ob/ob) resulted in persistent hypophagia and loss of adipose tissue and body weight. LIF’s peripheral role of initiating lipolysis in adipose loss was confirmed in pair-fed ob/ob mouse studies. Our studies demonstrate that (a) LIF is a tumor-secreted factor that promotes cachexia-like adipose loss when administered peripherally, (b) LIF directly induces adipocyte lipolysis, (c) LIF has the ability to sustain adipose and body weight loss through an equal combination of peripheral and central contributions, and (d) LIF’s central effect is counterbalanced by decreased leptin signaling, providing insight into cachexia’s wasting, despite normophagia.
Gurpreet K. Arora, Arun Gupta, Sriram Narayanan, Tong Guo, Puneeth Iyengar, Rodney E. Infante
The role of posttranscriptional metabolic gene regulatory programs in diabetes is not well understood. Here, we show that the RNA-binding protein tristetraprolin (TTP) is reduced in the livers of diabetic mice and humans and is transcriptionally induced in response to insulin treatment in murine livers in vitro and in vivo. Liver-specific Ttp-KO (lsTtp-KO) mice challenged with high-fat diet (HFD) have improved glucose tolerance and peripheral insulin sensitivity compared with littermate controls. Analysis of secreted hepatic factors demonstrated that fibroblast growth factor 21 (FGF21) is posttranscriptionally repressed by TTP. Consistent with increased FGF21, lsTtp-KO mice fed HFD have increased brown fat activation, peripheral tissue glucose uptake, and adiponectin production compared with littermate controls. Downregulation of hepatic Fgf21 via an adeno-associated virus–driven shRNA in mice fed HFD reverses the insulin-sensitizing effects of hepatic Ttp deletion. Thus, hepatic TTP posttranscriptionally regulates systemic insulin sensitivity in diabetes through liver-derived FGF21.
Konrad T. Sawicki, Hsiang-Chun Chang, Jason S. Shapiro, Marina Bayeva, Adam De Jesus, Brian N. Finck, Jason A. Wertheim, Perry J. Blackshear, Hossein Ardehali
While several molecular targets are under consideration, mechanistic underpinnings of the transition from uncomplicated nonalcoholic fatty liver disease (NAFLD) to nonalcoholic steatohepatitis (NASH) remain unresolved. Here we apply multiscale chemical profiling technologies to mouse models of deranged hepatic ketogenesis to uncover potential NAFLD driver signatures. Use of stable-isotope tracers, quantitatively tracked by nuclear magnetic resonance (NMR) spectroscopy, supported previous observations that livers of wild-type mice maintained long term on a high-fat diet (HFD) exhibit a marked increase in hepatic energy charge. Fed-state ketogenesis rates increased nearly 3-fold in livers of HFD-fed mice, a greater proportionate increase than that observed for tricarboxylic acid (TCA) cycle flux, but both of these contributors to overall hepatic energy homeostasis fueled markedly increased hepatic glucose production (HGP). Thus, to selectively determine the role of the ketogenic conduit on HGP and oxidative hepatic fluxes, we studied a ketogenesis-insufficient mouse model generated by knockdown of the mitochondrial isoform of 3-hydroxymethylglutaryl-CoA synthase (HMGCS2). In response to ketogenic insufficiency, TCA cycle flux in the fed state doubled and HGP increased more than 60%, sourced by a 3-fold increase in glycogenolysis. Finally, high-resolution untargeted metabolomics and shotgun lipidomics performed using ketogenesis-insufficient livers in the fed state revealed accumulation of bis(monoacylglycero)phosphates, which also accumulated in livers of other models commonly used to study NAFLD. In summary, natural and interventional variations in ketogenesis in the fed state strongly influence hepatic energy homeostasis, glucose metabolism, and the lipidome. Importantly, HGP remains tightly linked to overall hepatic energy charge, which includes both terminal fat oxidation through the TCA cycle and partial oxidation via ketogenesis.
D. André d’Avignon, Patrycja Puchalska, Baris Ercal, YingJu Chang, Shannon E. Martin, Mark J. Graham, Gary J. Patti, Xianlin Han, Peter A. Crawford
Androgen excess predisposes women to type 2 diabetes (T2D), but the mechanism of this is poorly understood. We report that female mice fed a Western diet and exposed to chronic androgen excess using dihydrotestosterone (DHT) exhibit hyperinsulinemia and insulin resistance associated with secondary pancreatic β cell failure, leading to hyperglycemia. These abnormalities are not observed in mice lacking the androgen receptor (AR) in β cells and partially in neurons of the mediobasal hypothalamus (MBH) as well as in mice lacking AR selectively in neurons. Accordingly, i.c.v. infusion of DHT produces hyperinsulinemia and insulin resistance in female WT mice. We observe that acute DHT produces insulin hypersecretion in response to glucose in cultured female mouse and human pancreatic islets in an AR-dependent manner via a cAMP- and mTOR-dependent pathway. Acute DHT exposure increases mitochondrial respiration and oxygen consumption in female cultured islets. As a result, chronic DHT exposure in vivo promotes islet oxidative damage and susceptibility to additional stress induced by streptozotocin via AR in β cells. This study suggests that excess androgen predisposes female mice to T2D following AR activation in neurons, producing peripheral insulin resistance, and in pancreatic β cells, promoting insulin hypersecretion, oxidative injury, and secondary β cell failure.
Guadalupe Navarro, Camille Allard, Jamie J. Morford, Weiwei Xu, Suhuan Liu, Adrien J.R. Molinas, Sierra M. Butcher, Nicholas H.F. Fine, Manuel Blandino-Rosano, Venkata N. Sure, Sangho Yu, Rui Zhang, Heike Münzberg, David A. Jacobson, Prasad V. Katakam, David J. Hodson, Ernesto Bernal-Mizrachi, Andrea Zsombok, Franck Mauvais-Jarvis
AMPK activated protein kinase (AMPK), a master regulator of energy homeostasis, is activated in response to an energy shortage imposed by physical activity and caloric restriction. We here report on the identification of PAN-AMPK activator O304, which — in diet-induced obese mice — increased glucose uptake in skeletal muscle, reduced β cell stress, and promoted β cell rest. Accordingly, O304 reduced fasting plasma glucose levels and homeostasis model assessment of insulin resistance (HOMA-IR) in a proof-of-concept phase IIa clinical trial in type 2 diabetes (T2D) patients on Metformin. T2D is associated with devastating micro- and macrovascular complications, and O304 improved peripheral microvascular perfusion and reduced blood pressure both in animals and T2D patients. Moreover, like exercise, O304 activated AMPK in the heart, increased cardiac glucose uptake, reduced cardiac glycogen levels, and improved left ventricular stroke volume in mice, but it did not increase heart weight in mice or rats. Thus, O304 exhibits a great potential as a novel drug to treat T2D and associated cardiovascular complications.
Pär Steneberg, Emma Lindahl, Ulf Dahl, Emmelie Lidh, Jurate Straseviciene, Fredrik Backlund, Elisabet Kjellkvist, Eva Berggren, Ingela Lundberg, Ingela Bergqvist, Madelene Ericsson, Björn Eriksson, Kajsa Linde, Jacob Westman, Thomas Edlund, Helena Edlund
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