Endocrinology
Abstract
Under insulin-resistant conditions, such as obesity, pancreatic β cells adaptively proliferate and secrete more insulin to prevent blood glucose elevation. We previously reported hepatic ERK activation during obesity development to stimulate a neuronal relay system, consisting of afferent splanchnic nerves from the liver and efferent vagal nerves to the pancreas, thereby triggering adaptive β cell proliferation. However, the mechanism linking obesity with the interorgan system originating in hepatic ERK activation remains unclear. Herein, we clarified that colonic inflammation promotes β cell proliferation through this interorgan system from the liver to the pancreas. First, dextran sodium sulfate (DSS) treatment induced colonic inflammation and hepatic ERK activation as well as β cell proliferation, all of which were suppressed by blockades of the neuronal relay system by several approaches. In addition, treatment with anti–lymphocyte Peyer’s patch adhesion molecule-1 (anti-LPAM1) antibody suppressed β cell proliferation induced by DSS treatment. Importantly, high-fat diet (HFD) feeding also elicited colonic inflammation, and its inhibition by anti-LPAM1 antibody administration suppressed hepatic ERK activation and β cell proliferation induced by HFD. Thus, colonic inflammation triggers adaptive β cell proliferation via the interorgan mechanism originating in hepatic ERK activation. The present study revealed a potentially novel role of the gastrointestinal tract in the maintenance of β cell regulation.
Authors
Haremaru Kubo, Junta Imai, Tomohito Izumi, Masato Kohata, Yohei Kawana, Akira Endo, Hiroto Sugawara, Junro Seike, Takahiro Horiuchi, Hiroshi Komamura, Toshihiro Sato, Shinichiro Hosaka, Yoichiro Asai, Shinjiro Kodama, Kei Takahashi, Keizo Kaneko, Hideki Katagiri
Abstract
Glycine and β-alanine activate glycine receptors (GlyRs), with glycine known to enhance insulin secretion from pancreatic islet β cells, primarily through GlyR activation. However, the effects of GlyR activation on β cell proliferation have not been examined. Here, we aim to investigate the potential proliferative effects of glycine and β-alanine on islets. In vitro experiments on mouse and human islets revealed that glycine and β-alanine, via GlyR activation, stimulated the proliferation of β cells and α cells, without affecting insulin or glucagon secretion. Further analysis indicated the involvement of the PI3K/mTORC1/p70S6K signaling pathway in this process. Inhibition of GlyRs and PI3K/mTORC1/p70S6K signaling attenuated proliferative effects of glycine and β-alanine. In vivo and ex vivo studies supported these findings, showing increased β and α cell mass after 12 weeks of oral administration of glycine and β-alanine, with no changes in insulin secretion or glucose homeostasis under normal conditions. However, during an acute insulin resistance induced by insulin receptor antagonist S961, glycine and β-alanine enhanced insulin secretion and reduced blood glucose levels by increasing β cell secretory capacity. These findings demonstrate glycine and β-alanine in vivo and in vitro promote islet cell proliferation via GlyR activation and the PI3K/mTORC1/p70S6K pathway, potentially providing a target to enhance islet capacity.
Authors
Ziyi Zhang, Wenyue W. Ye, Anthony L. Piro, Dian-Shi Wang, Ashley Untereiner, Sulayman A. Lyons, Alpana Bhattacharjee, Ishnoor Singh, Jacqueline L. Beaudry, Beverley A. Orser, Feihan F. Dai, Michael B. Wheeler
Abstract
This study examined the involvement of fibroblast growth factor-23 (FGF-23) in primary aldosteronism (PA), a condition characterized by elevated aldosterone levels and hypertension. We recruited patients with unilateral PA (uPA) and observed increased levels of C-terminal FGF-23 (cFGF-23) and C-terminal to intact FGF-23 (iFGF-23) in patients with uPA compared with essential hypertension control participants. Elevated preoperative cFGF-23 levels were associated with adverse outcomes, including mortality and cardiovascular or kidney events. Plasma cFGF-23 levels demonstrated a nonlinear rise with aldosterone, but iFGF-23 levels were not correlated with plasma aldosterone concentration. Higher cFGF-23 levels independently predicted hypertension remission after adrenalectomy for patients with uPA. Patients with uPA, who exhibited elevated cFGF-23 levels, had decreased levels after adrenalectomy. In cell cultures, aldosterone enhanced cleavage of iFGF-23, leading to increased levels of cFGF-23 fragments, an effect mitigated by silencing of family with sequence similarity 20, member C (FAM20C). However, the enhancement of cFGF-23 levels remained unaffected by the furin inhibitor. The study suggests that aldosterone influences FGF-23 phosphorylation by interacting with FAM20C, with docking experiments indicating aldosterone’s binding to FAM20C. This work highlights that patients with uPA with elevated cFGF-23 levels are associated with cardiovascular risks, and adrenalectomy reduces cFGF-23. Aldosterone likely promotes cFGF-23 production through FAM20C-mediated phosphorylation of iFGF-23.
Authors
Vin-Cent Wu, Kang-Yung Peng, Tsu-I Chen, Chiao-Yin Sun, Hung-Wei Liao, Chieh-Kai Chan, Yen-Hung Lin, Hung-Hsiang Liou, Jeff S. Chueh
Abstract
Lower urinary tract symptoms (LUTS) affect approximately 50% of the population over 40 years of age and are strongly associated with obesity and metabolic syndrome. Adipose tissue plays a key role in obesity/metabolic syndrome by releasing adipokines that regulate systemic energy/lipid metabolism, insulin resistance, and inflammation. Adiponectin (ADPN), the most abundant adipokine, modulates energy/metabolism homeostasis through its insulin-sensitizing and antiinflammatory effects. Human plasma ADPN levels are inversely associated with obesity and diabetes. To the best of our knowledge, the role of adipokines such as ADPN in the LUTS associated with obesity/metabolic syndrome remains unknown. We have tested such a possible role in a global ADPN-knockout (Adpn–/–) mouse model. Adpn–/– mice exhibited increased voiding frequency, small voids, and reduced bladder smooth muscle (BSM) contractility, with absence of purinergic contraction. Molecular examination indicated significantly altered metabolic and purinergic pathways. The ADPN receptor agonist AdipoRon was found to abolish acute BSM contraction. Intriguingly, both AMPK activators and inhibitors also abolished BSM purinergic contraction. These data indicate the important contribution of what we believe is a novel ADPN signaling pathway to the regulation of BSM contractility. Dysregulation of this ADPN signaling pathway might be an important mechanism leading to LUTS associated with obesity/metabolic syndrome.
Authors
Zhaobo Luo, Ali Wu, Simon Robson, Seth L. Alper, Weiqun Yu
Abstract
BACKGROUND. 80% of patients with multiple endocrine neoplasia type 1 (MEN1) develop duodenopancreatic neuroendocrine tumors (dpNETs), of whom, 15% to 25% die of metastasis. There is a need to identify biomarkers to predict aggressive disease. MEN1 genotype affords an attractive possibility as a biomarker as it remains constant during lifetime. Currently, patients are clinically diagnosed with MEN1 by the presence of ≥ 2 primary endocrine tumors (pituitary, parathyroid and pancreas) or ≥ 1 primary endocrine tumor(s) with a positive family history. 10-30% of patients diagnosed clinically with MEN1 have no pathogenic germline MEN1 variants. METHODS. Retrospective study of 162 index patients or probands with genotype-positive and 47 with genotype-negative MEN1 enrolled from 1977–2022. RESULTS. Compared to patients with genotype-negative disease, patients with genotype-positive disease were younger at diagnosis and had an increased frequency of recurrent parathyroid tumors, dpNETs and angiofibromas or collagenomas. We propose a novel weighted scoring system to diagnose genotype-positive MEN1 based on clinical characteristics. No evidence of MEN1 mosaicism was seen in 30 tumors from 17 patients with genotype-negative MEN1. Patients with germline MEN1 variants in exons 2 and 3 have a reduced risk of distant metastases. CONCLUSIONS. The clinical course of genotype-negative MEN1 is distinct from genotype-positive disease raising uncertainty about the benefits of lifetime surveillance inpatients with genotype-negative disease. MEN1 mosaicism is rare. TRIAL REGISTRATION. ClinicalTrials.gov NCT04969926. FUNDING. Intramural Research Program of NIDDK (ZIA DK043006-46).
Authors
Charlita C. Worthy, Rana Tora, Chandra N. Uttarkar, James M. Welch, Lynn Bliss, Craig Cochran, Anisha Ninan, Sheila Kumar, Stephen Wank, Sungyoung Auh, Lee S. Weinstein, William F. Simonds, Sunita K. Agarwal, Jenny E. Blau, Smita Jha
Abstract
Kenny-Caffey syndrome (KCS) is a rare genetic disorder characterized by extreme short stature, cortical thickening and medullary stenosis of tubular bones, facial dysmorphism, abnormal T-cell function, and hypoparathyroidism. Biallelic loss-of-function variants in TBCE cause autosomal recessive type 1 KCS (KCS1). By contrast, heterozygous missense variants in a restricted region of the FAM111A gene have been identified in autosomal dominant type 2 KCS (KCS2) and a more severe lethal phenotype, osteocraniostenosis (OCS) that have recently been shown to confer a gain-of-function. In this study, we describe two unrelated children with KCS and OCS who were homozygous for different FAM111A variant alleles that result in replacement of the same residue, Tyr414 (c.1241A>G, p.Y414C and c.1240T>A, p.Y414N), in the mature FAM111A protein. Their heterozygous relatives are asymptomatic. Functional studies of recombinant FAM111AY414C demonstrated normal dimerization and a mild gain-of-function effect. This study provides evidence that both biallelic and monoallelic variants of FAM111A with varying degrees of activation can lead to dominant or recessive KCS2 and OCS.
Authors
Dong Li, Niels Mailand, Emma U. Ewing, Saskia Hoffmann, Richard C. Caswell, Lewis Pang, Jacqueline Eason, Ying Dou, Kathleen E. Sullivan, Hakon Hakonarson, Michael A. Levine
Abstract
BACKGROUND. We aimed to characterize factors associated with the under-studied complication of cognitive decline in aging people with long-duration type 1 diabetes (T1D). METHODS. Joslin “Medalists” (n = 222; T1D ≥ 50 years) underwent cognitive testing. Medalists (n = 52) and age-matched non-diabetic controls (n = 20) underwent neuro- and retinal imaging. Brain pathology (n = 26) was examined. Relationships amongst clinical, cognitive and neuroimaging parameters were evaluated. RESULTS. Compared to controls, Medalists had worse psychomotor function and recall, which associated with female gender, lower visual acuity, reduced physical activity, longer diabetes duration and higher inflammatory cytokines. On neuroimaging, compared to controls, Medalists had significantly lower total and regional brain volumes, equivalent to 9 years of accelerated aging, but small vessel disease markers did not differ. Reduced brain volumes associated with female sex, reduced psychomotor function, worse visual acuity, longer diabetes duration and higher inflammation, but not with glycemic control. Worse cognitive function, lower brain volumes, and diabetic retinopathy correlated with thinning of the outer retinal nuclear layer. Worse baseline visual acuity associated with declining psychomotor function in longitudinal analysis. Brain volume mediated the association between visual acuity and psychomotor function by 57%. Brain pathologies showed decreased volumes, but predominantly mild vascular or Alzheimer’s-related pathology. CONCLUSION. This first comprehensive study of cognitive function, neuroimaging and pathology in aging T1D individuals demonstrated that cognitive decline was related to parenchymal rather than neurovascular abnormalities, unlike type 2 diabetes, suggestive of accelerated aging in T1D. Improving visual acuity could perhaps be an important preventive measure against cognitive decline in people with T1D.
Authors
Hetal S. Shah, Matthew N. DeSalvo, Anastasia Haidar, Surya Vishva Teja Jangolla, Marc Gregory Yu, Rebecca S. Roque, Amanda Hayes, John Gauthier, Nolan Ziemniak, Elizabeth Viebranz, I-Hsien Wu, Kyoungmin Park, Ward Fickweiler, Tanvi J. Chokshi, Tashrif Billah, Lipeng Ning, Atif Adam, Jennifer K. Sun, Lloyd Paul Aiello, Yogesh Rathi, Mel B. Feany, George L. King
Abstract
Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) are gut-derived peptide hormones that potentiate glucose-dependent insulin secretion. The clinical development of GIP receptor (GIPR)–GLP-1 receptor (GLP-1R) multi-agonists exemplified by tirzepatide and emerging GIPR antagonist-GLP-1R agonist therapeutics such as maritide is increasing interest in the extra-pancreatic actions of incretin therapies. Both GLP-1 and GIP modulate inflammation, with GLP-1 also acting locally to alleviate gut inflammation in part through anti-inflammatory actions on GLP-1R+ intestinal intraepithelial lymphocytes. In contrast, whether GIP modulates gut inflammation is not known. Here, using gain and loss of function studies, we show that GIP alleviates 5-fluorouracil (5FU)-induced gut inflammation, whereas genetic deletion of Gipr exacerbates the proinflammatory response to 5FU in the murine small bowel (SB). Bone marrow (BM) transplant studies demonstrated that BM-derived Gipr-expressing cells suppress 5FU-induced gut inflammation in the context of global Gipr deficiency. Within the gut, Gipr was localized to non-immune cells, specifically stromal CD146+ cells. Hence, the extra-pancreatic actions of GIPR signaling extend to the attenuation of gut inflammation, findings with potential translational relevance for clinical strategies modulating GIPR action in people with type 2 diabetes or obesity.
Authors
Rola Hammoud, Kiran Deep Kaur, Jacqueline A. Koehler, Laurie L. Baggio, Chi Kin Wong, Katie E. Advani, Bernardo Yusta, Irina Efimova, Fiona M. Gribble, Frank Reimann, Sigal Fishman, Chen Varol, Daniel J. Drucker
Abstract
BACKGROUND Sodium-glucose cotransporter 2 inhibitors slow down progression of chronic kidney disease (CKD). We tested whether the circulating substrate mix is related to CKD progression and cardiovascular outcomes in patients with type 2 diabetes (T2D) and albuminuric CKD in the CREDENCE trial.METHODS We measured fasting substrates in 2,543 plasma samples at baseline and 1 year after randomization to either 100 mg canagliflozin or placebo and used multivariate Cox models to explore their association with CKD progression, heart failure hospitalization/cardiovascular death (hHF/CVD), and mortality.RESULTS Higher baseline lactate and free fatty acids (FFAs) were independently associated with a lower risk of CKD progression (HR = 0.73 [95% CI: 0.54–0.98] and HR = 0.67 [95% CI: 0.48–0.95], respectively) and hHF/CVD HR = 0.70 [95% CI: 0.50–0.99] and HR = 0.63 [95% CI: 0.42–0.94]). Canagliflozin led to a rise in plasma FFAs, glycerol, β-hydroxybutyrate, and acetoacetate. Changes in substrate between baseline and year 1 predicted an approximately 30% reduction in relative risk of both CKD progression and hHF/CVD independently of treatment. More patients who did not respond to canagliflozin treatment in terms of CKD progression belonged to the bottom lactate and FFA distribution tertiles.CONCLUSION In T2D patients with albuminuric CKD, basic energy substrates selectively influenced major long-term endpoints; canagliflozin treatment amplified their effects by chronically raising their circulating levels.
Authors
Ele Ferrannini, Simona Baldi, Maria Tiziana Scozzaro, Giulia Ferrannini, Michael K. Hansen
Abstract
Mechanisms underpinning signals from genome wide association studies remain poorly understood, particularly for non-coding variation and for complex diseases such as type 2 diabetes mellitus (T2D) where pathogenic mechanisms in multiple different tissues may be disease driving. One approach is to study relevant endophenotypes, a strategy we applied to the UBE2E2 locus where non-coding SNVs are associated with both T2D and visceral adiposity (a pathologic endophenotype). We integrated CRISPR targeting of SNV-containing regions and unbiased CRISPRi screening to establish candidate cis-regulatory regions, complemented by genetic loss of function in murine diet-induced obesity or ex vivo adipogenesis assays. Nomination of a single causal gene was complicated, however, because targeting of multiple genes near UBE2E2 attenuated adipogenesis in vitro, CRISPR excision of SNV-containing non-coding regions and a CRISPRi regulatory screen across the locus suggested concomitant regulation of UBE2E2, the more distant UBE2E1, and other neighborhood genes, and compound heterozygous loss of function of both Ube2e2 and Ube2e1 better replicated pathological adiposity and metabolic phenotypes than homozygous loss of either gene in isolation. This study advances a model whereby regulatory effects of non-coding variation not only extend beyond the nearest gene but may also drive complex diseases through polygenic regulatory effects.
Authors
Yang Zhang, Natalie L. David, Tristan Pesaresi, Rosemary E. Andrews, G.V. Naveen Kumar, Hongyin Chen, Wanning Qiao, Jinzhao Yang, Kareena Patel, Tania Amorim, Ankit X. Sharma, Silvia Liu, Matthew L. Steinhauser
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