The islet-expressed Lhx1 transcription factor interacts with Islet-1 and contributes to glucose homeostasis

The LIM-homeodomain (LIM-HD) transcription factor Islet-1 (Isl1) interacts with the LIM domain-binding protein 1 (Ldb1) coregulator to control expression of key pancreatic β-cell genes. However, Ldb1 also has Isl1-independent effects, supporting that another LIM-HD factor interacts with Ldb1 to impact β-cell development and/or function. LIM homeobox 1 (Lhx1) is an Isl1-related LIM-HD transcription factor that appears to be expressed in the developing mouse pancreas and in adult islets. However, roles for this factor in the pancreas are unknown. This study aimed to determine Lhx1 interactions and elucidate gene regulatory and physiological roles in the pancreas. Co-immunoprecipitation using β-cell extracts demonstrated an interaction between Lhx1 and Isl1, and thus we hypothesized that Lhx1 and Isl1 regulate similar target genes. To test this, we employed siRNA-mediated Lhx1 knockdown in β-cell lines and discovered reduced Glp1R mRNA. Chromatin immunoprecipitation revealed Lhx1 occupancy at a domain also known to be occupied by Isl1 and Ldb1. Through development of a pancreas-wide knockout mouse model ( Lhx1∆Panc), we demonstrate that aged Lhx1∆Panc mice have elevated fasting blood glucose levels, altered intraperitoneal and oral glucose tolerance, and significantly upregulated glucagon, somatostatin, pancreatic polypeptide, MafB, and Arx islet mRNAs. Additionally, Lhx1∆Panc mice exhibit significantly reduced Glp1R, an mRNA encoding the insulinotropic receptor for glucagon-like peptide 1 along with a concomitant dampened Glp1 response and mild glucose intolerance in mice challenged with oral glucose. These data are the first to reveal that the Lhx1 transcription factor contributes to normal glucose homeostasis and Glp1 responses.

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SSBP3 Interacts With Islet-1 and Ldb1 to Impact Pancreatic β-Cell Target Genes

Molecular Endocrinology ◽

10.1210/me.2015-1165 ◽

2015 ◽

Vol 29 (12) ◽

pp. 1774-1786 ◽

Cited By ~ 9

Author(s):

Jamie R. Galloway ◽

Maigen Bethea ◽

Yanping Liu ◽

Rachel Underwood ◽

James A. Mobley ◽

...

Keyword(s):

Transcription Factor ◽

Target Genes ◽

Binding Protein ◽

Β Cells ◽

Β Cell ◽

Complex Activity ◽

Pancreatic Islet Cell ◽

Cell Target ◽

Islet 1

Abstract Islet-1 (Isl1) is a Lin11, Isl1, Mec3 (LIM)-homeodomain transcription factor important for pancreatic islet cell development, maturation, and function, which largely requires interaction with the LIM domain-binding protein 1 (Ldb1) coregulator. In other tissues, Ldb1 and Isl1 interact with additional factors to mediate target gene transcription, yet few protein partners are known in β-cells. Therefore, we hypothesize that Ldb1 and Isl1 participate in larger regulatory complexes to impact β-cell gene expression. To test this, we used cross-linked immunoprecipitation and mass spectrometry to identify interacting proteins from mouse β-cells. Proteomic datasets revealed numerous interacting candidates, including a member of the single-stranded DNA-binding protein (SSBP) coregulator family, SSBP3. SSBPs potentiate LIM transcription factor complex activity and stability in other tissues. However, nothing was known of SSBP3 interaction, expression, or activity in β-cells. Our analyses confirmed that SSBP3 interacts with Ldb1 and Isl1 in β-cell lines and in mouse and human islets and demonstrated SSBP3 coexpression with Ldb1 and Isl1 pancreas tissue. Furthermore, β-cell line SSBP3 knockdown imparted mRNA deficiencies similar to those observed upon Ldb1 reduction in vitro or in vivo. This appears to be (at least) due to SSBP3 occupancy of known Ldb1-Isl1 target promoters, including MafA and Glp1r. This study collectively demonstrates that SSBP3 is a critical component of Ldb1-Isl1 regulatory complexes, required for expression of critical β-cell target genes.

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Differential Effects of Short-term Ketogenic, High Fat and Fructose-enriched Diets on Metabolic Parameters in Mice (P08-042-19)

Current Developments in Nutrition ◽

10.1093/cdn/nzz044.p08-042-19 ◽

2019 ◽

Vol 3 (Supplement_1) ◽

Author(s):

Natalia Cortez ◽

John Solitro ◽

Brian Hong ◽

Emily Villarreal ◽

Gerardo Mackenzie

Keyword(s):

Body Composition ◽

Body Weight ◽

Grip Strength ◽

Glucose Homeostasis ◽

Control Diet ◽

Oral Glucose ◽

High Fat ◽

Carbohydrate Source ◽

Strength Performance ◽

Glucose Levels

Abstract Objectives Dietary composition influences multiple facets of human health and is inextricably linked to chronic metabolic conditions such as obesity, type 2 diabetes, cardiovascular disease and cancer. Thus, the objective of this study was to evaluate the effects of a ketogenic (KD), a high fat (HF), and a fructose-enriched (FR) diets on glucose homeostasis, body composition and grip strength performance in mice. Methods Healthy C57BL/6 J mice (5–6 mice/group) were fed, either a control diet containing approximately 16% total calories from fat (CT), a diet containing 89% fat (KD), a diet with 50% total calories from fat (HF), or a diet with 32% fructose as carbohydrate source (FR). All diets contained 10% protein and all mice were fed ad libitum for 8 weeks. At baseline and 8 weeks, we evaluated body composition using NMR relaxometry, grip strength, non-fasting glucose levels, and ketone levels. In addition, oral glucose tolerance test (OGTT) was conducted by administering glucose by oral gavage (1 g/kg body weight) after 15 hour-fasting and blood glucose levels were measured at 0, 30, 60, 90, and 120 min after glucose administration. Results All mice, irrespectively of their experimental diet groups, increased their body weight, fat mass and adiposity without significant differences among them. After 4 weeks, the HF (P < 0.05) and FR (P < 0.01) groups had significantly higher glucose levels than control. At 8 weeks, the KD groups showed an improved glucose homeostasis compared to CT group, as determined by OGTT. Moreover, compared to the CT group, grip strength performance increased (although did not reached significance) in the KD group (P = 0.054), and decreased in the FR group (P < 0.05). Moreover, when compared to their respective baseline values, grip strength performance increased in KD-fed mice and decreased in FR-fed mice, but differences among them were not statistically significant (P = 0.07). Conclusions Our preliminary findings indicate that altering macronutrient composition can lead to metabolic and physiological changes. Among the three diets tested, the KD showed an improved glucose utilization and better grip strength performance in mice. Additional mechanistic studies are warranted to better understand these metabolic differences among the experimental diets. Funding Sources funds from the University of California, Davis.

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Parameters of Glucose Homeostasis in the Recognition of the Metabolic Syndrome in Young Adults with Prader–Willi Syndrome

Journal of Clinical Medicine ◽

10.3390/jcm10235635 ◽

2021 ◽

Vol 10 (23) ◽

pp. 5635

Author(s):

Graziano Grugni ◽

Antonio Fanolla ◽

Fiorenzo Lupi ◽

Silvia Longhi ◽

Antonella Saezza ◽

...

Keyword(s):

Metabolic Syndrome ◽

Glucose Homeostasis ◽

Tolerance Test ◽

Oral Glucose ◽

Prader Willi Syndrome ◽

Insulinogenic Index ◽

Glucose Levels ◽

The Metabolic Syndrome ◽

Diagnostic Threshold ◽

Age Related

To verify the accuracy of different indices of glucose homeostasis in recognizing the metabolic syndrome in a group of adult patients with Prader–Willi syndrome (PWS), 102 PWS patients (53 females/49 males), age ±SD 26.9 ± 7.6 yrs, Body Mass Index (BMI) 35.7 ± 10.7, were studied. The following indices were assessed in each subject during an oral glucose tolerance test (OGTT): 1 h (>155 mg/dL) and 2 h (140–199 mg/dL) glucose levels, the oral disposition index (ODI), the insulinogenic index (IGI), the insulin resistance (HOMA-IR) were evaluated at baseline, 1 h and 2 h. Although minor differences among indices were found, according to the ROC analysis, no index performed better in recognizing MetS. Furthermore, the diagnostic threshold levels changed over the years and therefore the age-related thresholds were calculated. The easily calculated HOMA-IR at baseline may be used to accurately diagnose MetS, thus avoiding more complicated procedures.

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BBT improves glucose homeostasis by ameliorating β-cell dysfunction in type 2 diabetic mice

Journal of Endocrinology ◽

10.1530/joe-14-0721 ◽

2015 ◽

Vol 224 (3) ◽

pp. 327-341 ◽

Cited By ~ 11

Author(s):

Xin-gang Yao ◽

Xin Xu ◽

Gai-hong Wang ◽

Min Lei ◽

Ling-ling Quan ◽

...

Keyword(s):

Cell Death ◽

Protective Action ◽

Fasting Blood Glucose ◽

Oral Glucose ◽

Diabetic Mice ◽

Β Cells ◽

Β Cell ◽

Cell Functions ◽

Type 2 Diabetic

Impaired glucose-stimulated insulin secretion (GSIS) and increasing β-cell death are two typical dysfunctions of pancreatic β-cells in individuals that are destined to develop type 2 diabetes, and improvement of β-cell function through GSIS enhancement and/or inhibition of β-cell death is a promising strategy for anti-diabetic therapy. In this study, we discovered that the small molecule, N-(2-benzoylphenyl)-5-bromo-2-thiophenecarboxamide (BBT), was effective in both potentiating GSIS and protecting β-cells from cytokine- or streptozotocin (STZ)-induced cell death. Results of further studies revealed that cAMP/PKA and long-lasting (L-type) voltage-dependent Ca2+ channel/CaMK2 pathways were involved in the action of BBT against GSIS, and that the cAMP/PKA pathway was essential for the protective action of BBT on β-cells. An assay using the model of type 2 diabetic mice induced by high-fat diet combined with STZ (STZ/HFD) demonstrated that BBT administration efficiently restored β-cell functions as indicated by the increased plasma insulin level and decrease in the β-cell loss induced by STZ/HFD. Moreover, the results indicated that BBT treatment decreased fasting blood glucose and HbA1c and improved oral glucose tolerance further highlighting the potential of BBT in anti-hyperglycemia research.

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Glucose homeostasis is regulated by pancreatic β-cell cilia via endosomal EphA-processing

Nature Communications ◽

10.1038/s41467-019-12953-5 ◽

2019 ◽

Vol 10 (1) ◽

Cited By ~ 11

Author(s):

Francesco Volta ◽

M. Julia Scerbo ◽

Anett Seelig ◽

Robert Wagner ◽

Nils O’Brien ◽

...

Keyword(s):

Insulin Secretion ◽

Glucose Homeostasis ◽

Basal Body ◽

Primary Cilia ◽

Epithelial To Mesenchymal Transition ◽

Human Islets ◽

Β Cells ◽

Β Cell ◽

Mesenchymal Transition ◽

Glucose Levels

Abstract Diabetes mellitus affects one in eleven adults worldwide. Most suffer from Type 2 Diabetes which features elevated blood glucose levels and an inability to adequately secrete or respond to insulin. Insulin producing β-cells have primary cilia which are implicated in the regulation of glucose metabolism, insulin signaling and secretion. To better understand how β-cell cilia affect glucose handling, we ablate cilia from mature β-cells by deleting key cilia component Ift88. Here we report that glucose homeostasis and insulin secretion deteriorate over 12 weeks post-induction. Cilia/basal body components are required to suppress spontaneous auto-activation of EphA3 and hyper-phosphorylation of EphA receptors inhibits insulin secretion. In β-cells, loss of cilia/basal body function leads to polarity defects and epithelial-to-mesenchymal transition. Defective insulin secretion from IFT88-depleted human islets and elevated pEPHA3 in islets from diabetic donors both point to a role for cilia/basal body proteins in human glucose homeostasis.

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Prevention of Diabetes in db/db Mice by Dietary Soy Is Independent of Isoflavone Levels

Endocrinology ◽

10.1210/en.2012-1490 ◽

2012 ◽

Vol 153 (11) ◽

pp. 5200-5211 ◽

Cited By ~ 19

Author(s):

Céline Zimmermann ◽

Christopher R. Cederroth ◽

Lucie Bourgoin ◽

Michelangelo Foti ◽

Serge Nef

Keyword(s):

Glucose Homeostasis ◽

Cell Function ◽

Hepatic Glucose Production ◽

Cell Mass ◽

Glucose Production ◽

Metabolic Effects ◽

Pancreatic Β Cell ◽

Β Cell ◽

Glucose Levels ◽

Hepatic Glucose

Abstract Recent evidence points towards the beneficial use of soy proteins and isoflavones to improve glucose control and slow the progression of type 2 diabetes. Here, we used diabetic db/db mice fed a high soy-containing diet (SD) or a casein soy-free diet to investigate the metabolic effects of soy and isoflavones consumption on glucose homeostasis, hepatic glucose production, and pancreatic islet function. Male db/db mice fed with a SD exhibited a robust reduction in hyperglycemia (50%), correlating with a reduction in hepatic glucose production and preserved pancreatic β-cell function. The rapid decrease in fasting glucose levels resulted from an inhibition of gluconeogenesis and an increase in glycolysis in the liver of db/db mice. Soy consumption also prevented the loss of pancreatic β-cell mass and thus improved glucose-stimulated insulin secretion (3-fold), which partly accounted for the overall improvements in glucose homeostasis. Comparison of SD effects on hyperglycemia with differing levels of isoflavones or with purified isoflavones indicate that the beneficial physiological effects of soy are not related to differences in their isoflavone content. Overall, these findings suggest that consumption of soy is beneficial for improving glucose homeostasis and delaying the progression of diabetes in the db/db mice but act independently of isoflavone concentration.

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Case Report: A Novel ABCC8 Variant in a Chinese Pedigree of Maturity-Onset Diabetes of the Young

Frontiers in Endocrinology ◽

10.3389/fendo.2021.758723 ◽

2021 ◽

Vol 12 ◽

Author(s):

Chaoyan Tang ◽

Liheng Meng ◽

Ping Zhang ◽

Xinghuan Liang ◽

Chaozhi Dang ◽

...

Keyword(s):

Blood Glucose ◽

Glucose Homeostasis ◽

Fasting Blood Glucose ◽

Family Members ◽

Missense Variant ◽

Postprandial Blood Glucose ◽

Chinese Family ◽

Oral Glucose ◽

Maturity Onset Diabetes ◽

Onset Diabetes

BackgroundWe aimed to analyze a novel ABCC8 variant of a Chinese patient with suspected maturity-onset diabetes of the young (MODY) and to provide evidence for precise diagnosis and appropriate treatment.MethodA Chinese family with suspected MODY was recruited in this study, which included a 15-year-old female patient with diabetes. Clinical data and blood samples were collected from the proband and other family members. All of the living relatives were given an oral glucose tolerance test. Next-generation sequencing was performed to identify the mutated genes in the proband. Sanger sequencing was utilized to confirm the location of the pathogenic variant in all subjects. Further treatment was referred to targeted family members according to genetic testing.ResultsThe proband was found to have a random blood glucose level of 244.8 mg/dl and an HbA1c level of 9.2%. Before this investigation, her grandparents had been diagnosed with diabetes. The second uncle, two aunts, mother, and cousin of the proband were diagnosed with diabetes by abnormal HbA1C (6.5–12.1%) and fasting blood glucose (FBG, 91.4–189.7 mg/dl). The second aunt of the proband had impaired glucose homeostasis (HbA1C = 6.4% and FBG = 88.0 mg/dl). One novel missense variant c.1432G>A (p.A478T) in exon 9 of the ABCC8 gene was detected in the proband with suspected MODY. The variant was also found in six family members with diabetes or impaired glucose homeostasis, including her second uncle, two aunts, mother, and cousin. After the treatment was switched to glimepiride, the fasting blood glucose was adjusted to 99.54 mg/dl, the 2-h postprandial blood glucose was 153.54 mg/dl, serum fructosamine was 259 μmol/l, and HbA1c was 5.8%. The glycemic control remained optimal, and no hypoglycemic episodes were observed in the living relatives.ConclusionThis study revealed one novel missense variant of the ABCC8 gene in Chinese families. The present findings indicated that the members of this family responded to treatment with sulfonylureas as previously seen in ABCC8 MODY.

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Transcription Factor HMG Box-Containing Protein 1 (HBP1) Regulates Glycemic Homeostasis Through Modulation of Gluconeogenesis

Current Developments in Nutrition ◽

10.1093/cdn/nzaa058_005 ◽

2020 ◽

Vol 4 (Supplement_2) ◽

pp. 1247-1247

Author(s):

Chin-Ming Chang ◽

Chun-Yin Huang

Keyword(s):

Transcription Factor ◽

Blood Glucose ◽

Glucose Homeostasis ◽

Molecular Mechanisms ◽

Ectopic Expression ◽

Tolerance Test ◽

Public Health Issue ◽

Oral Glucose ◽

Hmg Box ◽

Blood Glucose Homeostasis

Abstract Objectives Glycemic dysregulation is one of the major metabolic disorders, which has long been a significant public health issue. The liver plays a pivotal role in the maintenance of blood glucose homeostasis. Previous studies indicate that upon refeeding a high carbohydrate diet, the expression of transcription factor HMG box-containing protein 1 (HBP1) was elevated in mice livers, suggesting a role of HBP1 in carbohydrate metabolism. Therefore, the objective of the current study was to understand the molecular mechanisms through which HBP1 regulates glucose generation in the liver. Methods Both in vivo HBP1 knockdown mice and in vitro HepG2 cell line were employed as the experimental models. Results First, we observed that overnight fasting led to increased PEPCK but decreased HBP1 expression in mice livers, and subsequent addition of insulin reversed the expression pattern. More importantly, HBP1 knockout (KO) mice displayed a significantly higher blood glucose level (173 mg/dL) than that of the controls (98 mg/dL). Also, HBP1 KO led to impaired OGTT (oral glucose tolerance test) and ITT (insulin tolerance test). These data suggest that HBP1 might have a role in the regulation of gluconeogenesis in the liver. To unveil the molecular mechanism by which HBP1 regulates glucose homeostasis, we examined its role in gluconeogenesis. Administration of gluconeogenic stimulators glucagon (100 nM) and cAMP (0.5 ng/mL) resulted in increased expression of Phosphoenolpyruvate carboxykinase (PEPCK; encoded by the PCK1 gene), a key enzyme in gluconeogenesis, but decreased HBP1 expression in HepG2 cells. Last, HBP1 siRNA-mediated mRNA disruption led to elevated PEPCK expression, whereas ectopic expression of HBP1 (pcDNA3-HBP1-Flag) significantly suppressed it. Conclusions In conclusion, our data indicate that HBP1 might negatively regulate glucose production and support HBP1 as a novel biological regulator of blood glucose homeostasis. Funding Sources This work was supported by the grant to MOST 108–2320-B-039–051-MY3 C-Y Huang.

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Incretin secretion and glucose metabolism in morbidly obese patients in the early and late periods after biliopancreatic diversion

Terapevticheskii arkhiv ◽

10.17116/terarkh201688109-18 ◽

2016 ◽

Vol 88 (10) ◽

pp. 9-18

Author(s):

I I Dedov ◽

G A Melnichenko ◽

E A Troshina ◽

E V Ershova ◽

N V Mazurina ◽

...

Keyword(s):

Glucose Metabolism ◽

Biliopancreatic Diversion ◽

Fasting Blood Glucose ◽

Early Period ◽

Control Group ◽

Immunoreactive Insulin ◽

Morbidly Obese ◽

Oral Glucose ◽

Late Period ◽

Glucose Levels

Aim. To estimate the parameters of glucose metabolism and to assess the secretion of incretins in patients after biliopancreatic diversion (BPD) for morbid obesity (MO) in the early and late postoperative periods. Subjects and methods. The prospective part of the investigation included 22 patients with a body mass index of 35.8 to 68.4 kg/m2 and type 2 diabetes mellitus (T2DM). All the patients were examined before, 3 weeks and 3 months after BPD. The retrospective part covered 23 patients who were examined after BPD for MO; the postoperative period was 4.7 [2.3; 7.2] years. A control group consisted of 22 healthy, normal weight volunteers. A 75-g oral glucose tolerance test was carried out in all the groups to study the levels of glucose, immunoreactive insulin (IRI), glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP) and glucagon at 0, 30, 60, and 120 min. Results. T2DM patients showed improvement in glucose metabolism just 3 weeks after BPD; following 3 months, they had normalized fasting blood glucose levels (5.6 [5.0; 6.0] mmol/l). During 3 months, glycated hemoglobin decreased from 7.5 [6.6; 8.5] to 5.7 [5.3; 5.9]%. In the early period following BPD, there was an increase in basal and postprandial GLP-1 levels associated with the peak IRI concentration. In the late period after BPD, the enhanced secretion of IRI and GLP-1 persisted, which was followed by a reduction in postprandial glucose levels in 4 of the 23 patients. Conclusion. T2DM remission does not depend on weight loss in the early period after BPD. In this period, the significant improvement of glucose metabolic parameters in patients with obesity and T2DM is associated with elevated GLP-1 levels. The altered incretin response is a stable effect of BPD and remains in its late period.

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