scholarly journals Chemical induction of gut β-like-cells by combined FoxO1/Notch inhibition as a glucose-lowering treatment for diabetes

2021 ◽  
Author(s):  
Takumi Kitamoto ◽  
Yun-Kyoung Lee ◽  
Wendy M. McKimpson ◽  
Hitoshi Watanabe ◽  
Nishat Sultana ◽  
...  
Keyword(s):  
Small Molecule ◽  
Genetic Effect ◽  
Intestinal Epithelial ◽  
Diabetes Treatment ◽  
Chemical Induction ◽  
Enteroendocrine Cell ◽  
Glucose Lowering ◽  
Cell Conversion ◽  
Plasma Insulin Levels

Lifelong insulin replacement remains the mainstay of type 1 diabetes treatment. Genetic FoxO1 ablation promotes enteroendocrine cell (EECs) conversion into glucose-responsive β-like cells. Here, we tested whether chemical FoxO1 inhibitors can generate β-like gut cells. Pan-intestinal epithelial FoxO1 ablation expanded the EEC pool, induced β-like cells, and improved glucose tolerance in Ins2Akita/+ mice. This genetic effect was phenocopied by small molecule FoxO1 inhibitor, Cpd10. Cpd10 induced β-like cells that released insulin in response to glucose in mouse gut organoids, and this effect was strengthened by the Notch inhibitor, DBZ. In Ins2Akita/+ mice, a five-day course of either Cpd10 or DBZ induced insulin-immunoreactive β-like cells in the gut, lowered glycemia, and increased plasma insulin levels without apparent adverse effects. These results provide proof of principle of gut cell conversion into β-like cells by a small molecule FoxO1 inhibitor, paving the way for clinical applications.

scholarly journals Lower plasma insulin levels during overnight closed-loop in school children with type 1 diabetes: Potential advantage? A randomized cross-over trial

PLoS ONE ◽  
2019 ◽  
Vol 14 (3) ◽  
pp. e0212013 ◽  
Author(s):  
Ulrike Schierloh ◽  
Malgorzata E. Wilinska ◽  
Ineke M. Pit-ten Cate ◽  
Petra Baumann ◽  
Roman Hovorka ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
School Children ◽  
Plasma Insulin ◽  
Closed Loop ◽  
Lower Plasma ◽  
Insulin Levels ◽  
Plasma Insulin Levels

scholarly journals P fimbriae and other adhesins enhance intestinal persistence of Escherichia coli in early infancy

1998 ◽  
Vol 121 (3) ◽  
pp. 599-608 ◽  
Author(s):  
I. ADLERBERTH ◽  
C. SVANBORG ◽  
B. CARLSSON ◽  
L. MELLANDER ◽  
L.-Å. HANSON ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Cell Line ◽  
Intestinal Epithelial Cells ◽  
Antigen Expression ◽  
Intestinal Epithelial ◽  
E Coli ◽  
O Antigen ◽  
Ht 29 ◽  
Intestinal Persistence

Resident and transient Escherichia coli strains were identified in the rectal flora of 22 Pakistani infants followed from birth to 6 months of age. All strains were tested for O-antigen expression, adhesin specificity (P fimbriae, other mannose-resistant adhesins or type 1 fimbriae) and adherence to the colonic cell line HT-29. Resident strains displayed higher mannose- resistant adherence to HT-29 cells, and expressed P fimbriae (P=0·0036) as well as other mannose-resistant adhesins (P=0·012) more often than transient strains. In strains acquired during the first month of life, P fimbriae were 12 times more frequent in resident than in transient strains (P=0·0006). The O-antigen distribution did not differ between resident and transient strains, and none of the resident P-fimbriated strains belonged to previously recognized uropathogenic clones. The results suggest that adhesins mediating adherence to intestinal epithelial cells, especially P fimbriae, enhance the persistence of E. coli in the large intestine of infants.

Interleukin-1β enhances retinoic acid-mediated expression of bone-type alkaline phosphatase in rat IEC-6 cells

2001 ◽  
Vol 280 (3) ◽  
pp. G510-G517 ◽  
Author(s):  
Takeshi Nikawa ◽  
Madoka Ikemoto ◽  
Kaori Tokuoka ◽  
Shigetada Teshima ◽  
David H. Alpers ◽  
...  
Keyword(s):  
Alkaline Phosphatase ◽  
Retinoic Acid ◽  
Retinoic Acid Receptor ◽  
Transcript Level ◽  
Intestinal Epithelial ◽  
Alp Activity ◽  
Kinase C ◽  
Fetal Rat ◽  
Epidermal Growth

We previously showed that vitamin A upregulated the expression of bone-type alkaline phosphatase (ALP) in fetal rat small intestine and rat intestinal IEC-6 cells. In this study, we examined interactions between retinoic acid (RA) and several growth factors/cytokines on the isozyme expression in IEC-6 cells. Epidermal growth factor and interleukins (ILs)-2, -4, -5, and -6 completely blocked the RA-mediated increase in ALP activity. In contrast, IL-1β markedly increased the activity, protein, and mRNA of the bone-type ALP only when RA was present. IL-1β and/or RA did not change the type 1 IL-1 receptor transcript level, whereas IL-1β enhanced the RA-induced expressions of retinoic acid receptor-β (RAR-β) and retinoid X receptor-β (RXR-β) mRNAs and RA-mediated RXR response element binding. The synergism of IL-1β and RA on ALP activity was completely blocked by protein kinase C (PKC) inhibitors. Our results suggest that IL-1β may modify the ALP isozyme expression in small intestinal epithelial cells by stimulating PKC-dependent, RAR-β- and/or RXR-β-mediated signaling pathways.

scholarly journals Differential effects of insulin deprivation and systemic insulin treatment on plasma protein synthesis in type 1 diabetic people

2009 ◽  
Vol 297 (4) ◽  
pp. E889-E897 ◽  
Author(s):  
Abdul Jaleel ◽  
Katherine A. Klaus ◽  
Dawn M. Morse ◽  
Helen Karakelides ◽  
Lawrence E. Ward ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Plasma Protein ◽  
Plasma Proteins ◽  
Insulin Treatment ◽  
Two Dimensional Gel Electrophoresis ◽  
Differential Effects ◽  
Glucose Levels ◽  
Protein Gel ◽  
Plasma Insulin Levels

It remains to be determined whether systemic insulin replacement normalizes synthesis rates of different plasma proteins and whether there are differential effects on various plasma proteins. We tested a hypothesis that insulin deprivation differentially affects individual plasma protein synthesis and that systemic insulin treatment may not normalize synthesis of all plasma proteins. We measured synthesis rates of 41 plasma proteins in seven each of type 1 diabetic (T1DM) and nondiabetic participants (ND) using [ ring-13C6]phenylalanine as a tracer. T1DM were studied while on chronic insulin treatment and during 8 h insulin deprivation. Insulin treatment normalized glucose levels, but plasma insulin levels were higher during insulin treatment than during insulin deprivation in T1DM and ND. Individual plasma proteins were purified by affinity chromatography and two-dimensional gel electrophoresis. Only 41 protein gel spots from over 300 were chosen based on their protein homogeneity. Insulin deprivation and hyperglycemia either significantly increased ( n = 12) or decreased ( n = 12) synthesis rates of 24 of 41 plasma proteins in T1DM compared with ND. Insulin treatment normalized synthesis rates of 13 of these 24 proteins, which were altered during insulin deprivation. However, insulin treatment significantly altered the synthesis of 14 additional proteins. In conclusion, acute insulin deprivation caused both a decrease and increase in synthesis rates of many plasma proteins with various functions. Moreover, chronic systemic insulin treatment not only did not normalize synthesis of all plasma proteins but also altered synthesis of several additional proteins that were unaltered during insulin deprivation.

scholarly journals Pharmacokinetics and Pharmacodynamics of Three Different Formulations of Insulin Aspart: A Randomized, Double-blind, Crossover Study in Men With Type 1 Diabetes

2020 ◽  
Author(s):  
Eva Svehlikova ◽  
Ines Mursic ◽  
Thomas Augustin ◽  
Christoph Magnes ◽  
David Gerring ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Crossover Study ◽  
Insulin Aspart ◽  
Pharmacokinetics And Pharmacodynamics ◽  
Onset Of Action ◽  
Double Blind ◽  
Glucose Lowering ◽  
Lowering Effect ◽  
Glucose Lowering Effect

OBJECTIVE <p>To investigate the pharmacokinetic and pharmacodynamic properties, and safety of a novel formulation of insulin aspart (AT247) versus currently marketed insulin aspart formulations (IAsp and faster IAsp).</p> <p> </p> <p>RESEARCH DESIGN AND METHODS</p> <p>This single-center, randomized, double-blind, three-period, crossover study was conducted in 19 men with type 1 diabetes, receiving single dosing of trial products (0.3 U/kg) in a random order on three visits. Pharmacokinetics and pharmacodynamics were assessed during a euglycemic clamp lasting up to 8 hours. </p> <p> </p> <p>RESULTS</p> <p>Onset of insulin appearance was earlier for AT247 compared with IAsp (−12 minutes [95% CI −14;−8] p=0.0004) and faster IAsp (−2 minutes [−5;−2] p=0.0003). Onset of action was accelerated compared with IAsp (−23 minutes [−37;−15] p=0.0004) and faster IAsp (−9 minutes [−11;−3] p=0.0006). Within the first 60 minutes, a higher exposure was observed for AT247 compared with IAsp (AUC<sub>Asp,0-60min</sub>: treatment ratio vs IAsp 2.3 [1.9;2.9]; vs faster IAsp 1.5 [1.3;1.8]), which was underpinned by a greater early glucose-lowering effect (AUC<sub>GIR,0-60min</sub>: treatment ratio vs IAsp 2.8 [2.0;5.5]; vs faster IAsp 1.7 [1.3;2.3]). Furthermore, an earlier offset of exposure was observed for AT247 compared with IAsp (−32 minutes [−58;−15] p=0.0015) and faster IAsp (−27 minutes [−85;−15] p=0.0017), while duration of glucose-lowering effect, measured by t<sub>Late50%GIRmax</sub>, did not differ significantly.</p> <p> </p> <p>CONCLUSIONS</p> <p>AT247 exhibited an earlier insulin appearance, exposure and offset, with corresponding enhanced early glucose-lowering effect compared with IAsp and faster IAsp. It therefore represents a promising candidate in the pursuit for second generation prandial insulin analogs to improve postprandial glycemic control.</p>

scholarly journals Epigallocatechin gallate delays the onset of type 1 diabetes in spontaneous non-obese diabetic mice

2010 ◽  
Vol 105 (8) ◽  
pp. 1218-1225 ◽  
Author(s):  
Zhuo Fu ◽  
Wei Zhen ◽  
Julia Yuskavage ◽  
Dongmin Liu
Keyword(s):  
Type 1 Diabetes ◽  
Cell Mass ◽  
Epigallocatechin Gallate ◽  
Nod Mice ◽  
Cost Effective ◽  
Treated Group ◽  
Control Group ◽  
Plasma Insulin Levels ◽  
Glucose Lowering Effect

Type 1 diabetes (T1D) results from the autoimmune-mediated destruction of pancreatic β-cells, leading to deficiency of insulin production. Successful islet transplantation can normalise hyperglycaemia in T1D patients; however, the limited availability of the islets, loss of islet cell mass through apoptosis after islet isolation and potential autoimmune destruction of the transplanted islets prevent the widespread use of this procedure. Therefore, the search for novel and cost-effective agents that can prevent or treat T1D is extremely important to decrease the burden of morbidity from this disease. In the present study, we discovered that ( − )-epigallocatechin gallate (EGCG, 0·05 % in drinking-water), the primary polyphenolic component in green tea, effectively delayed the onset of T1D in non-obese diabetic (NOD) mice. At 32 weeks of age, eight (66·7 %) out of twelve mice in the control group developed diabetes, whereas only three (25 %) out of twelve mice in the EGCG-treated group became diabetic (P < 0·05). Consistently, mice supplemented with EGCG had significantly higher plasma insulin levels and survival rate but lower glycosylated Hb concentrations compared with the control animals. EGCG had no significant effects on food or water intake and body weight in mice, suggesting that the glucose-lowering effect was not due to an alteration in these parameters. While EGCG did not modulate insulitis, it elevated the circulating anti-inflammatory cytokine IL-10 level in NOD mice. These findings demonstrate that EGCG may be a novel, plant-derived compound capable of reducing the risk of T1D.

scholarly journals Type 1 diabetes: treatment without tears?

Diabetologia ◽  
2005 ◽  
Vol 48 (10) ◽  
pp. 1963-1964 ◽  
Author(s):  
S. A. Amiel
Keyword(s):  
Type 1 Diabetes ◽  
Diabetes Treatment

scholarly journals Burkholderia pseudomallei as an Enteric Pathogen: Identification of Virulence Factors Mediating Gastrointestinal Infection

2020 ◽  
Vol 89 (1) ◽  
pp. e00654-20
Author(s):  
Javier I. Sanchez-Villamil ◽  
Daniel Tapia ◽  
Grace I. Borlee ◽  
Bradley R. Borlee ◽  
David H. Walker ◽  
...  
Keyword(s):  
Virulence Factors ◽  
Burkholderia Pseudomallei ◽  
Enteric Pathogen ◽  
Epithelial Cell Line ◽  
Intestinal Epithelial ◽  
Gastrointestinal Infection ◽  
Content Type ◽  
Route Of Infection ◽  
The Impact

ABSTRACTBurkholderia pseudomallei is a Gram-negative bacterium and the causative agent of melioidosis. Despite advances in our understanding of the disease, B. pseudomallei poses a significant health risk, especially in regions of endemicity, where treatment requires prolonged antibiotic therapy. Even though the respiratory and percutaneous routes are well documented and considered the main ways to acquire the pathogen, the gastrointestinal tract is believed to be an underreported and underrecognized route of infection. In the present study, we describe the development of in vitro and in vivo models to study B. pseudomallei gastrointestinal infection. Further, we report that the type 6 secretion system (T6SS) and type 1 fimbriae are important virulence factors required for gastrointestinal infection. Using a human intestinal epithelial cell line and mouse primary intestinal epithelial cells (IECs), we demonstrated that B. pseudomallei adheres, invades, and forms multinucleated giant cells, ultimately leading to cell toxicity. We demonstrated that mannose-sensitive type 1 fimbria is involved in the initial adherence of B. pseudomallei to IECs, although the impact on full virulence was limited. Finally, we also showed that B. pseudomallei requires a functional T6SS for full virulence, bacterial dissemination, and lethality in mice infected by the intragastric route. Overall, we showed that B. pseudomallei is an enteric pathogen and that type 1 fimbria is important for B. pseudomallei intestinal adherence, and we identify a new role for T6SS as a key virulence factor in gastrointestinal infection. These studies highlight the importance of gastrointestinal melioidosis as an understudied route of infection and open a new avenue for the pathogenesis of B. pseudomallei.

scholarly journals Mitigating RNA Toxicity in Myotonic Dystrophy using Small Molecules

2019 ◽  
Vol 20 (16) ◽  
pp. 4017 ◽  
Author(s):  
Kaalak Reddy ◽  
Jana R. Jenquin ◽  
John D. Cleary ◽  
J. Andrew Berglund
Keyword(s):  
Small Molecules ◽  
Myotonic Dystrophy ◽  
Small Molecule ◽  
Disease Onset ◽  
Myotonic Dystrophy Type 1 ◽  
Myotonic Dystrophy Type ◽  
Rna Toxicity ◽  
Complex Mechanisms ◽  
Potential Use

This review, one in a series on myotonic dystrophy (DM), is focused on the development and potential use of small molecules as therapeutics for DM. The complex mechanisms and pathogenesis of DM are covered in the associated reviews. Here, we examine the various small molecule approaches taken to target the DNA, RNA, and proteins that contribute to disease onset and progression in myotonic dystrophy type 1 (DM1) and 2 (DM2).

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