Pancreatic Sirtuin 3 deficiency promotes hepatic steatosis by enhancing 5-hydroxytryptamine synthesis in diet-induced obese mice

Sirtuin 3 (SIRT3) is a protein deacetylase regulating beta cell function through inhibiting oxidative stress in obese and diabetic mice, but the detailed mechanism and potential effect of beta cell specific SIRT3 on metabolic homeostasis, and its potential effect on other metabolic organs are unknown. We found glucose tolerance and glucose stimulated insulin secretion (GSIS) were impaired in high fat diet (HFD)-fed beta cell selective Sirt3 knockout (Sirt3f/f;Cre/+) mice. In addition, Sirt3f/f;Cre/+ mice had more severe hepatic steatosis than Sirt3f/f mice upon HFD feeding. RNA sequencing (RNA-Seq) of islets suggested that Sirt3 deficiency over-activated 5-hydroxytryptamine (5-HT) synthesis as evidenced by up-regulation of tryptophan hydroxylase 1 (TPH1). 5-HT concentration was increased in both islets and serum of Sirt3f/f;Cre/+ mice. 5-HT also facilitated the effect of palmitate to increase lipid deposition. Treatment with TPH1 inhibitor ameliorated hepatic steatosis and reduced weight gain in HFD-fed Sirt3f/f;Cre/+ mice. These data suggested that under HFD feeding, SIRT3 deficiency in beta cells not only regulates insulin secretion but also modulates hepatic lipid metabolism via the release of 5-HT.

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Recovery of human type 2 diabetes beta cell function associates with transcriptomic signatures that point to novel therapeutic targets

10.21203/rs.3.rs-871924/v1 ◽

2021 ◽

Author(s):

Mara Suleiman ◽

Xiaoyan Yi ◽

Emanuele Bosi ◽

Frederic Burdet ◽

Carmela De Luca ◽

...

Keyword(s):

Type 2 Diabetes ◽

Insulin Secretion ◽

Beta Cell ◽

Beta Cell Function ◽

Molecular Mechanisms ◽

Cell Function ◽

Therapeutic Targets ◽

Glucose Stimulated Insulin Secretion ◽

Novel Therapeutic

Abstract Remission of type 2 diabetes (T2D) may occur after very low-calorie diets or bariatric surgery, and is associated with improved pancreatic beta cell function. Here, we evaluated if T2D beta cell dysfunction can be rescued ex-vivo and which are the molecular mechanisms involved. Islets from 19 T2D donors were studied after isolation (“basal”) and following culture at 5.5 or 11.1 mmol/l glucose (“cultured”). We evaluated glucose-stimulated insulin secretion (GSIS) and transcriptomes by RNA sequencing, correlated insulin secretion changes (“cultured” vs “basal”) to global gene expression, and searched for potential therapeutic gene targets and compounds that mimic gene signatures of recovered beta cell function in T2D islets. GSIS improved in 12 out of 19 islet preparations from T2D donors after culture at 5.5 mmol/l glucose (insulin stimulation index increased from 1.4±0.1 to 2.3±0.2, p<0.01), mainly due to greater insulin response to high glucose. No improvement was seen in islets cultured at 11.1 mmol/l glucose. Functional improvement was accompanied by changes in expression of 438 genes, many of which involved in functional and inflammatory processes. Of them, 123 were significantly correlated with changes in glucose-stimulated insulin secretion. Drug repurposing and target identification analyses for beta cell functional recovery predicted several chemical (including Src inhibitors and anti-inflammatory drugs) and genetic hits in pathways such as chemokine, MAPK, ERBB signaling, and autophagy. In conclusion, defective insulin secretion in T2D can be rescued, at least in part, by a “non-diabetic” milieu, demonstrating important T2D beta cell functional plasticity. This recovery associates with specific transcriptomic traits, pointing to known as well as novel therapeutic targets to induce T2D remission.

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Paired box 6 programs essential exocytotic genes in the regulation of glucose-stimulated insulin secretion and glucose homeostasis

Science Translational Medicine ◽

10.1126/scitranslmed.abb1038 ◽

2021 ◽

Vol 13 (600) ◽

pp. eabb1038

Author(s):

Wing Yan So ◽

Wai Nam Liu ◽

Adrian Kee Keong Teo ◽

Guy A. Rutter ◽

Weiping Han

Keyword(s):

Insulin Secretion ◽

Beta Cell ◽

Pancreatic Islets ◽

Beta Cells ◽

Pancreatic Beta Cells ◽

Cell Function ◽

Pancreatic Beta Cell ◽

Beta Cell Line ◽

Pathophysiological Role ◽

Glucose Stimulated Insulin Secretion

The paired box 6 (PAX6) transcription factor is crucial for normal pancreatic islet development and function. Heterozygous mutations of PAX6 are associated with impaired insulin secretion and early-onset diabetes mellitus in humans. However, the molecular mechanism of PAX6 in controlling insulin secretion in human beta cells and its pathophysiological role in type 2 diabetes (T2D) remain ambiguous. We investigated the molecular pathway of PAX6 in the regulation of insulin secretion and the potential therapeutic value of PAX6 in T2D by using human pancreatic beta cell line EndoC-βH1, the db/db mouse model, and primary human pancreatic islets. Through loss- and gain-of-function approaches, we uncovered a mechanism by which PAX6 modulates glucose-stimulated insulin secretion (GSIS) through a cAMP response element–binding protein (CREB)/Munc18-1/2 pathway. Moreover, under diabetic conditions, beta cells and pancreatic islets displayed dampened PAX6/CREB/Munc18-1/2 pathway activity and impaired GSIS, which were reversed by PAX6 replenishment. Adeno-associated virus–mediated PAX6 overexpression in db/db mouse pancreatic beta cells led to a sustained amelioration of glycemic perturbation in vivo but did not affect insulin resistance. Our study highlights the pathophysiological role of PAX6 in T2D-associated beta cell dysfunction in humans and suggests the potential of PAX6 gene transfer in preserving and restoring beta cell function.

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502 Beta cell function (insulin secretion) is impaired in patients with stable chronic heart failure

European Journal of Heart Failure Supplements ◽

10.1016/s1567-4215(04)90369-4 ◽

2004 ◽

Vol 3 (1) ◽

pp. 129

Author(s):

C MAMMINI

Keyword(s):

Heart Failure ◽

Insulin Secretion ◽

Chronic Heart Failure ◽

Beta Cell ◽

Beta Cell Function ◽

Cell Function

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2072-P: Deletion of the Mitofusins 1 and 2 (Mfn1 and Mfn2) in the Pancreatic Beta Cell Disrupts Mitochondrial Structure and Function In Vitro and Strongly Impairs Glucose-Stimulated Insulin Secretion In Vivo

Diabetes ◽

10.2337/db20-2072-p ◽

2020 ◽

Vol 69 (Supplement 1) ◽

pp. 2072-P

Author(s):

ELENI GEORGIADOU ◽

PAULINE L. CHABOSSEAU ◽

ALEJANDRA TOMAS ◽

ISABELLE LECLERC ◽

GUY A. RUTTER

Keyword(s):

Insulin Secretion ◽

Beta Cell ◽

Pancreatic Beta Cell ◽

Structure And Function ◽

Insulin Secretion In Vivo ◽

Mitochondrial Structure ◽

Glucose Stimulated Insulin Secretion ◽

And Function

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A new phase of insulin secretion. How will it contribute to our understanding of beta-cell function?

Diabetes ◽

10.2337/diabetes.38.6.673 ◽

1989 ◽

Vol 38 (6) ◽

pp. 673-678 ◽

Cited By ~ 18

Author(s):

G. M. Grodsky

Keyword(s):

Insulin Secretion ◽

Beta Cell ◽

Beta Cell Function ◽

Cell Function ◽

New Phase

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Faculty Opinions recommendation of High-throughput luminescent reporter of insulin secretion for discovering regulators of pancreatic Beta-cell function.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.725299717.793502897 ◽

2015 ◽

Author(s):

Anna Gloyn ◽

Søren Krogsgaard Thomsen

Keyword(s):

Insulin Secretion ◽

Beta Cell ◽

High Throughput ◽

Beta Cell Function ◽

Cell Function ◽

Pancreatic Beta Cell ◽

Pancreatic Beta Cell Function

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In Vitro Studies to Assess the α-Glucosidase Inhibitory Activity and Insulin Secretion Effect of Isorhamnetin 3-O-Glucoside and Quercetin 3-O-Glucoside Isolated from Salicornia herbacea

Processes ◽

10.3390/pr9030483 ◽

2021 ◽

Vol 9 (3) ◽

pp. 483

Author(s):

Dahae Lee ◽

Jun Yeon Park ◽

Sanghyun Lee ◽

Ki Sung Kang

Keyword(s):

Insulin Secretion ◽

Cell Function ◽

Ethanolic Extract ◽

Ethyl Acetate Fraction ◽

Gradient Elution ◽

Glucosidase Activity ◽

Β Cell Function ◽

Glucose Stimulated Insulin Secretion ◽

Salicornia Herbacea

In this study, we examined the effect of ethanolic extract of Salicornia herbacea (ESH), isorhamnetin 3-O-glucoside (I3G), quercetin 3-O-glucoside (Q3G), quercetin, and isorhamnetin on α-glucosidase activity and glucose-stimulated insulin secretion (GSIS) in insulin-secreting rat insulinoma (INS-1) cells. A portion of the ethyl acetate fraction of ESH was chromatographed on a silica gel by a gradient elution with chloroform and methanol to provide Q3G and I3G. ESH, Q3G, and quercetin inhibited α-glucosidase activity, and quercetin (IC50 value was 29.47 ± 3.36 μM) inhibited the activity more effectively than Q3G. We further demonstrated that ESH, Q3G, quercetin, I3G, and isorhamnetin promote GSIS in INS-1 pancreatic β-cells without inducing cytotoxicity. Among them, I3G was the most effective in enhancing GSIS. I3G enhanced the phosphorylation of total extracellular signal-regulated kinase (ERK), insulin receptor substrate-2 (IRS-2), phosphatidylinositol 3-kinase (PI3K), Akt, and activated pancreatic and duodenal homeobox-1 (PDX-1), which are associated with insulin secretion and β-cell function. As components of ESH, Q3G has the potential to regulate blood glucose by inhibiting α-glucosidase activity, and I3G enhances the insulin secretion, but its bioavailability should be considered in determining biological importance.

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Effects of Extra Virgin Olive Oil Polyphenols on Beta-Cell Function and Survival

Plants ◽

10.3390/plants10020286 ◽

2021 ◽

Vol 10 (2) ◽

pp. 286

Author(s):

Nicola Marrano ◽

Rosaria Spagnuolo ◽

Giuseppina Biondi ◽

Angelo Cignarelli ◽

Sebastio Perrini ◽

...

Keyword(s):

Insulin Secretion ◽

Beta Cell ◽

Olive Oil ◽

Beta Cells ◽

Intracellular Signaling ◽

Beta Cell Function ◽

Cell Function ◽

Virgin Olive Oil ◽

Extra Virgin Olive Oil ◽

Insulin Biosynthesis

Extra virgin olive oil (EVOO) is a major component of the Mediterranean diet and is appreciated worldwide because of its nutritional benefits in metabolic diseases, including type 2 diabetes (T2D). EVOO contains significant amounts of secondary metabolites, such as phenolic compounds (PCs), that may positively influence the metabolic status. In this study, we investigated for the first time the effects of several PCs on beta-cell function and survival. To this aim, INS-1E cells were exposed to 10 μM of the main EVOO PCs for up to 24 h. Under these conditions, survival, insulin biosynthesis, glucose-stimulated insulin secretion (GSIS), and intracellular signaling activation (protein kinase B (AKT) and cAMP response element-binding protein (CREB)) were evaluated. Hydroxytyrosol, tyrosol, and apigenin augmented beta-cell proliferation and insulin biosynthesis, and apigenin and luteolin enhanced the GSIS. Conversely, vanillic acid and vanillin were pro-apoptotic for beta-cells, even if they increased the GSIS. In addition, oleuropein, p-coumaric, ferulic and sinapic acids significantly worsened the GSIS. Finally, a mixture of hydroxytyrosol, tyrosol, and apigenin promoted the GSIS in human pancreatic islets. Apigenin was the most effective compound and was also able to activate beneficial intracellular signaling. In conclusion, this study shows that hydroxytyrosol, tyrosol, and apigenin foster beta-cells’ health, suggesting that EVOO or supplements enriched with these compounds may improve insulin secretion and promote glycemic control in T2D patients.

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Glycemia, Beta-Cell Function and Sensitivity to Insulin in Mildly to Critically Ill Covid-19 Patients

Medicina ◽

10.3390/medicina57010068 ◽

2021 ◽

Vol 57 (1) ◽

pp. 68 ◽

Cited By ~ 1

Author(s):

Ioannis Ilias ◽

Aristidis Diamantopoulos ◽

Maria Pratikaki ◽

Efthymia Botoula ◽

Edison Jahaj ◽

...

Keyword(s):

Insulin Secretion ◽

Beta Cell ◽

Critically Ill ◽

Beta Cell Function ◽

Cell Function ◽

Model Assessment ◽

Secondary Diabetes ◽

C Peptide ◽

Number Of Patients ◽

Patients With Diabetes

Background and objectives: Critically and non-critically ill patients with SARS-CoV-2 infection (Covid-19) may present with higher-than-expected glycemia, even in the absence of diabetes. With this study we aimed to assess glucose, glycemic gap (GlyG) and insulin secretion/sensitivity measures in patients with Covid-19. Materials and Methods: We studied, upon admission, 157 patients with Covid-19 (84: in wards and 73: in intensive care units; ICU); 135 had no history of diabetes. We measured blood glucose upon admission as well as glycated hemoglobin (A1c), plasma insulin and C-peptide. We calculated the GlyG and the Homeostasis Model Assessment 2 (HOMA2) estimates of steady state beta cell function (HOMA2%B) and insulin sensitivity (HOMA2%S). Statistical assessment was done with analysis or the Kruskal-Wallis test. Results: Compared to patients in the wards without diabetes, patients with diabetes in the wards, as well as patients in the ICU (without or with diabetes) had higher admission glycemia. The GlyG was significantly higher in patients without diabetes in the ICU compared to patients without diabetes in the wards, while HOMA2%B based on glucose and insulin was significantly higher in the ICU patients compared to patients in the wards. Of all the parameters, HOMA2%S based on C-peptide/glucose was higher in survivors (n = 133). Conclusions: In our series of patients with Covid-19, a substantial number of patients with and without diabetes had admission hyperglycemia and those who were critically ill may have had compromised insulin secretion and lowered sensitivity to insulin. These findings lend credence to reports of association between Covid-19 and hyperglycemia/secondary diabetes.

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