Defective Amplifying Pathway of β-Cell Secretory Response to Glucose in Type 2 Diabetes: Integrated Modeling of In Vitro and In Vivo Evidence

Grespan, Eleonora; Giorgino, Toni; Arslanian, Silva; Natali, Andrea; Ferrannini, Ele; Mari, Andrea

doi:10.2337/db17-1039

Cited by 20 publications

(28 citation statements)

References 35 publications

(62 reference statements)

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“…It has been reported that impairment of amplifying pathways could be one of the major causes underlying the beta cells dysfunction in T2D . In 2006 our research group observed the absence of amplifying pathways in islets from MSG‐obese rats, which was also found in the present study.…”

Section: Discussionsupporting

confidence: 86%

“…Our data show that chronic exercise training reduces GSIS by inhibiting amplifying pathways in pancreatic islets; an effect that was more evident in islets from MSG‐EXE rats. To date, the accurate molecular and biochemical mechanisms involved in amplifying pathways and how these events are coupled to the exocytosis of insulin granules are still unclear . Interestingly, cholinergic effects on beta cells are also considered to be amplifying pathways .…”

Section: Discussionmentioning

confidence: 99%

“…To date, the accurate molecular and biochemical mechanisms involved in amplifying pathways and how these events are coupled to the exocytosis of insulin granules are still unclear. 42 Interestingly, cholinergic effects on beta cells are also considered to be amplifying pathways. 44 Thus, it is possible that the intense inhibitory effect of amplifying pathways, induced by exercise, could attenuate cholinergic responses without affecting M3R, PKC nor PKA immunocontent.…”

Section: Discussionmentioning

confidence: 99%

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Swimming training reduces glucose‐amplifying pathway and cholinergic responses in islets from lean‐ and MSG‐obese rats

Borck

Leite

Valcanaia

et al. 2019

Clin Exp Pharma Physio

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Here, we investigate the effects of exercise training on glucose‐ and cholinergic‐induced insulin secretion in pancreatic islets from obese and lean rats. Male Wistar rats were treated with monosodium glutamate (MSG) for the first 5 days of life, while control (CON) rats received saline. At 21 days, the rats were divided into exercised (EXE) and sedentary (SED) groups. The EXE rats swam for 30 minutes, three times/week, for 10 weeks. After this, MSG‐SED rats showed hyperglycaemia, hypertriglyceridaemia and hyperinsulinaemia. Besides, islets from MSG‐SED rats exhibited increased glucose‐stimulated insulin secretion (GSIS), followed by impaired glucose sensitivity, absence of glucose‐amplifying pathway and weak cholinergic response. In contrast, adiposity, hyperinsulinaemia and hypertriglyceridaemia were reduced in MSG‐EXE rats. Moreover, islets from MSG‐EXE rats exhibited lower GSIS and improved islet glucose sensitivity, without restoration of the glucose‐amplifying pathway or alteration in the weak cholinergic effect of these islets. In islets from CON‐EXE rats we also observed reduced GSIS and absence of glucose‐amplifying effects and an accentuated reduction in cholinergic insulinotropic responses, without effect on glucose sensitivity in pancreatic islets from this group. Neither obesity nor exercise modified Muscarinic Receptor 3 (M3R) immunocontent or its downstream pathways (PKC and PKA). Moreover, only CON‐EXE showed increased GSIS in the presence of calcium blocker, Thapsigargin. In conclusion, swimming training reduces GSIS and cholinergic responsiveness in isolated pancreatic islets from lean and hypothalamic obese rats, which could be due to the inhibition of glucose‐amplifying pathways.

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Section: Discussionsupporting

confidence: 86%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Swimming training reduces glucose‐amplifying pathway and cholinergic responses in islets from lean‐ and MSG‐obese rats

Borck

Leite

Valcanaia

et al. 2019

Clin Exp Pharma Physio

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“…Based on these indices we calculated the Disposition Index (Matsuda ISI x InsAUC30/GluAUC30) which is a measure of beta-cell function adjusted for prevailing insulin sensitivity, and suitable for large population-based studies. Mathematical modeling to determine beta-cell function need multiple measurements in an OGTT, and is not feasible for large scale population-based studies [82], [83].…”

Section: Future Of the Biomarker Studiesmentioning

confidence: 99%

Biomarkers for type 2 diabetes

Laakso

2019

Molecular Metabolism

142

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BackgroundThe prevalence and incidence of type 2 diabetes (T2D), representing >90% of all cases of diabetes, are increasing rapidly worldwide. Identification of individuals at high risk of developing diabetes is of great importance as early interventions might delay or even prevent full-blown disease. T2D is a complex disease caused by multiple genetic loci in interplay with lifestyle and environmental factors. Recently over 400 distinct association signals were published; these explain 18% of the risk of T2D.Scope of reviewIn this review there is a major focus on risk factors and genetic and non-genetic biomarkers for the risk of T2D identified especially in large prospective population-based studies, and studies testing causality of the biomarkers for T2D in Mendelian randomization studies. Another focus is on understanding genome-phenome interplay in the classification of individuals with T2D into subgroups.Major conclusionsSeveral recent large population-based studies and their meta-analyses have identified multiple potential genetic and non-genetic biomarkers for the risk of T2D. Combination of genetic variants and physiologically characterized pathways improves the classification of individuals with T2D into subgroups, and is also paving the way to a precision medicine approach, in T2D.

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“…In addition to the ATP‐dependent depolarization, action potential firing, and increases in intracellular Ca 2+ stimulated by glucose (collectively called the ‘triggering’ pathway), a secondary pathway which may be mediated by multiple possible metabolic signals (Prentki, Matschinsky, and Madiraju, 2013) acts to facilitate exocytotic responses to the increased Ca 2+ . In fact, these ‘metabolic amplification’ pathways may act early to set the amplitude of glucose‐induced secretory responses – and reduced efficacy of this pathway may contribute to impaired insulin secretion in type 2 diabetes (T2D) (Grespan et al, 2018). One important pathway that contributes to the metabolic amplification of insulin secretion links the mitochondrial export of (iso)citrate and cytosolic generation of NADPH (Joseph et al, 2006; Ronnebaum et al, 2006) which facilitates insulin exocytosis (Ivarsson et al, 2005; Reinbothe et al, 2009) via the deSUMOylating enzyme sentrin‐specific protease‐1 (SENP1) (Ferdaoussi et al, 2015) acting on proteins at the exocytotic site (Dai et al, 2011; Ferdaoussi et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Improved glucose tolerance with DPPIV inhibition requires β‐cell SENP1 amplification of glucose‐stimulated insulin secretion

et al. 2020

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Pancreatic islet insulin secretion is amplified by both metabolic and receptor-mediated signaling pathways. The incretin-mimetic and DPPIV inhibitor anti-diabetic drugs increase insulin secretion, but in humans this can be variable both in vitro and in vivo. We examined the correlation of GLP-1 induced insulin secretion from human islets with key donor characteristics, glucose-responsiveness, and the ability of glucose to augment exocytosis in β-cells. No clear correlation was observed between several donor or organ processing parameters and the ability of Exendin 4 to enhance insulin secretion. The ability of glucose to facilitate β-cell exocytosis was, however, significantly correlated with responses to Exendin 4. We therefore studied the effect of impaired glucose-dependent amplification of insulin exocytosis on responses to DPPIV inhibition (MK-0626) in vivo using pancreas and β-cell specific sentrin-specific protease-1 (SENP1) mice which exhibit impaired metabolic amplification of insulin exocytosis. Glucose tolerance was improved, and plasma insulin was increased, following either acute or 4 week treatment of wild-type (βSENP1 +/+ ) mice with MK-0626. This DPPIV inhibitor was ineffective in βSENP1 +/− or βSENP1 −/− mice. Finally, we confirm impaired exocytotic responses of β-cells and reduced insulin secretion from islets of βSENP1 −/− mice and show that the ability of Exendin 4 to enhance exocytosis is lost in these cells. Thus, an impaired ability of glucose to amplify insulin exocytosis results in a deficient effect of DPPIV inhibition to improve in vivo insulin responses and glucose tolerance.

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Defective Amplifying Pathway of β-Cell Secretory Response to Glucose in Type 2 Diabetes: Integrated Modeling of In Vitro and In Vivo Evidence

Cited by 20 publications

References 35 publications

Swimming training reduces glucose‐amplifying pathway and cholinergic responses in islets from lean‐ and MSG‐obese rats

Swimming training reduces glucose‐amplifying pathway and cholinergic responses in islets from lean‐ and MSG‐obese rats

Biomarkers for type 2 diabetes

Improved glucose tolerance with DPPIV inhibition requires β‐cell SENP1 amplification of glucose‐stimulated insulin secretion

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