Insulin modulation of glucagon secretion: The role of insulin and other factors in the regulation of glucagon secretion

Kawamori, Dan; Kulkarni, Rohit

doi:10.4161/isl.1.3.9967

Cited by 38 publications

(35 citation statements)

References 34 publications

(44 reference statements)

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“…Considering that both CB 1 R −/− and MAGL −/− mice are lean (7,8), we suggest that their mixed pancreatic islets allow for improved short-range insulin signaling between α and β cells ("histoarchitectural gain of function"), which can serve as a feedback mechanism increasing the ratio of insulin to glucagon secretion under high glucose availability. This hypothesis is also supported by genetic data upon conditional insulin receptor knockout in α cells (56), which induces hyperglucagonemia and glucose intolerance. Nevertheless, islet morphologies of adult CB 1 R −/− and MAGL −/− mice might represent either the outcome of developmental mechanisms or use-dependent and transient postnatal reorganization.…”

Section: Discussionsupporting

confidence: 65%

“…These data cumulatively link α cells infiltrating the core of pancreatic islets to enhanced α/β cell interplay and hormonal responsiveness. Therefore, we formulate the hypothesis that the increased number of α and β cell contacts drives paracrine signaling in the endocrine pancreas (19,73), possibly with insulin and glucagon secretion serving as a dual feedback mechanism for α and β cells, respectively (56,75,76).…”

Section: Discussionmentioning

confidence: 99%

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Fetal endocannabinoids orchestrate the organization of pancreatic islet microarchitecture

Malenczyk

Keimpema

Piscitelli

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Endocannabinoids are implicated in the control of glucose utilization and energy homeostasis by orchestrating pancreatic hormone release. Moreover, in some cell niches, endocannabinoids regulate cell proliferation, fate determination, and migration. Nevertheless, endocannabinoid contributions to the development of the endocrine pancreas remain unknown. Here, we show that α cells produce the endocannabinoid 2-arachidonoylglycerol (2-AG) in mouse fetuses and human pancreatic islets, which primes the recruitment of β cells by CB 1 cannabinoid receptor (CB 1 R) engagement. Using subtractive pharmacology, we extend these findings to anandamide, a promiscuous endocannabinoid/endovanilloid ligand, which impacts both the determination of islet size by cell proliferation and α/β cell sorting by differential activation of transient receptor potential cation channel subfamily V member 1 (TRPV1) and CB 1 Rs. Accordingly, genetic disruption of TRPV1 channels increases islet size whereas CB 1 R knockout augments cellular heterogeneity and favors insulin over glucagon release. Dietary enrichment in ω-3 fatty acids during pregnancy and lactation in mice, which permanently reduces endocannabinoid levels in the offspring, phenocopies CB 1 R −/− islet microstructure and improves coordinated hormone secretion. Overall, our data mechanistically link endocannabinoids to cell proliferation and sorting during pancreatic islet formation, as well as to life-long programming of hormonal determinants of glucose homeostasis.A nandamide (AEA) and 2-arachydonoylglycerol (2-AG), major endocannabinoids (eCBs), are involved in the regulation of energy homeostasis through coordinated actions in peripheral organs (adipose tissue, liver, and pancreas) and brain (hypothalamus, ventral striatum) (1). eCB signals are particularly significant to coordinate the regulated release of insulin and glucagon from mature pancreatic islets (2-6). Genetic evidence from CB 1 cannabinoid receptor −/− (CB 1 R −/− ) mice supports these findings because CB 1 R −/− mice are lean, resistant to high fat diet-induced obesity and diabetes (4, 7-9). Whether eCBs impact the formation of the endocrine pancreas and predispose it to long-lasting changes in hormone release postnatally remains unknown.Because eCBs broadly affect cell proliferation, fate, motility, and differentiation (e.g., in sperm, hematopoietic and T cells, and neurons) (10-13), it is likely that they play a role in the cellular organization of developing pancreatic islets, possibly by affecting the spatial segregation of α and β cells. A contribution of eCBs to cell diversification and positioning in the developing pancreas is supported by the temporal control of their levels in fetal tissues (14) and circulation (15). Moreover, α and β cells in mature pancreatic islets express the molecular machinery for eCB metabolism together with CB 1 Rs and transient receptor potential cation channels, particularly subfamily V member 1 (TRPV1) (2,16,17). Understanding these developmental processes is also relevant to po...

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Section: Discussionsupporting

confidence: 65%

Section: Discussionmentioning

confidence: 99%

Fetal endocannabinoids orchestrate the organization of pancreatic islet microarchitecture

Malenczyk

Keimpema

Piscitelli

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…GIP contributes more to secretion of insulin than does GLP-1 [26] on the basis of the baseline HbA 1c in this study. Thus, although we did not measure GLP-1 and GIP levels as well as glucose and lipid parameters at 30 min during the CLT in this study, we expect that this difference can be partly explained by the fact that glucagon, in addition to GIP rather than GLP-1, is regulated by insulin levels [27].…”

Section: Parameters Related To Lipid Metabolismmentioning

confidence: 97%

Effects of miglitol <i>versus</i> sitagliptin on postprandial glucose and lipoprotein metabolism in patients with type 2 diabetes mellitus

et al. 2013

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PostPrandial hyPerglycemia and hyperlipidemia have been shown to be risk factors for atherosclerosis [1][2][3]. Potential agents to target postprandial hyperglycemia and hyperlipidemia in patients with type 2 diabetes mellitus (T2DM) include α-glucosidase inhibitors (AGIs) and dipeptidyl peptidase (DPP)-4 inhibitors. Miglitol is an AGI that improves postprandial hyperglycemia and hyperlipidemia [4] abstract. Postprandial hyperglycemia and/or hyperlipidemia can contribute to development of atherosclerosis in patients with type 2 diabetes mellitus (T2DM). The objective of this study was to compare the effects of miglitol and sitagliptin on postprandial glucose and lipid metabolism in patients with T2DM. Thirty-five patients with T2DM were randomized to 2 groups receiving miglitol (150 mg/day) or sitagliptin (50 mg/day). Serum variables related to glucose and lipid metabolism were measured before and after treatment for 10 weeks and at 0, 60, and 120 min using a cookie-loading test (CLT). After 10 weeks of treatment, miglitol (n = 16) and sitagliptin (n = 18) caused a similarly significant decrease in hemoglobin A 1c (mean: 7.6% to 7.3% versus 8.0% to 7.6%) and a significant increase in fasting insulin levels, with a greater increase observed in the miglitol group than in the sitagliptin group (p=0.03). In addition, a significant decrease in the change in glucose levels after the CLT was observed in both groups, with a greater decrease observed in the miglitol group than in the sitagliptin group (p=0.02). The miglitol group also showed a greater decrease in the change in insulin levels after the CLT than the sitagliptin group (p<0.01). The lipid and lipoprotein levels did not show any significant differences between the groups after the CLT. Our results suggested that miglitol and sitagliptin treatment resulted in similar glycemic control but that a greater decrease in postprandial glucose and insulin levels was observed with miglitol compared with sitagliptin in patients with T2DM.

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“…cell function). For instance, insulin represses glucagon expression and release from the α cell, whereas glucagon stimulates β cell insulin secretion (Kawai et al, 1995;Kawamori and Kulkarni, 2009). Dysregulation of insulin and glucagon signaling consequent to β cell dysfunction or destruction causes diabetes mellitus, a devastating disease that afflicts more than 360 million people worldwide (Whiting et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

glucagon is essential for alpha cell transdifferentiation and beta cell neogenesis

et al. 2015

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The interconversion of cell lineages via transdifferentiation is an adaptive mode of tissue regeneration and an appealing therapeutic target. However, its clinical exploitation is contingent upon the discovery of contextual regulators of cell fate acquisition and maintenance. In murine models of diabetes, glucagon-secreting alpha cells transdifferentiate into insulin-secreting beta cells following targeted beta cell depletion, regenerating the form and function of the pancreatic islet. However, the molecular triggers of this mode of regeneration are unknown. Here, using lineage-tracing assays in a transgenic zebrafish model of beta cell ablation, we demonstrate conserved plasticity of alpha cells during islet regeneration. In addition, we show that glucagon expression is upregulated after injury. Through gene knockdown and rescue approaches, we also find that peptides derived from the glucagon gene are necessary for alpha-to-beta cell fate switching. Importantly, whereas beta cell neogenesis was stimulated by glucose, alpha-to-beta cell conversion was not, suggesting that transdifferentiation is not mediated by glucagon/GLP-1 control of hepatic glucose production. Overall, this study supports the hypothesis that alpha cells are an endogenous reservoir of potential new beta cells. It further reveals that glucagon plays an important role in maintaining endocrine cell homeostasis through feedback mechanisms that govern cell fate stability.

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Insulin modulation of glucagon secretion: The role of insulin and other factors in the regulation of glucagon secretion

Cited by 38 publications

References 34 publications

Fetal endocannabinoids orchestrate the organization of pancreatic islet microarchitecture

Fetal endocannabinoids orchestrate the organization of pancreatic islet microarchitecture

Effects of miglitol <i>versus</i> sitagliptin on postprandial glucose and lipoprotein metabolism in patients with type 2 diabetes mellitus

glucagon is essential for alpha cell transdifferentiation and beta cell neogenesis

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