Pulsatile insulin secretion, impaired glucose tolerance and type 2 diabetes

Satin, Leslie S.; Butler, Peter C.; Ha, Joon; Sherman, Arthur

doi:10.1016/j.mam.2015.01.003

Cited by 203 publications

(218 citation statements)

References 146 publications

(215 reference statements)

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“…1) suggest a potential integration of islets with the nervous system in the regulation of hormone secretion. This result and the neuro-insular association identified in mice [10] support a neurally mediated synchronisation of islet hormone secretion across species [40]. Importantly, in fatty infiltration, the formation of an adipose-ganglionic complex indicates that the pancreatic neural tissues are not bystanders in the remodelling of parenchyma (Fig.…”

Section: Discussionsupporting

confidence: 56%

Human pancreatic neuro-insular network in health and fatty infiltration

et al. 2017

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Aims/hypothesis Identification of a pancreatic neuro-insular network in mice suggests that a similar integration of islets and nerves may be present in the human pancreas. To characterise the neuro-insular network and the intra-pancreatic ganglia in a clinically related setting, we examined human pancreases in health and with fatty infiltration via 3-dimensional (3D) histology and compared the human pancreatic microenvironment with its counterpart in mice. Methods Human pancreatic specimens from individuals with normal BMI, high BMI (≥ 25) and type 2 diabetes were used to investigate the neuro-insular network. Transparent specimens were prepared by tissue clearing for transmitted light and deeptissue fluorescence imaging to simultaneously visualise infiltrated adipocytes, islets and neurovascular networks. Results High-definition images of human islets reveal that both the sympathetic and parasympathetic nerves enter the islet core and reside in the immediate microenvironment of islet cells. Around the islets, the neuro-insular network is visualised with 3D histology to identify the intra-pancreatic ganglia (peri-lobular and intra-parenchymal ganglia) and the islet-ganglionic association. In humans, but not in mice, pancreatic fatty infiltration (BMI dependent) features adipocytes infiltrating into the parenchyma and accumulating in the perilobular space, in which the peri-lobular ganglia also reside. We identified the formation of adipose-ganglionic complexes in the peri-lobular space and enlargement of ganglia around adipocytes. In the specimen from the individual with type 2 diabetes, an increase in the number of nerve projections from the intra-parenchymal ganglia is associated with severe fatty infiltration. Conclusions/interpretation We present new perspectives of human pancreas and islet innervation via 3D histology. Our results strongly suggest that fatty infiltration in the human pancreas creates a neurotrophic microenvironment and promotes remodelling of pancreatic innervation.

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Section: Discussionsupporting

confidence: 56%

Human pancreatic neuro-insular network in health and fatty infiltration

et al. 2017

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“…EC 50 = 8 nM for serotonin receptor 5-HT 1F ; (Adham et al, 1993)]. The glucose-dependence and pulsatile pattern of serotonin release were similar to insulin secretion (Almaca et al, 2015; Satin et al, 2015). Biosensor responses were blocked by the 5-HT 2 antagonist mianserin, indicating that serotonin was detected (Figure 2F).…”

Section: Resultsmentioning

confidence: 86%

Human Beta Cells Produce and Release Serotonin to Inhibit Glucagon Secretion from Alpha Cells

et al. 2016

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SUMMARY In the pancreatic islet serotonin is an autocrine signal increasing beta cell mass during metabolic challenges such as those associated with pregnancy or high-fat diet. It is still unclear if serotonin is relevant for regular islet physiology and hormone secretion. Here we show that human beta cells produce and secrete serotonin when stimulated with increases in glucose concentration. Serotonin secretion from beta cells decreases cAMP levels in neighboring alpha cells via 5-HT1F receptors and inhibits glucagon secretion. Without serotonergic input, alpha cells lose their ability to regulate glucagon secretion in response to changes in glucose concentration, suggesting that diminished serotonergic control of alpha cells can cause glucose blindness and the uncontrolled glucagon secretion associated with diabetes. Supporting this model, pharmacological activation of 5-HT1F receptors reduces glucagon secretion and has hypoglycemic effects in diabetic mice. Thus, modulation of serotonin signaling in the islet represents a drug intervention opportunity.

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“…Insulin resistance may be modulated by oscillatory dynamics of insulin secretion (Marsh et al 1986, Shanik et al 2008, and indeed, the loss of pulsatile insulin secretion is one of the earliest detectable defects in individuals who are at risk for type 2 diabetes (O'Rahilly et al 1988, Satin et al 2015. Currently, it is unclear whether hyperinsulinemia or altered insulin secretion dynamics play causal roles in the progression of type 2 diabetes.…”

Section: Hyperinsulinemia In the Etiology Of Insulin Resistance And Tmentioning

confidence: 99%

A causal role for hyperinsulinemia in obesity

Templeman

Skovsø

Page

et al. 2017

Journal of Endocrinology

137

116

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Insulin modulates the biochemical pathways controlling lipid uptake, lipolysis and lipogenesis at multiple levels. Elevated insulin levels are associated with obesity, and conversely, dietary and pharmacological manipulations that reduce insulin have occasionally been reported to cause weight loss. However, the causal role of insulin hypersecretion in the development of mammalian obesity remained controversial in the absence of direct loss-of-function experiments. Here, we discuss theoretical considerations around the causal role of excess insulin for obesity, as well as recent studies employing mice that are genetically incapable of the rapid and sustained hyperinsulinemia that normally accompanies a high-fat diet. We also discuss new evidence demonstrating that modest reductions in circulating insulin prevent weight gain, with sustained effects that can persist after insulin levels normalize. Importantly, evidence from long-term studies reveals that a modest reduction in circulating insulin is not associated with impaired glucose homeostasis, meaning that body weight and lipid homeostasis are actually more sensitive to small changes in circulating insulin than glucose homeostasis in these models. Collectively, the evidence from new studies on genetic loss-of-function models forces a re-evaluation of current paradigms related to obesity, insulin resistance and diabetes. The potential for translation of these findings to humans is briefly discussed.

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Pulsatile insulin secretion, impaired glucose tolerance and type 2 diabetes

Cited by 203 publications

References 146 publications

Human pancreatic neuro-insular network in health and fatty infiltration

Human pancreatic neuro-insular network in health and fatty infiltration

Human Beta Cells Produce and Release Serotonin to Inhibit Glucagon Secretion from Alpha Cells

A causal role for hyperinsulinemia in obesity

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