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In diabetes, macrophages and inflammation are increased in the islets, along with β-cell dysfunction. Here, we demonstrate that galectin-3 (Gal3), mainly produced and secreted by macrophages, is elevated in islets from both high-fat diet (HFD)-fed and diabetic db/db mice. Gal3 acutely reduces glucose-stimulated insulin secretion (GSIS) in β-cell lines and primary islets in mice and humans. Importantly, Gal3 binds to calcium voltage-gated channel auxiliary subunit gamma 1 (CACNG1) and inhibits calcium influx via the cytomembrane and subsequent GSIS. β-Cell CACNG1 deficiency phenocopies Gal3 treatment. Inhibition of Gal3 through either genetic or pharmacologic loss of function improves GSIS and glucose homeostasis in both HFD-fed and db/db mice. All animal findings are applicable to male mice. Here we show a role of Gal3 in pancreatic β-cell dysfunction, and Gal3 could be a therapeutic target for the treatment of type 2 diabetes., (© 2024. The Author(s).)

Zinc biology, featuring intertwining signaling networks and critical importance to human health, witnesses exciting opportunities in the big data era of physiology. Here, we report a class of red- and far-red-emitting Zn 2+ probes with K d values ranging from 190 nM to 74 μM, which are particularly suitable for real-time monitoring the high concentration of Zn 2+ co-released with insulin during vesicular secretory events. Compared to the prototypical rhodamine-based Zn 2+ probes, the new class exploits morpholino auxochromes which eliminates phototoxicity during long-term live recording of isolated islets. A Si-rhodamine-based Zn 2+ probe with high turn-on ratio (>100), whose synthesis was enabled by a new route featuring late-stage N-alkylation, allowed simultaneous recording of Ca 2+ influx, mitochondrial signal, and insulin secretion in isolated mouse islets. The time-lapse multicolor fluorescence movies and their analysis, enabled by red-shifted Zn 2+ and other orthogonal physiological probes, highlight the potential impact of biocompatible fluorophores on the fields of islet endocrinology and system biology., (© 2021 Wiley-VCH GmbH.)

Incretin-potentiated glucose-stimulated insulin secretion (GSIS) is critical to maintaining euglycemia, of which GLP-1 receptor (GLP-1R) on β-cells plays an indispensable role. Recently, α-cell-derived glucagon but not intestine-derived GLP-1 has been proposed as the critical hormone that potentiates GSIS via GLP-1R. However, the function of glucagon receptors (GCGR) on β-cells remains elusive. Here, using GCGR or GLP-1R antagonists, in combination with glucagon, to treat single β-cells, α-β cell clusters and isolated islets, we found that glucagon potentiates insulin secretion via β-cell GCGR at physiological but not high concentrations of glucose. Furthermore, we transfected primary mouse β-cells with RAB-ICUE (a genetically encoded cAMP fluorescence indicator) to monitor cAMP level after glucose stimulation and GCGR activation. Using specific inhibitors of different adenylyl cyclase (AC) family members, we revealed that high glucose concentration or GCGR activation independently evoked cAMP elevation via AC5 in β-cells, thus high glucose stimulation bypassed GCGR in promoting insulin secretion. Additionally, we generated β-cell-specific GCGR knockout mice which glucose intolerance was more severe when fed a high-fat diet (HFD). We further found that β-cell GCGR activation promoted GSIS more than GLP-1R in HFD, indicating the critical role of GCGR in maintaining glucose homeostasis during nutrient overload.

Insulin secretion by pancreatic islet β-cells is regulated by glucose levels and is accompanied by proton generation. The voltage-gated proton channel Hv1 is present in pancreatic β-cells and extremely selective for protons. However, whether Hv1 is involved in insulin secretion is unclear. Here we demonstrate that Hv1 promotes insulin secretion of pancreatic β-cells and glucose homeostasis. Hv1-deficient mice displayed hyperglycemia and glucose intolerance because of reduced insulin secretion but retained normal peripheral insulin sensitivity. Moreover, Hv1 loss contributed much more to severe glucose intolerance as the mice got older. Islets of Hv1-deficient and heterozygous mice were markedly deficient in glucose- and K + -induced insulin secretion. In perifusion assays, Hv1 deletion dramatically reduced the first and second phase of glucose-stimulated insulin secretion. Islet insulin and proinsulin content was reduced, and histological analysis of pancreas slices revealed an accompanying modest reduction of β-cell mass in Hv1 knockout mice. EM observations also indicated a reduction in insulin granule size, but not granule number or granule docking, in Hv1-deficient mice. Mechanistically, Hv1 loss limited the capacity for glucose-induced membrane depolarization, accompanied by a reduced ability of glucose to raise Ca 2+ levels in islets, as evidenced by decreased durations of individual calcium oscillations. Moreover, Hv1 expression was significantly reduced in pancreatic β-cells from streptozotocin-induced diabetic mice, indicating that Hv1 deficiency is associated with β-cell dysfunction and diabetes. We conclude that Hv1 regulates insulin secretion and glucose homeostasis through a mechanism that depends on intracellular Ca 2+ levels and membrane depolarization., (© 2020 Pang et al.)

Zinc biology, featuring intertwining signaling networks and critical importance to human health, witnesses exciting opportunities in the big data era of physiology. Here, we report a class of red‐ and far‐red‐emitting Zn2+ probes with Kd values ranging from 190 nM to 74 μM, which are particularly suitable for real‐time monitoring the high concentration of Zn2+ co‐released with insulin during vesicular secretory events. Compared to the prototypical rhodamine‐based Zn2+ probes, the new class exploits morpholino auxochromes which eliminates phototoxicity during long‐term live recording of isolated islets. A Si‐rhodamine‐based Zn2+ probe with high turn‐on ratio (>100), whose synthesis was enabled by a new route featuring late‐stage N‐alkylation, allowed simultaneous recording of Ca2+ influx, mitochondrial signal, and insulin secretion in isolated mouse islets. The time‐lapse multicolor fluorescence movies and their analysis, enabled by red‐shifted Zn2+ and other orthogonal physiological probes, highlight the potential impact of biocompatible fluorophores on the fields of islet endocrinology and system biology. [ABSTRACT FROM AUTHOR]

Aims: To investigate the progression of obesity‐related type 2 diabetes mellitus (T2DM) in rhesus monkeys, especially dynamic changes in insulin and glucagon. Materials and methods: We followed a cohort of 52 rhesus monkeys for 7 years throughout the progression of obesity‐related T2DM. Intravenous glucose tolerance tests were performed every 6 months to evaluate dynamic changes in glucose, insulin and glucagon levels. Results: Obesity in rhesus monkeys increased the overall mortality and T2DM morbidity. During the progression of T2DM, glucagon remained consistently elevated, while insulin initially increased in compensation but then dropped to below normal levels when the monkeys developed overt T2DM. After a glucose challenge, both the first and second phases of insulin secretion increased during the early stage of T2DM; in later stages the first phase was delayed and the second phase was diminished. Conclusion: Our findings showed that, beside the decreased insulin level, hyperglucagonaemia also plays an important role in the development of T2DM. [ABSTRACT FROM AUTHOR]

Innentitelbild: Red- and Far-Red-Emitting Zinc Probes with Minimal Phototoxicity for Multiplexed Recording of Orchestrated Insulin Secretion (Angew. 4D islet physiology, biocompatibility, fluorescent probe, insulin secretion, zinc Keywords: 4D islet physiology; biocompatibility; fluorescent probe; insulin secretion; zinc EN 4D islet physiology biocompatibility fluorescent probe insulin secretion zinc 25790 25790 1 11/26/21 20211201 NES 211201 B Die Insulinsekretion b aus -Zellen kann nun zusammen mit dem Kalziumsignal und den Organellen aufgezeichnet werden. [Extracted from the article]

Inside Cover: Red- and Far-Red-Emitting Zinc Probes with Minimal Phototoxicity for Multiplexed Recording of Orchestrated Insulin Secretion (Angew. Keywords: 4D islet physiology; biocompatibility; fluorescent probe; insulin secretion; zinc EN 4D islet physiology biocompatibility fluorescent probe insulin secretion zinc 25586 25586 1 11/26/21 20211201 NES 211201 B Insulin secretion b from -cells in intact islets can now be recorded together with calcium signal and organelles. Tailored for 4D, long-term, and multiple-color recording of Zn SP 2+ sp /insulin co-secretion in -cells and islets, the new probes promise to unveil the spatial-temporal regulation of islet endocrinology. [Extracted from the article]