Dynamics of insulin secretion and the clinical implications for obesity and diabetes

Abstract

Insulin secretion is a highly dynamic process regulated by various factors including nutrients, hormones, and neuronal inputs. The dynamics of insulin secretion can be studied at different levels: the single β cell, pancreatic islet, whole pancreas, and the intact organism. Studies have begun to analyze cellular and molecular mechanisms underlying dynamics of insulin secretion. This review focuses on our current understanding of the dynamics of insulin secretion in vitro and in vivo and discusses their clinical relevance. IntroductionInsulin, which is secreted from pancreatic β cells, is the key hormone in regulating glucose metabolism. Insulin secretion is a highly dynamic process regulated by complex mechanisms. It is regulated by nutrient status, hormonal factors such as gastrointestinal hormone incretins (i.e., glucagon-like peptide 1 [GLP-1] and glucose-dependent insulinotropic polypeptide [GIP; originally termed "gastric inhibitory polypeptide"]), and neural factors (1-5). In addition, the regulation of insulin secretion is a multi-tiered process, occurring at the level of the single β cell, the pancreatic islet, the whole pancreas, and the intact organism. Thus, in vivo, the dynamics of insulin secretion is the consequence of an integration of all of these systems.

Dynamin 2 regulates biphasic insulin secretion and plasma glucose homeostasis

“…To directly test this idea, we incubated β cells for 1 hour with 20 mM glucose and 10 nM glucagon-like peptide-1 (GLP-1), an incretin peptide that increases insulin secretion through cAMPand VAMP8-dependent mechanisms (68). Indeed, the treatment revealed a significant decrease of insulin granule density under TIRFM in KO β cells (Figure 8, F and G), suggesting a defect of insulin granule recruitment during GSIS, which is consistent with the proposed actin function in granule replenishment (11,61).…”

“…The second possibility is that dynamin-induced actin reorganization retards granule recruitment at a later stage of secretion. This is supported by the positive role of actin in vesicle transport (64)(65)(66)(67) and the pronounced defect in the second-phase secretion (Figure 3), which largely relies on new granule recruitment to the PM (8,11). To directly test this idea, we incubated β cells for 1 hour with 20 mM glucose and 10 nM glucagon-like peptide-1 (GLP-1), an incretin peptide that increases insulin secretion through cAMPand VAMP8-dependent mechanisms (68).…”

“…In patients with T2D, the second phase is strongly reduced and the first phase is nearly abolished (7). Multiple factors contribute to the biphasic nature of glucose-stimulated insulin secretion (GSIS), including distinct pools of insulin granules, metabolic signaling, and actin cytoskeleton remodeling (8)(9)(10)(11)(12). The granules docked to the PM, also known as the readily releasable pool (RRP) granules, mainly contribute to the first phase.…”

“…Direct total internal reflection fluorescence (TIRF) imaging suggests that the granules near the PM participate in the first phase and the "newcomer" granules mobilized from a reserve pool located a distance away from the PM produce the second phase of GSIS (12). Moreover, increasing evidence supports an emerging model in which the actin cytoskeleton plays a critical role in biphasic GSIS (10,11) through granule mobilization and recruitment from the reserve pool to the PM. Many actin remodeling molecules, such as the Rho GTPase family proteins Cdc42 (13) and RAC1 (14), PAK1 (15), N-WASP (16), and PPARβ/δ (17), selectively regulate the second phase of GSIS, and perturbations of microtubules (18) and kinesin-1 (19) disrupt the second phase.…”

MicroRNAs: An adaptive mechanism in the pancreatic β-cell…and beyond?

“…Therefore, it is reasonable to speculate that the profile of miRNAs present in the β-cell may have diversified to specifically suppress these genes due to their unique functional mandate: to systematically regulate insulin release. It is widely reported that the β-cell releases only a small percentage of its stored granule pool in response to glucose further supporting the notion that exocytosis from the β-cell is a highly regulated process [29] [28]. Therefore the presence of miRNAs may simply serve to manage and synchronize the efficient output of insulin.…”