What do we know about the secretion and degradation of incretin hormones?

The incretin hormones, glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1) are secreted from endocrine cells located in the intestinal mucosa, and act to enhance meal-induced insulin secretion. GIP and GLP-1 concentrations in the plasma rise rapidly after food ingestion, and the presence of unabsorbed nutrients in the intestinal lumen is a strong stimulus for their secretion. Nutrients can stimulate release of both hormones by direct contact with the K-cell (GIP) and L-cell (GLP-1), and this may be the most important signal. However, nutrients also stimulate GLP-1 and GIP secretion indirectly via other mechanisms. Incretin hormone secretion can be modulated neurally, with cholinergic muscarinic, beta-adrenergic and peptidergic (gastrin-releasing peptide, GRP) fibres generally having positive effects, while secretion is restrained by alpha-adrenergic and somatostatinergic fibres. Hormonal factors may also influence incretin hormone secretion. Somatostatin exerts a local inhibitory effect on the activity of both K- and L-cells via a paracrine mechanism, while, in rodents at least, GIP from the proximal intestine has a stimulatory effect on GLP-1 secretion, possibly mediated via a neural loop involving GRP. Once they have been released, both GLP-1 and GIP are subject to rapid degradation. The ubiquitous enzyme, dipeptidyl peptidase IV (DPP IV) cleaves N-terminally, removing a dipeptide and thereby inactivating both peptides, because the N-terminus is crucial for receptor binding. Subsequently, the peptides may be degraded by other enzymes and extracted in an organ-specific manner. The intact peptides are inactivated during passage across the hepatic bed and further metabolised by the peripheral tissues, while the kidney is important for the final elimination of the metabolites.     

Hyperoxia reverses glucotoxicity-induced inhibition of insulin secretion in rat INS-1 β cells

Chronic hyperglycemia has deleterious effects on pancreatic β-cell function, a process known as glucotoxicity. This study examined whether chronic high glucose (CHG) induces cellular hypoxia in rat INS-1 β cells, and whether hyperoxia (35% O₂) can reverse glucotoxicity-induced inhibition of insulin secretion. CHG (33.3?mm, 96?h) reduced insulin secretion, and down-regulated insulin and pancreatic duodenal homeobox factor 1 gene expression. CHG also increased intracellular pimonidazole-protein adducts, a marker for hypoxia. CHG also enhanced hypoxia-inducible factor 1α (HIF-1α) protein expression and its DNA-binding activity, which was accompanied by a decrease in mRNA expression of glucose transporter 2 (GLUT2), glucokinase and uncoupling protein-2 and an increase in mRNA expression of GLUT1 and pyruvate dehydrogenase kinase 1. Hyperoxia restored the decrease in insulin secretion and the gene expression except for GLUT2, and suppressed intracellular hypoxia and HIF-1α activation. These results suggest that glucotoxicity may cause β-cell hypoxia. Hyperoxia might prevent glucotoxicity-induced β-cell dysfunction and improve insulin secretion.     

Role of miRNAs in the pathogenesis of T2DM,insulin secretion,insulin resistance,and β cell dysfunction: the story so far

Journal of Physiology and Biochemistry - Diabetes, the most common endocrine disorder, also known as a silent killer disease, is characterized by uncontrolled hyperglycemia. According to the...     

DNA polymerases β and λ and their roles in cell

Among the set of mammalian DNA polymerases, DNA polymerases belonging to the X and Y families have a special place. The majority of these enzymes are involved in repair, including base excision repair and non-homologous end joining. Some of them play a crucial role during the specific process which is referred to as translesion synthesis (TLS). TLS intends for the cell surviving during the replication of damaged DNA templates. Additionally, specific activities of TLS-polymerases have to be useful for repair of double-stranded clustered lesions: if the synthesis is proceeded via base excision repair process, the role of DNA polymerases β or λ will be important. In this review we discussed the biochemical properties and functional relevance of X family DNA polymerases β and λ.     

Transcellular neuroligin-2 interactions enhance insulin secretion and are integral to pancreatic β cell function

Normal glucose-stimulated insulin secretion is dependent on interactions between neighboring β cells. Elucidation of the reasons why this cell-to-cell contact is essential will probably yield critical insights into β cell maturation and function. In the central nervous system, transcellular protein interactions (i.e. interactions between proteins on the surfaces of different cells) involving neuroligins are key mediators of synaptic functional development. We previously demonstrated that β cells express neuroligin-2 and that insulin secretion is affected by changes in neuroligin-2 expression. Here we show that the effect of neuroligin-2 on insulin secretion is mediated by transcellular interactions. Neuroligin-2 binds with nanomolar affinity to a partner on the β cell surface and contributes to the increased insulin secretion brought about by β cell-to-β cell contact. It does so in a manner seemingly independent of interactions with neurexin, a known binding partner. As in the synapse, transcellular neuroligin-2 interactions enhance the functioning of the submembrane exocytic machinery. Also, as in the synapse, neuroligin-2 clustering is important. Neuroligin-2 in soluble form, rather than presented on a cell surface, decreases insulin secretion by rat islets and MIN-6 cells, most likely by interfering with endogenous neuroligin interactions. Prolonged contact with neuroligin-2-expressing cells increases INS-1 β cell proliferation and insulin content. These results extend the known parallels between the synaptic and β cell secretory machineries to extracellular interactions. Neuroligin-2 interactions are one of the few transcellular protein interactions thus far identified that directly enhance insulin secretion. Together, these results indicate a significant role for transcellular neuroligin-2 interactions in the establishment of β cell function.     

From insulin synthesis to secretion: Alternative splicing of type 2 ryanodine receptor gene is essential for insulin secretion in pancreatic β cells

Increases in the intracellular Ca²⁺ concentration in pancreatic islets, resulting from the Ca²⁺ mobilization from the intracellular source through the ryanodine receptor, are essential for insulin secretion by glucose. Cyclic ADP-ribose, a potent Ca²⁺ mobilizing second messenger synthesized from NAD⁺ by CD38, regulates the opening of ryanodine receptor. A novel ryanodine receptor mRNA (the islet-type ryanodine receptor) was found to be generated from the type 2 ryanodine receptor gene by the alternative splicing of exons 4 and 75. The islet-type ryanodine receptor mRNA is expressed in a variety of tissues such as pancreatic islets, cerebrum, cerebellum, and other neuro-endocrine cells, whereas the authentic type 2 ryanodine receptor mRNA (the heart-type ryanodine receptor) was found to be generated using GG/AG splicing of intron 75 and is expressed in the heart and the blood vessel. The islet-type ryanodine receptor caused a greater increase in the Ca²⁺ release by caffeine when expressed in HEK293 cells pre-treated with cyclic ADP-ribose, suggesting that the novel ryanodine receptor is an intracellular target for the CD38-cyclic ADP-ribose signal system in mammalian cells and that the tissue-specific alternative splicing of type 2 ryanodine receptor mRNA plays an important role in the functioning of the cyclic ADP-ribose-sensitive Ca²⁺ release.     

Exogenous and endogenous ghrelin counteracts GLP-1 action to stimulate cAMP signaling and insulin secretion in islet β-cells

We studied interactive effects of insulinotropic GLP-1 and insulinostatic ghrelin on rat pancreatic islets. GLP-1 potentiated glucose-induced insulin release and cAMP production in isolated islets and [Ca(2+)](i) increases in single β-cells, and these potentiations were attenuated by ghrelin. Ghrelin suppressed [Ca(2+)](i) responses to an adenylate cyclase activator forskolin. Moreover, GLP-1-induced insulin release and cAMP production were markedly enhanced by [D-lys(3)]-GHRP-6, a ghrelin receptor antagonist, in isolated islets. These results indicate that both exogenous and endogenous islet-derived ghrelin counteracts glucose-dependent GLP-1 action to increase cAMP production, [Ca(2+)](i) and insulin release in islet β-cells, positioning ghrelin as a modulator of insulinotropic GLP-1.     

The physiological role of GLP-1 in human: incretin, ileal brake or more?

The proglucagon-derived peptide glucagon-like peptide-1 (GLP-1) is an intestinal signal peptide postprandially released from the L cells of the lower gut. Exogenously administered the synthetic hormone exerts a glucose-dependent insulinotropic effect at the pancreatic beta-cells and lowers plasma glucagon by an inhibitory effect against the alpha-cells. It delays gastric emptying by relaxation of the gastric fundus, inhibition of antral contractility, and stimulation of both the tonic and phasic motility of the pyloric sphincter. Enhancement of insulin, suppression of glucagon, and inhibition of gastric emptying are the main determinants controlling glucose homeostasis with GLP-1. Human studies employing the specific GLP-1 receptor antagonist exendin(9-39) show that endogenously released GLP-1 likewise controls fasting plasma glucagon, stimulates insulin, and influences all the motoric mechanisms known to control gastric emptying. Therefore, GLP-1 is discussed as an incretin hormone and as an enterogastrone in man. Synthetic GLP-1 also suppresses gastric acid and pancreatic enzyme secretion. The inhibitory effects on upper gastrointestinal functions are at least partly mediated by vagal-cholinergic inhibition and may involve interactions with vagal afferent pathways and/or circumventricular regions within the CNS. GLP-1 is a candidate humoral mediator of the 'ileal brake' exerting inhibition of upper gastrointestinal function preventing malabsorption and postprandial metabolic disturbances. As human studies indicate a central action of GLP-1 in reduction of food intake, it is uncertain if this is a consequence of induction of satiety or of transduction of visceral aversive stress signals.     

Regulation of insulin sensitivity,insulin production,and pancreatic β cell survival by angiotensin-(1-7) in a rat model of streptozotocin-induced diabetes mellitus

The aim of this study is to determine the antidiabetic activity of Ang-(1-7), an important component of the renin–angiotensin system, in a rat model of streptozotocin (STZ)-induced type 2 diabetes mellitus (DM). A total of 36 male Wistar rats were randomly divided into 3 groups: control group fed standard laboratory diet, DM group fed high-fat diet and injected with STZ, and Ang-(1-7) group receiving injection of STZ followed by Ang-(1-7) treatment. Body weight, blood glucose levels, fasting serum Ang II and insulin levels, and homeostasis model assessment of insulin resistance (HOMA-IR) were measured. The pancreas was collected for histological examination and gene expression analysis. Notably, the Ang-(1-7) group showed a significant decrease in fasting blood glucose and serum Ang II levels and HOMA-IR values and increase in fasting serum insulin levels. Pancreatic β cells in the control and Ang-(1-7) groups were normally distributed in the center of pancreatic islets with large clear nuclei. In contrast, pancreatic β cells in the DM group had a marked shrinkage of the cytoplasm and condensation of nuclear chromatin. Ang-(1-7) treatment significantly facilitated insulin production by β cells in diabetic rats. The DM-associated elevation of inducible nitric oxide synthase (iNOS), caspase-3, caspase-9, caspase-8, and Bax and reduction of Bcl-2 was significantly reversed by Ang-(1-7) treatment. Taken together, Ang-(1-7) protects against STZ-induced DM through improvement of insulin resistance, insulin secretion, and pancreatic β cell survival, which is associated with reduction of iNOS expression and alteration of the Bcl-2 family.     

Enhanced expression of VEGF-A in β cells increases endothelial cell number but impairs islet morphogenesis and β cell proliferation

There is a reciprocal interaction between pancreatic islet cells and vascular endothelial cells (EC) in which EC-derived signals promote islet cell differentiation and islet development while islet cell-derived angiogenic factors promote EC recruitment and extensive islet vascularization. To examine the role of angiogenic factors in the coordinated development of islets and their associated vessels, we used a "tet-on" inducible system (mice expressing rat insulin promoter-reverse tetracycline activator transgene and a tet-operon-angiogenic factor transgene) to increase the β cell production of vascular endothelial growth factor-A (VEGF-A), angiopoietin-1 (Ang1), or angiopoietin-2 (Ang2) during islet cell differentiation and islet development. In VEGF-A overexpressing embryos, ECs began to accumulate around epithelial tubes residing in the central region of the developing pancreas (associated with endocrine cells) as early as embryonic day 12.5 (E12.5) and increased dramatically by E16.5. While α and β cells formed islet cell clusters in control embryos at E16.5, the increased EC population perturbed endocrine cell differentiation and islet cell clustering in VEGF-A overexpressing embryos. With continued overexpression of VEGF-A, α and β cells became scattered, remained adjacent to ductal structures, and never coalesced into islets, resulting in a reduction in β cell proliferation and β cell mass at postnatal day 1. A similar impact on islet morphology was observed when VEGF-A was overexpressed in β cells during the postnatal period. In contrast, increased expression of Ang1 or Ang2 in β cells in developing or adult islets did not alter islet differentiation, development, or morphology, but altered islet EC ultrastructure. These data indicate that (1) increased EC number does not promote, but actually impairs β cell proliferation and islet formation; (2) the level of VEGF-A production by islet endocrine cells is critical for islet vascularization during development and postnatally; (3) angiopoietin-Tie2 signaling in endothelial cells does not have a crucial role in the development or maintenance of islet vascularization.     

Effects of the soluble fiber complex PolyGlycopleX® (PGX®) on glycemic control, insulin secretion, and GLP-1 levels in Zucker diabetic rats

AimsThe effects of the novel water soluble, viscous fiber complex PolyGlycopleX® [(α-d-glucurono-α-d-manno-β-d-manno-β-d-gluco), (α-l-gulurono-β-d mannurono), β-d-gluco-β-d-mannan (PGX®)] on body weight, food consumption, glucose, insulin, and glucagon-like peptide (GLP-1) levels were determined in Zucker diabetic rats (ZDFs). Such fibers are thought to improve glycemic control through increased GLP-1 induced insulin secretion.Main methodsZDFs were treated 12 weeks with normal rodent chow supplemented with cellulose (control, inert fiber), inulin or PGX® at 5% wt/wt and effects on body weight, glycemic control, and GLP-1 determined.Key findingsIn the fed state, PGX® reduced blood glucose compared to the other groups from week 5 until study termination while insulin was significantly elevated when measured at week 9, suggesting an insulin secretagogue effect. Fasting blood glucose was similar among groups until 7–8 weeks when levels began to climb with a modest reduction caused by PGX®. An oral glucose tolerance test in fasted animals (week 11) showed no change in insulin sensitivity scores among diets, suggesting an insulinotropic effect for PGX® rather than increased insulin sensitivity. PGX® increased plasma levels of GLP-1, while HbA_1c was markedly reduced by PGX®. Body weights were not changed despite a significant reduction in food consumption induced by PGX® up to week 8 when the PGX®-treated group showed an increase in body weight despite a continued reduction in food consumption.SignificancePGX® improved glycemic control and reduced protein glycation, most likely due to the insulin secretagogue effects of increased GLP-1.     

Molecular physiology of glucagon-like peptide-1 insulin secretagogue action in pancreatic β cells

Insulin secretion from pancreatic β cells is stimulated by glucagon-like peptide-1 (GLP-1), a blood glucose-lowering hormone that is released from enteroendocrine L cells of the distal intestine after the ingestion of a meal. GLP-1 mimetics (e.g., Byetta) and GLP-1 analogs (e.g., Victoza) activate the β cell GLP-1 receptor (GLP-1R), and these compounds stimulate insulin secretion while also lowering levels of blood glucose in patients diagnosed with type 2 diabetes mellitus (T2DM). An additional option for the treatment of T2DM involves the administration of dipeptidyl peptidase-IV (DPP-IV) inhibitors (e.g., Januvia, Galvus). These compounds slow metabolic degradation of intestinally released GLP-1, thereby raising post-prandial levels of circulating GLP-1 substantially. Investigational compounds that stimulate GLP-1 secretion also exist, and in this regard a noteworthy advance is the demonstration that small molecule GPR119 agonists (e.g., AR231453) stimulate L cell GLP-1 secretion while also directly stimulating β cell insulin release. In this review, we summarize what is currently known concerning the signal transduction properties of the β cell GLP-1R as they relate to insulin secretion. Emphasized are the cyclic AMP, protein kinase A, and Epac2-mediated actions of GLP-1 to regulate ATP-sensitive K⁺ channels, voltage-dependent K⁺ channels, TRPM2 cation channels, intracellular Ca²⁺ release channels, and Ca²⁺-dependent exocytosis. We also discuss new evidence that provides a conceptual framework with which to understand why GLP-1R agonists are less likely to induce hypoglycemia when they are administered for the treatment of T2DM.     

PACAP stimulates insulin secretion by PAC1 receptor and ion channels in β-cells

Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) plays a crucial role in the endocrine system. The present study aimed to investigate the effect of PACAP38 on insulin secretion and the underlying mechanism in rat pancreatic β-cells. The insulin secretion results showed that PACAP38 stimulated insulin secretion in a glucose- and dose-dependent manner. The insulinotropic effect was mediated by PAC₁ receptor, but not by VPAC₁ and VPAC₂ receptors. Inhibition of adenylyl cyclase and protein kinase A suppressed PACAP38-augmented insulin secretion. Glucose-regulated insulin secretion is dependent on a series of electrophysiological activities. Current-clamp technology suggested that PACAP38 prolonged action potential duration. Voltage-clamp recordings revealed that PACAP38 blocked voltage-dependent potassium currents, and this effect was reversed by inhibition of PAC₁ receptor, adenylyl cyclase, or protein kinase A. Activation of Ca²⁺ channels by PACAP38 was also observed, which could be antagonized by the PAC₁ receptor antagonist. In addition, calcium-imaging analysis indicated that PACAP38 increased intracellular Ca²⁺ concentration, which was decreased by PAC₁ receptor antagonist. These findings demonstrate that PACAP38 stimulates glucose-induced insulin secretion mainly by acting on PAC₁ receptor, inhibiting voltage-dependent potassium channels, activating Ca²⁺ channels and increasing intracellular Ca²⁺ concentration. Further, PACAP blocks voltage-dependent potassium currents via the adenylyl cyclase/protein kinase A signaling pathway.     

Nuclear SREBP-1a causes loss of pancreatic β-cells and impaired insulin secretion

Transgenic mice expressing nuclear sterol regulatory element-binding protein-1a under the control of the insulin promoter were generated to determine the role of SREBP-1a in pancreatic β-cells. Only low expressors could be established, which exhibited mild hyperglycemia, impaired glucose tolerance, and reduced plasma insulin levels compared to C57BL/6 controls. The islets isolated from the transgenic mice were fewer and smaller, and had decreased insulin content and unaltered glucagon staining. Both glucose- and potassium-stimulated insulin secretions were decreased. The transgenic islets consistently expressed genes for fatty acids and cholesterol synthesis, resulting in accumulation of triglycerides but not cholesterol. PDX-1, ΒΕΤΑ2, MafA, and IRS-2 were suppressed, partially explaining the loss and dysfunction of β-cell mass. The transgenic mice on a high fat/high sucrose diet still exhibited impaired insulin secretion and continuous β-cell growth defect. Therefore, nuclear SREBP-1a, even at a low level, strongly disrupts β-cell mass and function.     

PINK1 deficiency in β-cells increases basal insulin secretion and improves glucose tolerance in mice

The Parkinson''s disease (PD) gene, PARK6, encodes the PTEN-induced putative kinase 1 (PINK1) mitochondrial kinase, which provides protection against oxidative stress-induced apoptosis. Given the link between glucose metabolism, mitochondrial function and insulin secretion in β-cells, and the reported association of PD with type 2 diabetes, we investigated the response of PINK1-deficient β-cells to glucose stimuli to determine whether loss of PINK1 affected their function. We find that loss of PINK1 significantly impairs the ability of mouse pancreatic β-cells (MIN6 cells) and primary intact islets to take up glucose. This was accompanied by higher basal levels of intracellular calcium leading to increased basal levels of insulin secretion under low glucose conditions. Finally, we investigated the effect of PINK1 deficiency in vivo and find that PINK1 knockout mice have improved glucose tolerance. For the first time, these combined results demonstrate that loss of PINK1 function appears to disrupt glucose-sensing leading to enhanced insulin release, which is uncoupled from glucose uptake, and suggest a key role for PINK1 in β-cell function.     

The mTORC2/PKC pathway sustains compensatory insulin secretion of pancreatic β cells in response to metabolic stress

BackgroundCompensation of the pancreatic β cell functional mass in response to metabolic stress is key to the pathogenesis of Type 2 Diabetes. The mTORC2 pathway governs fuel metabolism and β cell functional mass. It is unknown whether mTORC2 is required for regulating metabolic stress-induced β cell compensation.MethodsWe challenged four-week-old β-cell-specific Rictor (a key component of mTORC2)-knockout mice with a high fat diet (HFD) for 4 weeks and measured metabolic and pancreatic morphological parameters. We performed ex vivo experiments to analyse β cell insulin secretion and electrophysiology characteristics. Adenoviral-mediated overexpression and lentiviral-ShRNA-mediated knocking down proteins were applied in Min6 cells and cultured primary mouse islets.ResultsβRicKO mice showed a significant glucose intolerance and a reduced plasma insulin level and an unchanged level β cell mass versus the control mice under HFD. A HFD or palmitate treatment enhanced both glucose-induced insulin secretion (GIIS) and the PMA (phorbol 12-myristate 13-acetate)-induced insulin secretion in the control islets but not in the βRicKO islets. The KO β cells showed similar glucose-induced Ca^2 + influx but lower membrane capacitance increments versus the control cells. The enhanced mTORC2/PKC proteins levels in the control HFD group were ablated by Rictor deletion. Replenishing PKCα by overexpression of PKCα-T638D restored the defective GIIS in βRicKO islets.ConclusionsThe mTORC2/Rictor pathway modulates β cell compensatory GIIS under nutrient overload mediated by its phosphorylation of PKCα.General significanceThis study suggests that the mTORC2/PKC pathway in β cells is involved in the pathogenesis of T2D.     

Postnatal pancreatic islet β cell function and insulin sensitivity at different stages of lifetime in rats born with intrauterine growth retardation

Epidemiological studies have linked intrauterine growth retardation (IUGR) to the metabolic diseases, consisting of insulin resistance, type 2 diabetes, obesity and coronary artery disease, during adult life. To determine the internal relationship between IUGR and islet β cell function and insulin sensitivity, we established the IUGR model by maternal nutrition restriction during mid- to late-gestation. Glucose tolerance test and insulin tolerance test (ITT) in vivo and glucose stimulated insulin secretion (GSIS) test in vitro were performed at different stages in IUGR and normal groups. Body weight, pancreas weight and pancreas/body weight of IUGR rats were much lower than those in normal group before 3 weeks of age. While the growth of IUGR rats accelerated after 3 weeks, pancreas weight and pancreas/body weight remained lower till 15 weeks of age. In the newborns, the fasting glucose and insulin levels of IUGR rats were both lower than those of controls, whereas glucose levels at 120 and 180 min after glucose load were significantly higher in IUGR group. Between 3 and 15 weeks of age, both the fasting glucose and insulin levels were elevated and the glucose tolerance was impaired with time in IUGR rats. At age 15 weeks, the area under curve of insulin (AUCi) after glucose load in IUGR rats elevated markedly. Meanwhile, the stimulating index of islets in IUGR group during GSIS test at age 15 weeks was significantly lower than that of controls. ITT showed no significant difference in two groups before 7 weeks of age. However, in 15-week-old IUGR rats, there was a markedly blunted glycemic response to insulin load compared with normal group. These findings demonstrate that IUGR rats had both impaired pancreatic development and deteriorated glucose tolerance and insulin sensitivity, which would be the internal causes why they were prone to develop type 2 diabetes.     

GLP-1-related proteins attenuate the effects of mitochondrial membrane damage in pancreatic β cells

Glucagon-like peptide (GLP)-1 analog based therapies are used not only for their insulinotropic effects, but also for their pleiotropic effects that improve pancreatic β cell function. Liraglutide is a long acting derivative of human GLP-1(7–37), which is a cleavage product encompassing amino acids 7–37 of GLP-1. In this study, we examined whether Liraglutide treatment restore the glucose-stimulated mitochondrial response of β cells with chemically induced mitochondrial damage. We tested three GLP-1-related proteins: human GLP-1(1–37), GLP-1(7–37) and Liraglutide. To measure changes of the mitochondrial pH quantitatively in real-time, we have developed a bioengineered β cell line. We generated a mitochondrial damaged model by treating β cells with ethidium bromide (EtBr; 0.5 or 1 μg/mL for 48 h). EtBr treatment reduced the response to 25 mM glucose in mitochondrial pH in a dose- and time-dependent manner. GLP-1(7–37) (100 nM) enhanced the response of mitochondria to glucose stimulation in undamaged β cells. Preincubation with Liraglutide (1 nM) or GLP-1 (100 nM) for 3 h recovered the mitochondrial response to glucose in damaged β cells, however, GLP-1(7–37) (100 nM) did not. When GLP-1(7–37) was administered in stepwise increments (i.e., starting with 20 nM to reach 100 nM in 3 h), similar recovery of the mitochondrial function was observed. The results suggest that Liraglutide is effective to recover glucose-stimulated mitochondrial response in damaged β cells.     

Increased secretion of insulin and proliferation of islet β-cells in rats with mesenteric lymph duct ligation

Background &; aimsIt has been suggested that intestinal lymph flow plays an important role in insulin secretion and glucose metabolism after meals. In this study, we investigated the influence of ligation of the mesenteric lymph duct on glucose metabolism and islet β-cells in rats.MethodsMale Sprague–Dawley rats (10 weeks old) were divided into two groups: one underwent ligation of the mesenteric lymph duct above the cistern (ligation group), and the other underwent a sham operation (sham group). After 1 and 2 weeks, fasting plasma concentrations of glucose, insulin, triglyceride, glucose-dependent insulinotropic polypeptide (GIP), and the active form of glucagon-like peptide-1 (GLP-1) were measured. At 2 weeks after the operation, the oral glucose tolerance test (OGTT) and intravenous glucose tolerance test (IVGTT) were performed. After the rats had been sacrificed, the insulin content of the pancreas was measured and the proliferation of β-cells was assessed immunohistochemically using antibodies against insulin and Ki-67.ResultsDuring the OGTT, the ligation group showed a significant decrease in the plasma glucose concentration at 120 min (p < 0.05) and a significant increase in the plasma insulin concentration by more than 2-fold at 15 min (p < 0.01). On the other hand, the plasma GIP concentration was significantly decreased at 60 min (p < 0.01) in the ligated group, while the active form of GLP-1 showed a significantly higher level at 90 min (1.7-fold; p < 0.05) and 120 min (2.5-fold; p < 0.01). During the IVGTT, the plasma insulin concentration in the ligation group was significantly higher at 2 min (more than 1.4-fold; p < 0.05). Immunohistochemistry showed that the ratios of β-cell area/acinar cell area and β-cell area/islet area, and also β-cell proliferation, were significantly higher in the ligation group than in the sham group (p < 0.05, p < 0.01 and p < 0.01, respectively). The insulin content per unit wet weight of pancreas was also significantly increased in the ligation group (p < 0.05).ConclusionsIn rats with ligation of the mesenteric lymph duct, insulin secretion during the OGTT or IVGTT was higher, and the insulin content and β-cell proliferation in the pancreas were also increased. Our data show that mesenteric lymph duct flow has a role in glucose metabolism.