The VGF-derived peptide TLQP-62 modulates insulin secretion and glucose homeostasis

Insulin secretion control is critical for glucose homeostasis. Paracrine and autocrine molecules secreted by cells of the islet of Langerhans, as well as by intramural and autonomic neurons, control the release of different hormones that modulate insulin secretion. In pancreatic islets, the abundant presence of the granin protein VGF (nonacronymic; unrelated to VEGF) suggests that some of its proteolytically derived peptides could modulate hormone release. Thus, in the present study, we screened several VGF-derived peptides for their ability to induce insulin secretion, and we identified the VGF C-terminal peptide TLQP-62 as the most effective fragment. TLQP-62 induced a potent increase in basal insulin secretion as well as in glucose-stimulated insulin secretion in several insulinoma cell lines. We found that this peptide stimulated insulin release via increased intracellular calcium mobilization and fast expression of the insulin 1 gene. Moreover, the peripheral injection of TLQP-62 in mice improved glucose tolerance. Together, the present findings suggest that TLQP-62, acting as an endocrine, paracrine, or autocrine factor, can be considered a new, strong insulinotropic peptide that can be targeted for innovative antidiabetic drug discovery programs.

Download Full-text

Limited role for SREBP-1c in defective glucose-induced insulin secretion from Zucker diabetic fatty rat islets: a functional and gene profiling analysis

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00067.2006 ◽

2006 ◽

Vol 291 (5) ◽

pp. E982-E994 ◽

Cited By ~ 37

Author(s):

Laura E. Parton ◽

Patrick J. McMillen ◽

Yingnian Shen ◽

Elizabeth Docherty ◽

Erin Sharpe ◽

...

Keyword(s):

Insulin Secretion ◽

Basal Insulin ◽

Regulatory Element ◽

Dominant Negative ◽

Gene Profiling ◽

Rat Islets ◽

Zdf Rat ◽

Element Binding Protein ◽

Basal Insulin Secretion ◽

Glucose Stimulated Insulin Secretion

Accumulation of intracellular lipid may contribute to defective insulin secretion in type 2 diabetes. Although Zucker diabetic fatty (ZDF; fa/fa) rat islets are fat-laden and overexpress the lipogenic master gene, sterol regulatory element binding protein 1c (SREBP-1c), the contribution of SREBP-1c to the secretory defects observed in this model remains unclear. Here we compare the gene expression profile of lean control ( fa/+) and ZDF rat islets in the absence or presence of dominant-negative SREBP-1c (SREBP-1c DN). ZDF islets displayed elevated basal insulin secretion at 3 mmol/l glucose but a severely depressed response to 17 mmol/l glucose. While SREBP-1c DN reduced basal insulin secretion from ZDF islets, glucose-stimulated insulin secretion was not improved. Of 57 genes differentially regulated in ZDF islets and implicated in glucose metabolism, vesicle trafficking, ion fluxes, and/or exocytosis, 21 were upregulated and 5 were suppressed by SREBP-1c DN. Genes underrepresented in ZDF islets were either unaffected ( Glut-2, Kir6.2, Rab3), stimulated (voltage-dependent Ca2+ channel subunit α1D, CPT2, SUR2, rab9, syt13), or inhibited ( syntaxin 7, secretogranin-2) by SREBP-1c inhibition. Correspondingly, SREBP-1c DN largely corrected decreases in the expression of the transcription factors Pdx-1 and MafA but did not affect the abnormalities in Pax6, Arx, hepatic nuclear factor-1α (HNF1α), HNF3β/Forkhead box-a2 (Foxa2), inducible cyclic AMP early repressor (ICER), or transcription factor 7-like 2 (TCF7L2) expression observed in ZDF islets. We conclude that upregulation of SREBP-1c and mild increases in triglyceride content do not explain defective glucose-stimulated insulin secretion from ZDF rats. However, overexpression of SREBP-1c may contribute to enhanced basal insulin secretion in this model.

Download Full-text

Glucose regulates microtubule disassembly and the dose of insulin secretion via tau phosphorylation

10.2337/figshare.12448715.v1 ◽

2020 ◽

Author(s):

Ada Admin ◽

Kung-Hsien Ho ◽

Xiaodun Yang ◽

Anna B. Osipovich ◽

Over Cabrera ◽

...

Keyword(s):

Insulin Secretion ◽

High Glucose ◽

Tau Phosphorylation ◽

Β Cells ◽

Glucose Stimulation ◽

Microtubule Network ◽

Mouse Islet ◽

Protein Tau ◽

Basal Insulin Secretion ◽

Glucose Stimulated Insulin Secretion

The microtubule cytoskeleton of pancreatic islet β-cells regulates glucose-stimulated insulin secretion (GSIS). We have reported that the microtubule-mediated movement of insulin vesicles away from the plasma membrane limits insulin secretion. High glucose-induced remodeling of microtubule network facilitates robust GSIS. This remodeling involves disassembly of old microtubules and nucleation of new microtubules. Here, we examine the mechanisms whereby glucose stimulation decreases microtubule lifetimes in β-cells. Using real-time imaging of photoconverted microtubules, we demonstrate that high levels of glucose induce rapid microtubule disassembly preferentially in the periphery of individual β-cells, and this process is mediated by the phosphorylation of microtubule-associated protein tau. Specifically, high glucose induces tau hyper-phosphorylation via glucose-responsive kinases GSK3, PKA, PKC, and CDK5. This causes dissociation of tau from and subsequent destabilization of microtubules. Consequently, tau-knockdown in mouse islet β-cells facilitates microtubule turnover, causing increased basal insulin secretion, depleting insulin vesicles from the cytoplasm, and impairing GSIS. More importantly, tau-knockdown uncouples microtubule destabilization from glucose stimulation. These findings suggest that tau suppresses peripheral microtubules turning-over to restrict insulin over-secretion at basal conditions and preserve the insulin pool that can be released in following stimulation; high glucose promotes tau phosphorylation to enhance microtubule disassembly to acutely enhance GSIS.

Download Full-text

ROCK1 regulates insulin secretion from β-cells

10.1101/2021.06.25.449947 ◽

2021 ◽

Author(s):

Byung-Jun Sung ◽

Sung-Bin Lim ◽

Jae Hyeon Kim ◽

Won-Mo Yang ◽

Rohit N Kulkarni ◽

...

Keyword(s):

Insulin Secretion ◽

Pyruvate Kinase ◽

Glucose Homeostasis ◽

Isolated Islets ◽

Whole Body ◽

Proximity Ligation Assay ◽

Β Cells ◽

Β Cell ◽

Pancreatic Β Cells ◽

Glucose Stimulated Insulin Secretion

Objective: The endocrine pancreatic β-cells play a pivotal role in the maintenance of whole-body glucose homeostasis and its dysregulation is a consistent feature in all forms of diabetes. However, knowledge of intracellular regulators that modulate b-cell function remains incomplete. We investigated the physiological role of ROCK1 in the regulation of insulin secretion and glucose homeostasis. Methods: Mice lacking ROCK1 in pancreatic β-cells (RIP-Cre; ROCK1loxP/loxP, β-ROCK1-/-) were studied. Glucose and insulin tolerance tests as well as glucose-stimulated insulin secretion (GSIS) were measured. Insulin secretion response to a direct glucose or pyruvate or pyruvate kinase (PK) activator stimulation in isolated islets from β-ROCK1-/- mice or β-cell lines with knockdown of ROCK1 were also evaluated. Proximity ligation assay was performed to determine the physical interactions between PK and ROCK1. Results: Mice with a deficiency of ROCK1 in pancreatic β-cells exhibited significantly increased blood glucose levels and reduced serum insulin without changes in body weight. Interestingly, β-ROCK1-/- mice displayed progressive impairment of glucose tolerance while maintaining insulin sensitivity mostly due to impaired GSIS. Consistently, GSIS was markedly decreased in ROCK1-deficient islets and ROCK1 knockdown INS-1 cells. Concurrently, ROCK1 blockade led to a significant decrease in intracellular calcium levels, ATP levels, and oxygen consumption rates in isolated islets and INS-1 cells. Treatment of ROCK1-deficient islets or ROCK1 knockdown β-cells either with pyruvate or a PK activator rescued the impaired GSIS. Mechanistically, we observed that ROCK1 binding to PK is greatly enhanced by glucose stimulation in β-cells. Conclusions: Our findings demonstrate that β-cell ROCK1 is essential for glucose-stimulated insulin secretion and maintenance of glucose homeostasis and that ROCK1 acts as an upstream regulator of glycolytic pyruvate kinase signaling.

Download Full-text

The Drosophila HNF4 nuclear receptor promotes glucose-stimulated insulin secretion and mitochondrial function in adults

eLife ◽

10.7554/elife.11183 ◽

2016 ◽

Vol 5 ◽

Cited By ~ 38

Author(s):

William E Barry ◽

Carl S Thummel

Keyword(s):

Insulin Secretion ◽

Nuclear Receptor ◽

Transition To Adulthood ◽

Glucose Homeostasis ◽

Mitochondrial Function ◽

Fat Body ◽

Insulin Producing Cells ◽

Glucose Stimulated Insulin Secretion ◽

Developmental Reprogramming ◽

Developmental Switch

Although mutations in HNF4A were identified as the cause of Maturity Onset Diabetes of the Young 1 (MODY1) two decades ago, the mechanisms by which this nuclear receptor regulates glucose homeostasis remain unclear. Here we report that loss of Drosophila HNF4 recapitulates hallmark symptoms of MODY1, including adult-onset hyperglycemia, glucose intolerance and impaired glucose-stimulated insulin secretion (GSIS). These defects are linked to a role for dHNF4 in promoting mitochondrial function as well as the expression of Hex-C, a homolog of the MODY2 gene Glucokinase. dHNF4 is required in the fat body and insulin-producing cells to maintain glucose homeostasis by supporting a developmental switch toward oxidative phosphorylation and GSIS at the transition to adulthood. These findings establish an animal model for MODY1 and define a developmental reprogramming of metabolism to support the energetic needs of the mature animal.

Download Full-text

Spontaneous restoration of functional β-cell mass in obese SM/J mice

10.1101/2020.05.19.104588 ◽

2020 ◽

Author(s):

Mario A Miranda ◽

Caryn Carson ◽

Celine L St Pierre ◽

Juan F Macias-Velasco ◽

Jing W Hughes ◽

...

Keyword(s):

Insulin Secretion ◽

Mitotic Index ◽

Cell Function ◽

Cell Mass ◽

Β Cell ◽

Physiological Mechanisms ◽

Β Cell Function ◽

Basal Insulin Secretion ◽

Glucose Stimulated Insulin Secretion ◽

Mass Expansion

AbstractMaintenance of functional β-cell mass is critical to preventing diabetes, but the physiological mechanisms that cause β-cell populations to thrive or fail in the context of obesity are unknown. High fat-fed SM/J mice spontaneously transition from hyperglycemic-obese to normoglycemic-obese with age, providing a unique opportunity to study β-cell adaptation. Here, we characterize insulin homeostasis, islet morphology, and β-cell function during SM/J’s diabetic remission. As they resolve hyperglycemia, obese SM/J mice dramatically increase circulating and pancreatic insulin levels while improving insulin sensitivity. Immunostaining of pancreatic sections reveals that obese SM/J mice selectively increase β-cell mass but not α-cell mass. Obese SM/J mice do not show elevated β-cell mitotic index, but rather elevated α-cell mitotic index. Functional assessment of isolated islets reveals that obese SM/J mice increase glucose stimulated insulin secretion, decrease basal insulin secretion, and increase islet insulin content. These results establish that β-cell mass expansion and improved β-cell function underlie the resolution of hyperglycemia, indicating that obese SM/J mice are a valuable tool for exploring how functional β-cell mass can be recovered in the context of obesity.

Download Full-text

Insulin Secretion Is Increased in Pancreatic Islets of Neuropeptide Y-Deficient Mice

Endocrinology ◽

10.1210/en.2007-0404 ◽

2007 ◽

Vol 148 (12) ◽

pp. 5716-5723 ◽

Cited By ~ 44

Author(s):

Yumi Imai ◽

Hiral R. Patel ◽

Evan J. Hawkins ◽

Nicolai M. Doliba ◽

Franz M. Matschinsky ◽

...

Keyword(s):

Insulin Secretion ◽

Neuropeptide Y ◽

Pancreatic Islets ◽

High Fat Diet ◽

Basal Insulin ◽

High Fat ◽

Y1 Receptor ◽

Basal Insulin Secretion ◽

Glucose Stimulated Insulin Secretion ◽

Deficient Mice

Neuropeptide Y (NPY), whose role in appetite regulation is well known, is also expressed in pancreatic islets. Although previous studies indicated that application of NPY to pancreatic islets inhibits insulin secretion, its physiological role in the regulation of insulin secretion is not fully understood. We hypothesized that NPY in islets tonically suppresses insulin secretion and the reduction of islet NPY increases insulin secretion. To address the hypothesis, islet function of NPY-deficient mice was analyzed. Although there was little change in glucose homeostasis in vivo, pancreatic islets from NPY-deficient mice had higher basal insulin secretion (1.5 times), glucose-stimulated insulin secretion (1.5 times), and islet mass (1.7 times), compared with wild-type mouse. Next we sought to determine whether the expression of NPY and Y1 receptor in islets was altered in hyperinsulinemia associated with obesity. Islets from C57BL/6J mice on a high-fat diet had 1.9 times higher basal insulin secretion and 2.4 times higher glucose-stimulated insulin secretion than control mice, indicating islet adaptation to obesity. Expression of NPY and Y1 receptor mRNA levels was decreased by 70 and 64%, respectively, in high-fat diet islets, compared with controls. NPY and Y1 receptor in islets were also reduced by 91 and 80%, respectively, in leptin-deficient ob/ob mice that showed marked hyperinsulinemia. Together these results suggest that endogenous NPY tonically inhibits insulin secretion from islets and a reduction of islet NPY may serve as one of the mechanisms to increase insulin secretion when islets compensate for insulin resistance associated with obesity.

Download Full-text

Regulation of Insulin Secretion From Novel Engineered Insulinoma Cell Lines

Diabetes ◽

10.2337/diab.46.6.968 ◽

1997 ◽

Vol 46 (6) ◽

pp. 968-977 ◽

Cited By ~ 35

Author(s):

H. E. Hohmeier ◽

H. BeltrandelRio ◽

S. A. Clark ◽

R. Henkel-Rieger ◽

K. Normington ◽

...

Keyword(s):

Insulin Secretion ◽

Cell Lines ◽

Insulinoma Cell ◽

Insulinoma Cell Lines

Download Full-text

Mitochondrial Efflux of Citrate and Isocitrate is Fully Dispensable for Glucose-Stimulated Insulin Secretion and Pancreatic Islet β-Cell Function

10.2337/figshare.14666160.v1 ◽

2021 ◽

Author(s):

Casey J. Bauchle ◽

Kristen E. Rohli ◽

Cierra K. Boyer ◽

Vidhant Pal ◽

Jonathan V. Rocheleau ◽

...

Keyword(s):

Insulin Secretion ◽

Pancreatic Islet ◽

Glucose Homeostasis ◽

Cell Function ◽

Normal Glucose Tolerance ◽

Coupling Factor ◽

Β Cell ◽

Metabolic Coupling ◽

Β Cell Function ◽

Glucose Stimulated Insulin Secretion

The defining feature of pancreatic islet β-cell function is the precise coordination of changes in blood glucose levels with insulin secretion to regulate systemic glucose homeostasis. While ATP has long been heralded as a critical metabolic coupling factor to trigger insulin release, glucose-derived metabolites have been suggested to further amplify fuel-stimulated insulin secretion. The mitochondrial export of citrate and isocitrate through the citrate-isocitrate carrier (CIC) has been suggested to initiate a key pathway that amplifies glucose-stimulated insulin secretion, though the physiological significance of β-cell CIC to glucose homeostasis has not been established. Here, we generated constitutive and adult CIC β-cell knockout mice and demonstrate these animals have normal glucose tolerance, similar responses to diet-induced obesity, and identical insulin secretion responses to various fuel secretagogues. Glucose-stimulated NADPH production was impaired in β-cell CIC KO islets, whereas glutathione reduction was retained. Furthermore, suppression of the downstream enzyme, cytosolic isocitrate dehydrogenase, Idh1, inhibited insulin secretion in wild type islets, but failed to impact β-cell function in β-cell CIC KO islets. Our data demonstrate that the mitochondrial citrate-isocitrate carrier is not required for glucose-stimulated insulin secretion, and that additional complexities exist for the role of Idh1 and NADPH in the regulation of β-cell function.

Download Full-text

GIP and GLP-1 Potentiate Sulfonylurea-Induced Insulin Secretion in Hepatocyte Nuclear Factor 1-Alpha Mutation Carriers

10.2337/figshare.12410447 ◽

2020 ◽

Author(s):

Ada Admin ◽

Alexander S. Christensen ◽

Sofie Hædersdal ◽

Heidi Storgaard ◽

Kathrine Rose ◽

...

Keyword(s):

Insulin Secretion ◽

Glucagon Secretion ◽

Nuclear Factor ◽

Hepatocyte Nuclear Factor ◽

Mutation Carriers ◽

Glucagon Like Peptide 1 ◽

Glucose Stimulated Insulin Secretion ◽

Nuclear Factor 1 ◽

Double Blinded ◽

Insulinotropic Peptide

Sulfonylureas (SUs) provide an efficacious first-line treatment in patients with hepatocyte nuclear factor 1-alpha (HNF1A)-diabetes, but SUs have limitations due to risk of hypoglycemia. Treatment based on the incretin hormones, glucose-dependent insulinotropic peptide (GIP) and glucagon-like-peptide 1 (GLP-1), are characterized by their glucose-dependent insulinotropic actions without risk of hypoglycemia. The effect of SUs together with GIP or GLP-1, respectively, on insulin and glucagon secretion in patients with HNF1A-diabetes is currently unknown. To investigate this, ten HNF1A mutation carriers and ten non-diabetic controls were recruited for a double-blinded, placebo-controlled, crossover study including six experimental days in a randomized order involving 2h euglycemic-hyperglycemic clamps with co-administration of 1) SU (glimepiride 1 mg) or placebo, combined with 2) infusions of either GIP (1.5 pmol/kg/min), GLP-1 (0.5 pmol/kg/min) or saline (NaCl). In HNF1A mutation carriers we observed: 1) hypoinsulinemia, 2) insulinotropic effects of both GIP and GLP-1, 3) <a>additive to supra-additive effects on insulin secretion when combining SU+GIP and SU+GLP1, respectively, </a>and 4) increased fasting and arginine-induced glucagon levels compared to non-diabetic controls. Our study suggests that a combination of SU and incretin-based treatment may be efficacious in patients with HNF1A-diabetes via potentiation of glucose-stimulated insulin secretion.

Download Full-text