scholarly journals ARHGAP21 Acts as an Inhibitor of the Glucose-Stimulated Insulin Secretion Process

2020 ◽  
Vol 11 ◽  
Author(s):  
Sandra M. Ferreira ◽  
José M. Costa-Júnior ◽  
Mirian A. Kurauti ◽  
Nayara C. Leite ◽  
Fernanda Ortis ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Energy Metabolism ◽  
Cell Interaction ◽  
Tolerance Test ◽  
Functional Maturation ◽  
Secretion Process ◽  
Insulin Tolerance ◽  
Intracellular Calcium Dynamics ◽  
Glucose Stimulated Insulin Secretion ◽  
Adult Islet

ARHGAP21 is a RhoGAP protein implicated in the modulation of insulin secretion and energy metabolism. ARHGAP21 transient-inhibition increase glucose-stimulated insulin secretion (GSIS) in neonatal islets; however, ARHGAP21 heterozygote mice have a reduced insulin secretion. These discrepancies are not totally understood, and it might be related to functional maturation of beta cells and peripheral sensitivity. Here, we investigated the real ARHGAP21 role in the insulin secretion process using an adult mouse model of acute ARHGAP21 inhibition, induced by antisense. After ARHGAP21 knockdown induction by antisense injection in 60-day old male mice, we investigated glucose and insulin tolerance test, glucose-induced insulin secretion, glucose-induced intracellular calcium dynamics, and gene expression. Our results showed that ARHGAP21 acts negatively in the GSIS of adult islet. This effect seems to be due to the modulation of important points of insulin secretion process, such as the energy metabolism (PGC1α), Ca2+ signalization (SYTVII), granule-extrusion (SNAP25), and cell-cell interaction (CX36). Therefore, based on these finds, ARHGAP21 may be an important target in Diabetes Mellitus (DM) treatment.

scholarly journals Tissue-dependent loss of phosphofructokinase-M in mice with interrupted activity of the distal promoter: impairment in insulin secretion

2007 ◽  
Vol 293 (3) ◽  
pp. E794-E801 ◽  
Author(s):  
Ann-Marie T. Richard ◽  
Dominic-Luc Webb ◽  
Jessie M. Goodman ◽  
Vera Schultz ◽  
John N. Flanagan ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Glucose Sensor ◽  
Tolerance Test ◽  
Proximal Promoter ◽  
M Gene ◽  
Glucose Levels ◽  
Insulin Tolerance ◽  
Key Enzyme ◽  
Glucose Stimulated Insulin Secretion ◽  
Distal Promoter

Phosphofructokinase is a key enzyme of glycolysis that exists as homo- and heterotetramers of three subunit isoforms: muscle, liver, and C type. Mice with a disrupting tag inserted near the distal promoter of the phosphofructokinase-M gene showed tissue-dependent differences in loss of that isoform: 99% in brain and 95–98% in islets, but only 50–75% in skeletal muscle and little if any loss in heart. This correlated with the continued presence of proximal transcripts specifically in muscle tissues. These data strongly support the proposed two-promoter system of the gene, with ubiquitous use of the distal promoter and additional use of the proximal promoter selectively in muscle. Interestingly, the mice were glucose intolerant and had somewhat elevated fasting and fed blood glucose levels; however, they did not have an abnormal insulin tolerance test, consistent with the less pronounced loss of phosphofructokinase-M in muscle. Isolated perifused islets showed about 50% decreased glucose-stimulated insulin secretion and reduced amplitude and regularity of secretory oscillations. Oscillations in cytoplasmic free Ca2+ and the rise in the ATP/ADP ratio appeared normal. Secretory oscillations still occurred in the presence of diazoxide and high KCl, indicating an oscillation mechanism not requiring dynamic Ca2+ changes. The results suggest the importance of phosphofructokinase-M for insulin secretion, although glucokinase is the overall rate-limiting glucose sensor. Whether the Ca2+ oscillations and residual insulin oscillations in this mouse model are due to the residual 2–5% phosphofructokinase-M or to other phosphofructokinase isoforms present in islets or involve another metabolic oscillator remains to be determined.

scholarly journals Acid Hydrolyzed Silk Peptide Consumption Improves Anti-Diabetic Symptoms by Potentiating Insulin Secretion and Preventing Gut Microbiome Dysbiosis in Non-Obese Type 2 Diabetic Animals

Nutrients ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 311 ◽  
Author(s):  
Sunmin Park ◽  
Ting Zhang ◽  
Jing Yi Qiu ◽  
Xuangao Wu ◽  
Jeong-Yong Lee ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Insulin Sensitivity ◽  
Glucose Tolerance ◽  
Normal Control ◽  
Positive Control ◽  
Control Group ◽  
Sensitivity Testing ◽  
Insulin Tolerance ◽  
Glucose Stimulated Insulin Secretion

Silk fibroin hydrolysates have been reported to reduce hyperglycemia, but the mechanism has not been determined in Asian type 2 diabetes (T2DM). We hypothesized that the consumption of acid hydrolyzed silk peptides (SPs) alleviates hyperglycemia by improving insulin sensitivity and subsequently normalizing glucose-stimulated insulin secretion in T2DM. We investigated this hypothesis in a partial pancreatectomized (Px) rat model. Px rats was assigned randomly to the following six groups and fed assigned diet for 8 weeks: the Px-control (0.5 g/kg/day dextrin), the SP-L (0.05 g/kg/day), the SP-M (0.1 g/kg/day), the SP-H (0.5 g/kg/day), the positive-control (40 mg/kg/day metformin), or the normal-control (sham-operated rats; 0.5 g/kg/day dextrin). SPs contained high levels of glycine, alanine, and serine. We found SPs dose-dependently increased food efficiency and body weight gain in Px rats. Animals in the Px-control group rats exhibited lower glucose metabolism, as evidenced by impaired glucose-stimulated insulin secretion coupled with impaired insulin sensitivity, and reduced bone mineral density (BMD) and lean body mass (LBM), compared to the normal-control. SPs and metformin similarly partially protected against Px-induced BMD loss in the lumbar spine and femur. Px-induced decreases in LBM were dose-dependently prevented by SPs, and muscle forces in the SP-M and SP-H groups were maintained at the normal-control level. Glucose tolerance was dose-dependently improved by SPs as determined by oral glucose tolerance and oral maltose tolerance tests, and glucose tolerances were similar in the SP-H and positive-control groups. Insulin tolerance, an index of insulin sensitivity, was dose-dependently enhanced by SPs, and the SP-H group exhibited better insulin tolerance than the positive-control group as determined by intraperitoneal insulin sensitivity testing. Insulin secretory capacity assessed using a hyperglycemic clamp improved in the following order: Px-control <SA-L <SA-M <positive-control <SA-H <normal-control. SP-M prevented gut microbiota dysbiosis. In conclusion, SPs administered at 0.1–0.5 g/kg/day improved glucose regulation by potentiating both insulin secretion and insulin sensitivity in non-obese T2DM rats.

scholarly journals Neuroligin-2-derived peptide-covered polyamidoamine-based (PAMAM) dendrimers enhance pancreatic β-cells' proliferation and functions

MedChemComm ◽  
2019 ◽  
Vol 10 (2) ◽  
pp. 280-293
Author(s):  
Anna Munder ◽  
Yoni Moskovitz ◽  
Aviv Meir ◽  
Shirin Kahremany ◽  
Laura Levy ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Cellular Stress ◽  
Pamam Dendrimers ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Cell Functions ◽  
Functional Maturation ◽  
Glucose Stimulated Insulin Secretion

The nanoscale composite improved β-cell functions in terms of rate of proliferation, glucose-stimulated insulin secretion, resistance to cellular stress and functional maturation.

scholarly journals Gastric inhibitory polypeptide is the major insulinotropic factor in K(ATP) null mice

2004 ◽  
pp. 407-412 ◽  
Author(s):  
K Tsukiyama ◽  
Y Yamada ◽  
K Miyawaki ◽  
A Hamasaki ◽  
K Nagashima ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Knockout Mice ◽  
Insulin Response ◽  
Gastric Inhibitory Polypeptide ◽  
Tolerance Test ◽  
Insulin Tolerance Test ◽  
Oral Glucose ◽  
Double Knockout ◽  
Insulin Tolerance ◽  
Deficient Mice

OBJECTIVE: ATP-sensitive K(+) (K(ATP)) channels in pancreatic beta-cells are crucial in the regulation of glucose-induced insulin secretion. Recently, K(ATP) channel-deficient mice were generated by genetic disruption of Kir6.2, the pore-forming component of K(ATP) channels, but the mice still showed a significant insulin response after oral glucose loading in vivo. Gastric inhibitory polypeptide (GIP) is a physiological incretin that stimulates insulin release upon ingestion of nutrients. To determine if GIP is the insulinotropic factor in insulin secretion in K(ATP) channel-deficient mice, we generated double-knockout Kir6.2 and GIP receptor null mice and compared them with Kir6.2 knockout mice. METHODS: Double-knockout mice were generated by intercrossing Kir6.2-knockout mice with GIP receptor-knockout mice. An oral glucose tolerance test, insulin tolerance test and batch incubation study of pancreatic islets were performed on double-knockout mice and Kir6.2-knockout mice. RESULTS: Fasting glucose and insulin levels were similar in both groups. After oral glucose loading, blood glucose levels of double-knockout mice became elevated compared with Kir6.2-knockout mice, especially at 15 min (345+/-10 mg/dl vs 294+/-20 mg/dl, P<0.05) and 30 min (453+/-20 mg/dl vs 381+/-26 mg/dl, P<0.05). The insulin response was almost completely lost in double-knockout mice, although insulin secretion from isolated islets was stimulated by another incretin, glucagon-like peptide-1 in the double-knockout mice. Double-knockout mice and Kir6.2-knockout mice were similarly insulin sensitive as assessed by the insulin tolerance test. CONCLUSION: GIP is the major insulinotropic factor in the secretion of insulin in response to glucose load in K(ATP) channel-deficient mice.

scholarly journals Increased Energy Expenditure and Energy Loss through Feces Contribute to the Long-term Outcome of Roux-en-Y Gastric Bypass on Diet Induced Obese Mouse Model

2020 ◽  
Author(s):  
Kai Chen ◽  
Boen Xiao ◽  
Zhe Zhou ◽  
Weihui Peng ◽  
wei liu
Keyword(s):  
Body Weight ◽  
Energy Metabolism ◽  
Energy Expenditure ◽  
High Fat Diet ◽  
Sham Group ◽  
Tolerance Test ◽  
Term Outcome ◽  
Long Term Outcome ◽  
Insulin Tolerance

Abstract Background Roux-en-Y gastric bypass (RYGB) has been proved to be more effective than other bariatric procedures in long-term on body weight loss and remission of diabetes. However, the mechanism remains poorly understood. Long-term change of energy metabolism after RYGB has rarely been reported. Objectives To investigate the long-term outcome of RYGB on mouse model and its mechanism from the perspective of energy metabolism. Methods High-fat diet induced obesity (DIO) mice were assigned to two groups receiving RYGB(n=8) and sham operation(n=7), followed by high-fat diet feeding until 12 weeks after surgery. Body weight and food intake were recorded weekly, measurement of body composition and energy metabolism by metabolic chamber were conducted on week 4, 8 and 12 after surgery. Fecal energy measurement, Intraperitoneal Glucose Tolerance Test (IPGTT) and Insulin Tolerance Test (ITT) were conducted on week 12 after surgery.Results Food intake was reduced in RYGB group within the first 3 weeks after surgery and increased to be the same withSham group from postoperative week 4. At 12 weeks after surgery, body weight reduced by 36±3.2% in RYGB group comparing to 16±2% body weight gain in Sham group, while fat mass was significantly reduced in RYGB group than in Sham group (9.2±1.5% versus 30.1±0.7%). Energy expenditure was significantly higher on postoperative week 8 in RYGB group than in Sham group. In comparison with Sham group, respiratory exchange ratio (RER) was unchanged, decreased and increased in RYGB group at postoperative week 4, 8 and 12, respectively. Fecal energy measurementshowed that feces from mice in RYGB group contained higher energy level than Sham group. Glucose metabolism was significantly improved in RYGB group in contrast to Sham group, demonstrated by the result of Intraperitoneal Glucose Tolerance Test (IPGTT) (AUC: 1502± 104 versus 2277±198, respectively) and the Insulin Tolerance Test (ITT) (AUC: 524 ±50 versus 838±63, respectively). Conclusions Increased energy expenditure and energy loss through feces contribute to the long-term body weight control after RYGB. Enhanced glucose utilization might play a role in the long-term improvement of glucose metabolism.

scholarly journals The Mitochondrial Citrate Carrier (CIC) Is Present and Regulates Insulin Secretion by Human Male Gamete

Endocrinology ◽  
2012 ◽  
Vol 153 (4) ◽  
pp. 1743-1754 ◽  
Author(s):  
Anna R. Cappello ◽  
Carmela Guido ◽  
Antonella Santoro ◽  
Marta Santoro ◽  
Loredana Capobianco ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Energy Metabolism ◽  
Acrosome Reaction ◽  
Male Gamete ◽  
Human Sperm ◽  
Morphological Evidence ◽  
Specific Substrate ◽  
Similar Action ◽  
Citrate Carrier ◽  
Glucose Stimulated Insulin Secretion

The mechanisms through which sperm manage their energy metabolism are poorly understood. The present study provides biochemical and morphological evidence that mitochondrial citrate carrier (CIC) is present in ejaculated human sperm and is restricted to the midpiece. The inhibition of CIC with the specific substrate analog 1,2,3-benzenetricarboxylate resulted in the reduction of cholesterol efflux, protein tyrosine phosphorylation, phospho-AKT, phospho-p60src, hyperactivated motility and acrosome reaction, suggesting a role for this mitochondrial carrier in sperm physiology. Furthermore, inhibition of CIC by 1,2,3-benzenetricarboxylate resulted in a reduction of glucose-stimulated insulin secretion and autocrine insulin secretion by sperm. Remarkably, blocking CIC also reduced glucose-6-phosphate dehydrogenase activity, probably in accordance with its regulation on insulin secretion. Capacitation and glucose metabolism were stimulated by glucose as well as citrate, the specific substrate of CIC, implying a similar action because glucose and citrate both induced insulin secretion by sperm. In the present finding, we discovered a new site of action for CIC in the regulation of metabolism, and it may be assumed that CIC works with other factors in the regulation of sperm energy metabolism to sustain capacitation process and acrosome reaction.

scholarly journals RIPK2 Dictates Insulin Responses to Tyrosine Kinase Inhibitors in Obese Male Mice

Endocrinology ◽  
2020 ◽  
Vol 161 (8) ◽  
Author(s):  
Brittany M Duggan ◽  
Joseph F Cavallari ◽  
Kevin P Foley ◽  
Nicole G Barra ◽  
Jonathan D Schertzer
Keyword(s):  
Insulin Secretion ◽  
Blood Glucose ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Blood Glucose Control ◽  
Tolerance Test ◽  
Independent Manner ◽  
Glucose Stimulated Insulin Secretion ◽  
Insulin Responses

Abstract Tyrosine kinase inhibitors (TKIs) used in cancer are also being investigated in diabetes. TKIs can improve blood glucose control in diabetic cancer patients, but the specific kinases that alter blood glucose or insulin are not clear. We sought to define the role of Receptor Interacting Serine/Threonine Kinase 2 (RIPK2) in mouse models of insulin resistance. We tested the TKI gefitinib, which inhibits RIPK2 activity, in wild-type (WT), Nod1–/–, Nod2–/–, and Ripk2–/– mice fed an obesogenic high-fat diet. Gefitinib lowered blood glucose during a glucose tolerance test (GTT) in a nucleotide-binding oligomerization domain (NOD)–RIPK2-independent manner in all obese mice. However, gefitinib lowered glucose-stimulated insulin secretion only in obese Ripk2–/– mice. Gefitinib had no effect on insulin secretion in obese WT, Nod1–/–, or Nod2–/– mice. Hence, genetic deletion of Ripk2 promoted the insulin-sensitizing potential of gefitinib, since this TKI lowered both blood glucose and insulin only in Ripk2–/– mice. Gefitinib did not alter the inflammatory profile of pancreas, adipose, liver, or muscle tissues in obese Ripk2–/– mice compared with obese WT mice. We also tested imatinib, a TKI that does not inhibit RIPK2 activity, in obese WT mice. Imatinib lowered blood glucose during a GTT, consistent with TKIs lowering blood glucose independently of RIPK2. However, imatinib increased glucose-stimulated insulin secretion during the glucose challenge. These data show that multiple TKIs lower blood glucose, where actions of TKIs on RIPK2 dictate divergent insulin responses, independent of tissue inflammation. Our data show that RIPK2 limits the insulin sensitizing effect of gefitinib, whereas imatinib increased insulin secretion.

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