scholarly journals Impaired glucose homeostasis in Shb−/− mice

2009 ◽  
Vol 203 (2) ◽  
pp. 271-279 ◽  
Author(s):  
Björn Åkerblom ◽  
Sebastian Barg ◽  
Gabriela Calounova ◽  
Dariush Mokhtari ◽  
Leif Jansson ◽  
...  
Keyword(s):  
Gene Expression ◽  
Insulin Secretion ◽  
Blood Glucose ◽  
Endothelial Cell ◽  
Glucose Homeostasis ◽  
Glucose Concentration ◽  
Cell Function ◽  
Blood Glucose Concentration ◽  
Β Cell ◽  
Islet Volume

Src homology 2 domain-containing protein B (SHB) is an adapter protein involved in the regulation of β-cell and endothelial cell function. We have recently obtained the Shb knockout mouse, and consequently, the aim of this study was to assess the effect of Shb deletion upon β-cell function and blood glucose homeostasis. Shb−/− mice display an elevated basal blood glucose concentration, and this increase is maintained during insulin challenge in insulin sensitivity tests. To assess glucose-induced insulin secretion, pancreata were perfused, and it was observed that Shb−/− first phase insulin secretion was blunted during glucose stimulation. Gene expression of Shb−/− islets shortly after isolation was altered, with increased pancreatic and duodenal homeobox gene-1 (Pdx1) gene expression and reduced expression of Vegf-A. Islet culture normalized Pdx1 gene expression. The microvascular density of the Shb−/− islets was reduced, and islet capillary endothelial cell morphology was changed suggesting an altered microvascular function as a contributing cause to the impaired secretory activity. Capacitance measurements of depolarization-induced exocytosis indicate a direct effect on the exocytotic machinery, in particular a dramatic reduction in readily releasable granules, as responsible for the insulin-secretory defect operating in Shb−/− islets. Shb−/− mice exhibited no alteration of islet volume or β-cell area. In conclusion, loss of Shb impairs insulin secretion, alters islet microvascular morphology, and increases the basal blood glucose concentration. The impaired insulin secretory response is a plausible underlying cause of the metabolic impairment observed in this mutant mouse.

Impact of lack of suppression of glucagon on glucose tolerance in humans

1999 ◽  
Vol 277 (2) ◽  
pp. E283-E290 ◽  
Author(s):  
Pankaj Shah ◽  
Ananda Basu ◽  
Rita Basu ◽  
Robert Rizza
Keyword(s):  
Insulin Secretion ◽  
Glucose Concentration ◽  
Cell Function ◽  
Hormone Secretion ◽  
Glucose Production ◽  
Glucagon Secretion ◽  
Β Cell ◽  
Β Cell Function ◽  
Glucagon Suppression

People with type 2 diabetes have defects in both α- and β-cell function. To determine whether lack of suppression of glucagon causes hyperglycemia when insulin secretion is impaired but not when insulin secretion is intact, twenty nondiabetic subjects were studied on two occasions. On both occasions, a “prandial” glucose infusion was given over 5 h while endogenous hormone secretion was inhibited. Insulin was infused so as to mimic either a nondiabetic ( n = 10) or diabetic ( n = 10) postprandial profile. Glucagon was infused at a rate of 1.25 ng ⋅ kg−1 ⋅ min−1, beginning either at time zero to prevent a fall in glucagon (nonsuppressed study day) or at 2 h to create a transient fall in glucagon (suppressed study day). During the “diabetic” insulin profile, lack of glucagon suppression resulted in a marked increase ( P < 0.002) in both the peak glucose concentration (11.9 ± 0.4 vs. 8.9 ± 0.4 mmol/l) and the area above basal of glucose (927 ± 77 vs. 546 ± 112 mmol ⋅ l−1 ⋅ 6 h) because of impaired ( P < 0.001) suppression of glucose production. In contrast, during the “nondiabetic” insulin profile, lack of suppression of glucagon resulted in only a slight increase ( P< 0.02) in the peak glucose concentration (9.1 ± 0.4 vs. 8.4 ± 0.3 mmol/l) and the area above basal of glucose (654 ± 146 vs. 488 ± 118 mmol ⋅ l−1 ⋅ 6 h). Of interest, when glucagon was suppressed, glucose concentrations differed only minimally during the nondiabetic and diabetic insulin profiles. These data indicate that lack of suppression of glucagon can cause substantial hyperglycemia when insulin availability is limited, therefore implying that inhibitors of glucagon secretion and/or glucagon action are likely to be useful therapeutic agents in such individuals.

scholarly journals Inactivation of the dual Bmp/Wnt inhibitor Sostdc1 enhances pancreatic islet function

2012 ◽  
Vol 303 (6) ◽  
pp. E752-E761 ◽  
Author(s):  
Kathryn D. Henley ◽  
Kimberly A. Gooding ◽  
Aris N. Economides ◽  
Maureen Gannon
Keyword(s):  
Insulin Secretion ◽  
Glucose Homeostasis ◽  
High Fat Diet ◽  
Cell Function ◽  
Metabolic Stress ◽  
Islet Function ◽  
High Fat ◽  
Β Cell ◽  
Β Cell Function ◽  
Bmp Pathway

Current endeavors in the type 2 diabetes (T2D) field include gaining a better understanding of extracellular signaling pathways that regulate pancreatic islet function. Recent data suggest that both Bmp and Wnt pathways are operative in pancreatic islets and play a positive role in insulin secretion and glucose homeostasis. Our laboratory found the dual Bmp and Wnt antagonist Sostdc1 to be upregulated in a mouse model of islet dysmorphogenesis and nonimmune-mediated lean diabetes. Because Bmp signaling has been proposed to enhance β-cell function, we evaluated the role of Sostdc1 in adult islet function using animals in which Sostdc1 was globally deleted. While Sostdc1-null animals exhibited no pancreas development phenotype, a subset of mutants exhibited enhanced insulin secretion and improved glucose homeostasis compared with control animals after 12-wk exposure to high-fat diet. Loss of Sostdc1 in the setting of metabolic stress results in altered expression of Bmp-responsive genes in islets but did not affect expression of Wnt target genes, suggesting that Sostdc1 primarily regulates the Bmp pathway in the murine pancreas. Furthermore, our data indicate that removal of Sostdc1 enhances the downregulation of the closely related Bmp inhibitors Ctgf and Gremlin in islets after 8-wk exposure to high-fat diet. These data imply that Sostdc1 regulates expression of these inhibitors and provide a means by which Sostdc1-null animals show enhanced insulin secretion and glucose homeostasis. Our studies provide insights into Bmp pathway regulation in the endocrine pancreas and reveal new avenues for improving β-cell function under metabolic stress.

scholarly journals Glucocorticoid-Induced Preterm Birth and Neonatal Hyperglycemia Alter Ovine β-Cell Development

Endocrinology ◽  
2015 ◽  
Vol 156 (10) ◽  
pp. 3763-3776 ◽  
Author(s):  
Amita Bansal ◽  
Frank H. Bloomfield ◽  
Kristin L. Connor ◽  
Mike Dragunow ◽  
Eric B. Thorstensen ◽  
...  
Keyword(s):  
Blood Glucose ◽  
Preterm Birth ◽  
Glucose Tolerance ◽  
Impaired Glucose Tolerance ◽  
Glucose Concentration ◽  
Blood Glucose Concentration ◽  
Cell Mass ◽  
Β Cell ◽  
High Blood Glucose ◽  
Increased Risk

Adults born preterm are at increased risk of impaired glucose tolerance and diabetes. Late gestation fetuses exposed to high blood glucose concentration also are at increased risk of impaired glucose tolerance as adults. Preterm babies commonly become hyperglycemic and are thus exposed to high blood glucose concentration at an equivalent stage of pancreatic maturation. It is not known whether preterm birth itself, or complications of prematurity, such as hyperglycemia, alter later pancreatic function. To distinguish these, we made singleton preterm lambs hyperglycemic (HYPER) for 12 days after birth with a dextrose infusion and compared them with vehicle-treated preterm and term controls and with HYPER lambs made normoglycemic with an insulin infusion. Preterm birth reduced β-cell mass, apparent by 4 weeks after term and persisting to adulthood (12 mo), and was associated with reduced insulin secretion at 4 months (juvenile) and reduced insulin mRNA expression in adulthood. Hyperglycemia in preterm lambs further down-regulated key pancreatic gene expression in adulthood. These findings indicate that reduced β-cell mass after preterm birth may be an important factor in increased risk of diabetes after preterm birth and may be exacerbated by postnatal hyperglycemia.

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

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.<b> </b>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.

STUDY OF GLUCOSE TOLERANCE AND THE DYNAMIC PROPERTY OF INSULIN SECRETION. ANALYSIS OF INTRAVENOUS GLUCOSE TOLERANCE TEST WITH THE AID OF A CONTROL THEORY

1979 ◽  
Vol 90 (2) ◽  
pp. 283-294 ◽  
Author(s):  
Ryuzo Kawamori ◽  
Motoaki Shichiri ◽  
Teishi Murata ◽  
Makoto Nomura ◽  
Yukio Shigeta ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Blood Glucose ◽  
Glucose Tolerance ◽  
Dynamic Property ◽  
Glucose Concentration ◽  
Weighting Function ◽  
Blood Glucose Concentration ◽  
Rate Of Change ◽  
Intravenous Glucose ◽  
K Value

ABSTRACT The dynamic property of insulin secretion in relation to glucose tolerance was investigated quantitatively during iv glucose tolerance tests in 237 cases. The following results were obtained; 1) Glucose clearance constant (k-value) was not constant but variable with time and should be expressed as a function of time, K(t). In normal glucose tolerance, K(t) became greater with time. 2) Glucose-induced insulin secretion was expressed as the function of a proportional plus derivative response to glucose concentration. A weighting function of derivative response, reflecting the insulin secretion per unit of rate of change in blood glucose concentration, was calculated from blood glucose concentration (input) and insulin concentration (output) by the deconvolution method. It was clearly shown that the gain in weighting function was small and the response was slow even in the individual whose glucose tolerance was slightly impaired. 3) The greater the weighting function, the larger the change in K(t).

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