scholarly journals Abnormal regulation of insulin secretion in the genetically obese (ob/ob) mouse

1986 ◽  
Vol 238 (3) ◽  
pp. 863-869 ◽  
Author(s):  
M Black ◽  
H M Heick ◽  
N Bégin-Heick
Keyword(s):  
Insulin Secretion ◽  
Cyclic Amp ◽  
Secretory Activity ◽  
Obese Mouse ◽  
Obese Mice ◽  
Bathing Medium ◽  
Primary Stimulus ◽  
Lean Mouse

To determine whether the abnormal insulin-secretory activity encountered in obese mice is due to an anomaly in the production of cyclic AMP, islets of lean and obese mice were incubated with forskolin under various conditions. Our data show that, in addition to the well-known quantitative differences in insulin-secretory activity between islets of lean and obese mice, there are important qualitative differences. The islets of obese mice accumulated less cyclic AMP than did those of lean mice in response to given doses of forskolin, yet their insulin secretion was enhanced to much higher values. In the islets of obese mice, but not in those of lean mice, the stimulatory effect of forskolin on insulin secretion was evident even at non-stimulatory concentrations of glucose or in Ca2+-deprived incubation media, showing that the islet of the obese mouse is less dependent on a primary stimulus (glucose) and on the provision of normal concentrations of Ca2+ in the bathing medium than is the islet of the lean mouse.

INFLUENCE OF THE PITUITARY GLAND ON INSULIN SECRETION IN THE GENETICALLY OBESE (ob/ob) MOUSE

1975 ◽  
Vol 65 (1) ◽  
pp. 109-116 ◽  
Author(s):  
ANNE BELOFF-CHAIN ◽  
J. A. EDWARDSON ◽  
JANET HAWTHORN
Keyword(s):  
Insulin Secretion ◽  
Pituitary Gland ◽  
Obese Mouse ◽  
Obese Mice ◽  
Experimental Conditions ◽  
Lean Mouse ◽  
In Series ◽  
Mouse Islets ◽  
Microdissected Pancreatic Islets ◽  
Stimulation Of

SUMMARY The influence of the pituitary gland of lean and genetically obese (ob/ob) mice on insulin secretion from microdissected pancreatic islets of lean and ob/ob mice has been studied by perifusing the pituitaries of these animals in series with the isolated islets and measuring insulin secretion at 5-min intervals over a period of 60 min. It has been shown that the pituitary perifusate of both lean and obese mice stimulate insulin secretion from lean mouse islets but not from obese mouse islets. The maximum stimulation occurs in the first 10 min and with the lean mouse pituitaries returns to the basal level in about 20 min, whereas with the obese mouse pituitaries insulin secretion is about double that from the control islets even after 40 min. A concentration of pure porcine ACTH equivalent to about three times the amount released from the pituitary gland under the experimental conditions used, caused only a small stimulation of insulin release. Possible interpretations of these findings and further lines of investigation are discussed.

scholarly journals Different insulin-secretory responses to calcium-channel blockers in islets of lean and obese (ob/ob) mice

1988 ◽  
Vol 249 (2) ◽  
pp. 401-407 ◽  
Author(s):  
M A Black ◽  
L A Fournier ◽  
H M Heick ◽  
N Bégin-Heick
Keyword(s):  
Insulin Secretion ◽  
Calcium Channel ◽  
Calcium Channel Blockers ◽  
Potent Inhibitor ◽  
Secretory Activity ◽  
Obese Mouse ◽  
Channel Blockers ◽  
Obese Mice ◽  
Voltage Dependent ◽  
Glucose Stimulated Insulin Secretion

The purpose of these experiments was to determine whether the activity of the voltage-dependent Ca2+ channel was modulated in the same manner in islets of the ob/ob mouse as in islets of homozygous lean mice of the same strain. The effect of agents that are known to alter the concentrations and movements of intracellular Ca2+ were investigated in relation to glucose-stimulated insulin secretion and in relation to the effect of forskolin. In islets of obese mice, verapamil and nifedipine both inhibited glucose-induced insulin release, nifedipine being the more potent inhibitor. Forskolin-stimulated secretion was inhibited either not at all (verapamil) or much less (nifedipine) in islets of the ob/ob mouse compared with those of lean mice. At basal glucose concentrations, verapamil initiated insulin secretion in islets of the ob/ob mouse and acted synergistically with forskolin to evoke a secretory activity that was 3-fold greater than that evoked by 20 mM-glucose. Nifedipine also initiated secretion at basal glucose concentrations and acted synergistically with forskolin, but its effect was considerably smaller than that of verapamil. A comparison of the effect of forskolin in the presence of Ca2+-channel blockers and in the absence of Ca2+ suggests that, in the obese mouse, the operation of the voltage-dependent Ca2+ channel is impaired.

Abnormal regulation of cAMP accumulation in pancreatic islets of obese mice

1988 ◽  
Vol 255 (6) ◽  
pp. E833-E838 ◽  
Author(s):  
M. A. Black ◽  
H. M. Heick ◽  
N. Begin-Heick
Keyword(s):  
Insulin Secretion ◽  
Adenylate Cyclase ◽  
Obese Mouse ◽  
Adenylate Cyclase System ◽  
Camp Accumulation ◽  
Obese Mice ◽  
Camp Production ◽  
Impaired Ability ◽  
Gating Mechanism ◽  
Inhibit Insulin Secretion

The present study was undertaken 1) to determine whether a defect in the regulation of adenosine 3',5'-cyclic monophosphate (cAMP) accumulation was present in the beta-cell of the ob/ob mouse, 2) to determine how such a defect, if present, would alter the regulation of insulin secretion in these islets, and 3) to find out if epinephrine had similar effects on insulin secretion and cAMP production in islets of lean and obese mice. In the obese mouse, inhibitory modulators neither inhibited cAMP accumulation in intact islets nor adenylate cyclase activity in islet homogenates. These anomalies in the modulation of cAMP accumulation were not correlated with a failure to inhibit insulin secretion. It is concluded that, first, a defect in cAMP modulation is present in the islets of Langerhans of the obese mouse; second, epinephrine produces its effects on insulin secretion and cAMP accumulation via distinct mediators; and third, an anomaly in the adenylate cyclase system is unlikely to be the cause of the exaggerated insulin secretion in the islet of the ob/ob mouse. It is more likely that the exaggerated insulin secretion is due to a faulty cation gating mechanism that, in turn, may contribute to the impaired ability of the islet to accumulate cAMP.

Hormone-substrate responses to total fasting in lean and obese mice

1975 ◽  
Vol 228 (1) ◽  
pp. 276-283 ◽  
Author(s):  
GS Cuendet ◽  
EG Loten ◽  
DP Cameron ◽  
AE Renold ◽  
EB Marliss
Keyword(s):  
Molar Ratio ◽  
Obese Mouse ◽  
Obese Mice ◽  
Molar Ratios ◽  
Lean Mouse ◽  
Fat Mobilization ◽  
Catabolic State ◽  
Obob Mice ◽  
Protein Conservation ◽  
Glucagon And Insulin

The hormone-substrate milieu has been investigated in male fasted lean (C57BL/6-+/+) mice and mutant obese mice of the same strain (C57BL/6-obob). The lean mouse, in winter, mobilized insufficient fat (due to inadequate stores) to permit survival beyong 3 days and was unable to achieve any degree of conservation of vital protein stores. By contrast, in summer, the same animals survived 7 days and showed evidence of greater and more sustained fat mobilization and ketosis and the ability to conserve protein. The insulin, glucagon, and insulin/glucagon molar ratios changed in both groups in a direction consistent with conversion to a catabolic state, and hence were probably largely responsible for the mobilization of substrates and stimulation of gluconeogenesis and ketogenesis. The seasonal difference in response is unexplained. The obob mice, generally employed as a model for obesity, hyperglycemia, and hyperinsulinemia showed these features but also adapted to fasting in a fashion permitting prolonged survival during this state. In a fashion analogous to that known to occur in man, these animals developed fall in glycemia, rise in circulating fat-derived substrates, and marked protein conservation. Profound fall in insulinemia was associated with a fall in glucagonemia, the latter from normal levels. Thus the initial markedly "anabolic" insulin/glucagon molar ratio diminished, but nevertheless remained higher than at any time in the lean mice. Pancreatic contents of insulin showed markedly different changes with fasting in obob compared with lean mice. The ability of the obese mouse to adapt to prolonged fasting in a fashion largely analogous to that of man renders it a useful model for the study of metabolism in this state, with the potential of applicability of findings to man.

scholarly journals Ultrafine particles altered gut microbial population and metabolic profiles in a sex-specific manner in an obese mouse model

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Kundi Yang ◽  
Mengyang Xu ◽  
Jingyi Cao ◽  
Qi Zhu ◽  
Monica Rahman ◽  
...  
Keyword(s):  
Ultrafine Particles ◽  
Microbial Population ◽  
Phosphate Buffer Solution ◽  
Biodiesel Fuel ◽  
Control Group ◽  
Obese Mouse ◽  
Rrna Gene ◽  
Obese Mice ◽  
Microbial Composition ◽  
Increased Risk

AbstractEmerging evidence has highlighted the connection between exposure to air pollution and the increased risk of obesity, metabolic syndrome, and comorbidities. Given the recent interest in studying the effects of ultrafine particle (UFP) on the health of obese individuals, this study examined the effects of gastrointestinal UFP exposure on gut microbial composition and metabolic function using an in vivo murine model of obesity in both sexes. UFPs generated from light-duty diesel engine combustion of petrodiesel (B0) and a petrodiesel/biodiesel fuel blend (80:20 v/v, B20) were administered orally. Multi-omics approaches, including liquid chromatography–mass spectrometry (LC–MS) based targeted metabolomics and 16S rRNA gene sequence analysis, semi-quantitatively compared the effects of 10-day UFP exposures on obese C57B6 mouse gut microbial population, changes in diversity and community function compared to a phosphate buffer solution (PBS) control group. Our results show that sex-specific differences in the gut microbial population in response to UFP exposure can be observed, as UFPs appear to have a differential impact on several bacterial families in males and females. Meanwhile, the alteration of seventy-five metabolites from the gut microbial metabolome varied significantly (ANOVA p < 0.05) across the PBS control, B0, and B20 groups. Multivariate analyses revealed that the fuel-type specific disruption to the microbial metabolome was observed in both sexes, with stronger disruptive effects found in females in comparison to male obese mice. Metabolic signatures of bacterial cellular oxidative stress, such as the decreased concentration of nucleotides and lipids and increased concentrations of carbohydrate, energy, and vitamin metabolites were detected. Furthermore, blood metabolites from the obese mice were differentially affected by the fuel types used to generate the UFPs (B0 vs. B20).

scholarly journals Obesity-Activated Lung Stromal Cells Promote Myeloid Lineage Cell Accumulation and Breast Cancer Metastasis

Cancers ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 1005
Author(s):  
Lauren E. Hillers-Ziemer ◽  
Abbey E. Williams ◽  
Amanda Janquart ◽  
Caitlin Grogan ◽  
Victoria Thompson ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Stromal Cells ◽  
Cancer Metastasis ◽  
Transforming Growth Factor ◽  
Breast Cancer Metastasis ◽  
Tumor Formation ◽  
Obese Mouse ◽  
Obese Mice ◽  
Myeloid Lineage ◽  
Primary Tumors

Obesity is correlated with increased incidence of breast cancer metastasis; however, the mechanisms underlying how obesity promotes metastasis are unclear. In a diet-induced obese mouse model, obesity enhanced lung metastasis in both the presence and absence of primary mammary tumors and increased recruitment of myeloid lineage cells into the lungs. In the absence of tumors, obese mice demonstrated increased numbers of myeloid lineage cells and elevated collagen fibers within the lung stroma, reminiscent of premetastatic niches formed by primary tumors. Lung stromal cells isolated from obese tumor-naïve mice showed increased proliferation, contractility, and expression of extracellular matrix, inflammatory markers and transforming growth factor beta-1 (TGFβ1). Conditioned media from lung stromal cells from obese mice promoted myeloid lineage cell migration in vitro in response to colony-stimulating factor 2 (CSF2) expression and enhanced invasion of tumor cells. Together, these results suggest that prior to tumor formation, obesity alters the lung microenvironment, creating niches conducive to metastatic growth.

scholarly journals Pancreatic beta-cells expressing the Arg64 variant of the beta(3)-adrenergic receptor exhibit abnormal insulin secretory activity

2001 ◽  
Vol 27 (2) ◽  
pp. 133-144 ◽  
Author(s):  
R Perfetti ◽  
H Hui ◽  
K Chamie ◽  
S Binder ◽  
M Seibert ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Beta Cells ◽  
Western Blotting ◽  
Adrenergic Receptor ◽  
Pancreatic Beta Cells ◽  
Secretory Activity ◽  
Host Cells ◽  
Human Pancreas ◽  
Dependent Manner ◽  
Wild Type

The Arg64 beta(3)-adrenergic receptor (beta(3)AR) variant is associated with an earlier age of onset of diabetes and lower levels of insulin secretion in humans. The aims of this study were to investigate whether beta(3)AR is expressed by islet cells, if receptor binding affects insulin secretion and, finally, if the beta(3)AR Arg64 variant induces abnormal insulin secretory activity. Human pancreas extracts were subjected to RT-PCR, Western blotting and immunostaining analyses. DNA sequencing and Western blotting demonstrated that the beta(3)AR gene is transcribed and translated in the human pancreas; immunostaining showed that it is expressed by the islets of Langerhans. Cultured rat beta-cells responded to human beta(3)AR agonists in a dose- and time-dependent manner. Transfection of cultured rat beta-cells with the wild-type human beta(3)AR produced an increased baseline and ligand-dependent insulin secretion compared with parental cells. On the other hand, cells transfected with the Arg64 variant of the beta(3)AR secreted less insulin, both spontaneously and after exposure to human beta(3)AR agonists. Furthermore, while transfection with the wild-type beta(3)AR preserved the glucose-dependent secretion of insulin, expression of the variant receptor rendered the host cells significantly less responsive to glucose. In summary, cells express the beta(3)AR, and its activation contributes to the regulation of insulin secretion. These findings may help explain the low levels of insulin secretion in response to an i.v. glucose tolerance test observed in humans carrying the Arg64 polymorphism.

scholarly journals Ca2+-induced insulin secretion from electrically permeabilized islets. Loss of the Ca2+-induced secretory response is accompanied by loss of Ca2+-induced protein phosphorylation

1992 ◽  
Vol 285 (3) ◽  
pp. 973-978 ◽  
Author(s):  
P M Jones ◽  
S J Persaud ◽  
S L Howell
Keyword(s):  
Protein Kinase C ◽  
Insulin Secretion ◽  
Protein Kinase ◽  
Cyclic Amp ◽  
Protein Phosphorylation ◽  
Prolonged Exposure ◽  
Kinase C ◽  
Dependent Protein ◽  
32P Incorporation ◽  
Rat Islets Of Langerhans

Increasing the cytosolic Ca2+ concentration of electrically permeabilized rat islets of Langerhans caused rapid increases in insulin secretion and in 32P incorporation into islet proteins. However, the secretory responsiveness of permeabilized islets was relatively transient, with insulin secretion approaching basal levels within 20-30 min despite the continued presence of stimulatory concentrations of Ca2+. The loss of Ca2(+)-induced insulin secretion was accompanied by a marked reduction in Ca2(+)-dependent protein phosphorylation, but not in cyclic AMP-dependent protein phosphorylation. Similarly, permeabilized islets which were no longer responsive to Ca2+ were able to mount appropriate secretory responses to cyclic AMP and to a protein kinase C-activating phorbol ester. These results suggest that prolonged exposure to elevated cytosolic Ca2+ concentrations results in a specific desensitization of the secretory mechanism to Ca2+, perhaps as a result of a decrease in Ca2(+)-dependent kinase activity. Furthermore, these studies suggest that secretory responses of B-cells to cyclic AMP and activators of protein kinase C are not dependent upon the responsiveness of the cells to changes in cytosolic Ca2+.

Tumor necrosis factor activity of pancreatic islets

1997 ◽  
Vol 273 (2) ◽  
pp. E433-E437 ◽  
Author(s):  
S. K. Leeper-Woodford ◽  
B. W. Tobin
Keyword(s):  
Insulin Secretion ◽  
Tumor Necrosis Factor ◽  
Pancreatic Islets ◽  
Tumor Necrosis ◽  
Cell Function ◽  
Secretory Activity ◽  
Organ Injury ◽  
Pancreatic Islet Cell ◽  
Islet Cell Function ◽  
Necrosis Factor

Tumor necrosis factor (TNF) is involved in the pathogenesis of acute sepsis-induced organ injury and has been implicated as a mediator of metabolic alterations observed during sepsis. Pancreatic islet cell function may be significantly compromised during sepsis or endotoxemia, and sepsis also increases plasma levels of epinephrine, a modifier of islet insulin secretion. We proposed that islets exposed to bacterial lipopolysaccharide (LPS) produce TNF and that epinephrine attenuates islet secretory activity. We monitored the effects of LPS and epinephrine on TNF and insulin activity of isolated Wistar-Furth rat islets (pancreas digested with collagenase, islets isolated using Ficoll gradients; n = 4 islet populations, each with 632 +/- 11 islets/2.5 ml culture medium). Islets were incubated (37 degrees C, 5% CO2) 3 days. LPS (Escherichia coli, 1 microgram/ml) and epinephrine (14 micrograms/ml) were added to the islets, and incubations were continued for 1-4 h. Glucose (Beckman Glucose Analyzer), insulin (radioimmunoassay), and TNF (L929 cytotoxicity assay) were measured in the islet medium samples at 1- to 4-h time points. In the conditioned medium, glucose decreased (P < 0.05), insulin increased (P < 0.05), and exposure to LPS did not alter these levels [P = not significant (NS)] but did increase TNF activity by 400% (P < 0.05). Epinephrine reduced insulin by 38-43% (P < 0.05) and TNF by 20-25% (P < 0.05) but had no effect on glucose levels (P = NS). We conclude that insulin is secreted from isolated islets and that exposure to LPS acutely increases islet-derived TNF activity, whereas epinephrine modifies TNF and insulin secretion of rat pancreatic islets.

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