Maternal adaptations of pancreatic islets and glucose metabolism after lactation

Pancreatic islets adapt to metabolic requirements and the hormonal milieu by modifying their size and hormone secretions. Maternal glucose demands and hormonal changes occur after weaning, to rapidly re-establish bone mineralization. Minimal information exists about glucose metabolism and pancreatic islets after lactation. This study investigated islet morphology and glucose homeostasis for 14 days after lactation in C57BL/6NHHsd mice. Compared to the day of weaning, rapid increases in the islets’ area and number of beta cells were found from the first day post-lactation, attaining maximum values on the third day post-weaning. These changes were accompanied by modifications in glucose-induced insulin secretion, glucose tolerance and insulin sensitivity. Islet-cell proliferation was already augmented before lactation ceased. Serum undercarboxylated osteocalcin concentrations increased significantly post-lactation; however, it is unlikely that this enhancement participates in earlier cell proliferation augmentation or in decreasing insulin sensitivity. Islet serotonin content was barely expressed, and serum calcium concentrations decreased. By the 14th day post-weaning, islets’ area and glucose homeostasis returned to age-matched virgin mice levels. These findings recognize for the first time that increases in islet area and insulin secretion occur during physiological post-weaning conditions. These results open up new opportunities to identify molecules and mechanisms participating in these processes, which will help in developing strategies to combat diabetes.

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β Cell GHS-R Regulates Insulin Secretion and Sensitivity

International Journal of Molecular Sciences ◽

10.3390/ijms22083950 ◽

2021 ◽

Vol 22 (8) ◽

pp. 3950

Author(s):

Geetali Pradhan ◽

Chia-Shan Wu ◽

Daniel Villarreal ◽

Jong Han Lee ◽

Hye Won Han ◽

...

Keyword(s):

Insulin Secretion ◽

Insulin Sensitivity ◽

Pancreatic Islets ◽

Glucose Homeostasis ◽

Fluorescent Protein ◽

Therapeutic Potential ◽

Fasting Blood Glucose ◽

Β Cell ◽

Growth Hormone Secretagogue ◽

Isolated Pancreatic Islets

Growth hormone secretagogue receptor (GHS-R) is widely known to regulate food intake and adiposity, but its role in glucose homeostasis is unclear. In this study, we investigated the expression of GHS-R in mouse pancreatic islets and its role in glycemic regulation. We used Ghsr-IRES-tauGFP mice, with Green Fluorescent Protein (GFP) as a surrogate for GHS-R, to demonstrate the GFP co-localization with insulin and glucagon expression in pancreatic islets, confirming GHS-R expression in β and α cells. We then generated β-cell-specific GHSR-deleted mice with MIP-Cre/ERT and validated that GHS-R suppression was restricted to the pancreatic islets. MIP-Cre/ERT;Ghsrf/f mice showed normal energy homeostasis with similar body weight, body composition, and indirect calorimetry profile. Interestingly, MIP-Cre/ERT;Ghsrf/f mice exhibited an impressive phenotype in glucose homeostasis. Compared to controls, MIP-Cre/ERT;Ghsrf/f mice showed lower fasting blood glucose and insulin; reduced first-phase insulin secretion during a glucose tolerance test (GTT) and glucose-stimulated insulin secretion (GSIS) test in vivo. The isolated pancreatic islets of MIP-Cre/ERT;Ghsrf/f mice also showed reduced insulin secretion during GSIS ex vivo. Further, MIP-Cre/ERT;Ghsrf/f mice exhibited improved insulin sensitivity during insulin tolerance tests (ITT). Overall, our results confirmed GHS-R expression in pancreatic β and α cells; GHS-R cell-autonomously regulated GSIS and modulated systemic insulin sensitivity. In conclusion, β cell GHS-R was an important regulator of glucose homeostasis, and GHS-R antagonists may have therapeutic potential for Type 2 Diabetes.

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Vitamin B6 deficiency disrupts serotonin signaling in pancreatic islets and induces gestational diabetes in mice

Communications Biology ◽

10.1038/s42003-021-01900-0 ◽

2021 ◽

Vol 4 (1) ◽

Author(s):

Ashley M. Fields ◽

Kevin Welle ◽

Elaine S. Ho ◽

Clementina Mesaros ◽

Martha Susiarjo

Keyword(s):

Cell Proliferation ◽

Insulin Secretion ◽

Pancreatic Islets ◽

Glucose Intolerance ◽

Vitamin B6 ◽

Serotonin Receptor ◽

Dependent Manner ◽

Β Cell ◽

Vitamin B6 Deficiency ◽

Maternal Glucose

AbstractIn pancreatic islets, catabolism of tryptophan into serotonin and serotonin receptor 2B (HTR2B) activation is crucial for β-cell proliferation and maternal glucose regulation during pregnancy. Factors that reduce serotonin synthesis and perturb HTR2B signaling are associated with decreased β-cell number, impaired insulin secretion, and gestational glucose intolerance in mice. Albeit the tryptophan-serotonin pathway is dependent on vitamin B6 bioavailability, how vitamin B6 deficiency impacts β-cell proliferation during pregnancy has not been investigated. In this study, we created a vitamin B6 deficient mouse model and investigated how gestational deficiency influences maternal glucose tolerance. Our studies show that gestational vitamin B6 deficiency decreases serotonin levels in maternal pancreatic islets and reduces β-cell proliferation in an HTR2B-dependent manner. These changes were associated with glucose intolerance and insulin resistance, however insulin secretion remained intact. Our findings suggest that vitamin B6 deficiency-induced gestational glucose intolerance involves additional mechanisms that are complex and insulin independent.

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The effect of starvation on insulin secretion and glucose metabolism in mouse pancreatic islets

Biochemical Journal ◽

10.1042/bj1400423 ◽

1974 ◽

Vol 140 (3) ◽

pp. 423-433 ◽

Cited By ~ 52

Author(s):

Carl J. Hedeskov ◽

Kirsten Capito

Keyword(s):

Insulin Secretion ◽

Glucose Metabolism ◽

Pancreatic Islets ◽

Glucose Utilization ◽

Secretory Response ◽

Secretory Process ◽

Fed State ◽

Lactate Output ◽

Extracellular Glucose ◽

Km Value

1. Rates of insulin secretion, glucose utilization, lactate output, incorporation of glucose into glycogen, contents of glucose 6-phosphate, fructose 1,6-diphosphate and ATP, and maximally extractable enzyme activities of hexokinase, high-Km glucose-phosphorylating activity (`glucokinase'), glucose 6-phosphatase and unspecific acid phosphatase were measured in isolated pancreatic islets from fed and 48-h-starved mice. 2. In the fed state insulin secretion from isolated islets was increased five- to six-fold when the extracellular glucose concentration was raised from 2.5mm to 16.7mm; 5mm-caffeine potentiated this effect. The secretory response to glucose of islets from mice starved for 48h was diminished at all glucose concentrations from 2.5mm up to approx. 40mm. Very high glucose concentrations (60mm and above) restored the secretory response to that found in the fed state, suggesting that the Km value for the overall secretory process had been increased (approx. fourfold) by starvation. Addition of 5mm-caffeine to islets from starved mice also restored the insulin secretory response to 2.5–16.7mm-glucose to normal values. 3. Extractable hexokinase, `glucokinase', glucose 6-phosphatase and unspecific phosphatase activities were not changed by starvation. 4. Glucose utilization and glycolysis (measured as the rate of formation of 3H2O from [5-3H]glucose over a 2h period) was decreased in islets from starved mice at all glucose concentrations up to approx. 55mm. At still higher glucose concentrations up to approx. 100mm, there was no difference between the fed and starved state, suggesting that the Km value for the rate-limiting glucose phosphorylation had been increased (approx. twofold) by starvation. Preparation of islets omitting substrates (glucose, pyruvate, fumarate and glutamate) from the medium during collagenase treatment lowered the glucose utilization measured subsequently at 16.7mm-glucose by 38 and 30% in islets from fed and starved mice respectively. Also the 2h lactate output by the islets at 16.7mm extracellular glucose was diminished by starvation. Incorporation of glucose into glycogen was extremely low, but the rate of incorporation was more than doubled by starvation. 5. After incubation for 30min at 16.7mm-glucose the content of glucose 6-phosphate was unchanged by starvation, that of ATP was increased and the concentration of (fructose 1,6-diphosphate plus triose phosphates) was decreased. 6. Possible mechanisms behind the correlated impairment in insulin secretion and islet glucose metabolism during starvation are discussed.

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Regulation of glucokinase in pancreatic islets by prolactin: a mechanism for increasing glucose-stimulated insulin secretion during pregnancy

Journal of Endocrinology ◽

10.1677/joe-07-0043 ◽

2007 ◽

Vol 193 (3) ◽

pp. 367-381 ◽

Cited By ~ 55

Author(s):

Anthony J Weinhaus ◽

Laurence E Stout ◽

Nicholas V Bhagroo ◽

T Clark Brelje ◽

Robert L Sorenson

Keyword(s):

Insulin Secretion ◽

Glucose Metabolism ◽

Pancreatic Islets ◽

Glucose Transporter ◽

Β Cells ◽

Glucose Transporter 2 ◽

Underlying Mechanisms ◽

Glucose Stimulated Insulin Secretion ◽

Induced Changes

Glucokinase activity is increased in pancreatic islets during pregnancy and in vitro by prolactin (PRL). The underlying mechanisms that lead to increased glucokinase have not been resolved. Since glucose itself regulates glucokinase activity in β-cells, it was unclear whether the lactogen effects are direct or occur through changes in glucose metabolism. To clarify the roles of glucose metabolism in this process, we examined the interactions between glucose and PRL on glucose metabolism, insulin secretion, and glucokinase expression in insulin 1 (INS-1) cells and rat islets. Although the PRL-induced changes were more pronounced after culture at higher glucose concentrations, an increase in glucose metabolism, insulin secretion, and glucokinase expression occurred even in the absence of glucose. The presence of comparable levels of insulin secretion at similar rates of glucose metabolism from both control and PRL-treated INS-1 cells suggests the PRL-induced increase in glucose metabolism is responsible for the increase in insulin secretion. Similarly, increases in other known PRL responsive genes (e.g. the PRL receptor, glucose transporter-2, and insulin) were also detected after culture without glucose. We show that the upstream glucokinase promoter contains multiple STAT5 binding sequences with increased binding in response to PRL. Corresponding increases in glucokinase mRNA and protein synthesis were also detected. This suggests the PRL-induced increase in glucokinase mRNA and its translation are sufficient to account for the elevated glucokinase activity in β-cells with lactogens. Importantly, the increase in islet glucokinase observed with PRL is in line with that observed in islets during pregnancy.

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Specific Deletion of CASK in Pancreatic β Cells Affects Glucose Homeostasis and Improves Insulin Sensitivity in Obese Mice by Reducing Hyperinsulinemia Running Title: β Cell CASK Deletion Reduces Hyperinsulinemia

10.2337/figshare.16797871 ◽

2021 ◽

Author(s):

Xingjing Liu ◽

Peng Sun ◽

Qingzhao Yuan ◽

Jinyang Xie ◽

Ting Xiao ◽

...

Keyword(s):

Insulin Resistance ◽

Insulin Secretion ◽

Insulin Sensitivity ◽

Glucose Homeostasis ◽

Chow Diet ◽

Β Cells ◽

Pancreatic Β Cells ◽

Calcium Calmodulin Dependent ◽

Normal Chow

Calcium/calmodulin-dependent serine protein kinase (CASK) is involved in the secretion of insulin vesicles in pancreatic β-cells. The present study revealed a new in vivo role of CASK in glucose homeostasis during the progression of type 2 diabetes mellitus (T2DM). A Cre-loxP system was used to specifically delete the Cask gene in mouse β-cells (βCASKKO), and the glucose metabolism was evaluated in <a>βCASKKO</a> mice fed a normal chow diet (ND) or a high-fat diet (HFD). ND-fed mice exhibited impaired insulin secretion in response to glucose stimulation. Transmission electron microscopy showed significantly reduced numbers of insulin granules at or near the cell membrane in the islets of βCASKKO mice. By contrast, HFD-fed βCASKKO mice showed reduced blood glucose and a partial relief of hyperinsulinemia and insulin resistance when compared to HFD-fed wildtype mice. The IRS1/PI3K/AKT signaling pathway was upregulated in the adipose tissue of HFD-βCASKKO mice. These results indicated that knockout of the Cask gene in β cells had a diverse effect on glucose homeostasis: reduced insulin secretion in ND-fed mice, but improves insulin sensitivity in HFD-fed mice. Therefore, CASK appears to function in the insulin secretion and contributes to hyperinsulinemia and insulin resistance during the development of obesity-related T2DM.

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Glucose homeostasis is impaired in mice deficient in the neuropeptide 26RFa (QRFP)

BMJ Open Diabetes Research & Care ◽

10.1136/bmjdrc-2019-000942 ◽

2020 ◽

Vol 8 (1) ◽

pp. e000942

Author(s):

Mouna El-Mehdi ◽

Saloua Takhlidjt ◽

Fayrouz Khiar ◽

Gaëtan Prévost ◽

Jean-Luc do Rego ◽

...

Keyword(s):

Glucose Metabolism ◽

Pancreatic Islets ◽

Glucose Homeostasis ◽

Gene Knockout ◽

Hepatic Glucose Production ◽

Biologically Active ◽

Mutant Mice ◽

Insulin Production ◽

Coding Region ◽

The Impact

Introduction26RFa (pyroglutamyl RFamide peptide (QRFP)) is a biologically active peptide that has been found to control feeding behavior by stimulating food intake, and to regulate glucose homeostasis by acting as an incretin. The aim of the present study was thus to investigate the impact of 26RFa gene knockout on the regulation of energy and glucose metabolism.Research design and methods26RFa mutant mice were generated by homologous recombination, in which the entire coding region of prepro26RFa was replaced by the iCre sequence. Energy and glucose metabolism was evaluated through measurement of complementary parameters. Morphological and physiological alterations of the pancreatic islets were also investigated.ResultsOur data do not reveal significant alteration of energy metabolism in the 26RFa-deficient mice except the occurrence of an increased basal metabolic rate. By contrast, 26RFa mutant mice exhibited an altered glycemic phenotype with an increased hyperglycemia after a glucose challenge associated with an impaired insulin production, and an elevated hepatic glucose production. Two-dimensional and three-dimensional immunohistochemical experiments indicate that the insulin content of pancreatic β cells is much lower in the 26RFa−/− mice as compared with the wild-type littermates.ConclusionDisruption of the 26RFa gene induces substantial alteration in the regulation of glucose homeostasis, with in particular a deficit in insulin production by the pancreatic islets. These findings further support the notion that 26RFa is an important regulator of glucose homeostasis.

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Cafeteria diet inhibits insulin clearance by reduced insulin-degrading enzyme expression and mRNA splicing

Journal of Endocrinology ◽

10.1530/joe-13-0177 ◽

2013 ◽

Vol 219 (2) ◽

pp. 173-182 ◽

Cited By ~ 28

Author(s):

P Brandimarti ◽

J M Costa-Júnior ◽

S M Ferreira ◽

A O Protzek ◽

G J Santos ◽

...

Keyword(s):

Skeletal Muscle ◽

Insulin Secretion ◽

Alternative Splicing ◽

Insulin Sensitivity ◽

Glucose Homeostasis ◽

Insulin Clearance ◽

Cafeteria Diet ◽

Mrna Levels ◽

Insulin Degrading Enzyme ◽

Diet Induced Obesity

Insulin clearance plays a major role in glucose homeostasis and insulin sensitivity in physiological and/or pathological conditions, such as obesity-induced type 2 diabetes as well as diet-induced obesity. The aim of the present work was to evaluate cafeteria diet-induced obesity-induced changes in insulin clearance and to explain the mechanisms underlying these possible changes. Female Swiss mice were fed either a standard chow diet (CTL) or a cafeteria diet (CAF) for 8 weeks, after which we performed glucose tolerance tests, insulin tolerance tests, insulin dynamics, and insulin clearance tests. We then isolated pancreatic islets for ex vivo glucose-stimulated insulin secretion as well as liver, gastrocnemius, visceral adipose tissue, and hypothalamus for subsequent protein analysis by western blot and determination of mRNA levels by real-time RT-PCR. The cafeteria diet induced insulin resistance, glucose intolerance, and increased insulin secretion and total insulin content. More importantly, mice that were fed a cafeteria diet demonstrated reduced insulin clearance and decay rate as well as reduced insulin-degrading enzyme (IDE) protein and mRNA levels in liver and skeletal muscle compared with the control animals. Furthermore, the cafeteria diet reduced IDE expression and alternative splicing in the liver and skeletal muscle of mice. In conclusion, a cafeteria diet impairs glucose homeostasis by reducing insulin sensitivity, but it also reduces insulin clearance by reducing IDE expression and alternative splicing in mouse liver; however, whether this mechanism contributes to the glucose intolerance or helps to ameliorate it remains unclear.

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Effects of acute intermittent hypoxia on glucose metabolism in awake healthy volunteers

Journal of Applied Physiology ◽

10.1152/japplphysiol.91523.2008 ◽

2009 ◽

Vol 106 (5) ◽

pp. 1538-1544 ◽

Cited By ~ 198

Author(s):

Mariam Louis ◽

Naresh M. Punjabi

Keyword(s):

Obstructive Sleep Apnea ◽

Insulin Secretion ◽

Sleep Apnea ◽

Insulin Sensitivity ◽

Glucose Metabolism ◽

Healthy Volunteers ◽

Intermittent Hypoxia ◽

Metabolic Dysfunction ◽

Glucose Effectiveness ◽

Obstructive Sleep

Accumulating evidence suggests that obstructive sleep apnea is associated with alterations in glucose metabolism. Although the pathophysiology of metabolic dysfunction in obstructive sleep apnea is not well understood, studies of murine models indicate that intermittent hypoxemia has an important contribution. However, corroborating data on the metabolic effects of intermittent hypoxia on glucose metabolism in humans are not available. Thus the primary aim of this study was to characterize the acute effects of intermittent hypoxia on glucose metabolism. Thirteen healthy volunteers were subjected to 5 h of intermittent hypoxia or normoxia during wakefulness in a randomized order on two separate days. The intravenous glucose tolerance test (IVGTT) was used to assess insulin-dependent and insulin-independent measures of glucose disposal. The IVGTT data were analyzed using the minimal model to determine insulin sensitivity (SI) and glucose effectiveness (SG). Drops in oxyhemoglobin saturation were induced during wakefulness at an average rate of 24.3 events/h. Compared with the normoxia condition, intermittent hypoxia was associated with a decrease in SI [4.1 vs. 3.4 (mU/l)−1·min−1; P = 0.0179] and SG (1.9 vs. 1.3 min−1×10−2, P = 0.0065). Despite worsening insulin sensitivity with intermittent hypoxia, pancreatic insulin secretion was comparable between the two conditions. Heart rate variability analysis showed the intermittent hypoxia was associated with a shift in sympathovagal balance toward an increase in sympathetic nervous system activity. The average R-R interval on the electrocardiogram was 919.0 ms during the normoxia condition and 874.4 ms during the intermittent hypoxia condition ( P < 0.04). Serum cortisol levels after intermittent hypoxia and normoxia were similar. Hypoxic stress in obstructive sleep apnea may increase the predisposition for metabolic dysfunction by impairing insulin sensitivity, glucose effectiveness, and insulin secretion.

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