Pancreatic islet beta cell-specific deletion of G6pc2 reduces fasting blood glucose

The G6PC1, G6PC2 and G6PC3 genes encode distinct glucose-6-phosphatase catalytic subunit (G6PC) isoforms. In mice, germline deletion of G6pc2 lowers fasting blood glucose (FBG) without affecting fasting plasma insulin (FPI) while, in isolated islets, glucose-6-phosphatase activity and glucose cycling are abolished and glucose-stimulated insulin secretion (GSIS) is enhanced at submaximal but not high glucose. These observations are all consistent with a model in which G6PC2 regulates the sensitivity of GSIS to glucose by opposing the action of glucokinase. G6PC2 is highly expressed in human and mouse islet beta cells however, various studies have shown trace G6PC2 expression in multiple tissues raising the possibility that G6PC2 also affects FBG through non-islet cell actions. Using real-time PCR we show here that expression of G6pc1 and/or G6pc3 are much greater than G6pc2 in peripheral tissues, whereas G6pc2 expression is much higher than G6pc3 in both pancreas and islets with G6pc1 expression not detected. In adult mice, beta cell-specific deletion of G6pc2 was sufficient to reduce FBG without changing FPI. In addition, electronic health record-derived phenotype analyses showed no association between G6PC2 expression and phenotypes clearly unrelated to islet function in humans. Finally, we show that germline G6pc2 deletion enhances glycolysis in mouse islets and that glucose cycling can also be detected in human islets. These observations are all consistent with a mechanism by which G6PC2 action in islets is sufficient to regulate the sensitivity of GSIS to glucose and hence influence FBG without affecting FPI.

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Functional cytochrome P450 1A enzymes are induced in mouse and human islets following pollutant exposure

Diabetologia ◽

10.1007/s00125-019-05035-0 ◽

2019 ◽

Vol 63 (1) ◽

pp. 162-178 ◽

Cited By ~ 4

Author(s):

Muna Ibrahim ◽

Erin M. MacFarlane ◽

Geronimo Matteo ◽

Myriam P. Hoyeck ◽

Kayleigh R. C. Rick ◽

...

Keyword(s):

Enzyme Activity ◽

Insulin Secretion ◽

Beta Cell ◽

Human Islets ◽

High Dose ◽

Single High Dose ◽

Direct Exposure ◽

Mouse Islets

Abstract Aims/hypothesis Exposure to environmental pollution has been consistently linked to diabetes incidence in humans, but the potential causative mechanisms remain unclear. Given the critical role of regulated insulin secretion in maintaining glucose homeostasis, environmental chemicals that reach the endocrine pancreas and cause beta cell injury are of particular concern. We propose that cytochrome P450 (CYP) enzymes, which are involved in metabolising xenobiotics, could serve as a useful biomarker for direct exposure of islets to pollutants. Moreover, functional CYP enzymes in islets could also impact beta cell physiology. The aim of this study was to determine whether CYP1A enzymes are activated in islets following direct or systemic exposure to environmental pollutants. Methods Immortalised liver (HepG2) and rodent pancreatic endocrine cell lines (MIN6, βTC-6, INS1, α-TC1, α-TC3), as well as human islets, were treated in vitro with known CYP1A inducers 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and 3-methylcholanthrene (3-MC). In addition, mice were injected with either a single high dose of TCDD or multiple low doses of TCDD in vivo, and islets were isolated 1, 7 or 14 days later. Results CYP1A enzymes were not activated in any of the immortalised beta or alpha cell lines tested. However, both 3-MC and TCDD potently induced CYP1A1 gene expression and modestly increased CYP1A1 enzyme activity in human islets after 48 h. The induction of CYP1A1 in human islets by TCDD was prevented by cotreatment with a cytokine mixture. After a systemic single high-dose TCDD injection, CYP1A1 enzyme activity was induced in mouse islets ~2-fold, ~40-fold and ~80-fold compared with controls after 1, 7 and 14 days, respectively, in vivo. Multiple low-dose TCDD exposure in vivo also caused significant upregulation of Cyp1a1 in mouse islets. Direct TCDD exposure to human and mouse islets in vitro resulted in suppressed glucose-induced insulin secretion. A single high-dose TCDD injection resulted in lower plasma insulin levels, as well as a pronounced increase in beta cell death. Conclusions/interpretation Transient exposure to TCDD results in long-term upregulation of CYP1A1 enzyme activity in islets. This provides evidence for direct exposure of islets to lipophilic pollutants in vivo and may have implications for islet physiology.

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Peripheral insulin resistance rather than beta cell dysfunction accounts for geographical differences in impaired fasting blood glucose among sub-Saharan African individuals: findings from the RODAM study

Diabetologia ◽

10.1007/s00125-017-4216-4 ◽

2017 ◽

Vol 60 (5) ◽

pp. 854-864 ◽

Cited By ~ 11

Author(s):

Karlijn A. C. Meeks ◽

Karien Stronks ◽

Adebowale Adeyemo ◽

Juliet Addo ◽

Silver Bahendeka ◽

...

Keyword(s):

Insulin Resistance ◽

Blood Glucose ◽

Beta Cell ◽

Fasting Blood Glucose ◽

Beta Cell Dysfunction ◽

Geographical Differences ◽

Cell Dysfunction ◽

Peripheral Insulin Resistance ◽

Sub Saharan ◽

Rodam Study

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Non-invasive monitoring of glycemia-induced regulation of GLP-1R expression in murine and human islets of langerhans

10.2337/figshare.12840770.v1 ◽

2020 ◽

Author(s):

Ada Admin ◽

Mijke Buitinga ◽

Christian M.Cohrs ◽

Wael A.Eter ◽

Lieke Claessens-Joosten ◽

...

Keyword(s):

Blood Glucose ◽

Beta Cell ◽

Cell Mass ◽

Beta Cell Mass ◽

Human Islets ◽

Tracer Uptake ◽

Expression Levels ◽

Glucose Levels ◽

Blood Glucose Levels ◽

Islet Volume

GLP-1R imaging with radiolabelled exendin has proven to be a powerful tool to quantify beta-cell mass (BCM) <i>in vivo</i>. As GLP-1R expression is thought to be influenced by glycemic control, we examined the effect of blood glucose levels on GLP-1R-mediated exendin uptake in both murine and human islets and its implications for BCM quantification. Periods of hyperglycemia significantly reduced exendin uptake in murine and human islets, which was paralleled by a reduction in GLP-1R expression. Detailed mapping of the tracer uptake and insulin and GLP-1R expression conclusively demonstrated that the observed reduction in tracer uptake directly correlates to GLP-1R expression levels. Importantly, the linear correlation between tracer uptake and beta-cell area was maintained in spite of the reduced GLP-1R expression levels. Subsequent normalization of blood glucose levels restored absolute tracer uptake and GLP-1R expression in beta-cells and the observed loss in islet volume was halted. <p>This manuscript emphasizes the potency of nuclear imaging techniques to monitor receptor regulation non-invasively. Our findings have significant implications for clinical practice, indicating that blood glucose levels should be near-normalized for at least three weeks prior to GLP-1R agonist treatment or quantitative radiolabeled exendin imaging for BCM analysis.</p>

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Age-dependent transition from islet insulin hypersecretion to hyposecretion in mice with the long QT-syndrome loss-of-function mutation Kcnq1-A340V

Scientific Reports ◽

10.1038/s41598-021-90452-8 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Anniek F. Lubberding ◽

Jinyi Zhang ◽

Morten Lundh ◽

Thomas Svava Nielsen ◽

Mathilde S. Søndergaard ◽

...

Keyword(s):

Beta Cell ◽

Ex Vivo ◽

Fasting Blood Glucose ◽

Qt Prolongation ◽

Cell Area ◽

Loss Of Function ◽

Glucose Levels ◽

Blood Glucose Levels ◽

Glucose Stimulated Insulin Secretion ◽

Beta Cell Area

AbstractLoss-of-function (LoF) mutations in KCNQ1, encoding the voltage-gated K+ channel Kv7.1, lead to long QT syndrome 1 (LQT1). LQT1 patients also present with post-prandial hyperinsulinemia and hypoglycaemia. In contrast, KCNQ1 polymorphisms are associated with diabetes, and LQTS patients have a higher prevalence of diabetes. We developed a mouse model with a LoF Kcnq1 mutation using CRISPR-Cas9 and hypothesized that this mouse model would display QT prolongation, increased glucose-stimulated insulin secretion and allow for interrogation of Kv7.1 function in islets. Mice were characterized by electrocardiography and oral glucose tolerance tests. Ex vivo, islet glucose-induced insulin release was measured, and beta-cell area quantified by immunohistochemistry. Homozygous mice had QT prolongation. Ex vivo, glucose-stimulated insulin release was increased in islets from homozygous mice at 12–14 weeks, while beta-cell area was reduced. Non-fasting blood glucose levels were decreased at this age. In follow-up studies 8–10 weeks later, beta-cell area was similar in all groups, while glucose-stimulated insulin secretion was now reduced in islets from hetero- and homozygous mice. Non-fasting blood glucose levels had normalized. These data suggest that Kv7.1 dysfunction is involved in a transition from hyper- to hyposecretion of insulin, potentially explaining the association with both hypoglycemia and hyperglycemia in LQT1 patients.

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THE EFFECT OF SOURSOP LEAF EXTRACT ON PANCREATIC BETA CELL COUNT AND FASTING BLOOD GLUCOSE IN MALE WISTAR RATS EXPOSED TO A HIGH-FAT DIET AND STREPTOZOTOCIN

Folia Medica Indonesiana ◽

10.20473/fmi.v53i1.5484 ◽

2017 ◽

Vol 53 (1) ◽

pp. 12 ◽

Cited By ~ 1

Author(s):

Dewa Ayu Agung Alit Suka Astini ◽

H Ari Gunawan ◽

R Mochamad Wirono Aman Santoso ◽

Susilowati Andajani ◽

Ahmad Basori

Keyword(s):

Blood Glucose ◽

Beta Cell ◽

Beta Cells ◽

High Fat Diet ◽

Pancreatic Beta Cells ◽

Wistar Rats ◽

Leaf Extract ◽

Fasting Blood Glucose ◽

High Fat ◽

Male Wistar Rats

Based on some researches known that soursop leaf extract can improve beta cell injury. The aims of this study was to analyze the effect of soursop leaf extract on fasting blood glucose (FBG) and pancreatic beta cell number in male Wistar rats wich were exposed to a high-fat diet and streptozotocin. This study design is the only randomized posttest control group design. The total sample size is 50 male Wistar rats. The independent variable: high-fat diet, STZ, and soursop leaf extract; the dependent variable: pancreatic beta cells number, and FBG3. Data tested for normality with Kolmogorov-Smirnov (a=0.05) and tested of homogeneity with Levene (a =0.05). Comparison test between groups with Kruskal-Wallis (a=0.05), followed by Mann Whitney. Correlation test with Pearson (a=0.05) between dose of the soursop leaf extract and FBG3, and between dose and the number of pancreatic beta cells. The results of this study showed that the soursop leaf extract at a dose of 100 mg/kg and 150 mg/kg have an effect on fasting blood glucose levels and panreatic beta cells number;2)There is a significant negative correlation between the orograstric lavage of soursop leaf extract with FBG3 (r=-0.647;p<0.001), the increasing doses of soursop leaf extract, further lowering fasting blood glucose levels;3)There is a significant positive correlation between the orograstric lavage of soursop leaf extract with the number of pancreatic beta cells (r=0,759;p<0,001), the increasing doses of soursop leaf extract, further increasing pancreatic beta cells number. In conclusion, increasing doses of soursop leaf extract, further lowering fasting blood glucose and increasing the number of pancreatic beta cells.

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Decreased Insulin Sensitivity, but Not Beta-Cell Dysfunction, Is the Primary Cause of Rising Fasting Blood Glucose in Glucose-Tolerant Subjects

10.1210/endo-meetings.2011.part3.p7.p2-545 ◽

2011 ◽

pp. P2-545-P2-545

Author(s):

Rudruidee Karnchanasorn ◽

Horng-Yi Ou ◽

Lee-Ming Chuang ◽

Ken C Chiu

Keyword(s):

Blood Glucose ◽

Insulin Sensitivity ◽

Beta Cell ◽

Fasting Blood Glucose ◽

Beta Cell Dysfunction ◽

Cell Dysfunction ◽

Glucose Tolerant

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Therapeutic effect of tolbutamide in non-insulin dependent diabetes mellitus (NIDDM). Relation to beta-cell function

Acta Endocrinologica ◽

10.1530/acta.0.1000416 ◽

1982 ◽

Vol 100 (3) ◽

pp. 416-420 ◽

Cited By ~ 3

Author(s):

Else M. Damsgaard ◽

Ole Faber ◽

Anders Frøland ◽

Steffen Iversen

Keyword(s):

Diabetes Mellitus ◽

Blood Glucose ◽

Beta Cell ◽

Therapeutic Effect ◽

Test Meal ◽

Fasting Blood Glucose ◽

Insulin Dependent Diabetes Mellitus ◽

Dependent Diabetes Mellitus ◽

C Peptide ◽

Insulin Dependent

Abstract. The therapeutic effect of tolbutamide (1.5 g daily) in a random sample of patients with non-insulin dependent diabetes mellitus (NIDDM), was studied in a controlled, double-blind cross-over trial of 13 women and 6 men, aged 40–65 years and of 85–155% ideal body weight. The trial comprised C-peptide determinations during a standard carbohydrate rich meal followed by four periods of 3 months in which alternating tolbutamide and placebo were given. From the beginning to the end of the treatment periods fasting blood glucose was reduced from 11.9 ± 1.1 (mean ± sem) to 10.0 ± 0.8 mmol/l (P < 0.025), glycohaemoglobin from 12.8% ± 0.7 to 11.3% ± 0.5 (P < 0.02) with a close correlation between fasting blood glucose and glycohaemoglobin (r = 0.87, P < 0.001). The observations during the first 3 months of study was not included in the calculations. Fasting C-peptide and fasting insulin concentrations were not significantly altered by tolbutamide treatment. The effect of tolbutamide was inversely correlated to the C-peptide response to the standard test meal at the start of the trial (r = 0.76, P < 0.001), so that patients with the most pronounced beta-cell failure had the greatest therapeutical effect. The beta-cell response to the test meal could not identify patients, whose fasting blood glucose would be normalized by tolbutamide treatment.

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Beta Cell Function and Insulin Resistance in Nondiabetic, Prediabetic and Diabetic in a Subset of Obese Pakistani Population

Journal of Pharmaceutical Research International ◽

10.9734/jpri/2021/v33i44b32669 ◽

2021 ◽

pp. 214-219

Author(s):

Shaheen Bhatty ◽

Syed Muhammad Kashif ◽

Mohammad Nashit ◽

Faiza Zafar Sayeed ◽

Fariha Asad

Keyword(s):

Insulin Resistance ◽

Blood Glucose ◽

Beta Cell ◽

Beta Cell Function ◽

Cell Function ◽

Fasting Blood Glucose ◽

Abdominal Circumference ◽

Family History Of Diabetes ◽

Pakistani Population ◽

Obese Subjects

Objective: To compare insulin resistance and beta-cell function in nondiabetic, prediabetic, and diabetic subjects in a subset of obese Pakistani population. Materials and Methods: Two hundred and ten obese subjects underwent anthropometric measurements. After overnight fasting for 8 hours, 6 cc blood was drawn for fasting blood glucose level, fasting insulin level. Blood glucose samples were taken after drinking 75 gm glucose in 260 ml water. HOMA IR and HOMA BETA% were calculated by the formula. Subjects were divided into obese nondiabetic, obese prediabetic and obese diabetic according to WHO criteria. Results: Out of 210 obese subjects, 53 (25.2%) were males and 157 (74.8%) were females. The mean BMI was 32.39±5.21. Mean abdominal circumference was 102.78±10.16. There were 101(48%) obese nondiabetic, 51(24%) were found to be obese prediabetic, 58(28%) were found to be obese diabetic. Mean insulin resistance in obese nondiabetic subjects was 2.8 ±3.7, in prediabetic 8.5± 12.3, in diabetic was 17.7±24.6. Mean HOMA beta was 245.3±267.4 in obese nondiabetic subjects, 290.5±298.4 in prediabetic, and 16.6±57 in diabetic. Conclusion: There was a significantly increased incidence of prediabetes and diabetes in obese subjects. Prediabetic and diabetic subjects were found to have marked insulin resistance. Beta-cell function was markedly reduced in diabetic subjects having a family history of diabetes, emphasizing the genetic predisposition to develop beta-cell exhaustion.

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