scholarly journals MON-639 Melanocortin 4 Receptor Contributes to Glucose Homeostasis by Regulating Kidney Glucose Reabsorption via the Glucose Transporter GLUT2

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Leticia M de Souza Cordeiro ◽  
Nagavardhini Devisetty ◽  
Kavaljit H Chhabra
Keyword(s):  
Insulin Resistance ◽  
Glucose Tolerance ◽  
Glucose Homeostasis ◽  
Molecular Mechanisms ◽  
Area Under The Curve ◽  
Glucose Transporters ◽  
Oral Glucose ◽  
Melanocortin 4 Receptor ◽  
Glucose Reabsorption ◽  
Deficient Mice

Abstract Melanocortin 4 receptor (MC4R) is essential for normal body weight and food intake. Deficiency of MC4R causes obesity in humans and mice. While the function of MC4R is well established in appetite regulation, its direct role in glucose homeostasis is unclear. Humans and mice with MC4R deficiency exhibit hyperinsulinemia and insulin resistance; however, they remain protected from fasting hyperglycemia/diabetes. To determine the role of MC4R in glucose homeostasis, we performed oral glucose and intra-peritoneal insulin tolerance tests (OGTT / ITT) in male and female Mc4r knockout (KO) and wild type (WT) mice. Remarkably, Mc4r KO mice exhibited improved glucose tolerance compared to WT mice (Area under the curve for OGTT, male: 29,125±2,028 vs. 38,493±1,161 mg/dL.min; female: 36,322±1,100 vs. 49,539±1,911 mg/dL.min, p<0.0001). The improvement in glucose tolerance was despite insulin resistance in Mc4r KO mice (Plasma insulin, male: 9.9±1.7 vs. 0.7±0.1 ng/mL, female: 6.2±2.0 vs. 1.1±0.3 ng/mL, p<0.05; Area under the curve for ITT, male: 13,174±1,073 vs. 8,132±255 mg/dL.min; female: 13,927±1,253 vs. 7,506±267 mg/dL.min, p<0.01). Based on our previous findings from POMC deficient mice, we hypothesized that the improved glucose tolerance in the Mc4r KO mice is due to their elevated glycosuria (excretion of glucose in urine). To test this hypothesis, we challenged Mc4r KO and WT mice with oral glucose (250 mg) and collected their 24h urine to evaluate glycosuria. Indeed, the KO mice demonstrated elevated glycosuria compared to their WT littermates (Urine glucose, male: 284±48 vs. 0.4±0.03 mg/24h, female: 63.4±14 vs. 1±0.6 mg/24h, p<0.002). To assess molecular mechanisms underlying elevated glycosuria in Mc4r KO mice, we measured the gene expression and levels of the kidney glucose transporters GLUT1, GLUT2, SGLT1 and SGLT2. Glut2 mRNA was reduced by ̴ 40% and the protein level was decreased by ̴ 20% in Mc4r KO mice compared to their WT littermates. The other glucose transporters remained unchanged. Altogether, our study demonstrates that MC4R contributes to glucose homeostasis by regulating kidney glucose reabsorption via GLUT2. These findings may explain why MC4R deficient mice or humans remain protected from diabetes despite their longstanding obesity and insulin resistance.

scholarly journals OR26-01 Epinephrine Is Essential for Normal Renal Glucose Reabsorption via the Glucose Transporter GLUT2

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Arwa Mahmoud Elsheikh ◽  
Leticia M de Souza Cordeiro ◽  
Nagavardhini Devisetty ◽  
Steven N Ebert ◽  
Kavaljit H Chhabra
Keyword(s):  
Glucose Tolerance ◽  
Glucose Transporter ◽  
Area Under The Curve ◽  
Glucose Transporters ◽  
Adrenergic System ◽  
Oral Glucose ◽  
Urine Glucose ◽  
Glucose Reabsorption ◽  
Deficient Mice

Abstract Humans and mice with Melanocortin 4 receptor (MC4R) deficiency remain protected from hyperglycemia despite chronic obesity and insulin resistance. We have observed that elevated glycosuria in MC4R deficient mice protects them from hyperglycemia. Moreover, our results indicate that circulating epinephrine may couple MC4R signaling with kidney glucose reabsorption. However, the direct role of epinephrine in regulating kidney glucose reabsorption remains unclear. We hypothesize that epinephrine is essential for maintaining glucose homeostasis via kidney glucose reabsorption. To test this hypothesis, we performed oral glucose tolerance tests (OGTTs) and intraperitoneal insulin tolerance tests (ITTs) in phenylethanolamine-N-methyltransferase (Pnmt) knockout (KO) mice that specifically lack epinephrine but have normal norepinephrine levels. Pnmt KO mice exhibited reduced insulin sensitivity compared to their Wild-Type (WT) littermates (Area under the curve for ITT: 9,700±256 vs. 8,482±417 mg/dL.min, p<0.05). Paradoxically, we observed improved rather than impaired glucose tolerance in Pnmt KO mice compared to their WT controls (Area under the curve for OGTT: 32,546±1,592 vs. 40,058±1,918 mg/dL.min, p<0.05). To ascertain if Pnmt KO mice, like MC4R deficient mice, show elevated glycosuria, we quantified their 24 urine glucose levels after oral glucose (250 mg) challenge. Indeed, Pnmt KO mice demonstrated elevated glycosuria compared to their WT littermates (Urine glucose: Baseline, 24.63±2.2 vs. 11.14±0.82 mg/dl; post glucose challenge: 67.83±5 vs. 16.09±1.13 mg/dl, p<0.001), again validating the phenotype similar to that of MC4R deficient mice. To determine the glucose transporters involved in mediating elevated glycosuria in the Pnmt KO mice, we measured the levels of different renal glucose transporters using western blot. We found that GLUT2 was decreased by ~26% in Pnmt KO mice compared to their WT littermates. Levels of other glucose transporters were not changed, indicating that suppression of renal GLUT2 mediates elevated glycosuria in the epinephrine deficient mice. We validated the direct effect of epinephrine on GLUT2 levels in vitro using mouse primary renal proximal tubule epithelial cells. Indeed, epinephrine selectively increased GLUT2, but did not affect other glucose transporters in the mouse kidney primary cells. Our findings establish the essential role of epinephrine in glucose reabsorption via the renal glucose transporter GLUT2. Therefore, modulating the renal adrenergic system, or, kidney-specific GLUT2 may afford alternative strategies to regulate glycosuria and ultimately mitigate diabetes.

scholarly journals Renal GLUT2 is Essential in Regulating Systemic Glucose Homeostasis by Glycosuria

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A324-A324
Author(s):  
Leticia M de Souza Cordeiro ◽  
Nagavardhini Devisetty ◽  
David McDougal ◽  
Dorien J M Peters ◽  
Kavaljit H Chhabra
Keyword(s):  
Glucose Tolerance ◽  
Glucose Homeostasis ◽  
Serum Insulin ◽  
Urine Volume ◽  
Fold Increase ◽  
Normal Serum ◽  
Oral Glucose ◽  
Loss Of Function ◽  
Melanocortin System ◽  
Deficient Mice

Abstract Diabetes increases renal GLUT2 levels and consequently, worsens hyperglycemia by enhancing glucose reabsorption. We recently demonstrated that renal GLUT2 is a primary effector of the central melanocortin system in regulating glucose homeostasis. Therefore, we hypothesized that renal GLUT2 is essential for maintaining systemic glucose homeostasis by regulating glycosuria. To test the hypothesis, we generated kidney-specific inducible Glut2 knockout (KO) mice [Glut2LoxP/LoxP x KspCadCreERT2 (inducible by tamoxifen)]. These mice exhibited 90% reduction in Glut2 expression selectively in the kidneys, without affecting the expressions of other renal glucose transporters, such as Glut1, Sglt1, and Sglt2. To evaluate the physiological contribution of renal GLUT2 in systemic glucose homeostasis, we performed oral glucose tolerance tests (OGTT) in kidney-specific Glut2 KO mice and their control littermates (Ctrl). We observed that the kidney-specific GLUT2 deficient mice exhibited improved glucose tolerance compared to their Ctrls (AUC for OGTT, 41,950 ±2,014 vs. 52,165 ±1,686 mg/dL.min). To measure glycosuria in the kidney-specific Glut2 KO mice, we placed the mice in metabolic cages and collected 24h urine after acclimating the mice in the new cages. Indeed, the GLUT2 deficient mice had ~1,800-fold increase in urine glucose levels (53.5 ±11 vs. 0.03 ±0.005 mg/24h) and exhibited an increased urine volume (2.5 ±0.3 vs. 0.9 ±0.3 mL/24h) and water intake (7.6 ±0.7 vs. 4.9 ±0.7 mL/24h) compared to their Ctrl littermates. The improvement in glucose tolerance in the kidney-specific Glut2 KO mice was independent of the insulin signaling because we did not observe any changes in insulin tolerance tests (ITT) (AUC for ITT, 10,982 ±414 vs. 11,275 ±583 mg/dL.min) and serum insulin levels (1.07 ±0.14 vs. 1.05 ±0.13 ng/mL) between the groups. Importantly, the kidney-specific GLUT2 deficient mice had normal serum creatinine (0.42 ±0.02 vs. 0.41 ±0.03 mg/dL), free fatty acid (0.43 ±0.14 vs. 0.53±0.14 nmol/µL), β-hydroxybutyrate (0.29 ±0.01 vs. 0.27 ±0.02 mM) and glucagon (14 ±4 vs. 10 ±1 pg/mL) levels. Moreover, the kidney-specific Glut2 KO mice had normal glomerular area (4,190 ±119 vs. 4,219 ±186 µm2) as measured by kidney histology and normal glomerular filtration rate (153 ±9 vs. 173 ±10 [µL/min/b.w.]/100) compared with their Ctrl littermates, indicating the absence of any known renal injury. Altogether, we have developed a new mouse model in which we can knockout Glut2 selectively in the kidneys in adult mice. We show that loss-of-function of kidney-specific GLUT2 improves glucose tolerance due to elevated glycosuria without producing any known side effects. In conclusion, blocking kidney-specific GLUT2 has the potential to treat diabetes.

scholarly journals Metabolomics analysis reveals altered metabolites in lean compared with obese adolescents and additional metabolic shifts associated with hyperinsulinaemia and insulin resistance in obese adolescents: a cross-sectional study

Metabolomics ◽  
2021 ◽  
Vol 17 (1) ◽  
Author(s):  
Elisabeth Müllner ◽  
Hanna E. Röhnisch ◽  
Claudia von Brömssen ◽  
Ali A. Moazzami
Keyword(s):  
Insulin Resistance ◽  
Amino Acids ◽  
Glucose Tolerance ◽  
Insulin Response ◽  
Oral Glucose ◽  
Response Level ◽  
Metabolic Alterations ◽  
Obese Adolescents ◽  
Branched Chain ◽  
Metabolomics Analysis

Abstract Introduction Hyperinsulinaemia and insulin resistance (IR) are strongly associated with obesity and are forerunners of type 2 diabetes. Little is known about metabolic alterations separately associated with obesity, hyperinsulinaemia/IR and impaired glucose tolerance (IGT) in adolescents. Objectives To identify metabolic alterations associated with obesity, hyperinsulinaemia/IR and hyperinsulinaemia/IR combined with IGT in obese adolescents. Methods 81 adolescents were stratified into four groups based on body mass index (lean vs. obese), insulin responses (normal insulin (NI) vs. high insulin (HI)) and glucose responses (normal glucose tolerance (NGT) vs. IGT) after an oral glucose tolerance test (OGTT). The groups comprised: (1) healthy lean with NI and NGT, (2) obese with NI and NGT, (3) obese with HI and NGT, and (4) obese with HI and IGT. Targeted nuclear magnetic resonance-based metabolomics analysis was performed on fasting and seven post-OGTT plasma samples, followed by univariate and multivariate statistical analyses. Results Two groups of metabolites were identified: (1) Metabolites associated with insulin response level: adolescents with HI (groups 3–4) had higher concentrations of branched-chain amino acids and tyrosine, and lower concentrations of serine, glycine, myo-inositol and dimethylsulfone, than adolescents with NI (groups 1–2). (2) Metabolites associated with obesity status: obese adolescents (groups 2–4) had higher concentrations of acetylcarnitine, alanine, pyruvate and glutamate, and lower concentrations of acetate, than lean adolescents (group 1). Conclusions Obesity is associated with shifts in fat and energy metabolism. Hyperinsulinaemia/IR in obese adolescents is also associated with increased branched-chain and aromatic amino acids.

scholarly journals QOL-43. ENDOCRINE AND METABOLIC CHANGES IN CHILDREN TREATED FOR MEDULLOBLASTOMA

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii439-iii439
Author(s):  
Alexey Kalinin ◽  
Natalia Strebkova ◽  
Olga Zheludkova
Keyword(s):  
Insulin Resistance ◽  
Body Composition ◽  
Glucose Tolerance ◽  
Oral Glucose Tolerance Test ◽  
Impaired Glucose Tolerance ◽  
Glucose Tolerance Test ◽  
Tolerance Test ◽  
Hormone Deficiency ◽  
Oral Glucose ◽  
Oral Glucose Tolerance

Abstract We examined 63 patients (40 males/23 females) after complex treatment of medulloblastoma. Patients had a median age (range) of 11.3 (5.5 ÷ 17.9) years. The median time after the end of treatment was 3.7 (1.5 ÷ 11.6) years. Endocrine disorders were detected with the following frequency: growth hormone deficiency - 98.41% (62 of 63 patients), thyroid hormone deficiency – 69.8% (44/63), adrenal hormone deficiency - 17.4% (11/63). Three cases (4.7%) of premature sexual development were also detected. Lipids levels, beta-cell function and insulin resistance (IR) during 2-h oral glucose tolerance test were evaluated. A mono frequent bioelectrical impedanciometer was used to measure body composition. Overweight (SDS BMI> 1) was observed only in 16 patients (3 girls and 13 boys), obesity (SDS BMI> 2) in 1 boy. Dyslipidemia was found in 34 patients (54%). All patients underwent oral glucose tolerance test. Insulin resistance (ISI Matsuda <2.5 and/or HOMA-IR> 3.2) was detected in 7 patients (11/1%), impaired glucose tolerance (120 min glucose ≥7.8 mmol / l) was observed in 2 patients with IR and in 2 patients without IR. At the same time, IR and impaired glucose tolerance were encountered in only 5 children with overweight and no one with obesity. All patients with impaired glucose tolerance had normal values of fasting glucose (4.3 ÷ 5.04 mmol / l) and HbA1c (4.8 ÷ 5.8%). A bioelectrical impedanciometer was used to measure body composition in 49 cases, the percentage of adipose tissue was increased in 14 patients (28%) with normal BMI.

scholarly journals Plasma calcitonin gene-related peptide is increased prior to obesity, and sensory nerve desensitization by capsaicin improves oral glucose tolerance in obese Zucker rats

2005 ◽  
Vol 153 (6) ◽  
pp. 963-969 ◽  
Author(s):  
Dorte X Gram ◽  
Anker J Hansen ◽  
Michael Wilken ◽  
Torben Elm ◽  
Ove Svendsen ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Glucose Tolerance ◽  
Sensory Nerve ◽  
Zucker Rats ◽  
Oral Glucose ◽  
Oral Glucose Tolerance ◽  
Nerve Activity ◽  
Calcitonin Gene ◽  
Obese Rats ◽  
Obese Zucker Rats

Objective: It has earlier been demonstrated that capsaicin-induced desensitization improves insulin sensitivity in normal rats. However, whether increased capsaicin-sensitive nerve activity precedes the onset of insulin resistance in diet-induced obesity – and therefore might be involved in the pathophysiology – is not known. Further, it is of relevance to investigate whether capsaicin desensitization improves glycaemic control even in obese individuals and we therefore chose the obese Zucker rats to test this. Design and methods: Plasma levels of calcitonin gene-related peptide (CGRP; a marker of sensory nerve activity) was assessed in 8-week-old Zucker rats. To investigate whether capsaicin desensitization (100 mg/kg at 9 weeks of age) would also ameliorate glycaemia in this non-diabetic model, we assessed oral glucose tolerance at 7 weeks after capsaicin. Results: It was found that plasma CGRP levels were elevated in obese Zucker rats prior to the onset of obesity (16.1±3.4 pmol/l in pre-obese Zucker rats vs 6.9±1.1 pmol/l in lean littermates; P = 0.015) despite similar body weights. Furthermore, capsaicin desensitization reduced both fasting blood glucose (4.3±0.2 mmol/l vs 5.1±0.2 mmol/l in controls; P = 0.050) as well as the mean blood glucose level during an oral glucose tolerance test (OGTT) (6.8±0.3 mmol/l vs 8.6±0.5 mmol/l in control obese rats; P = 0.024) whereas the plasma insulin levels during the OGTT were unchanged. However this did not lead to an improvement in insulin resistance or to a reduction of tissue triglyceride accumulation in muscle or liver. Conclusion: We concluded that capsaicin-induced sensory nerve desensitization improves glucose tolerance in Zucker rats. Since, in this study, plasma CGRP levels, a marker of sensory nerve activity, were increased in the pre-obese rats, our data support the hypothesis that increased activity of sensory nerves precedes the development of obesity and insulin resistance in Zucker rats.

scholarly journals Effects of Micronutrient Supplementation on Glucose and Hepatic Lipid Metabolism in a Rat Model of Diet Induced Obesity

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1751
Author(s):  
Saroj Khatiwada ◽  
Virginie Lecomte ◽  
Michael F. Fenech ◽  
Margaret J. Morris ◽  
Christopher A. Maloney
Keyword(s):  
Insulin Resistance ◽  
Lipid Metabolism ◽  
Glucose Tolerance ◽  
Antioxidant Capacity ◽  
Fasting Glucose ◽  
Oral Glucose ◽  
Model Assessment ◽  
Micronutrient Supplementation ◽  
Sprague Dawley ◽  
Triglyceride Accumulation

Obesity increases the risk of metabolic disorders, partly through increased oxidative stress. Here, we examined the effects of a dietary micronutrient supplement (consisting of folate, vitamin B6, choline, betaine, and zinc) with antioxidant and methyl donor activities. Male Sprague Dawley rats (3 weeks old, 17/group) were weaned onto control (C) or high-fat diet (HFD) or same diets with added micronutrient supplement (CS; HS). At 14.5 weeks of age, body composition was measured by magnetic resonance imaging. At 21 weeks of age, respiratory quotient and energy expenditure was measured using Comprehensive Lab Animal Monitoring System. At 22 weeks of age, an oral glucose tolerance test (OGTT) was performed, and using fasting glucose and insulin values, Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) was calculated as a surrogate measure of insulin resistance. At 30.5 weeks of age, blood and liver tissues were harvested. Liver antioxidant capacity, lipids and expression of genes involved in lipid metabolism (Cd36, Fabp1, Acaca, Fasn, Cpt1a, Srebf1) were measured. HFD increased adiposity (p < 0.001) and body weight (p < 0.001), both of which did not occur in the HS group. The animals fed HFD developed impaired fasting glucose, impaired glucose tolerance, and fasting hyperinsulinemia compared to control fed animals. Interestingly, HS animals demonstrated an improvement in fasting glucose and fasting insulin. Based on insulin release during OGTT and HOMA-IR, the supplement appeared to reduce the insulin resistance developed by HFD feeding. Supplementation increased hepatic glutathione content (p < 0.05) and reduced hepatic triglyceride accumulation (p < 0.001) regardless of diet; this was accompanied by altered gene expression (particularly of CPT-1). Our findings show that dietary micronutrient supplementation can reduce weight gain and adiposity, improve glucose metabolism, and improve hepatic antioxidant capacity and lipid metabolism in response to HFD intake.

scholarly journals Glucose area under the curve during oral glucose tolerance test as an index of glucose intolerance

2015 ◽  
Vol 7 (1) ◽  
pp. 53-58 ◽  
Author(s):  
Kazuhiko Sakaguchi ◽  
Kazuo Takeda ◽  
Mitsuo Maeda ◽  
Wataru Ogawa ◽  
Toshiyuki Sato ◽  
...  
Keyword(s):  
Glucose Tolerance ◽  
Oral Glucose Tolerance Test ◽  
Glucose Intolerance ◽  
Glucose Tolerance Test ◽  
Area Under The Curve ◽  
Tolerance Test ◽  
Oral Glucose ◽  
Oral Glucose Tolerance

scholarly journals Interplay of Dinner Timing and MTNR1B Type 2 Diabetes Risk Variant on Glucose Tolerance and Insulin Secretion: A Randomized Crossover Trial

2022 ◽  
Author(s):  
Marta Garaulet ◽  
Jesus Lopez-Minguez ◽  
Hassan S Dashti ◽  
Céline Vetter ◽  
Antonio Miguel Hernández-Martínez ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Glucose Tolerance ◽  
Area Under The Curve ◽  
Serum Levels ◽  
Postprandial Glucose ◽  
Oral Glucose ◽  
Elevated Concentration ◽  
Endogenous Melatonin

<strong>Objective: </strong>We tested whether the concurrence of food intake and elevated concentration of endogenous melatonin, as occurs in late eating, results in impaired glucose control, in particular in carriers of the type 2 diabetes-associated G allele in the melatonin-receptor-1-b gene (<i>MTNR1B</i>).<strong> </strong> <p><strong>Research Design and Methods:</strong> In a Spanish natural late eating population, a randomized, cross-over study design was performed, following an 8-h fast. Each participant <strong>(n=845) </strong>underwent two evening 2-h 75g oral glucose tolerance tests (OGTT): an early condition scheduled 4 hours prior to habitual bedtime <strong>(“early dinner-timing”)</strong>, and a late condition scheduled 1 hour prior to habitual bedtime <strong>(“late dinner-timing”)</strong>, simulating an early and a late dinner timing, respectively.<strong> </strong>Differences in postprandial glucose and insulin responses were determined using incremental area under the curve (AUC) calculated by the trapezoidal method between <strong>early and late dinner-timing.</strong><strong></strong></p> <p><strong>Results:</strong> <strong>Melatonin serum levels were </strong>3.5-fold <strong>higher in the late <i>vs. </i>early condition, with late dinner-timing resulting in </strong>6.7% <strong>lower insulin</strong> <strong>area-under-the-curve (AUC) and </strong>8.3%<strong> higher glucose</strong> <strong>AUC. In the late condition<i> MTNR1B</i> G-allele carriers had lower glucose tolerance than non-carriers. Genotype differences in glucose tolerance were attributed to reductions in </strong>β-cell <strong>function (<i>P<sub>int</sub></i><sub> </sub>AUCgluc=0.009, <i>P<sub>int</sub></i><sub> </sub>CIR=0.022, <i>P<sub>int </sub></i>DI=0.018).</strong></p> <p><strong>Conclusions:</strong> <strong>Concurrently high endogenous melatonin and carbohydrate intake, as typical for late eating, impair glucose tolerance, especially in <i>MTNR1B</i> G-risk-allele carriers<i>, </i>attributable to insulin secretion defects.</strong></p>

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