MON-613 The Expression of TBC1 Domain Family, Member 4 (TBC1D4) in Skeletal Muscles of Insulin-Resistant Mice in Response to Sulforaphane

Abstract The Expression of TBC1 Domain Family, member 4 (TBC1D4) in Skeletal Muscles of Insulin-Resistant Mice in Response to Sulforaphane. Background: Obesity is commonly accompanied by impaired glucose homeostasis. Decreased glucose transport to the peripheral tissues, mainly skeletal muscle, leads to reduced total glucose disposal and hyperglycemia. TBC1D4 gene is involved in the trafficking of GLUT4 to the outer cell membrane in skeletal muscle. Sulforaphane (SFN) has been suggested as a new potential anti-diabetic compound acting by reducing blood glucose levels through mechanisms not fully understood (1). The aim of this study is to investigate the effects SFN on TBC1D4 and GLUT4 gene expression in skeletal muscles of DIO mice, in order to elucidate the mechanism(s) through which SFN improves glucose homeostasis. Methodology: C57BL/6 mice (n=20) were fed with a high fat diet (60%) for 16 weeks to generate diet induced obese (DIO) mice with body weights between 45–50 gm. Thereafter, DIO mice received either SFN (5mg/kg BW) (n=10) or vehicle (n=10) as controls daily by intraperitoneal injections for four weeks. Glucose tolerance test (1g/kg BW, IP) and insulin sensitivity test (ITT) were conducted (1 IU insulin/ g BW, IP route) at the beginning and end of the third week of the injection. At the end of 4 weeks of the injection, samples of blood and skeletal muscles of both hindlimbs were collected. The expression levels of GLUT4 and TBC1D4 genes were analyzed by qRT-PCR. Blood was also used for glucose, adiponectin and insulin measurements. Results: SFN-treated DIO mice had significantly lower non-fasting blood glucose levels than vehicle-treated mice (194.16 ± 14.12 vs. 147.44 ± 20.31 mg/dL, vehicle vs. SFN, p value=0.0003). Furthermore, GTT results indicate that the blood glucose levels at 120 minutes after glucose infusion in was (199.83±34.53 mg/dl vs. 138.55±221.78 mg/dl) for vehicle vs. SFN with p=0.0011 respectively. ITT showed that SFN treatment did not enhance insulin sensitivity in DIO mice. Additionally, SFN treatment did not significantly change the expression of TBC1D4, and GLUT4 genes in skeletal muscles compared to vehicle treatment (p values >0.05). Furthermore, SFN treatment did not significantly affect the systemic insulin (1.84±0.74 vs 1.54±0.55 ng/ml, p=0.436), or adiponectin (11.96 ±2.29 vs 14.4±3.33 ug/ml, p=0.551) levels in SFN vs. vehicle-treated DIO mice, respectively. Conclusion: SFN treatment improves glucose disposal in DIO mice, which is not linked to the gene expression of GLUT4 and TBC1D4 and its mechanism of glucose disposal in skeletal muscles. Furthermore, SFN treatment did not improve insulin level, and the insulin sensitizer hormone adiponectin as potential players for enhancing insulin sensitivity. 1. Axelsson AS, Tubbs E, Mecham B, Chacko S, Nenonen HA, Tang Y, et al. Sci Transl Med. 2017;9(394).

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Regulation of Postabsorptive and Postprandial Glucose Metabolism by Insulin-Dependent and Insulin-Independent Mechanisms: An Integrative Approach

Nutrients ◽

10.3390/nu13010159 ◽

2021 ◽

Vol 13 (1) ◽

pp. 159

Author(s):

George D. Dimitriadis ◽

Eirini Maratou ◽

Aikaterini Kountouri ◽

Mary Board ◽

Vaia Lambadiari

Keyword(s):

Skeletal Muscle ◽

Blood Glucose ◽

Glucose Homeostasis ◽

Glucose Production ◽

Postprandial Glucose ◽

Mass Action ◽

Glucose Disposal ◽

Nonesterified Fatty Acids ◽

Glucose Levels ◽

Blood Glucose Levels

Glucose levels in blood must be constantly maintained within a tight physiological range to sustain anabolism. Insulin regulates glucose homeostasis via its effects on glucose production from the liver and kidneys and glucose disposal in peripheral tissues (mainly skeletal muscle). Blood levels of glucose are regulated simultaneously by insulin-mediated rates of glucose production from the liver (and kidneys) and removal from muscle; adipose tissue is a key partner in this scenario, providing nonesterified fatty acids (NEFA) as an alternative fuel for skeletal muscle and liver when blood glucose levels are depleted. During sleep at night, the gradual development of insulin resistance, due to growth hormone and cortisol surges, ensures that blood glucose levels will be maintained within normal levels by: (a) switching from glucose to NEFA oxidation in muscle; (b) modulating glucose production from the liver/kidneys. After meals, several mechanisms (sequence/composition of meals, gastric emptying/intestinal glucose absorption, gastrointestinal hormones, hyperglycemia mass action effects, insulin/glucagon secretion/action, de novo lipogenesis and glucose disposal) operate in concert for optimal regulation of postprandial glucose fluctuations. The contribution of the liver in postprandial glucose homeostasis is critical. The liver is preferentially used to dispose over 50% of the ingested glucose and restrict the acute increases of glucose and insulin in the bloodstream after meals, thus protecting the circulation and tissues from the adverse effects of marked hyperglycemia and hyperinsulinemia.

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Gene expression analysis of the liver and skeletal muscle of psyllium-treated mice

British Journal Of Nutrition ◽

10.1017/s0007114512001250 ◽

2012 ◽

Vol 109 (3) ◽

pp. 383-393 ◽

Cited By ~ 7

Author(s):

Naoyuki Togawa ◽

Rumiko Takahashi ◽

Shizuka Hirai ◽

Tatsunobu Fukushima ◽

Yukari Egashira

Keyword(s):

Gene Expression ◽

Skeletal Muscle ◽

Fatty Acid ◽

Blood Glucose ◽

Total Cholesterol ◽

Lipid Transport ◽

Acid Oxidation ◽

Plasma Total Cholesterol ◽

Glucose Levels ◽

Blood Glucose Levels

Psyllium, a dietary fibre rich in soluble components, has both cholesterol- and TAG-lowering effects. Many studies have verified these actions using liver samples, whereas little information is available on the effects of psyllium treatment on other organs. The purpose of the present study was to evaluate the possible beneficial effects of psyllium. We investigated the gene expression profiles of both liver and skeletal muscle using DNA microarrays. C57BL/6J mice were fed a low-fat diet (LFD; 7 % fat), a high-fat diet (HFD; 40 % fat) or a HFD with psyllium (40 % fat+5 % psyllium; HFD+Psy) for 10 weeks. Body weights and food intake were measured weekly. After 10 weeks, the mice were killed and tissues were collected. Adipose tissues were weighed, and plasma total cholesterol and TAG blood glucose levels were measured. The expression levels of genes involved in glycolysis, gluconeogenesis, glucose transport and fatty acid metabolism were measured by DNA microarray in the liver and skeletal muscle. In the HFD+Psy group, plasma total cholesterol, TAG and blood glucose levels significantly decreased. There was a significant reduction in the relative weight of the epididymal and retroperitoneal fat tissue depots in mice fed the HFD+Psy. The expression levels of genes involved in fatty acid oxidation and lipid transport were significantly up-regulated in the skeletal muscle of the HFD+Psy group. This result suggests that psyllium stimulates lipid transport and fatty acid oxidation in the muscle. In conclusion, the present study demonstrates that psyllium can promote lipid consumption in the skeletal muscle; and this effect would create a slightly insufficient glucose state in the liver.

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Vanadyl Sulfate Treatment Stimulates Proliferation and Regeneration of Beta Cells in Pancreatic Islets

Journal of Diabetes Research ◽

10.1155/2014/540242 ◽

2014 ◽

Vol 2014 ◽

pp. 1-7 ◽

Cited By ~ 15

Author(s):

Samira Missaoui ◽

Khémais Ben Rhouma ◽

Mohamed-Tahar Yacoubi ◽

Mohsen Sakly ◽

Olfa Tebourbi

Keyword(s):

Blood Glucose ◽

Insulin Sensitivity ◽

Pancreatic Islets ◽

Beta Cells ◽

Control Level ◽

Diabetic Rats ◽

Diabetic Group ◽

Dependent Manner ◽

Glucose Levels ◽

Blood Glucose Levels

We examined the effects of vanadium sulfate (VOSO4) treatment at 5 and 10 mg/kg for 30 days on endocrine pancreas activity and histology in nondiabetic and STZ-induced diabetic rats. In diabetic group, blood glucose levels significantly increased while insulinemia level markedly decreased. At the end of treatment, VOSO4at a dose of 10 mg/Kg normalized blood glucose level in diabetic group, restored insulinemia, and significantly improved insulin sensitivity. VOSO4also increased in a dose-dependent manner the number of insulin immunopositive beta cells in pancreatic islets of nondiabetic rats. Furthermore, in the STZ-diabetic group, the decrease in the number of insulin immunopositive beta cells was corrected to reach the control level mainly with the higher dose of vanadium. Therefore, VOSO4treatment normalized plasma glucose and insulin levels and improved insulin sensitivity in STZ-experimental diabetes and induced beta cells proliferation and/or regeneration in normal or diabetic rats.

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Glycogen repletion following continuous and intermittent exercise to exhaustion

Journal of Applied Physiology ◽

10.1152/jappl.1980.49.4.722 ◽

1980 ◽

Vol 49 (4) ◽

pp. 722-728 ◽

Cited By ~ 49

Author(s):

G. A. Gaesser ◽

G. A. Brooks

Keyword(s):

Skeletal Muscle ◽

Blood Glucose ◽

Intermittent Exercise ◽

Lactate Concentration ◽

Glucose Levels ◽

Blood Glucose Levels ◽

Complete Restoration ◽

Female Wistar Rats ◽

Endogenous Substrates ◽

Glycogen Repletion

Patterns of postexercise glycogen repletion in heart, skeletal muscle, and liver in the absence of exogenously supplied substrates during the first 4 h of recovery were assessed. Female Wistar rats were run to exhaustion using continuous (1.0 mph, 15% grade) and intermittent (alternate 1-min intervals at 0.5 and 1.5 mph, 15% grade) exercise protocols. Rats at exhaustion were characterized by marked depletion of glycogen in heart (55%), skeletal muscle (94%), and liver (97%). Blood glucose levels at exhaustion (1.33 mumol/g) were only 37% of preexercise levels. There were no significant differences between continuous and intermittent exercise groups for any of the tissue glycogen or blood glucose values. Cardiac muscle was the only tissue capable of complete restoration of glycogen levels while relying exclusively upon endogenous substrates. Concentrations of endogenous substrates present at the end of exercise were insufficient to support restoration of blood glucose levels to preexercise values nor support glycogen repletion in skeletal muscle and liver during the initial 4-h food-restricted postexercise period. With subsequent feeding, skeletal muscle demonstrated a glycogen supercompensation effect at 24 h (181.1 and 191.8% of preexercise levels for continuous and intermittent exercise, respectively). Lactate concentration in all tissues at the point exhaustion (1.5--2.5 times resting levels) were only moderately elevated and returned to preexercise levels within 15 min. It was concluded that lactate removal after exercise contributed only minimally to the repletion of muscle glycogen.

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Feedback regulation of hepatic gluconeogenesis through modulation of SHP/Nr0b2 gene expression by Sirt1 and FoxO1

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00524.2010 ◽

2011 ◽

Vol 300 (2) ◽

pp. E312-E320 ◽

Cited By ~ 41

Author(s):

Dan Wei ◽

Rongya Tao ◽

Yao Zhang ◽

Morris F. White ◽

X. Charlie Dong

Keyword(s):

Gene Expression ◽

Blood Glucose ◽

Catalytic Domain ◽

Wild Type Mouse ◽

Diabetic Mouse ◽

Luciferase Reporter ◽

Wild Type ◽

Hepatic Gluconeogenesis ◽

Glucose Levels ◽

Blood Glucose Levels

Protein deacetylase Sirt1 has been implicated in the regulation of hepatic gluconeogenesis; however, the mechanisms are not fully understood. To further elucidate how Sirt1 regulates gluconeogenesis, we took a loss-of-function approach by deleting the coding DNA sequence for the catalytic domain of the Sirt1 gene in the liver of a wild-type mouse (LKOSirt1) or a genetic diabetic mouse in which hepatic insulin receptor substrates 1 and 2 are deleted (DKOIrs1/2). Whereas LKOSirt1 mice exhibited normal levels of fasting and fed blood glucose, inactivation of Sirt1 in DKOIrs1/2 mice (TKOIrs1/2:Sirt1) reduced blood glucose levels and moderately improved systemic glucose tolerance. Pyruvate tolerance was also significantly improved in TKOIrs1/2:Sirt1 mice, suggesting that Sirt1 promotes hepatic gluconeogenesis in this diabetic mouse model. To understand why inactivation of hepatic Sirt1 does not alter blood glucose levels in the wild-type background, we searched for a potential cause and found that expression of small heterodimer partner (SHP, encoded by the Nr0b2 gene), an orphan nuclear receptor, which has been shown to suppress the activity of forkhead transcription factor FoxO1, was decreased in the liver of LKOSirt1 mice. Furthermore, our luciferase reporter assays and chromatin immunoprecipitation analysis revealed that the Nr0b2 gene is a target of FoxO1, which is also regulated by Sirt1. After the gene is upregulated, Nr0b2 can feed back and repress FoxO1- and Sirt1-activated G6pc and Pdk4 gene expression. Thus, our results suggest that Sirt1 can both positively and negatively regulate hepatic gluconeogenesis through FoxO1 and Nr0b2 and keep this physiological process in control.

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Suppression of Prolactin Secretion Partially Explains the Antidiabetic Effect of Bromocriptine in ob/ob Mice

Endocrinology ◽

10.1210/en.2018-00629 ◽

2018 ◽

Vol 160 (1) ◽

pp. 193-204 ◽

Cited By ~ 5

Author(s):

Isadora C Furigo ◽

Miriam F Suzuki ◽

João E Oliveira ◽

Angela M Ramos-Lobo ◽

Pryscila D S Teixeira ◽

...

Keyword(s):

Insulin Resistance ◽

Blood Glucose ◽

Insulin Sensitivity ◽

Glucose Homeostasis ◽

Prolactin Secretion ◽

Dopamine Receptor Agonist ◽

Glucose Levels ◽

Blood Glucose Levels ◽

Insulin Tolerance ◽

Promising Therapeutic Approach

Abstract Previous studies have shown that bromocriptine mesylate (Bromo) lowers blood glucose levels in adults with type 2 diabetes mellitus; however, the mechanism of action of the antidiabetic effects of Bromo is unclear. As a dopamine receptor agonist, Bromo can alter brain dopamine activity affecting glucose control, but it also suppresses prolactin (Prl) secretion, and Prl levels modulate glucose homeostasis. Thus, the objective of the current study was to investigate whether Bromo improves insulin sensitivity via inhibition of Prl secretion. Male and female ob/ob animals (a mouse model of obesity and insulin resistance) were treated with Bromo and/or Prl. Bromo-treated ob/ob mice exhibited lower serum Prl concentration, improved glucose and insulin tolerance, and increased insulin sensitivity in the liver and skeletal muscle compared with vehicle-treated mice. Prl replacement in Bromo-treated mice normalized serum Prl concentration without inducing hyperprolactinemia. Importantly, Prl replacement partially reversed the improvements in glucose homeostasis caused by Bromo treatment. The effects of the Prl receptor antagonist G129R-hPrl on glucose homeostasis were also investigated. We found that central G129R-hPrl infusion increased insulin tolerance of male ob/ob mice. In summary, our findings indicate that part of Bromo effects on glucose homeostasis are associated with decrease in serum Prl levels. Because G129R-hPrl treatment also improved the insulin sensitivity of ob/ob mice, pharmacological compounds that inhibit Prl signaling may represent a promising therapeutic approach to control blood glucose levels in individuals with insulin resistance.

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Relationship of substrate level to turnover rate in fasted adult and newborn dogs

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1988.254.2.e137 ◽

1988 ◽

Vol 254 (2) ◽

pp. E137-E143 ◽

Cited By ~ 1

Author(s):

S. Hulman ◽

R. Kliegman ◽

J. Heng ◽

E. Crouser

Keyword(s):

Blood Glucose ◽

Glucose Metabolism ◽

Inverse Function ◽

Glucose Disposal ◽

Glucose Turnover ◽

Metabolic Clearance ◽

Glucose Levels ◽

Blood Glucose Levels ◽

Glucose Clearance ◽

Plasma Insulin Levels

Glucose turnover, clearance and response to insulin were determined in fasted newborn and adult dogs. Fasting levels of glucose and insulin and rates of glucose turnover and clearance were not different between the two groups. Blood glucose correlated with basal glucose turnover in newborn pups but not in adult dogs. Glucose turnover was not related to fasting plasma insulin levels. Glucose clearance was an inverse function of blood glucose levels among newborn but not adult dogs. Glucose clearance and blood glucose levels were not related to insulin concentrations. In response to euglycemic hyperinsulinemia, glucose metabolism increased 4-fold among adults but only 1.7-fold in pups. Hyperglycemic hyperinsulinemia increased glucose metabolism in both groups but to a much greater extent in the pups. Euglycemic hyperinsulinemia increased the metabolic clearance rate of glucose 4.2-fold among adults but only 1.8-fold in newborn dogs. In response to hyperglycemic hyperinsulinemia glucose clearance rates were now similar. Despite euglycemic hyperinsulinemia, the newborn dog had an attenuated response to insulin, demonstrating lower rates of glucose metabolism and glucose clearance. The response to the hyperglycemic stimuli suggests that maximal glucose uptake was not achieved during hyperinsulinemia alone. This response supports the concept of glucose-mediated regulation of glucose disposal in newborn animals.

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Effect of consumption of a carob pod inositol-enriched beverage on insulin sensitivity and inflammation in middle-aged prediabetic subjects

Food & Function ◽

10.1039/c6fo01021k ◽

2016 ◽

Vol 7 (10) ◽

pp. 4379-4387 ◽

Cited By ~ 6

Author(s):

Celia Bañuls ◽

Susana Rovira-Llopis ◽

Sandra López-Doménech ◽

Silvia Veses ◽

Víctor M. Víctor ◽

...

Keyword(s):

Body Mass Index ◽

Blood Glucose ◽

Insulin Sensitivity ◽

Body Mass ◽

Impaired Fasting Glucose ◽

Fasting Glucose ◽

Middle Aged ◽

Glucose Levels ◽

Blood Glucose Levels ◽

Carob Pod

This study assessed the effects of an inositol-enriched beverage (IEB) on blood glucose levels and inflammation status in subjects with an impaired fasting glucose (IFG) state according to body mass index (BMI).

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Inflammation but not Glycemic Control is Associated with Neurocognitive Decline After Cardiac Surgery

10.22541/au.162349776.69083213/v1 ◽

2021 ◽

Author(s):

Laura Scrimgeour ◽

Ian Ikeda ◽

Nicholas Sellke ◽

Guangbin Shi ◽

Jun Feng ◽

...

Keyword(s):

Gene Expression ◽

Cardiac Surgery ◽

Blood Glucose ◽

Glycemic Control ◽

Transcriptome Analysis ◽

Neurocognitive Function ◽

Human Transcriptome ◽

Glucose Levels ◽

Blood Glucose Levels ◽

Neurocognitive Decline

Background: Whether perioperative glycemic control or markers of inflammation is associated with neurocognitive decline (NCD) after cardiac surgery was examined. Methods: Thirty patients undergoing cardiac surgery utilizing cardiopulmonary bypass (CPB) were screened for NCD preoperatively and on post-operative day four (POD4). Serum cytokine levels were measured and human transcriptome analysis was performed on blood samples. Neurocognitive data are presented as a change from baseline to POD4 in a score standardized with respect to age and gender. Results: A decline in neurocognitive function was identified in 73% (22/30) of patients on POD4. Patients with postoperative leukocytosis (WBC ≥ 10.5) had more NCD when compared to their baseline function (p=0.03). Patients with elevated IL-8 levels at 6 hours postoperatively had a significant decline in NCD at POD4 (p=0.04). Surprisingly, TNF-α, IL-1β, IL-2, or IL-6 levels were not associated with NCD (p>0.3 for all). There was no difference in neurocognitive function between patients with elevated HbA1c levels preoperatively (p=0.973) or elevated fasting blood glucose levels the morning of surgery (>126mg/dL, p=0.910), or a higher maximum blood glucose levels during CPB (>180mg/dL, p=0.252), or higher average glucose levels during CPB (>160mg/dL, p=0.639). Human transcriptome analysis demonstrated unique and differential patterns of gene expression in patients depending on the presence of DM and NCD. Conclusions: Perioperative glycemic control does not have an effect on NCD soon after cardiac surgery. Postoperative leukocytosis and elevated IL-8 levels are associated with neurocognitive decline. The profile of gene expression was altered in patients with NCD with or without diabetes.

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Enzymatic digest of whey protein and wheylin-1, a dipeptide released in the digest, increase insulin sensitivity in an Akt phosphorylation-dependent manner

Food & Function ◽

10.1039/c8fo00919h ◽

2018 ◽

Vol 9 (9) ◽

pp. 4635-4641 ◽

Cited By ~ 4

Author(s):

Maiko Ogiwara ◽

Wakana Ota ◽

Takafumi Mizushige ◽

Ryuhei Kanamoto ◽

Kousaku Ohinata

Keyword(s):

Blood Glucose ◽

Insulin Sensitivity ◽

Whey Protein ◽

Dependent Manner ◽

Increase Insulin Sensitivity ◽

Akt Phosphorylation ◽

Glucose Levels ◽

Blood Glucose Levels

Wheylin-1 is the first whey-derived peptide that increases insulin sensitivity in an Akt phosphorylation-dependent manner and lowers blood glucose levels.

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