Glucose Utilization In Peripheral Tissues Research Articles

RF04 | PSUN297 Genetic Knockout of Intestinal Hexokinase Domain Containing Protein-1 Affects Enterocyte Glucose Transport in Mice Fed High Fat Diet

Abstract Hexokinase domain containing protein-1, or HKDC1, is a widely expressed novel hexokinase that is genetically associated with elevated 2-hour gestational blood glucose levels during an oral glucose tolerance test, suggesting a role for HKDC1 in postprandial glucose regulation during pregnancy. Our earlier studies utilizing transgenic mice containing whole-body HKDC1 knockdown, or mice in which hepatic HKDC1 was overexpressed or knocked out, indicated that HKDC1 is important for whole-body glucose homeostasis in aging and pregnancy, through modulation of glucose tolerance, peripheral tissue glucose utilization, and hepatic energy storage. However, our knowledge of the precise mechanisms by which HKDC1 regulates postprandial glucose homeostasis under normal and diabetic conditions is lacking. As the intestine is the main entry portal for dietary glucose, and since HKDC1 is highly expressed within the intestine, in this study we assessed and characterized the in vivo significance of intestine-specific HKDC1 in regulating glucose homeostasis under normal and obesogenic conditions. We developed an intestine-specific HKDC1 knockout mouse model, HKDC1Int-/-, utilizing Cre-mediated recombination of HKDC1 in which Cre was expressed under the control of the villin gene promoter, leading to genetic knockout of HKDC1 solely within the intestinal epithelium. Mice were maintained until 28 weeks of age on either a normal chow diet or a high fat diet to develop obesity, hyperglycemia, and insulin resistance. While no overt glycemic phenotype was observed, 28-week-old HKDC1Int-/- mice fed a high fat diet exhibited an increased glucose excursion following an oral glucose load compared to mice expressing intestinal HKDC1. This finding was not due to differences in insulin levels, whole-body insulin tolerance, or gluconeogenesis, nor was it a result of alterations in enterocyte glucose utilization or a reduction in peripheral skeletal muscle glucose uptake. Furthermore, the enhanced glucose excursion was related to transport of glucose through the intestinal epithelium, as mice administered an intraperitoneal glucose load did not exhibit alterations in post-load glycemic excursion. Assessment of intestinal glucose transporters in high fat diet-fed HKDC1Int-/- mice indicated an increased expression of GLUT2 in the enterocyte apical membrane in the fasting state. Taken together, our results indicate that intestine-specific HKDC1 contributes to postprandial glycemic regulation by modulating dietary glucose transport across the intestinal epithelium under conditions of enhanced metabolic stress, such as obesity, hyperglycemia, and diabetes. Presentation: Saturday, June 11, 2022 1:24 p.m. - 1:29 p.m., Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

240-OR: Quantifying Glucose Utilization and Endogenous Glucose Production during Resistance Exercise in People with Type 1 Diabetes (T1D)

Glucose dynamics during and after resistance exercise in people with T1D is not well understood. We recruited 25 people with T1D to perform 3 separate sessions of in-clinic resistance exercise under low (basal) , medium (1.5x basal) , or high (3.0x basal) insulin infusion levels. Blood glucose was clamped by intravenous dextrose infusion 3 hours prior to, and 4 hours after a 45-minute session of strength training. Glucose tracer was infused to match the rate of endogenous glucose production (EGP) . Glucose and tracer data were used to fit a two-compartment model and quantify the rate of glucose disposal (Rd) and EGP. For 58 sessions across 25 participants, blood glucose levels remained constant during and after resistance exercise. The mean change in area under the curve (AUC) for Rd was not higher during resistance exercise compared to baseline (+1.2 mM, p=0.69) , but increased during previously published aerobic exercise (+12.5 mM, p<0.01) . Mean AUC for EGP rose during resistance exercise (+6.5 mM, p<0.01) primarily due to non-insulin mediated factors and the increase was higher than during aerobic exercise (+2.mM, p<0.01) . Resistance exercise is characterized by a strong rise in EGP that is predominantly driven by non-insulin mediated effects. This may mitigate drops in blood glucose caused by increased glucose utilization in peripheral tissues during anaerobic activity. Disclosure G.Young: None. M.Riddell: Advisory Panel; Zealand Pharma A/S, Zucara Therapeutics, Consultant; Eli Lilly and Company, Jaeb Center for Health Research, Speaker's Bureau; Dexcom, Inc., Eli Lilly and Company, Novo Nordisk. J.El youssef: None. P.G.Jacobs: Other Relationship; Pacific Diabetes Technologies, Research Support; Dexcom, Inc. N.S.Tyler: None. T.P.Nguyen: None. J.R.Castle: Advisory Panel; Insulet Corporation, Novo Nordisk, Zealand Pharma A/S, Stock/Shareholder; Pacific Diabetes Technologies. L.M.Wilson: n/a. D.Branigan: None. V.Gabo: None. F.H.Guillot: Stock/Shareholder; Pacific Diabetes Technologies. Funding National Institutes of Health (5R01DK110175, 1F30DK128914)

Enterocyte HKDC1 Modulates Intestinal Glucose Absorption in Male Mice Fed a High-fat Diet.

Hexokinase domain containing protein-1, or HKDC1, is a widely expressed hexokinase that is genetically associated with elevated 2-hour gestational blood glucose levels during an oral glucose tolerance test, suggesting a role for HKDC1 in postprandial glucose regulation during pregnancy. Our earlier studies utilizing mice containing global HKDC1 knockdown, as well as hepatic HKDC1 overexpression and knockout, indicated that HKDC1 is important for whole-body glucose homeostasis in aging and pregnancy, through modulation of glucose tolerance, peripheral tissue glucose utilization, and hepatic energy storage. However, our knowledge of the precise role(s) of HKDC1 in regulating postprandial glucose homeostasis under normal and diabetic conditions is lacking. Since the intestine is the main entry portal for dietary glucose, here we have developed an intestine-specific HKDC1 knockout mouse model, HKDC1Int–/–, to determine the in vivo role of intestinal HKDC1 in regulating glucose homeostasis. While no overt glycemic phenotype was observed, aged HKDC1Int–/– mice fed a high-fat diet exhibited an increased glucose excursion following an oral glucose load compared with mice expressing intestinal HKDC1. This finding resulted from glucose entry via the intestinal epithelium and is not due to differences in insulin levels, enterocyte glucose utilization, or reduction in peripheral skeletal muscle glucose uptake. Assessment of intestinal glucose transporters in high-fat diet–fed HKDC1Int–/– mice suggested increased apical GLUT2 expression in the fasting state. Taken together, our results indicate that intestinal HKDC1 contributes to the modulation of postprandial dietary glucose transport across the intestinal epithelium under conditions of enhanced metabolic stress, such as high-fat diet.

CME/Answers: Metformin - Dos and Don'ts

CME/Answers: Metformin - Dos and Don'ts Abstract. CME/Answers: Metformin - Dos and Don'ts In the absence of contraindications metformin is still considered the initial medication in patients with diabetes mellitus type 2, although diabetes therapy is rapidly changing. Metformin is used both as monotherapy and in combination with any other diabetic medication. As a biguanide metformin improves glycemic control by inhibiting gluconeogenesis and increasing insulin-mediated glucose utilization in peripheral tissues. Metformin promotes modest weight reduction and provides several other advantages: no risk of hypoglycemia, excellent general tolerability, well-known long-term safety profile and low-cost. The most common gastrointestinal side effects are usually mild and transient, but vitamin B12 deficiency may develop. Metformin-associated lactic acidosis (MALA) is a rare, but relevant and life-threatening complication. The risk increases with renal impairment; therefore the metformin dose must be adjusted to the eGFR. The use of metformin is contraindicated with an eGFR <30 ml/min/1.73 m2. There are other contraindications: concurrent active or progressive severe liver disease, active alcohol abuse, unstable or acute heart failure, hypoperfusion and hemodynamic instability, as well as a past history of lactic acidosis. Since metformin remains a modern therapy, it is important to be aware of its indications and contraindications.

CME: Metformin - Dos and Don'ts

CME: Metformin - Dos and Don'ts Abstract. In the absence of contraindications metformin is still considered the initial medication in patients with diabetes mellitus type 2, although diabetes therapy is rapidly changing. Metformin is used both as monotherapy and in combination with any other diabetic medication. As a biguanide metformin improves glycemic control by inhibiting gluconeogenesis and increasing insulin-mediated glucose utilization in peripheral tissues. Metformin promotes modest weight reduction and provides several other advantages: no risk of hypoglycemia, excellent general tolerability, well-known long-term safety profile and low-cost. The most common gastrointestinal side effects are usually mild and transient, but vitamin B12 deficiency may develop. Metformin-associated lactic acidosis (MALA) is a rare, but relevant and life-threatening complication. The risk increases with renal impairment; therefore the metformin dose must be adjusted to the eGFR. The use of metformin is contraindicated with an eGFR <30 ml/min/1.73 m2. There are other contraindications: concurrent active or progressive severe liver disease, active alcohol abuse, unstable or acute heart failure, hypoperfusion and hemodynamic instability, as well as a past history of lactic acidosis. Since metformin remains a modern therapy, it is important to be aware of its indications and contraindications.

Gender characteristics of the circadian rhythm of carbohydrate metabolism

Aim of the study was to explore the gender characteristics of the circadian rhythm of carbohydrate metabolism in men and women with normal body weight. Materials and methods. 15 men and 22 women aged 18 to 56 entered the study and underwent clinical, antropometric, biochemical and hormonal examination. Standard oral glucose tolerance test (OGTT) was also performed in the morning and in the evening. Results and discussion. During OGTT performed in morning time there were no differences in mean baseline blood glucose levels between men and women. However higher glucose levels at 120th minute of the test in men demonstrated relative deceleration of glucose utilization in the morning in this group. Higher glucose levels at 120th minute during OGTT in the evening both in men and women comparing with baseline results, and also higher glucose levels at 120th minute of the test in the evening comparing with morning test, indicate decreased glucose tolerance. Insulin to glucose ratio values in men at all timepoints during OGTT were comparable in the morning and in the evening, but in women they were found to be higher in the evening than in the morning. Conclusion. In evening time both in men and women with normal body weight reduced rate of glucose utilization in peripheral tissues reflects circadian rhythm of carbohydrate metabolism. Gender differences of the circadian rhythm of carbohydrate metabolism consist in reduced glucose tolerance in the morning in men comparing to women that is associated with higher waist to hip circumference ratio in men which in turn is related to cumulation of visceral adipose tissue. Presumably greater amount of visceral adipose tissue in men determines more pronounced manifestations of insulin resistance in the morning.

Thiazolidine-2, 4-Diones as Non-Hepatotoxic Tri-action Drug Candidates: Design, Synthesis, Characterization, Biological Evaluation and Docking Studies

Thiazolidine-2, 4-diones and their derivatives are a well-established chemical class of compounds that express their pharmacological actions through insulin sensitization and enhanced glucose utilization in peripheral tissues. In the current research different approaches have been employed to synthesize thiazolidine-2, 4-dione derivatives and these synthesized compounds were chemically characterized for the establishment of their chemical structures. A series of thiazolidine-2, 4-dione (TZD) derivatives, Scheme 1 (3A-3V) 22 compounds, were synthesized and characterized by FT-IR, 1H NMR and mass spectral analysis. The title compounds were screened for their in vitro and in vivo antidiabetic, antioxidant, and cytotoxicity studies. In vivo antihyperglycemic effect was assessed by measuring plasma glucose (PG) levels in alloxan-induced type II diabetic rat models. The synthesized TZD derivatives were evaluated for hepatotoxicity and pancreatic tissue integrity. Antioxidant activity was evaluated by the DPPH method and H2O2 method. Thiazolidinedione derivatives were subjected to predict free energy of binding towards target PPAR&amp;#947;, using rosiglitazone as the reference compound for molecular docking visualization through the FlexX docking program. Molecular docking studies are also performed for understanding the binding of a ligand to a receptor. The compound 3V 4-(5- (naphthalen-1-ylmethylene)-2, 4-dioxothiazolidin-3-yl) benzoic acid exhibited better blood glucoselowering activity than that of the standard drug rosiglitazone. Compound 3T and 3U exhibited potent antioxidant activity. Among the tested compounds for cytotoxicity using an MTT assay, compound 3H 5-(4-chlorobenzylidene)-2, 4-dioxothiazolidin-3-yl) benzoic acid exhibited better viability and cytotoxicity activity. From selected anti-diabetic targets, the proposed derivatives exhibited better interaction with PPAR&amp;#947; receptor, for example, while rosiglitazone showed a docking score of -19.891 kJ/mol, compound 3V exhibited highest docking score of -31.6617 kJ/mol. Computational molecular docking study demonstrated the selectivity and provided a binding model for the further refinement of this chemotype. Therefore, this series of thiazolidine-2, 4-diones derivatives (3A-3V) have considerable importance for development as a potential antihyperglycemic and hypolipidemic agents.

Glucose regulates protein turnover and growth-related mechanisms in rainbow trout myogenic precursor cells

Rainbow trout are considered glucose intolerant because they are poor utilizers of glucose, despite having functional insulin receptors and glucose transporters. Following high carbohydrate meals, rainbow trout are persistently hyperglycemic, which is likely due to low glucose utilization in peripheral tissues including the muscle. Also, rainbow trout myogenic precursor cells (MPCs) treated in vitro with insulin and IGF1 increase glucose uptake and protein synthesis, whereas protein degradation is decreased. Given our understanding of glucose regulation in trout, we sought to understand how glucose concentrations affect protein synthesis, protein degradation; and expression of genes associated with muscle growth and proteolysis in MPCs. We found that following 24 h and 48 h of treatment with low glucose media (5.6 mM), myoblasts had significant decreases in protein synthesis. Also, low glucose treatments affected the expression of both mstn2a and igfbp5. These findings support that glucose is a direct regulator of protein synthesis and growth-related mechanisms in rainbow trout muscle.

Cortisol – inspection in the physiology and stress

Cortisol, also called “the” stress hormone is a glucocorticoid secreted by the adrenal cortex. This hormone plays a significant role in maintaining homeostasis, according to the body’s total stress. Cortisol interferes with many organs, affects glucose and fatty acids metabolism and neurotransmitter secretion. Predominantly, cortisol influences the carbohydrate metabolism, stimulating gluconeogenesis in the liver and inhibiting glucose utilization in peripheral tissues. As it is an element “fight or flight” it also stimulates central nervous system and enhances blood flow. To some extent cortisol influences also the renal handling of electrolytes, namely: increasing sodium resorption, and renal excretion of potassium, calcium and phosphates. Through its anti-inflammatory and immunosuppressive character this glucocorticoid modulates the immune system functioning. Cortisol has a circadian rhythm following ACTH (adrenocorticotropic hormone) secretion. Increased cortisol levels are observed physiologically during stress and pathologically in Cushing’s syndrome. Chronic hypercortisolism is harmful or the body, and its effects present an extremely wide spectrum, including insulin resistance, obesity, insomnia and even depression. Thus, laboratory diagnosis of cortisol level is important for the diagnosis, monitoring and evaluate the effectiveness of hypercortisolism treatment.

Preliminary structural characterization and hypoglycemic effects of an acidic polysaccharide SERP1 from the residue of Sarcandra glabra

An acidic polysaccharide (SERP1) was isolated from the residue of Sarcandra glabra (Thunb.) Nakai by water extraction and purified by decoloration and ion exchange chromatography. The structure of SERP1 was determined by HPLC, HPSEC-MALLS, FT-IR, and NMR. The results indicated that SERP1 was a homogeneous heteropolysaccharide with the absolute molecular weight of 4.208×104Da in the aqueous phase. 1,4-linked α-d-galacturonic acid, methyl esterified 1,4-linked α-d-galacturonic acid, 1,4-linked α-d-glucuronic acid, 1,5-linked α-l-arabinose, 1,3-linked β-d-galactose 1,4-linked α-d-glucose, 1,4,6-linked β-d-glucose, 1,6-linked β-d-glucose, and 1,2-linked rhamnose existed in SERP1. In vitro α-glucosidase inhibition assay indicated that SERP1 had a low IC50 value of 49.01μg/mL, which exhibited stronger α-glucosidase enzyme inhibitory activity than acarbose at the same concentration. The treatment of SERP1 to type 2 diabetes mellitus mice alleviated the hyperglycemia, increased glucose utilization of peripheral tissues of the liver and inhibited the liver injury. This study provides a possible exploration to use valuable industrial waste.

The Antidiabetic Potential of Quercetin: Underlying Mechanisms.

The dramatic increase in modern lifestyle diseases such as cancer, cardiovascular diseases and diabetes has renewed researchers' interest to explore nature as a source of novel therapeutic agents. Flavonoids are a large group of polyphenols that are widely present in the human diet. They have shown promising therapeutic activities against a wide variety of ailments. One of the most widely distributed and most extensively studied flavonoid is the flavonol quercetin. Its powerful antioxidant and anti-inflammatory activities are well documented and are thought to play a role in treating and protecting against diseases including diabetes, cancer, neurodegenerative and cardiovascular diseases. The purpose of this review is to shed light on quercetin therapeutic potential as an antidiabetic agent. Quercetin was reported to interact with many molecular targets in small intestine, pancreas, skeletal muscle, adipose tissue and liver to control whole-body glucose homeostasis. Mechanisms of action of quercetin are pleiotropic and involve the inhibition of intestinal glucose absorption, insulin secretory and insulin-sensitizing activities as well as improved glucose utilization in peripheral tissues. Initial studies suggested poor bioavailability of quercetin. However, recent reports have shown that quercetin was detected in the plasma after food or supplements consumption and has a long half-life in human body. Despite the wealth of in vitro and in vivo results supporting the antidiabetic potential of quercetin, its efficacy in diabetic human subjects is yet to be explored.

Molecular mechanisms of hypoglycemic effect of metformin

Metformin mainly gives play to the hypoglycemic effect by reducing hepatic gluconeogenesis and activating glucose utilization of peripheral tissues. It is especially important that inhibiting hepatic gluconeogenesis in the hypoglycemic effect of metformin, of which molecular mechanisms are complicated and diverse, and are related to drug concentrations. Metformin, at pharmacologic concentrations, may directly inhibit mitochondria glycerophosphate dehydrogenase, resulting in reduced nicotinamide adenine dinucleotide(NADH)accumulation in cytosol and reducing pyruvate/lactate ratio, thus inhibiting gluconeogenesis. This effect is dependent on neither AMP nor adenosine monophosphate-activated protein kinase(AMPK). Metformin at pharmacologic concentrations may also promote subunit assembly of AMPK to activate AMPK directly, thereby inhibiting hepatic gluconeogenesis. This effect is independent on AMP while dependent on AMPK. Metformin, at supra-pharmacologic concentrations, may inhibit mitochondrial complex Ⅰ, thus decrease ATP/AMP ratio, thereby activating AMPK and inhibiting hepatic gluconeogenesis. The reduction of ATP/AMP ratio also inhibits gluconeogenesis directly by energy chargeing mechanism; the accumulation of AMP inhibits adenylate cyclase, reducing levels of cyclic AMP and protein kinase A(PKA)activity, abrogating phosphorylation of critical protein targets of PKA, and blocking hepatic glucagon signaling. Metformin at supra-pharmacologic concentrations also inhibits AMP deaminase, and bypasses mitochondrial respiratory chain to increase AMP level, which activates AMPK and inhibits gluconeogenesis. Metformin at supra-pharmacologic concentrations also inhibits hepatic gluconeogenesis by protein kinase Cζ(PKCζ)-liver kinase B1(LKB1)-AMPK phosphorylation cascade. In addition, before metformin enters the blood, it activates intestinal mucosa(probablly L-cells)AMPK to increase glucagon-like peptide 1(GLP-1)secretion. GLP-1 acts on afferent neuron of intestines vagus to inhibit hepatic gluconeogenesis by vagus efferent neuron of nucleus tractus solitarii(intestines-brain-liver axis route). (Chin J Endocrinol Metab, 2016, 32: 716-722) Key words: Metformin; Diabetes mellitus; Adenosine monophosphate; AMP-activated protein kinase; Mitochondria; Gluconeogenesis

Nrf2-Mediated Regulation of Skeletal Muscle Glycogen Metabolism.

Nrf2 (NF-E2-related factor 2) contributes to the maintenance of glucose homeostasis in vivo Nrf2 suppresses blood glucose levels by protecting pancreatic β cells from oxidative stress and improving peripheral tissue glucose utilization. To elucidate the molecular mechanisms by which Nrf2 contributes to the maintenance of glucose homeostasis, we generated skeletal muscle (SkM)-specific Keap1 knockout (Keap1MuKO) mice that express abundant Nrf2 in their SkM and then examined Nrf2 target gene expression in that tissue. In Keap1MuKO mice, blood glucose levels were significantly downregulated and the levels of the glycogen branching enzyme (Gbe1) and muscle-type PhKα subunit (Phka1) mRNAs, along with those of the glycogen branching enzyme (GBE) and the phosphorylase b kinase α subunit (PhKα) protein, were significantly upregulated in mouse SkM. Consistent with this result, chemical Nrf2 inducers promoted Gbe1 and Phka1 mRNA expression in both mouse SkM and C2C12 myotubes. Chromatin immunoprecipitation analysis demonstrated that Nrf2 binds the Gbe1 and Phka1 upstream promoter regions. In Keap1MuKO mice, muscle glycogen content was strongly reduced and forced GBE expression in C2C12 myotubes promoted glucose uptake. Therefore, our results demonstrate that Nrf2 induction in SkM increases GBE and PhKα expression and reduces muscle glycogen content, resulting in improved glucose tolerance. Our results also indicate that Nrf2 differentially regulates glycogen metabolism in SkM and the liver.

Antidiabetic effect of total saponins from Polygonatum kingianum in streptozotocin-induced daibetic rats

BackgroundPolygonatum kingianum has been used in the prevention and treatment of diabetes, hyperlipidemia and related metabolic syndrome in Asian counties for centuries. In this study, the blood glucose regulation activity and mechanism of total saponins from P. kingianum (TSPK) were investigated in streptozotocin (STZ)-induced diabetic rats in this research. MethodsTSPK (0.025g/kg and 0.1mg/kg) was administrated by gavage to STZ-induced diabetic rats for 8 weeks. Changes of body weight, food intakes, blood glucose, serum insulin and lipid indexes were observed. Genome-wide expression profiling was applied to explore the gene expression alternation after treated with TSPK. Expressions of adenosine monophosphate activated protein kinase (AMPK), phosphoenolpyruvate carboxykinase (PEPCK), the relative transcript level of glucose kinase and glucose-6-phosphatase (GK/G6P) in the liver were investigated. Meanwhile, contents of AMPK, and glucose transporter subtype-4 (GLUT4) in skeletal muscle, and peroxysome proliferator-activated receptor (PPAR-γ) in adipose tissue were investigated. ResultsTSPK could effectively alleviate hyperglycemia and hyperlipidemia in diabetic rats. Genome-wide expression profiling showed that TSPK up-regulated the expression of GLUT4 while down-regulated the expression of G6P in insulin signal pathway. In the liver, the expression of AMPK and GK are increased. Further more, TSPK promoted the expressions of GLUT4 in skeletal muscle, and PPAR-γ in adipose tissue, respectively. ConclusionThese results provide possible mechanisms for the antidiabetic effects of TSPK. TSPK could promote not only glycogenesis but also glucose utilization in peripheral tissue. Our results suggested that TSPK may be used as adjuvant therapy to control blood glucose and insulin resistance in type 2 diabetic individuals.

Linking temperature to metabolism – The role of brown adipose tissue in humans

Insulin resistance is a metabolic disorder evident in most obese patients and characterized by reduced insulin-mediated glucose utilization of peripheral tissues as well as elevated plasma glucose concentrations. Increasing obesity prevalence is paralleled by related metabolic disorders such as insulin resistance and Typ 2 Diabetes mellitus (T2DM). Extensive research efforts across disciplines are made to reveal underlying mechanisms and develop effective therapies against obesity and its comorbidities. Since PET-CT studies provided evidence for functional brown adipose tissue (BAT) in adult humans, this specialized thermogenic compartment of adipocytes again attracted the attention of a large body of research. Activated by moderate cold BAT burns large amounts of carbohydrates and fatty acids as substrates for heat production, thereby significantly contributing to whole-body energy homeostasis. Beneficial metabolic effects of cold-activated BAT, e.g. improved peripheral glucose uptake and increased fatty acid clearance, have been shown in mice and men. To test our hypothesis that BAT enhances insulin sensitivity but not ß-cell-capacity we induced BAT activity by moderate cold assessed human glucose homeostasis by Botnia clamp, which allows measurement of insulin sensitivity and pancreatic ß-cell function within one session. Preliminary data of this pilot study in normal-weight men (n = 15) showed a highly significant 20% increase in glucose uptake due to improved insulin sensitivity during BAT-activation as compared to thermo-neutral conditions. Interestingly, resting energy expenditure as well as pituitary-thyroid axis activity as possible mediators linking BAT activation to glucose homeostasis were unchanged. Although underlying molecular mechanisms remain to be established in follow-up studies, these findings clearly highlight the metabolic significance of BAT activation in men. Therefore, BAT activation might be a promising target for novel treatment approaches in obesity and T2DM.

English

The rapidly increasing incidence of diabetes mellitus is becoming a serious threat to mankindʼs health in all parts of the world and is in a group of metabolic disorders having hyperglycemia as a common manifestation. Implication of oxidative stress in the pathogenesis of diabetes is proposed, not only by oxygen free-radical generation, but also due to non-enzymatic protein glycosylation, auto-oxidation of glucose, impaired glutathione metabolism, alteration in antioxidant enzymes, and lipid peroxides formation. Moreover, oxidative stress induces systemic inflammation, endothelial dysfunction, impaired secretion of pancreatic &beta; cells and impaired glucose utilization in peripheral tissues. Nowadays, the use of antioxidants still remains a controversy, but its use as a therapy for diabetes can be considered, because it demonstrated effectiveness in lowering the risk of diabetes and its complications. Therefore, this review provides an updated overview of experimental in vitro and in vivo investigations on the biological activities of saffron (Crocus sativus L.) and its principal phenolic ingredients, especially focusing on their anti-diabetics effect. This data has led to the suggestion that saffron (C. sativus L.) and its principal phenolic ingredients might be beneficial for preserving diabetes and its complications; however, the application remains controversial. Therefore, this review highlights the antidiabetic effects of saffron and its main ingredients, related to antioxidant properties of carotenoids of saffron. Key words: Antidiabetic, antioxidant, dyslipidemia, saffron.

In vitro anti-hyperglycemia properties of the aqueous stem bark extract from Strychnos henningsii (Gilg)

Strychnos henningsii (SH) is a plant commonly used in southern African traditional medicine for the management of diabetes mellitus. Previous in vivo studies showed that a stem bark extract improves glycemic control in a diabetic animal model. Meanwhile, the mechanism of action has not been elucidated. The present study therefore investigated various in vitro models known to target glucose homeostasis and its direct complications. The plant extract was found to stimulate both basal and insulin stimulated glucose uptake in differentiated 3T3-L1 cells but not in Chang liver cells. The effect on 3T3-L1 cells appears independent of PPARγ as the extract did not stimulate adipogenesis. Although, SH extract was inhibitory toward intestinal alpha glucosidase, the physiological relevance is doubtful based on the recommended dosages. The extract strongly inhibited protein glycation which, at least in part, may be explained by the antioxidant and phenolic content of this plant. Cytotoxicity in Chang liver cells yielded an IC50 value of 130.0 μg/mL raising concern that continual exposure to this herbal remedy may initiate hepatotoxicity. The finding from this study suggests that SH extract may attenuate hyperglycemia through enhanced peripheral tissue glucose utilization.

Assessment of insulin action on carbohydrate metabolism: physiological and non-physiological methods.

Carbohydrate metabolism in humans is regulated by insulin secretion from pancreatic β-cells and glucose disposal by insulin-sensitive tissues. Insulin facilitates glucose utilization in peripheral tissues and suppresses hepatic glucose production. Any defects in insulin action predispose an individual to glucose intolerance and Type 2 diabetes mellitus. Early detection of defects in insulin action could provide opportunities to prevent or delay progression of the disease state. There are different approaches to assess insulin action. Initial methods, such as peripheral insulin concentration and simple indices, have several limitations. Subsequently, researchers developed methodologies using intravenous glucose infusion to determine glucose fluxes. However, these methodologies are limited by being non-physiological. Newer, innovative techniques that have been developed are more sophisticated and physiological. By modelling glucose kinetics using isotope dilution techniques, several robust parameters can be obtained that are physiologically relevant and sound. This brief review summarizes most of the non-physiological and physiological methodologies used to measure the variables of insulin action.

Anti-inflammatory salicylate treatment alters the metabolic adaptations to lactation in dairy cattle

Adapting to the lactating state requires metabolic adjustments in multiple tissues, especially in the dairy cow, which must meet glucose demands that can exceed 5 kg/day in the face of negligible gastrointestinal glucose absorption. These challenges are met through the process of homeorhesis, the alteration of metabolic setpoints to adapt to a shift in physiological state. To investigate the role of inflammation-associated pathways in these homeorhetic adaptations, we treated cows with the nonsteroidal anti-inflammatory drug sodium salicylate (SS) for the first 7 days of lactation. Administration of SS decreased liver TNF-α mRNA and marginally decreased plasma TNF-α concentration, but plasma eicosanoids and liver NF-κB activity were unaltered during treatment. Despite the mild impact on these inflammatory markers, SS clearly altered metabolic function. Plasma glucose concentration was decreased by SS, but this was not explained by a shift in hepatic gluconeogenic gene expression or by altered milk lactose secretion. Insulin concentrations decreased in SS-treated cows on day 7 compared with controls, which was consistent with the decline in plasma glucose concentration. The revised quantitative insulin sensitivity check index (RQUICKI) was then used to assess whether altered insulin sensitivity may have influenced glucose utilization rate with SS. The RQUICKI estimate of insulin sensitivity was significantly elevated by SS on day 7, coincident with the decline in plasma glucose concentration. Salicylate prevented postpartum insulin resistance, likely causing excessive glucose utilization in peripheral tissues and hypoglycemia. These results represent the first evidence that inflammation-associated pathways are involved in homeorhetic adaptations to lactation.

Mesenchymal stem cell therapy to promote peripheral tissue insulin sensitivity in the high‐fat fed, myocardial infarcted mouse

OBJECTIVEIdentify the influence of mesenchymal stem cell (MSC) therapy on peripheral tissue glucose utilization following a myocardial infarction (MI) and dietary‐induced insulin resistance (IR).METHODSC57BL6 mice were high‐fat fed (HFF) for eight weeks. Mice were then segregated into three groups: HFF‐SHAM mice, HFF‐MI+PBS mice undergoing coronary artery ligation to induce a MI followed by intramyocardial injection of phospho‐buffered saline and the HFF‐MI+MSC group receiving MSCs. HFF groups were age‐matched with chow‐fed mice.RESULTSFive weeks post‐MI, glucose utilization was assessed in the conscious, unrestrained mouse by employing a hyperinsulinemic‐euglycemic (insulin) clamp combined with administration of [14C]‐2‐deoxyglucose. The MSC‐treated, chow‐fed mice displayed elevated glucose uptake in the soleus muscle. High‐fat feeding enhanced the MSC‐effect on insulin sensitivity. Whole body insulin responsiveness was higher in the HFF‐MI+MSC, as indicated by a 1.6‐fold increase in glucose infusion rate compared to HFF‐SHAM mice (n=8–12). Also, tissue‐specific glucose uptake (μg/mg/min) was elevated in the soleus (0.95 vs 1.46; HFF‐SHAM vs. HFF‐MI+MSC), gastrocnemius (0.19 vs 0.27), vastus lateralis (0.11 vs 0.23) and adipose tissue (0.03 vs 0.05).CONCLUSIONSMSC transplantation represents a novel therapy for IR induced by diet and a MI. Funded by CIHR and Killam Trusts.