Glucose Uptake In Peripheral Tissues Research Articles

Epidemiology and Management of Hypertension and Diabetes Mellitus in Patients with Mild Autonomous Cortisol Secretion: A Review.

Mild autonomous cortisol secretion (MACS) is associated with a higher cardiometabolic risk than that observed in patients with nonfunctioning adrenal adenomas and in the general population. In patients with MACS, the excess of glucocorticoids affects various metabolic pathways, leading to different manifestations of metabolic syndrome and other comorbidities. Hypertension and diabetes mellitus are two of the most common cardiometabolic comorbidities associated with MACS, reaching a prevalence of up to 80% and up to 40%, respectively. In addition, they are the comorbidities that experienced a greater improvement after adrenalectomy in patients with MACS. Hypertension pathogenesis is multifactorial, including the coexistence of comorbidities such as obesity or diabetes and the role of the different polymorphisms of the glucocorticoid receptor gene, among others. Glucocorticoid-induced diabetes mellitus is mainly related to the detrimental effects of glucocorticoids on insulin-dependent glucose uptake in peripheral tissues, gluconeogenesis and insulin secretion. There are no specific recommendations for hypertension and diabetes treatment in patients with MACS. Thus, considering the similar underlying pathogenesis of hypertension and diabetes mellitus in overt and mild hypercortisolism, our recommendation is to follow this general stepwise approach: surgically remove the adrenal culprit lesion to induce remission from hypercortisolism; control hypercortisolism with steroidogenesis inhibitors; and treat elevated blood pressure or high glucose levels using carefully selected anti-hypertensives and glucose-lowering medications if blood pressure and glucose levels remain uncontrolled, respectively. In this review, we summarize the epidemiology, physiopathology and management of diabetes mellitus and hypertension in patients with MACS.

The Effect of GLP-1 and GIP on the Microvascular Blood Flow after Consuming a Mixed Nutrient Meal: A Research Protocol

Introduction: Nutrient and gas exchange via microvascular blood flow is a key process of circulatory function. There is a significant decrease in the microvascular blood flow to skeletal muscle after orally ingesting glucose. Incretins like glucagon-like peptide-1 (GLP-1) and gastric inhibitory peptide (GIP), are released in response to glucose in the gut, stimulating insulin release. Incretins roles in promoting glucose uptake is thought to impact vascular blood flow. Our protocol plans to investigate if incretins and the subsequent insulin release contribute to the decrease in microvascular blood flow. Methods: 20 healthy young adults will consume a high glucose mixed nutrient meal. Using contrast-enhanced ultrasound (CEU) and a blood glucose meter, microvascular blood flow and blood glucose will be measured. Blood GLP-1 and GIP will be measured using a sandwich enzyme immunoassay, while an electrochemiluminescence technique using an autoanalyzer will measure insulin. Measurements will be recorded at 0, 1, and 2 hours post-prandial. In a randomized order, the protocol will be repeated with infusion of GIP and GLP-1 inhibitors, GIP(3-30)NH2 and exendin(9-39)NH2 or saline. Results: With normal incretin secretion, we anticipate a significant decrease in microvascular blood flow, along with an increase in blood insulin, GIP/GLP-1 levels. We postulate that supressing incretins will increase the microvascular blood flow along with decreased plasma insulin and no change in GLP-1/GIP levels. Discussion: Through our methods, we propose a study design which evaluates the relationship of incretins and insulin on post-prandial microvascular blood flow. Our expected results aim to provide data that can be applied to the progressive treatment of type II diabetes with incretins like GLP-1. Understanding the impact of incretin treatment on the microvascular blood flow could be beneficial to the discovery of an adverse effect or how glucose uptake in peripheral tissues is altered. These are vital aspects of developing a clinical treatment to diabetes and our results will provide a basis to work off. Conclusion: The goal of this protocol was to investigate and provide insight to fully understand incretins and their effects. It will propel research on the biochemical pathways involving incretin and microvascular blood flow, which then helps progress treatment of complications like diabetes.

Effect of adrenalectomy and insulin resistance on non‐shivering thermogenesis in the corpulent rat

Glucocorticoid hormones have been reported to impede optimal insulin sensitivity and glucose uptake in peripheral tissues via interactions with GLUT transporters, leading to insulin resistance and impaired glucose uptake via GLUT transporters. The LA/Ntul//‐cp rat expresses obesity in 25% of the offspring by 5 to 6 weeks of age but remains non diabetic throughout much if not all of its lifespan when normally reared. Groups of congenic lean and obese LA/Ntul//‐cp rats were fed low glycemic Purina Chow diets from 6 to 9 weeks of age or overfed with a high energy cafeteria diet (Café) from 9 until 12 weeks of age. Subgroups of obese animals were adrenalectomized (ADX) at 6 weeks of age (WoA) and subjected to the same dietary regimen to determine if the Café overfeeding could enhance the normal thermic response to norepinephrine (NE) in the obese phenotype and to determine if ADX would result in a restoration of glycemic status and NE‐induced thermogenesis in the obese phenotype. Measures of Oral Glucose Tolerance (OGT), Area under the glucose curve (AUC), and NE‐stimulated VO2 were determined (NE, 200 µg, s.c.) at 6, 9 and 12 WoA in all treatment groups and Insulin:Glucose ratios (I:G) at 12 WoA. Obese animal demonstrated hyperphagia at all ages studied, and Obese ADX hyperphagia from 9 to 12 WoA. OGT and AUC indicated modest glucose intolerance in the obese phenotype, and which was restored following ADX at 6 and 9 WoA. NE resulted in a progressive increase in VO2 in lean rats at each age studied, but NE‐stimulated VO2 was lower in the obese phenotype and decreased further after the Café feeding regimen. ADX was associated with a restoration of OGT, I:G and NE stimulated VO2 equivalent to that observed in lean animals at 12 weeks of age. These results are consistent with adrenocorticoid‐mediated insulin resistance likely due to a receptor level defect in insulin sensitivity as a contributory factor in the impairment in OGT and NST in the obese phenotype of this strain.

Adrenalectomy improves glycemic responses in congenic obese LA/Ntul//-cp RATS

To determine the effects of adrenalectomy on typical insulin-mediated glycemic responses in male obese rats, groups (n=6 -12 rats/phenotype) of normally reared congenic lean and obese animals were fed a Purina chow diet from 6 to 9 weeks of age, and the Chow diet plus a highly palatable cafeteria diet from 9 to 12 weeks of age. The congenic LA/Ntul//-cp rat strain is noted for its longevity and early expression of the obese trait but remains non-diabetic throughout much if not all of its normal lifespan. Subgroups of obese animals were subjected to bilateral adrenalectomy (ADX) at 6 weeks of age to remove glucocorticoid contributions to glycemic parameters. Measures of weight gain (WG )and of glucose tolerance (OGT) were obtained in the three treatment groups at 6, 9 and 12 weeks of age. WG on ADX-obese rats was similar to that of their lean littermates at 6 and 9 weeks of age on the chow diet but increased to twice that observed in their lean littermates from 9 to 12 weeks of age. OGT responses after 30 to 60 minutes and the area under the OGT curve were impaired but not diabetic in obese animals at all ages compared to lean littermates and returned toward those of normally lean rats after ADX. The Insulin to glucose ratio (I:G) was also consistent with insulin resistance in obese but not in ADX-obese or lean rats at 12 weeks of age. In conclusion, ADX resulted in normalization of OGT and glycemic parameters in the obese phenotype at 9 and 12 weeks of age. These results are consistent with normalization of typical insulin-mediated components of glycemic parameters and glucose uptake in peripheral tissues following adrenalectomy of congenic obese rats. The results further suggest that the counterregulatory effects of insulin and glucocorticoid hormones may be contributory to the impaired glycemic responses in the obese phenotype of the LA/N//-cp (corpulent) rat and are consistent with a receptor-mediated element in the development of insulin resistance and glucose uptake in peripheral tissues commonly associated with the early development of obesity in this strain.

Insulin Resistance Is Associated With Enhanced Brain Glucose Uptake During Euglycemic Hyperinsulinemia: A Large-Scale PET Cohort.

OBJECTIVEWhereas insulin resistance is expressed as reduced glucose uptake in peripheral tissues, the relationship between insulin resistance and brain glucose metabolism remains controversial. Our aim was to examine the association of insulin resistance and brain glucose uptake (BGU) during a euglycemic hyperinsulinemic clamp in a large sample of study participants across a wide range of age and insulin sensitivity.RESEARCH DESIGN AND METHODS[18F]-fluorodeoxyglucose positron emission tomography (PET) data from 194 participants scanned under clamp conditions were compiled from a single-center cohort. BGU was quantified by the fractional uptake rate. We examined the association of age, sex, M value from the clamp, steady-state insulin and free fatty acid levels, C-reactive protein levels, HbA1c, and presence of type 2 diabetes with BGU using Bayesian hierarchical modeling.RESULTSInsulin sensitivity, indexed by the M value, was associated negatively with BGU in all brain regions, confirming that in insulin-resistant participants BGU was enhanced during euglycemic hyperinsulinemia. In addition, the presence of type 2 diabetes was associated with additional increase in BGU. On the contrary, age was negatively related to BGU. Steady-state insulin levels, C-reactive protein and free fatty acid levels, sex, and HbA1c were not associated with BGU.CONCLUSIONSIn this large cohort of participants of either sex across a wide range of age and insulin sensitivity, insulin sensitivity was the best predictor of BGU.

Review: Obesity Induced Insulin Resistance, Type 2 Diabetes and Emerging Therapeutic Approaches.

There is a strong association between obesity, insulin resistance and type 2 diabetes mellitus. Abdominal obesity appears to be a major mediator of insulin resistance and hyperinsulinemia. Insulin resistance is a pathological condition in which cells fail to respond normally to the hormone insulin. leading to high blood sugar (impaired glucose uptake in peripheral tissues, particularly in skeletal muscle.) The more life-threatening problems fall into four main areas: type 2 diabetes, cardiovascular diseases (CVD), dyslipidemia and certain types of cancers and musculoskeletal disorders. There is considerable evidence that inflammation is a primary mediator of obesity induced insulin resistance and related co-morbidities, including diabetes and CVD whereby pro-inflammatory substances and other chemokines produced by adipocytes and macrophages are able to cause insulin resistance. The major inflammatory factors include pro-inflammatory interleukins (IL-1 & IL-6) and signaling intermediate-nuclear factor kappa B cells (NF-kB), chemokines and cytokines, tumor necrosis factor alpha (TNF-α), adiponectin (ADN), circulating C-reactive protein (CRP) concentrations, toll-like receptors (Tlr), free fatty acids (FFA), oxidative stress and dietary fatty acids. Considering this viewpoint, in the present review, we have selected ten well designed clinical studies with salsalates, thiazolidinediones (TZD) and TNF-α–antagonists to discuss and analyze these emerging therapeutic approaches for the treatment of obesity induced insulin resistance and type 2 diabetes mellitus. These therapeutics provide sufficient evidence of improved glycemic control post treatment in obese patients by targeting the state of chronic inflammation that characterizes obesity and resulted in improved insulin sensitivity by reducing adipocyte pro-inflammatory cytokine expression, adipose tissue macrophage content and immune cell infiltration into adipose tissue and other inflammatory markers. Even with looking at only few studies, analyzing each pathway, the hypothesis that targeting pro-inflammatory pathways in adipocytes with TZD and salicylates as a novel approach remains supported for reducing chronic inflammation-induced insulin resistance in obese patients, with TZD emerging with the strongest effects.

In vitro hypoglycemic effects of molokhia leaves (Corchorus olitorius L.)

Background: Corchorus olitorius L., commonly known as molokhia in Arabic, is a leafy vegetable containing large amounts of mucilaginous polysaccharides and reported to exhibit antidiabetic diabetic activity in experimental diabetes. Although antidiabetic effect of molokhia is attributed to the presence of phenolic and non-phenolic compounds, the precise mechanism of action is not explored. Materials and Methods: The present study investigated the ability of molokhia leaves powder (MLP) to modulate starch digestion and glucose diffusion in vitro. Results: MLP at 2% and 4% levels bound significantly higher amount of glucose than wheat bran (2%) and also reduced diffusion of glucose through dialysis membrane as reflected by significantly higher glucose dialysis retardation index. In starch–α-amylase system, MLP (4%) showed complete inhibition of starch digestion and glucose diffusion similar to that of acarbose till 120 min. Further, glucose diffusion was retarded to an extent of 83.7% and 63.5% by MLP (4%) at 180 and 240 min, respectively. On the other hand, MLP (2%) retarded glucose diffusion to an extent of 96%, 65%, and 51% at 120, 180, and 240 min respectively. Furthermore, molokhia leaf extract significantly enhanced uptake of glucose by rat hemidiaphragm in vitro. Conclusion: These findings conclusively demonstrate that the antidiabetic effect of molokhia leaves is mediated through delaying starch digestion and physical adsorption of liberated glucose limiting its diffusion across intestinal lumen and enhancing glucose uptake in peripheral tissues.

Effect of sidt2 Gene on Cell Insulin Resistance and Its Molecular Mechanism.

Background Sidt2 (SID1 transmembrane family, member 2) is a multiple transmembrane lysosomal membrane protein newly discovered in our previous study. In the previous study, we used gene targeting technique to make a mouse model of sidt2 gene knockout (sidt2−/−). It was found that sidt2−/− mice showed elevated fasting blood glucose and impaired glucose tolerance, showing a disorder of glucose metabolism, suggesting that sidt2 may be closely related to insulin resistance. We used 3T3-L1 adipocytes, C2-C12 myoblasts, and HEPA1-6 hepatoma cells as subjects to observe the effects of sidt2 on insulin-stimulated glucose uptake and the abovementioned insulin signal transduction pathways, and then to explore the effect of sidt2 on peripheral tissue insulin resistance and its possible molecular mechanism. Methods (1) Lentiviruses with sidt2 gene knockout and puromycin resistance were constructed by Crispr/cas9 vector and transfected into 3T3-L1 adipocytes, C2-C12 myoblasts, and HEPA1-6 hepatoma cells to construct sidt2 knockout cell line model. (2) Glucose uptake of 3T3-L1 adipocytes, C2-C12 myoblasts, and HEPA1-6 hepatoma cells stimulated by insulin was detected by glucose detection kit, and the results were analyzed. (3) Sidt2 knockout group and control group of 3T3-L1 adipocytes, C2-C12 myoblast, and HEPA1-6 hepatoma cells were cultured according to the routine method. The total proteins of the above cells were extracted, and the expression of PAKT (thr308), PI3-K, and PIRS-1 (ser307) in the IRS-1 signaling pathway of the three groups was detected by western blot technique. Results (1) The sidt2 elimination models of 3T3-L1 adipocytes, C2-C12 myoblasts, and HEPA1-6 hepatoma cells were successfully constructed. (2) It was found that the glucose uptake of cells in the sidt2 knockout group was lower than that in normal group under insulin stimulation through the detection of glucose concentration in the cell culture medium. (3) It was found that the expression of PAKT (thr308) and PI3-K protein decreased and the expression of PIRS-1 (ser307) protein increased in sidt2−/− group compared to the control group. Conclusions sidt2 knockout can reduce glucose uptake in peripheral tissue under insulin stimulation, which may lead to peripheral tissue insulin resistance by affecting the IRS-1 signal pathway.

Cancer causes metabolic perturbations associated with reduced insulin-stimulated glucose uptake in peripheral tissues and impaired muscle microvascular perfusion

BackgroundRedirecting glucose from skeletal muscle and adipose tissue, likely benefits the tumor's energy demand to support tumor growth, as cancer patients with type 2 diabetes have 30% increased mortality rates. The aim of this study was to elucidate tissue-specific contributions and molecular mechanisms underlying cancer-induced metabolic perturbations. MethodsGlucose uptake in skeletal muscle and white adipose tissue (WAT), as well as hepatic glucose production, were determined in control and Lewis lung carcinoma (LLC) tumor-bearing C57BL/6 mice using isotopic tracers. Skeletal muscle microvascular perfusion was analyzed via a real-time contrast-enhanced ultrasound technique. Finally, the role of fatty acid turnover on glycemic control was determined by treating tumor-bearing insulin-resistant mice with nicotinic acid or etomoxir. ResultsLLC tumor-bearing mice displayed reduced insulin-induced blood-glucose-lowering and glucose intolerance, which was restored by etomoxir or nicotinic acid. Insulin-stimulated glucose uptake was 30–40% reduced in skeletal muscle and WAT of mice carrying large tumors. Despite compromised glucose uptake, tumor-bearing mice displayed upregulated insulin-stimulated phosphorylation of TBC1D4Thr642 (+18%), AKTSer474 (+65%), and AKTThr309 (+86%) in muscle. Insulin caused a 70% increase in muscle microvascular perfusion in control mice, which was abolished in tumor-bearing mice. Additionally, tumor-bearing mice displayed increased (+45%) basal (not insulin-stimulated) hepatic glucose production. ConclusionsCancer can result in marked perturbations on at least six metabolically essential functions; i) insulin's blood-glucose-lowering effect, ii) glucose tolerance, iii) skeletal muscle and WAT insulin-stimulated glucose uptake, iv) intramyocellular insulin signaling, v) muscle microvascular perfusion, and vi) basal hepatic glucose production in mice. The mechanism causing cancer-induced insulin resistance may relate to fatty acid metabolism.

Research progress of oxytocin and diabetes

Oxytocin is a classic neuropeptide hormone. In recent years, basic and clinical researches have shown that oxytocin is involved in the regulation of blood glucose homeostasis by protecting islet β cells, promoting insulin secretion and peripheral tissue glucose uptake. This article reviews the recent evidence of the linkage between oxytocin and diabetes mellitus. Key words: Oxytocin; Diabetes mellitus; Pancreatic βcells; Insulin secretion; Glucose uptake

Non-peptidyl small molecule, adenosine, 5\u2032-Se-methyl-5\u2032-seleno-, 2\u2032,3\u2032-diacetate, activates insulin receptor and attenuates hyperglycemia in type 2 diabetic Leprdb/db mice

The pathophysiology of type 2 diabetes mellitus (T2D) is characterized by reduced or absent insulin receptor (INSR) responsiveness to its ligand, elevated hepatic glucose output and impaired glucose uptake in peripheral tissues, particularly skeletal muscle. Treatments to reduce hyperglycemia and reestablish normal insulin signaling are much sought after. Any agent which could be orally administered to restore INSR function, in an insulin-independent manner, would have major implications for the management of this global disease. We have discovered a non-peptidyl small molecule, adenosine, 5′-Se-methyl-5′-seleno-, 2′,3′-diacetate [referred to as non-peptidyl compound #43 (NPC43)], which restores INSR signaling in the complete absence of insulin. Initial screening of numerous compounds in human HepG2 liver cells revealed that NPC43 significantly inhibited glucose production. The compound was potently anti-hyperglycemic and anti-hyperinsulinemic in vivo, in insulin-resistant T2D Leprdb/db mice, following either acute or chronic treatment by oral gavage and intraperitoneal injection, respectively. The compound acted at the level of INSR and activated it in both liver and skeletal muscle of Leprdb/db mice. In cell culture, the compound activated INSR in both liver and skeletal muscle cells; furthermore, it cooperated with insulin to depress glucose-6-phosphatase catalytic subunit (G6pc) expression and stimulate glucose uptake, respectively. Our results indicated that the compound directly interacted with INSRα, triggering appropriate phosphorylation and activation of the receptor and its downstream targets. Unlike insulin, NPC43 did not activate insulin-like growth factor 1 receptor in either liver or skeletal muscle. We believe this compound represents a potential oral and/or injectable insulin replacement therapy for diabetes and diseases associated with insulin resistance.

Metformin increases glucose uptake and acts renoprotectively by reducing SHIP2 activity.

Metformin, the first-line drug to treat type 2 diabetes (T2D), inhibits mitochondrial glycerolphosphate dehydrogenase in the liver to suppress gluconeogenesis. However, the direct target and the underlying mechanisms by which metformin increases glucose uptake in peripheral tissues remain uncharacterized. Lipid phosphatase Src homology 2 domain-containing inositol-5-phosphatase 2 (SHIP2) is upregulated in diabetic rodent models and suppresses insulin signaling by reducing Akt activation, leading to insulin resistance and diminished glucose uptake. Here, we demonstrate that metformin directly binds to and reduces the catalytic activity of the recombinant SHIP2 phosphatase domain in vitro. Metformin inhibits SHIP2 in cultured cells and in skeletal muscle and kidney of db/db mice. In SHIP2-overexpressing myotubes, metformin ameliorates reduced glucose uptake by slowing down glucose transporter 4 endocytosis. SHIP2 overexpression reduces Akt activity and enhances podocyte apoptosis, and both are restored to normal levels by metformin. SHIP2 activity is elevated in glomeruli of patients with T2D receiving nonmetformin medication, but not in patients receiving metformin, compared with people without diabetes. Furthermore, podocyte loss in kidneys of metformin-treated T2D patients is reduced compared with patients receiving nonmetformin medication. Our data unravel a novel molecular mechanism by which metformin enhances glucose uptake and acts renoprotectively by reducing SHIP2 activity.—Polianskyte-Prause, Z., Tolvanen, T. A., Lindfors, S., Dumont, V., Van, M., Wang, H., Dash, S. N., Berg, M., Naams, J.-B., Hautala, L. C., Nisen, H., Mirtti, T., Groop, P.-H., Wähälä, K., Tienari, J., Lehtonen, S. Metformin increases glucose uptake and acts renoprotectively by reducing SHIP2 activity.

Hepatic tristetraprolin promotes insulin resistance through RNA destabilization of FGF21.

The role of posttranscriptional metabolic gene regulatory programs in diabetes is not well understood. Here, we show that the RNA-binding protein tristetraprolin (TTP) is reduced in the livers of diabetic mice and humans and is transcriptionally induced in response to insulin treatment in murine livers in vitro and in vivo. Liver-specific Ttp-KO (lsTtp-KO) mice challenged with high-fat diet (HFD) have improved glucose tolerance and peripheral insulin sensitivity compared with littermate controls. Analysis of secreted hepatic factors demonstrated that fibroblast growth factor 21 (FGF21) is posttranscriptionally repressed by TTP. Consistent with increased FGF21, lsTtp-KO mice fed HFD have increased brown fat activation, peripheral tissue glucose uptake, and adiponectin production compared with littermate controls. Downregulation of hepatic Fgf21 via an adeno-associated virus-driven shRNA in mice fed HFD reverses the insulin-sensitizing effects of hepatic Ttp deletion. Thus, hepatic TTP posttranscriptionally regulates systemic insulin sensitivity in diabetes through liver-derived FGF21.

Red Pepper (Capsicum annuum L.) Seed Extract Decreased Hepatic Gluconeogenesis and Increased Muscle Glucose Uptake In Vitro.

Red pepper seed, a by-product of red pepper, has been reported to have antioxidant and antiobesity activities. However, its role in diabetes has not yet been highly investigated. Glucose homeostasis is mainly maintained by insulin, which suppresses glucose production in the liver and enhances glucose uptake in peripheral tissues. In this study, we investigated the underlying mechanisms through which red pepper seed extract (RPSE) affects glucose production in AML12 hepatocytes and glucose uptake in C2C12 myotubes. RPSE reduced glucose production in a dose-dependent manner in AML12 cells. The levels of glucose 6 phosphatase, phosphoenolpyruvate carboxykinase, and critical enzymes for hepatic gluconeogenesis were decreased by RPSE. Gluconeogenesis regulating proteins, Akt and forkhead box protein O1, were also activated by RPSE. In addition, RPSE increased glucose uptake in C2C12 via inducing translocation of glucose transporter type 4 from cytosol to plasma membrane. Analysis of the insulin-dependent pathway showed that the activities of insulin receptor substrate 1, phosphatidylinositol 3-kinase, and Akt were significantly stimulated by RPSE. In conclusion, RPSE might improve glucose homeostasis by reducing hepatic gluconeogenesis and increasing peripheral glucose uptake. Results obtained also suggest that RPSE can be a compelling antidiabetic nutraceutical.

LEPTIN RESISTANCE AND TYPE 2 DIABETES

Leptin is one of adipocyte-secreted hormones. It signals to the brain and other tissues about the status of body energy reserves. Circulating leptin levels are directly proportional to the amount of the body fat. Leptin concentration increases when surfeit and decreases during fasting. Obese patients are hyperleptinemic compared with thin persons and they are tolerant to the central hypothalamic effects of leptin. The reduced sensitivity toward exogenous and endogenous leptin is commonly referred to as leptin resistance. Alterations in the signaling of the long isoform of the leptin receptor play the crucial role in leptin resistance. Surfeit may induce leptin resistance and other metabolic sequelae of obesity. Leptin insensitivity and insulin resistance play a major role in the development of type 2 diabetes. Metformin remains the preferred first-line pharmacologic agent for the treatment of type 2 diabetes. It reduces hepatic glucose production, increases glucose uptake in peripheral tissue and can lead to weight loss. Metformin decreases both insulin and leptin concentration, restores the sensitivity to these hormones. But some studies have shown poor relationship between metformin action and leptin level. And the mechanism of metformin action on leptin resistance remains unclear. Thus, these issues should be studied as well as polymorphisms in genes encoding metformin action.

Metformin in pregnancy

Metformin in pregnancy

Spatholobus suberectus Exhibits Antidiabetic Activity In Vitro and In Vivo through Activation of AKT-AMPK Pathway.

Glucose deposition in peripheral tissue is an important parameter for the treatment of type 2 diabetes mellitus. The aim of this study was to investigate the effects of Spatholobus suberectus (Ss) on glucose disposal in skeletal muscle cells and additionally explore its in vivo antidiabetic potential. Treatment of ethanolic extract of S. suberectus (EeSs) significantly enhanced the glucose uptake, mediated through the enhanced expression of GLUT4 in skeletal muscle via the stimulation of AKT and AMPK pathways in C2C12 cells. Moreover, EeSs have potential inhibitory action on α-glucosidase activity and significantly lowered the postprandial blood glucose levels in STZ-induced diabetic mice, associated with increased expression of GLUT4 and AKT and/or AMPK-mediated signaling cascade in skeletal muscle. Furthermore, administration of EeSs significantly boosted up the antioxidant enzyme expression and also mitigated the gluconeogenesis enzyme such as PEPCK and G-6-Pase enzyme expression in liver tissue of STZ-induced diabetic mice model. Collectively, these findings suggest that EeSs have a high potentiality to mitigate diabetic symptoms through stimulating glucose uptake in peripheral tissue via the activation of AKT and AMPK signaling cascade and augmenting antioxidant potentiality as well as blocking the gluconeogenesis process in diabetic mice.

Anti-diabetic actions of Berry polyphenols – Review on proposed mechanisms of action

The incidence of type 2 diabetes mellitus (T2DM) has reached near-epidemic proportions in the Western world with other parts of the world following close behind. Glycemic control is paramount in type 1 diabetes mellitus (T1DM) and T2DM. Berries may beneficially influence glycemic control through the action of their polyphenolic components. While clinical studies on the anti-diabetic effects of berry polyphenols are limited, epidemiological data have indicated favorable effects of berry/anthocyanins intake on development and/or management of T2DM. Furthermore, data derived from in vivo animal studies and in vitro cell culture models are promising. Various molecular targets and modulation of cell signaling pathways in pancreatic -cells, hepatocytes, adipocytes, and skeletal muscle cells are among the proposed mechanisms for berry polyphenols and their metabolites’ action. Berry polyphenols may exert anti-diabetic effects by (i) enhancing insulin production and reducing apoptosis and promoting proliferation of pancreatic -cells, (ii) regulating glucose metabolism by interfering with absorption or by increasing peripheral tissue glucose uptake through insulin receptor-dependent or independent mechanisms via modification of oxidative stress, inflammation or perceived energy status of cell. This mini review discusses recent findings from our laboratory and other studies on the anti-diabetic effects of berry polyphenolic compounds with special emphasis on the cellular and molecular mechanisms involved in the beneficial effects of berry polyphenol compounds.

Dual Actions of Apolipoprotein A-I on Glucose-Stimulated Insulin Secretion and Insulin-Independent Peripheral Tissue Glucose Uptake Lead to Increased Heart and Skeletal Muscle Glucose Disposal.

Apolipoprotein A-I (apoA-I) of HDL is central to the transport of cholesterol in circulation. ApoA-I also provides glucose control with described in vitro effects of apoA-I on β-cell insulin secretion and muscle glucose uptake. In addition, apoA-I injections in insulin-resistant diet-induced obese (DIO) mice lead to increased glucose-stimulated insulin secretion (GSIS) and peripheral tissue glucose uptake. However, the relative contribution of apoA-I as an enhancer of GSIS in vivo and as a direct stimulator of insulin-independent glucose uptake is not known. Here, DIO mice with instant and transient blockade of insulin secretion were used in glucose tolerance tests and in positron emission tomography analyses. Data demonstrate that apoA-I to an equal extent enhances GSIS and acts as peripheral tissue activator of insulin-independent glucose uptake and verify skeletal muscle as an apoA-I target tissue. Intriguingly, our analyses also identify the heart as an important target tissue for the apoA-I-stimulated glucose uptake, with potential implications in diabetic cardiomyopathy. Explorations of apoA-I as a novel antidiabetic drug should extend to treatments of diabetic cardiomyopathy and other cardiovascular diseases in patients with diabetes.

Berberine relieves insulin resistance via the cholinergic anti-inflammatory pathway in HepG2 cells.

Berberine (BBR) is an isoquinoline alkaloid extracted from Rhizoma coptidis and has been used for treating type 2 diabetes mellitus (T2DM) in China. The development of T2DM is often associated with insulin resistance and impaired glucose uptake in peripheral tissues. In this study, we examined whether BBR attenuated glucose uptake dysfunction through the cholinergic anti-inflammatory pathway in HepG2 cells. Cellular glucose uptake, quantified by the 2-[N-(7-Nitrobenz-2-oxa-1,3-diazol-4-yl)-amino]-2-deoxy-D-glucose (2-NBDG), was inhibited by 21% after HepG2 cells were incubated with insulin (10(-6) mol/L) for 36 h. Meanwhile, the expression of alpha7 nicotinic acetylcholine receptor (α7nAChR) protein was reduced without the change of acetylcholinesterase (AChE) activity. The level of interleukin-6 (IL-6) in the culture supernatant, the ratio of phosphorylated I-kappa-B kinase-β (IKκβ) Ser181/IKKβ and the expression of nuclear factor-kappa B (NF-κB) p65 protein were also increased. However, the treatment with BBR enhanced the glucose uptake, increased the expression of α7nAChR protein and inhibited AChE activity. These changes were also accompanied with the decrease of the ratio of pIKKβ Ser181/IKKβ, NF-κB p65 expression and IL-6 level. Taken together, these results suggest that BBR could enhance glucose uptake, and relieve insulin resistance and inflammation in HepG2 cells. The mechanism may be related to the cholinergic anti-inflammatory pathway and the inhibition of AChE activity.