Plasma Glucose Regulation Research Articles

Glucose homeostasis, obesity and diabetes

Plasma glucose levels are maintained within a narrow range in normal individuals. Both insulin-dependent and insulin-independent processes contribute to fasting and postprandial plasma glucose regulation. The brain and nervous system are insulin independent. Muscle and adipose tissue are responsive to insulin and can use either glucose or ketones and free fatty acids as their primary metabolic fuel. The essential components of metabolic syndrome are obesity, glucose intolerance, insulin resistance, lipid disturbances, and hypertension. The risk of type 2 diabetes increases exponentially as body mass index increases above about 25 kg/m2. The links between obesity and type 2 diabetes include proinflammatory cytokines, insulin resistance, deranged fatty acid metabolism, and cellular processes. Modest weight reduction can improve glycaemic control and reduce diabetes risk. Obesity also leads to hyperinsulinaemia and insulin resistance, with a progressive decrease in insulin secretory function. Ageing is another important risk factor for metabolic disorders, including obesity, impaired glucose tolerance, and type 2 diabetes.

Efficacy of azelaic acid on hepatic key enzymes of carbohydrate metabolism in high fat diet induced type 2 diabetic mice

Azelaic acid (AzA), a C9 linear α,ω-dicarboxylic acid, is found in whole grains namely wheat, rye, barley, oat seeds and sorghum. The study was performed to investigate whether AzA exerts beneficial effect on hepatic key enzymes of carbohydrate metabolism in high fat diet (HFD) induced type 2 diabetic C57BL/6J mice. C57BL/6J mice were fed high fat diet for 10 weeks and subjected to intragastric administration of various doses (20 mg, 40 mg and 80 mg/kg BW) of AzA daily for the subsequent 5 weeks. Rosiglitazone (RSG) was used as reference drug. Body weight, food intake, plasma glucose, plasma insulin, blood haemoglobin (Hb), blood glycosylated haemoglobin (HbA1c), liver glycolytic enzyme (hexokinase), hepatic shunt enzyme (glucose-6-phosphate dehydrogenase), gluconeogenic enzymes(glucose-6-phosphatase and fructose-1,6-bisphosphatase), liver glycogen, plasma and liver triglycerides were examined in mice fed with normal standard diet (NC), high fat diet (HFD), HFD with AzA (HFD + AzA) and HFD with rosiglitazone (HFD + RSG). Among the three doses, 80 mg/kg BW of AzA was able to positively regulate plasma glucose, insulin, blood HbA1c and haemoglobin levels by significantly increasing the activity of hexokinase and glucose-6-phosphate dehydrogenase and significantly decreasing the activity of glucose-6-phosphatase and fructose-1,6-bisphosphatase thereby increasing the glycogen content in the liver. From this study, we put forward that AzA could significantly restore the levels of plasma glucose, insulin, HbA1c, Hb, liver glycogen and carbohydrate metabolic key enzymes to near normal in diabetic mice and hence, AzA may be useful as a biomaterial in the development of therapeutic agents against high fat diet induced T2DM.

Choline Supplementation Promotes Hepatic Insulin Resistance in Phosphatidylethanolamine N-Methyltransferase-deficient Mice via Increased Glucagon Action

Biosynthesis of hepatic choline via phosphatidylethanolamine N-methyltransferase (PEMT) plays an important role in the development of type 2 diabetes and obesity. We investigated the mechanism(s) by which choline modulates insulin sensitivity. PEMT wild-type (Pemt(+/+)) and knock-out (Pemt(-/-)) mice received either a high fat diet (HF; 60% kcal of fat) or a high fat, high choline diet (HFHC; 4 g of choline/kg of HF diet) for 1 week. Hepatic insulin signaling and glucose and lipid homeostasis were investigated. Glucose and insulin intolerance occurred in Pemt(-/-) mice fed the HFHC diet, but not in their Pemt(-/-) littermates fed the HF diet. Plasma glucagon was elevated in Pemt(-/-) mice fed the HFHC diet compared with Pemt(-/-) mice fed the HF diet, concomitant with increased hepatic expression of glucagon receptor, phosphorylated AMP-activated protein kinase (AMPK), and phosphorylated insulin receptor substrate 1 at serine 307 (IRS1-s307). Gluconeogenesis and mitochondrial oxidative stress were markedly enhanced, whereas glucose oxidation and triacylglycerol biosynthesis were diminished in Pemt(-/-) mice fed the HFHC diet. A glucagon receptor antagonist (2-aminobenzimidazole) attenuated choline-induced hyperglycemia and insulin intolerance and blunted up-regulation of phosphorylated AMPK and IRS1-s307. Choline induces glucose and insulin intolerance in Pemt(-/-) mice through modulating plasma glucagon and its action in liver.

Reduced Plasma Glucose by Asparagine Synthetase Knockdown in the Mouse Liver

Expression of the asparagine synthetase gene is dependent on extracellular glucose concentration. This gene was knocked-down in livers of male Balb/c mice by a hydrodynamic tail vein injection of small interfering RNA (siRNA) against the gene. This knockdown resulted in a significant decrease in plasma glucose concentration. These results suggested that asparagine synthetase is a novel protein that regulates plasma glucose levels.

Blood Plasma Glucose Regulation in Wahlberg's Epauletted Fruit Bat

Frugivores feed on fruits and nectars that contain different types of sugars in different proportions, which provide these animals with energy. Wahlberg's epauletted fruit bat (Epomophorus wahlbergi) has a high glucose intake irrespective of sugar concentration of nectar. It is not known how these bats regulate their blood plasma glucose concentrations in order to avoid the negative effects associated with hyperglycemia. Fruit bats have a high amount of sugar intake in a short period of time which could cause a glucose challenge and it is therefore necessary to determine whether these bats are able to regulate their blood plasma glucose concentrations within normal concentrations. This study investigated the diel variations in blood plasma glucose concentrations of E. wahlbergi. Epomophorus wahlbergi's blood plasma glucose concentration was lower (5.24 ±0.38 mmol/1) at 18:00 before feeding and increased during/after feeding (8.19 ± 1.24 mmol/1) but bats appeared to regulate it within limits. Their range i...

Radio-Wave Heating of Iron Oxide Nanoparticles Can Regulate Plasma Glucose in Mice

Medical applications of nanotechnology typically focus on drug delivery and biosensors. Here, we combine nanotechnology and bioengineering to demonstrate that nanoparticles can be used to remotely regulate protein production in vivo. We decorated a modified temperature-sensitive channel, TRPV1, with antibody-coated iron oxide nanoparticles that are heated in a low-frequency magnetic field. When local temperature rises, TRPV1 gates calcium to stimulate synthesis and release of bioengineered insulin driven by a Ca(2+)-sensitive promoter. Studying tumor xenografts expressing the bioengineered insulin gene, we show that exposure to radio waves stimulates insulin release from the tumors and lowers blood glucose in mice. We further show that cells can be engineered to synthesize genetically encoded ferritin nanoparticles and inducibly release insulin. These approaches provide a platform for using nanotechnology to activate cells.

Beneficial Effect of Traditional Chinese Medicinal Formula Danggui-Shaoyao-San on Advanced Glycation End-Product-Mediated Renal Injury in Streptozotocin-Diabetic Rats

The present study was undertaken to characterize the effects of Danggui-Shaoyao-San (DSS), a famous traditional Chinese medicine formula consisting of six herbal medicines, on diabetic nephropathy. Streptozotocin-induced diabetic rats were orally administrated DSS (2.8 g kg−1 per day) for 12 consecutive weeks. DSS partially decreased the high plasma glucose level in diabetic rats. Diabetic-dependent alterations in urinary albumin, 24-hour urinary albumin excretion rate, and creatinine clearance as well as the kidney hypertrophy (kidney weight/body weight ratio) and glomerular mesangial matrix expansion were ameliorated after 12 weeks of DSS treatment. The increased expression of nuclear factor-κB as well as transforming growth factor-β 1 and the progressive accumulation of type IV collagen in kidney of diabetic rats were also attenuated by DSS. Not only the elevated levels of advanced glycation end products (AGEs) and N ε-(carboxymethyl)lysine but also the higher levels of lipid peroxidation products in kidney of diabetic rats were ameliorated by DSS. Decreased activity of superoxide diamutase and glutathione peroxidase in kidney of diabetic rats was enhanced by DSS. These data demonstrated that the renoprotective effects of DSS in STZ-diabetic rats not only were attributable to regulate plasma glucose to attenuate AGEs expression in diabetic glomeruli but also likely reflected its antioxidant activity.

The medicinal value of honey: a review on its benefits to human health, with a special focus on its effects on glycemic regulation

Honey, a natural substance produced by honeybees, is composed of a complex mixture of carbohydrates, water, and a small amount of proteins, vitamins, minerals, and phenolic compounds. Fructose, glucose and maltose are among the various types of sugars present in honey. Used for millennia as both food and medicine, honey has been associated with improved antioxidant capacity, modulation of the immune system, antimicrobial activities, influence on lipid values (through antihypercholesterolemic effects) and regulation of glycemic responses, among other benefits. The aim of this article was to review the effects of natural honey intake on human health, with particular reference to its influence on glycemic regulation. Several studies have focused on the potential use of honey as a nutritional supplement for healthy individuals and for those with impaired glucose tolerance, diabetes, and their related comorbidities. Such investigations have found that, compared to glucose and sucrose, the consumption of honey decreases glycemic levels and blood lipids in healthy, diabetic and hyperlipidemic individuals. Moreover, long periods of honey intake seem to reduce fasting glucose levels in humans, suggesting that honey consumption influences plasma glucose regulation, mainly through a normo- or hypoglycemic effect. Therefore, honey may be proposed as a nutritional dietary supplement for healthy individuals and for those suffering from alterations in glycemic regulation

Development of Sodium-Dependent Glucose Co-Transporter 2 Inhibitors as Potential Anti-Diabetic Therapeutics

The kidney plays an important role in the regulation of plasma glucose. It is estimated that greater than 99% of the renal glucose filtered by kidney glomerulus is resorbed by sodium-dependent glucose co-transporters (SGLTs), and that SGLT2 located in the proximal renal tubule achieves the most of this assignment. Studies of SGLT2 inhibitors indicate that raising renal glucose excretion by inhibiting SGLT2 helps effectively normalize the plasma glucose levels in individuals with type 2 diabetes mellitus (T2DM). This review discusses the discovery of SGLT2 inhibitors and the related structure-activity relationship (SAR) studies. The clinical trial data of dapagliflozin is also involved.

Optimal PI-fuzzy logic controller of glucose concentration using genetic algorithm

In this paper, an optimal PI-fuzzy controller to regulate plasma glucose in Type1 diabetic patients is introduced. This controller is designed to mimic the functionality of β -cell in pancreas. Complete lack of insulin resulting from β -cell deficien

Insulin: Potential Negative Consequences of Early Routine Use in Patients With Type 2 Diabetes

The lack of adequate insulin secretion characterizes all hyperglycemic states. When insulin action is normal, as in type 1 diabetes, there is a near total loss of insulin secretory function. In type 2 diabetes, the abnormalities in insulin secretion are multiple. One of the initial defects is a loss of the early phase of meal-stimulated insulin secretion. This is followed by an inability of the β-cell to increase insulin secretion sufficient to overcome hepatic and peripheral insulin resistance. Type 2 diabetes is characterized by a progressive decrease in both β-cell mass and secretory function so that, in most individuals, absolute insulin deficiency occurs in the late stages of the disease. It would seem logical that the ideal treatment for type 2 diabetes should be early and continuing insulin therapy. Unfortunately, there are several characteristics of insulin treatment and insulin action in type 2 diabetes that limit the usefulness of insulin treatment and that suggest that chronic insulin therapy is best used in the later stages of diabetes when there is an absolute deficiency of insulin. In normal physiology, β-cell insulin secretion is coupled immediately with changes in the plasma glucose level (1). The secretory response is rapid (within a minute or two), and because the half-life of insulin is ~5 min, there is little lag time in the glucose regulatory system. Endogenously secreted insulin goes via the portal vein to the liver, where 30–80% of it is either metabolized or used (2). The portal vein-to-peripheral arterial insulin ratio is ~2:1. The administration of insulin exogenously eliminates the rapid regulation of plasma glucose, since the insulin must be taken up slowly and without regulation from the subcutaneous injection site. The kinetics are determined by the nature of the injected insulin formulation. Additionally, as illustrated in Fig. 1, it is necessary …

Adiponectin Downregulates Hyperglycemia and Reduces Pancreatic Islet Apoptosis After Roux-En-Y Gastric Bypass Surgery

The resolution of type 2 diabetes mellitus is an additional outcome of Roux-en-Y gastric bypass (RYGB) surgery. The general objective was to explore whether RYGB could reduce beta cells apoptosis and what roles adiponectin played in downregulating hyperglycemia after RYGB. Twenty Goto-Kakizaki (GK) rats were allocated in RYGB group (ten) and GK group (ten), and ten Wistar (WS) rats were allocated in WS group. RYGB was performed in RYGB group and sham operation in the GK and WS groups. Fasting plasma glucose, body weight, food intake per 100g body weight, insulin, homeostasis model assessment of insulin resistance (HOMA-IR), C peptide, and adiponectin were measured pre- and postoperatively. Terminal deoxynucleotidyl transferase 2'-deoxyuridine 5'-triphosphate nick end-labeling and transmission electron microscopy were performed to detect apoptosis of pancreatic beta cells. Data were analyzed by analysis of variance, Student t test, and post hoc comparisons (Tukey's test). Animals in WS group had significant higher postprandial insulin, C peptide, and adiponectin concentrations compared to RYGB and GK groups preoperatively. Body weight and food intake in RYGB group significantly decreased compared to WS and GK groups postoperatively. Postprandial insulin, C peptide, and adiponectin concentrations significantly increased, while fasting plasma glucose and HOMA-IR values decreased in RYGB group compared to GK group postoperatively. More apoptotic beta cells were detected in GK group than RYGB and WS groups postoperatively. RYGB could increase postprandial insulin and reduce pancreatic islet apoptosis. Adiponectin played a key role in regulating plasma glucose and reducing pancreatic islet apoptosis after RYGB.

Glucose control by subcutaneous insulin administration: a DDE modelling approach

AbstractThis note investigates the problem of plasma glucose regulation by means of subcutaneous insulin administration. A discrete delay differential equation model of the glucose-insulin regulatory system has been considered, which properly takes into account also the pancreatic insulin release, in such a way to allow insulin therapies for both Type I and Type II diabetes (in this latter case the endogenous insulin delivery is not negligible). The method of exact input/output feedback linearization and stabilization is used, in order to ensure the local convergence of the tracking error to zero. Simulations are performed in a virtual environment, and numerical results show the effectiveness of the proposed approach.

Two susceptible diabetogenic variants near/in MTNR1B are associated with fasting plasma glucose in a Han Chinese cohort

To investigate the two variants (rs1387153 and rs10830963) near/in the melatonin receptor 1B gene (MTNR1B) and to determine their association with Type 2 diabetes, as well as with the regulation of fasting plasma glucose (FPG) in Han Chinese subjects. The two variants were genotyped in 1912 unrelated Type 2 diabetic patients and 2041 healthy individuals. Association with Type 2 diabetes was calculated by logistic regression with adjustments for sex, age and body mass index. The possible connection between the risk alleles and FPG was analysed by multiple linear regression. The two polymorphisms were associated with FPG levels in the healthy individuals (P = 0.003 and P = 0.002, respectively), and the G allele of rs10830963 was also associated with an increased risk of Type 2 diabetes in our patient sample (odds ratio, 1.12; 95% confidence interval, 1.02-1.23; P = 0.024). Moreover, the linkage disequilibrium degree of two single nucleotide polymorphisms was high (r(2) = 0.66), which is similar to that of Europeans. The common variant in MTNR1B confers the risk of Type 2 diabetes and modulates FPG in both the Han Chinese and European populations.

Glycation Isotopic Labeling with 13C-Reducing Sugars for Quantitative Analysis of Glycated Proteins in Human Plasma

Non-enzymatic glycation of proteins is a post-translational modification produced by a reaction between reducing sugars and amino groups located in lysine and arginine residues or in the N-terminal position. This modification plays a relevant role in medicine and food industry. In the clinical field, this undesired role is directly linked to blood glucose concentration and therefore to pathological conditions derived from hyperglycemia (>11 mm glucose) such as diabetes mellitus or renal failure. An approach for qualitative and quantitative analysis of glycated proteins is here proposed to achieve the three information levels for their complete characterization. These are: 1) identification of glycated proteins, 2) elucidation of sugar attachment sites, and 3) quantitative analysis to compare glycemic states. Qualitative analysis was carried out by tandem mass spectrometry after endoproteinase Glu-C digestion and boronate affinity chromatography for isolation of glycated peptides. For this purpose, two MS operational modes were used: higher energy collisional dissociation-MS2 and CID-MS3 by neutral loss scan monitoring of two selective neutral losses (162.05 and 84.04 Da for the glucose cleavage and an intermediate rearrangement of the glucose moiety). On the other hand, quantitative analysis was based on labeling of proteins with [(13)C(6)]glucose incubation to evaluate the native glycated proteins labeled with [(12)C(6)]glucose. As glycation is chemoselective, it is exclusively occurring in potential targets for in vivo modifications. This approach, named glycation isotopic labeling, enabled differentiation of glycated peptides labeled with both isotopic forms resulting from enzymatic digestion by mass spectrometry (6-Da mass shift/glycation site). The strategy was then applied to a reference plasma sample, revealing the detection of 50 glycated proteins and 161 sugar attachment positions with identification of preferential glycation sites for each protein. A predictive approach was also tested to detect potential glycation sites under high glucose concentration.

Low Plasma Apelin in Newly Diagnosed Type 2 Diabetes in Chinese People

It has been unclear whether there is a pathway that regulates plasma glucose through the action of peripheral tissue of apelin with the secretory function of insulin, which exerts a control in adipocytes in addition to the direct regulation of plasma glucose. Our study was designed to identify the changes in plasma apelin levels in newly diagnosed type 2 diabetes in Chinese people. We also tried to investigate the possible association of apelin, the status of hyperglycemia, and insulin secretion. The study population consisted of 75 patients with newly diagnosed and untreated type 2 diabetes and 36 healthy control subjects matched for …

Inhibition of lipolysis may contribute to the acute regulation of plasma FFA and glucose by FGF21 in ob/ ob mice

FGF21 is a unique member of the fibroblast growth factors (FGFs) and a novel hormone that regulates glucose, lipid, and energy homeostasis. The beneficial effects of FGF21 reported thus far have mostly been from chronic treatments. In order to better understand the mechanism for FGF21 action, we evaluated the acute effects of FGF21 in vivo and in vitro. Here we report that a single injection of FGF21 acutely reduced plasma free fatty acid levels similar to its acute effects on plasma glucose in ob/ ob mice. In vitro, FGF21 inhibited lipolysis in adipocytes during a short treatment and reduced total lipase activity. These results demonstrate the potential importance of adipocyte lipolysis to the observed acute improvements in plasma parameters.

Plasma Glucose and Insulin Regulation Is Abnormal Following Gastric Bypass Surgery with or Without Neuroglycopenia

Enhanced insulin sensitivity is commonly seen following Roux-en-Y gastric bypass surgery (RYGB) whereas symptomatic hypoglycemia post-RYGB seems to occur infrequently. It is unclear how different plasma glucose and insulin responses are in patients with symptomatic hypoglycemia (SX-RYGB) versus those who remain asymptomatic (ASX-RYGB), nor when compared with non-surgical controls with varying degrees of insulin sensitivity. Plasma glucose and insulin concentrations were determined following a 75-g oral glucose challenge in five groups: symptomatic and asymptomatic patients following RYGB (n = 9 each) and overweight/obese controls, divided into three subgroups (n = 30 each) on the basis of degree of insulin sensitivity measured by the insulin suppression test. SX-RYGB group had higher 30-min glucose after oral glucose compared with the ASX-RYGB group (p = 0.04). The two groups did not differ in peak glucose and insulin concentrations, nadir glucose concentration, or insulin-to-glucose ratio 30 min after oral glucose. These values were significantly different from the three control groups, and peak insulin concentrations post-RYGB were increased at every degree of insulin sensitivity as compared with the control groups. Plasma glucose and insulin responses to oral glucose in patients with symptomatic hypoglycemia post-RYGB are minimally different when compared to individuals who remain asymptomatic, and both groups demonstrate hyperinsulinemia out of proportion to their degree of insulin sensitivity.

Stimulation of Glucagon Like Peptide-1 Secretion in Enteroendocrine L cells

GLP-1 (glucagon like peptide-1) is new anti-diabetic drug with a number of beneficial effects. It stimulates glucose dependant insulin secretion and restoration of beta cell mass through enhancement of islet mass. However, it is easily inactivated after being secreted from enteroendocrine L cells. Recent trial to increased GLP-1 is to directly stimulate L cells through its receptor located in the surface of L cell. Taste receptor in the apical surface of L cell is activated by various tastants contained in the food. Tongue perceives taste sense through the heterotrimeric G-protein (-gustducin) and its downstream signaling cascades. Same taste receptors are also expressed in enteroendocrine cells. In duodenal L cell, -gustducin was detected by immunofluorescence stainig at the luminal projections of enteroendocrine cells. And several other taste signaling elements were also found in L cells. Ingestion of sweet or bitter compounds revealed stimulation of GLP-1 secretion and the regulation of plasma insulin and glucose. In this review, I will briefly introduce the possibilities to stimulate GLP-1 secretion though the membrane receptor in enteroendocrine cell. And it will be the good candidate to develop the treatment modality for obesity, diabetes and abnormal gut motility.

Role of sympathetic tone in the loss of syringin-induced plasma glucose lowering action in conscious Wistar rats

Syringin is an active principle purified from the rhizome and root parts of Eleutherococcus senticosus (Araliaceae). The present study is designed to clarify the role of sympathetic activation in the insulinotropic effect of syringin. Plasma glucose lowering effect accompanying with the increase of plasma insulin and C-peptide were obtained in pentobarbital anesthetized Wistar rats 60 min after an intravenous (i.v.) injection of syringin (100 μg/kg). However, neither the plasma glucose lowering action, nor the raised plasma levels of insulin and C-peptide can be obtained in conscious rats received same syringin treatment. Otherwise, the insulin-releasing and plasma glucose lowering actions of syringin (100 μg/kg, i.v.) were appeared in conscious rats under chemical sympathectomy using an intraperitoneal injection of guanethidine. In addition, plasma glucose lowering action of syringin (100 μg/kg, i.v.) was observed in conscious rats with α 1-adrenoceptor blockade by prazosin. The stimulatory actions of syringin on the secretion of plasma insulin and C-peptide were also obtained in prazosin-treated conscious rats. The obtained results suggest that insulinotropic effect of syringin on the plasma glucose regulation is impaired in conscious rats with a regular sympathetic tone; decrease of sympathetic tone as observed in anesthetized animal might be helpful in the therapeutic benefit of syringin.