Insulin Glucagon Research Articles

Controllability and observability of glucose insulin glucagon system in humans

Artificial pancreas is one of the solutions to control the type1 diabetes mellitus now days. Efforts are being made to develop the artificial pancreas. The controllability and observability of the glucose insulin glucagon dynamical model is calculated which is the modified form of composite model of glucose insulin glucagon dynamics for type 1 diabetes mellitus is considered. The concept of controllability and observability for the linearized control system is used to design a feedback control. This model completely describes the glucagon affects the safety of artificial pancreas to overcome the risk of hyperglycemia. Composite model of glucagon-glucose dynamics and its extension is treated for type 1 diabetes mellitus to check the linear controllability and observability. Two cases are discussed on the basis of input of the system. For case I, insulin as the only input and glucose as an output and in case II insulin and glucagon as inputs and glucose as only output. The model is observable but not controllable in each case. This may show vital part in the progress of fully automatic artificial pancreas and stabilize the control loop system for the glucose insulin glucagon (GIG) pump to control the type 1 diabetes mellitus.

The SGLT2 Inhibitor Canagliflozin Induces Catabolic Transcriptional and Metabolic Switching and Increases FGF-21 in Mice with Dietary Obesity

Given the impact of SGLT2 inhibitors to reduce overall mortality and CV risk in T2D, improved understanding of cellular and transcriptional mechanisms responsible for metabolic effects is required. We fed C57BL/6J mice a 60% high fat diet (HFD) for 4 weeks prior to assignment to one of 3 groups: (1) 60% HFD, (2) HFD with canagliflozin (CANA, 25 mg/kg/day), and (3) HFD weight-matched (WM) to CANA via caloric restriction. Mice were analyzed after 4-8 weeks. CANA reduced fasting glucose by 47% (P<0.0001), improved glucose tolerance, and 25% lower body weight vs. HFD (p<0.0001). CANA promoted shift toward lipid utilization, with respiratory quotient <0.7 even during feeding, and a 3.7 and 2.0-fold increase in plasma and liver β-hydroxybutyrate (both p<0.01 vs. HFD). In parallel, liver glycogen and cholesterol were reduced by 55% and 28%, and triglycerides were shifted toward polyunsaturated species. To identify potential mechanisms responsible for these fasting-like phenotypes, we analyzed the molecular impact of CANA. Liver transcriptomic analysis revealed marked downregulation of lipogenesis, glycolysis, and steroid synthesis pathways (p<0.01), while the lipid oxidative regulatory genes PPARα and PGC1α were increased by 2.8 and 4-fold, respectively. CANA significantly increased hepatic FAD+ (2.4-fold) and AMP (1.3-fold), in parallel with a 12-fold increase in AMPK phosphorylation and 50% reduction in Tor-dependent phosphorylation of S6. Hepatic gene expression of FGF-21, a hormonal regulator of fatty acid oxidation and ketogenesis, was increased by 4.5-fold, with parallel 2.2-fold increase in plasma FGF-21 in CANA-treated mice (p<0.vs. HFD for both). These effects were independent of insulin sensitivity or glucagon signaling. Collectively, these data demonstrate CANA induction of a fasting-like state by coordinated transcriptional-metabolic reprogramming, and identify FGF-21 as a potential molecular metabolic switch. Disclosure S. Osataphan: None. C. Macchi: None. V. Sales: None. C. Kozuka: None. J.I. Chimene-Weiss: None. Y. Tangjaroenpaisan: None. J. Morningstar: None. R. Gerszten: None. M.E. Patti: Research Support; Self; Janssen Pharmaceuticals, Inc.. Other Relationship; Self; Xeris Pharmaceuticals, Inc.. Research Support; Self; Ethicon US, LLC., Coviden, MedImmune. Other Relationship; Self; Novo Nordisk Inc., XOMA Corporation, AstraZeneca, Nestlé. Research Support; Self; Dexcom, Inc.. Consultant; Self; Eiger BioPharmaceuticals.

Low-adhesive ethylene vinyl alcohol-based packaging to xenogeneic islet encapsulation for type 1 diabetes treatment.

Transplantation of encapsulated porcine islets is proposed to treat type 1 diabetes. However, the envelopment of fibrous tissue and the infiltration of immune cells impair islet function and eventually cause implant failure. It is known that hemodialysis using an ethylene vinyl alcohol (EVOH) membrane results in minor tissue responses. Therefore, we hypothesized that using a low-adhesive EVOH membrane for encapsulation may prevent host cell accumulation and fibrous capsule formation. In this study, rat islets suspended in chitosan gel were encapsulated in bags made from highly porous EVOH membranes, and their in vitro insulin secretion function as well as in vivo performance was evaluated. The results showed that the EVOH bag did not affect islet survival or glucose-stimulated insulin secretion. Whereas naked islets were dysfunctional after 7 days of culture in vitro, islets within the EVOH bag produced insulin continuously for 30 days. Streptozotocin-induced diabetic mice were given islets-chitosan gel-EVOH implants intraperitoneally (650-800 islets equivalent) and exhibited lower blood glucose levels and regained body weight during a 4-week observation period. The transplanted mice had higher levels of serum insulin and C-peptide, with an improved blood glucose disappearance rate. Retrieved implants had minor tissue adhesion, and histology showed a limited number of mononuclear cells and fibroblasts surrounding the implants. No invasion of host cells into the EVOH bags was noticed, and the encapsulated islets were intact and positive for insulin-glucagon immunostaining. In conclusion, an EVOH bag can protect encapsulated islets, limit fibrous capsule formation, and extend graft function.

Stability analysis and control of the glucose insulin glucagon system in humans

The goal for the treatment of type-1 diabetes mellitus is the development of an artificial pancreas to regulate the blood glucose level in a closed loop design. A system of nonlinear differential equations having five variables (glucose, insulin, β-cell mass, α-cell mass, and glucagon) with seventeen parameters is considered. The Lyapunov function is used to check the stability analysis of the model. Controllability and observability of the linearized model are discussed under two different cases: in case 1 insulin is taken as an input, and in case 2 insulin and glucagon are taken as inputs for the system. This model played an important role in the development of a fully automatic artificial pancreas by stabilizing the control loop system for the glucose-insulin glucagon pump. A proportional integral derivative (PID) controller is designed for an artificial pancreas by using the transfer function. According to the desired value, the algorithm of an artificial pancreas measures the glucose level in the blood of a patient by using a glucose sensor that sends a signal to an insulin glucagon pump to adjust the basal insulin. A closed-loop system is tested in the Simulink environment, and the simulation results show the performance of the designed controller.

Utility of serum IGF-1 for diagnosis of growth hormone deficiency following traumatic brain injury and sport-related concussion

BackgroundGrowth hormone deficiency (GHD) is a potential consequence of traumatic brain injury (TBI), including sport-related concussion (SRC). GH stimulation testing is required for definitive diagnosis; however, this is resource intensive and can be associated with adverse symptoms or risks. Measurement of serum IGF-1 is more practical and accessible, and pituitary tumour patients with hypopituitarism and low serum IGF-1 have been shown to have a high probability of GHD. We aimed to evaluate IGF-1 measurement for diagnosing GHD in our local TBI population.MethodsWe conducted a retrospective chart review of patients evaluated for GHD at the TBI clinic and referred for GH stimulation testing with insulin tolerance test (ITT) or glucagon stimulation test (GST) since December 2013. We obtained demographics, TBI severity, IGF-1, data pertaining to pituitary function, and GH stimulation results. IGF-1 values were used to calculate z-scores per age and gender specific reference ranges. Receiver operator curve analysis was performed to evaluate diagnostic threshold of IGF-1 z-score for determining GHD by GST or ITT.ResultsSixty four patient charts were reviewed. 48 patients had mild, six had moderate, eight had severe TBI, and two had non-traumatic brain injuries. 47 patients underwent ITT or GST. 27 were confirmed to have GHD (peak hGH < 5 μg/L). IGF-1 level was within the age and gender specific reference range for all patients with confirmed GHD following GH stimulation testing. Only one patient had a baseline IGF-1 level below the age and gender specific reference range; this patient had a normal response to GH stimulation testing. ROC analysis showed IGF-1 z-score AUC f, confirming lack of diagnostic utility.ConclusionBaseline IGF-1 is not a useful predictor of GHD in our local TBI population, and therefore has no value as a screening tool. TBI patients undergoing pituitary evaluation will require a dynamic test of GH reserve.

Growth disturbances and metabolic disorders in childhood cancer survivors

Background. Endocrine consequences such as growth hormone deficiency (GHD), growth disturbances and metabolic disorders are common in childhood cancer survivors.Aim: to evaluate and compare the prevalence of growth disturbances and metabolic disorders in childhood posterior cranial fossa tumors (cPCFT) and acute lymphoblastic leukemia (cALL) survivors.Materials and methods. 40 subjects (21 men, 19 women) who had undergone treatment for cPCFT (group 1) and 25 subjects (9 men, 16 women) after treatment for cALL (group 2) were assessed. Group 1 underwent surgery, chemotherapy (CT) and craniospinal irradiation in a dose of 34.9 ± 1.6 Gy with a boost to the PCF 51.3 ± 9.2 Gy. Group 2 underwent CT (23 subjects were treated with ALL-BFM-90 protocol; 2 subjects were treated with ALL-MB-2002 protocol). All subjects of the group 2 received cranial irradiation in a dose 12,7±2 Gy. Age at the time of the survey in a group 1 and 2 – 19.8 ± 3.05 and 21.2±3.9 years; age at the time of treatment – 10.9 ± 3.4 and 6.9±3.4 years; follow-up – 7.2 ± 4.2 and 13.8±4.9 years, respectively. 16 age and sex matched healthy controls were included. Patient’s anthropometric and laboratory parameters were measured, GHD was diagnosed in group 1 by 2 tests – insulin tolerance test (ITT) and glucagon stimulation test (GST). In group 2 these tests didn't perform. At the time of the survey no one in both groups received GH replacement therapy. Only 5 subjects (3 boys and 2 girls) in group 1 were treated with recombinant human GH during childhood.Results.Final height SDS in the group 1 was significantly less than in the group 2 (p=0.001) and in healthy controls (p&lt;0.001). In the group 1 and 2 there were significantly less patients reached target height compared to healthy controls (p&lt;0.001). Subjects of group 1 rarely reached their target height in comparison to the group 2 (p=0.006). IGF-1 SDS was significantly less in the group 1 (-1.37±1.24) than in the group 2 (0.5±1.24, p&lt;0.001). In group 1 GHD according to GST was diagnosed in 60% of subjects, according to ITT in 82.1% of subjects. Waist circumference was significantly bigger in group 2 compared to the group 1 (p=0.046) and to healthy controls (p=0.001). Overweight was registered in 10% of patients in group 1 and in 16% - in group 2. Dyslipidemia was diagnosed in 50% in group 1, in 19% in group 2 (p=0.226). In group 1 16.7% and in group 2 66.7% of subjects were insulin resistant.Conclusions. After treatment for cPCFT growth disturbances occurred more often than after cALL therapy. Metabolic disorders were diagnosed with different frequency in both cPCFT and cALL survivors. These patients need endocrinologist’ observation.

The interaction between glucose, insulin, β-cells, α-cells and glucagon: Mathematical model

Background Pancreatic β-cells and α-cells are responsible of controlling the level of glucose in the blood. While insulin reduces the level of blood glucose by stimulating its uptake by muscles and adipose tissues and storing it as glycogen in the liver, glucagon supplies another source of glucose (produced through liver gluconeogenesis and glucogenolysis) for blood. Consequently, damage in either β-cells or α-cells can lead to a dysfunction in insulin secretion or glucagon production. Studies related to mathematical modelling of the relationship between glucose, insulin and β-cells have been the subject of several publications. However, the interaction between glucose, insulin, β-cells, α-cells and glucagon has been ignored. In this study, we propose a mathematical model dealing with the dynamics of glucose, insulin, β-cells, α-cells and glucagon. Material and methods Based on the mathematical models proposed by Boutayeb et al. and Ruby et al. our extended model introduces the dynamics of α-cells on the interaction of glucagon and glucose. Our study describes the roles of β-cells on secreting insulin and α-cells on producing glucagon, besides contribution of those two hormones on the control of glycaemia. The dynamics of glucose, insulin, β-cells, α-cells and glucagon are studied using ordinary differential equations. Results and conclusion The proposed model has four equilibrium points: P0 (G = 600, I = 0, β=0, α = 0, J = 0), P1 (G = 600, I = 0, β = 0, α = 300, J = 0), P2 (G = 80, I = 21, β=900, α = 300, J = 0.16), P3 (G = 73, I = 19, β = 900, α = 0, J = 0). Where G (mg), I (mU/mL), β (mg), α (mg) and J (mg) represent respectively concentrations of glucose, insulin, β-cell mass, α-cell mass and glucagon. The first point P0 is an unstable point describing a severe hyperglycaemia with zero levels of β-cell mass and α-cell mass leading to zero levels of insulin and glucagon and consequently raising the level of glucose. The second one is an unstable point corresponding to a severe hyperglycaemia. Despite the normal value of α-cell mass (300 mg), the glucagon cannot be produced in a case of hyperglycaemia. The third point is a stable point corresponding to a normal state with normal values of glucose, insulin, β-cell mass, α-cell mass and glucagon. The last equilibrium point P3 is an unstable point describing a hypoglycaemic state justified by zero levels of α-cell mass and glucagon and normal values of insulin and β-cell mass. Our mathematical model shows that A normal pancreatic β-cell mass and α-cell mass maintains the level of glycaemia in the normal range. The apoptosis of β-cells and α-cells is the origin of insulin and glucagon secretory defects causing severe hyperglycaemic state with high glucose rate in the blood. The death of β-cells leads to hyperglycaemia even without a deterioration of α-cell mass. The apoptosis of α-cells causes impairment in the glucagon response to hypoglycaemia, which reduces the level of glucose in the blood.

Higher insulin and lower glucagon levels in plasma and cerebrospinal fluid in suicide attempters compared to healthy controls

Higher insulin and lower glucagon levels in plasma and cerebrospinal fluid in suicide attempters compared to healthy controls

Insulin augmentation and glucagon inhibition in cinnamon treated diabetic rats

Insulin augmentation and glucagon inhibition in cinnamon treated diabetic rats

Growth hormone deficiency and metabolic disorders after radiotherapy and chemotherapy of malignant tumors of the posterior cranial fossa

Endocrine disorders are common in patients after treatment for brain tumors in childhood. Growth hormone (GH) deficiency is the most common consequence of cranial irradiation. Objective — to evaluate the prevalence of GH deficieny and metabolic disorders in patients after treatment for malignant tumors of the posterior cranial fossa (MT PCF) in childhood. Material and methods. In this study 40 patients (21 men, 19 women) who had undergone treatment for MT PCF were assessed. Patients underwent surgery, chemotherapy and craniospinal irradiation (CSI) in a dose of 34.9±1.6 Gy with a boost to the PCF 51.3±9.2 Gy. Age at the time of the survey — 19.8±3.05 years; age at the time of treatment — 10.9±3.4 years; follow-up — 7.2±4.2 years. Patient’s anthropometric and laboratory parameters were measured, GH failure was diagnosed by two tests – insulin tolerance test (ITT) and glucagon stimulation test (GST). Results. According to ITT GH deficiency was observed in 82.1% and according to GST in 60.0% of patients. When comparing two tests GST showed 100% specificity, but lower sensitivity (72.2%). Manifestation of GH deficiency depends on the age at the time of treatment (p=0.002). There is significant correlation between age at the time of treatment and SDS of final height (r=0.632; p&lt;0.001). We found a significant correlation between age at the time of treatment and BMI (r=–0,327; p=0.04). Dyslipidemia occurred in 50% of cases. Insulin resistance was recorded in 16.7% of patients. We found significant correlation between the HOMA-IR and BMI (r=0.336; p=0.034). Conclusions. In patients after treatment for MT PCF in childhood GH deficiency and metabolic disorders is highly prevalent. This group of patients should be monitored by endocrinologist for timely detection and treatment of GH deficiency and metabolic complications.

P-48THE GLUCAGON-LIKE PEPTIDE 1 ANALOGUE LIRAGLUTIDE ATTENUATES ALCOHOL-INDUCED REWARD, DECREASES ALCOHOL INTAKE AND PREVENTS RELAPSE-LIKE DRINKING TO ALCOHOL IN OUTBRED RODENTS AS WELL AS REDUCES OPERANT ALCOHOL SELF-ADMINISTRATION IN SARDINIAN ALCOHOL-PREFERRING RATS

The incretin hormone, glucagon-like peptide 1 (GLP-1), regulates gastric emptying, glucose-dependent stimulation of insulin secretion and glucagon release. GLP-1 analogs are therefore approved for treatment of diabetes type II. GLP-1 receptors are expressed in reward-related areas such …

Association between retinopathy and sleep disorder in patients with type 2 diabetes mellitus

To explore the association between retinopathy and sleep disorder in patients with type 2 diabetes mellitus (T2DM). A total of 440 patients with T2DM treated from July 2011 to July 2013 in Metabolic Disease Hospital of Tianjin Medical University were divided into 2 groups according to Pittsburgh Sleep Quality Index: non-sleep disorder group (258 cases) and sleep disorder group (182 cases). Biochemical parameters including hepatorenal function, blood lipids, glycosylated hemoglobin (HbA1c), fructosamine and hemorrheology were detected. Oral glucose tolerance test, insulin releasing test and glucagon releasing test were performed to detect the inteR-group differences of α-cell and β-cell function after fasting and glucose-load management. The logistic regression analysis was performed to identify the factors relevant to retinopathy. The ratio of retinopathy was 42.9% in sleep disorder group, which was higher compared to those in non-sleep disorder group (32.6%), P=0.027. The levels of fasting plasma glucose, postprandial blood glucose, HbA1c, fructosamine, systolic blood pressure, diastolic blood pressure and the indicators of hemorrheology (plasma viscosity, erythrocyte aggregation index, erythrocyte rigidity index, fibrinogen) were significantly higher in patients with sleep disorder compared to those without sleep disorder, while the erythrocyte defomation index was significantly lower in sleep disorder group (all P<0.05). The levels of glucagon and glucagon/insulin ratio at each time point as well as area under curve of glucagon were significantly higher in sleep disorder group (all P<0.05). The levels of fasting insulin, homeostasis model assessment for insulin resistance index (HOMA-IR) and area under curve of insulin were significantly higher in patients with sleep disorder compared to those without sleep disorder, while insulin sensitivity index was lower in patients with sleep disorder (all P<0.05). Logistic regression analysis showed that retinopathy was positively related to HbA1c (OR: 1.744-3.249), fibrinogen (OR: 1.687-2.998), systolic blood pressure (OR: 1.152-2.013), HOMA-IR (OR: 1.006-1.389) and sleep disorder (OR: 1.144-2.426), and negatively related to insulin sensitivity index (OR: 0.107-0.784) (all P<0.05). Sleep disorders may be associated with retinopathy through multiple mechanisms in patients with T2DM.

A preliminary study of pathogenesis of dawn phenomenon in patients with type 2 diabetes mellitus

Objective To study the preliminary pathogenesis of dawn phenomenon in patients with type 2 diabetes mellitus. Methods Two-hundred and sixty-four patients with type 2 diabetes had performed continuous glucose monitoring since Jan 2012 to July 2014. They were divided into two groups: patients without dawn phenomenon and patients with dawn phenomenon. Biochemical indicators including liver and kidney function, blood lipids, HbA1C, fructosamine(FMN), adrenocorticotropic hormone and cortisol were detected in the two groups. Oral glucose tolerance test, insulin releasing test and glucagon releasing test were performed. The differences in biochemical indicators, glucose level and α-cell and β-cell function after fasting and glucose-load were compared. The correlation and regression analysis were performed between dawn phenomenon and other indicators. Results The level of adrenocorticotropic hormone, cortisol, HbA1C, FMN, the increment of fasting glucose and nocturnal nadir glucose(BG1), the glucose increment before and after breakfast(BG2), 24-hour mean glucose, duration above high limit, and HOMA-IR were significantly higher in patients with dawn phenomenon compared to those in patients without dawn phenomenon[(6.6±2.4)vs(4.8±1.9)pmol/L, (523.8±84.2)vs(448.2±76.9)nmol/L, (8.1±2.0)% vs (7.5±1.8)%, (0.32±0.09)vs(0.29±0.08)mmol/L, (26.2±5.8)vs(18.0±4.9)mg/dl, (39.6±8.3)vs(28.8±7.4)mg/dl, (188.5±36.2)vs(164.5±31.2)mg/dl, 29∶31(41%)vs 20∶10(28%), 4.18±0.94 vs 3.82±0.82](all P<0.05). ISI and AUCG/AUCI were lower in patients with dawn phenomenon than those in patients without dawn phenomenon(-4.28±0.62 vs -4.04±0.54, -0.74±0.48 vs -0.63±0.30)(all P<0.05). The level of glucagon at each time point and area under curve of glucagon were significantly higher in patients with dawn phenomenon than those in patients without. 0, 60, 180 min glucagon/insulin ratio and 0, 30, 120, 180 min glucagon/glucose ratio were significantly higher in patients with dawn phenomenon(all P<0.05). Logistic regression analysis showed that dawn phenomenon was positively related to HOMA-IR, glucagon/insulin ratio, BG2, BG1and cortisol(all P<0.05), and negatively related to ISI(P<0.05). Conclusion Dawn phenomenon may be associated with increased secretion of cortisol and dysfunction of islet α-cell and β-cell. (Chin J Endocrinol Metab, 2015, 31: 492-496) Key words: Diabetes mellitus, type 2; Dawn phenomenon; Cortisol; Islet α-cell; Islet β-cell

Sodium-glucose cotransporter-2 inhibition and the insulin: Glucagon ratio: Unexplored dimensions.

The sodium-glucose cotransporter 2 (SGLT-2) inhibitors are a novel class of glucose-lowering drugs which act by inhibiting the reabsorption of filtered glucose from the kidneys. Their effect on insulin and glucagon levels has recently been studied but is not fully explained. This communication proposes various hypotheses: A direct effect of SGLT-2 inhibition on the alpha cell receptors, a paracrine or intra-islet mediated effect on alpha cell sensitivity to glucose, and a calorie restriction mimetic action, to explain the impact of these drugs on the insulin glucagon ratio.

GP3-3: The diagnostic accuracy of pegvisomant-primed glucagon stimulation test (PV-GST) compared to insulin tolerance (ITT) and glucagon stimulation (GST) tests in evaluating adult growth hormone (GH) reserve

GP3-3: The diagnostic accuracy of pegvisomant-primed glucagon stimulation test (PV-GST) compared to insulin tolerance (ITT) and glucagon stimulation (GST) tests in evaluating adult growth hormone (GH) reserve

Antagonistic Effects of Insulin Signaling and Glucagon Signaling on Controlling Hepatic Gluconeogenic Gene Expression

With the worldwide epidemics of obesity and diabetes, there is an urgent need for action at the global and national levels to prevent and to treat these metabolic disorders. Inappropriate hepatic glucose production is the major cause of hyperglycemia in obese and diabetic patients. In this mini-review, we summarize the antagonistic effects of insulin signaling and glucagon signaling on controlling gene expression related to hepatic glucose production through CREB co-activators and FOXO1. In the fasted state, phosphorylation of CREB at S133 recruits CBP/P300 and CRTC2 to CREB, leading to the formation of CREB co-activators complex. CREB and P300 also upregulate FOXO1 gene expression. CREB co-activators together with FOXO1 drive gluconeogenic gene expression to maintain euglycemia. In the fed state, insulin suppresses gluconeogenic gene expression through the phosphorylation of CBP, which results in the disassembly of CREB-CBP-CRTC2 complex, furthermore, phosphorylation of CRTC2 and FOXO1 by insulin excludes CRTC2 and FOXO1 from nucleus and promotes their degradation in cytoplasm.

Functions of pancreatic islet α-cells and β-cells in different disease courses of type 2 diabetes mellitus

Objective To evaluate the functions of pancreatic islet α-cells and β-cells in different disease courses of type 2 diabetes mellitus. Methods Two hundred and eighty three patients with type 2 diabetes mellitus were divided into 4 groups according to their disease courses: group A (course of disease≤1 years), group B (1 years 10 years). Oral glucose tolerance test (OGTT), insulin releasing test and glucagon releasing test were performed to observe the differences of glucagon, glucagon/insulin, ratio of insulin increment/glucose increment 30 min after glucose-load (ΔI30/ΔG30), area under curve (AUC) of insulin in receiver operational characteristic (ROC) curve of insulin (AUCI) and glucagon among 4 groups and the correlation analysis was performed between glucagon and other indicators. Results (1) Glucagon, glucagon/insulin and AUC of glucagon increased significantly with the prolonged course of disease (P 0.05); compared to group A, HOMA of β-cell function (HOMA-β), ΔI30/ΔG30, AUCI in groups B, C and D were significantly lower (F=3.75, 3.77 and 3.07 respectively, all P<0.05).(3) Multiple stepwise regression analysis showed that glucagon was positively correlated with FPG and AUC of glucose (AUCG) (t=6.23 and 3.41, all P<0.05), and negatively correlated with AUCI/AUCG (t=-2.13, P<0.05). Conclusions In order to reach the blood glucose control target, in the early stage of diabetes attentions should be given to regulation of glucagon while protect the β-cell function. Key words: Glucagon; Islet α-cell; Islet β-cell; Course of disease; Diabetes mellitus，type 2

RETRACTED: Evaluation of the positive effects on insulin-resistance and β-cell measurements of vildagliptin in addition to metformin in type 2 diabetic patients

We evaluated the positive effects of vildagliptin in addition to metformin on glycemic control and β-cell function in type 2 diabetic patients. One hundred and seventy-one type 2 diabetic patients were instructed to add vildaglipin 50mg twice a day or placebo to metformin for 12 months. Body mass index (BMI), glycemic control, fasting plasma insulin (FPI), HOMA-IR, HOMA-β, fasting plasma proinsulin (FPPr), proinsulin/fasting plasma insulin ratio (Pr/FPI ratio), C-peptide, glucagon, vaspin, visfatin, and omentin-1 were evaluated. Before, and after 12 months since the addition of vildagliptin, patients underwent a combined euglycemic hyperinsulinemic and hyperglycemic clamp, with subsequent arginine stimulation. Vildagliptin+metformin were more effective than placebo+metformin in reducing body weight and BMI, glycemic control, HOMA-IR, glucagon and insulin resistance measurements. Vildagliptin+metformin gave also a better increase of HOMA-β, and of all β-cell parameters after the clamp. We also recorded a significant correlation between M value increase and the decrease of vaspin, visfatin, and omentin-1 obtained with vildagliptin+metformin. Vildagliptin, in addition to metformin, proved to be effective in improving β-cell function and in reducing insulin resistance measurements.

Effects of somatostatin analogs on glucose homeostasis in rats

Pasireotide (SOM230) is a multireceptor-targeted somatostatin analog with high binding affinity for sstr(1,2,3) and sstr(5). The effects of pasireotide and octreotide on blood glucose, insulin, and glucagon levels in rats were evaluated alone and in combination. Single-dose s.c. pasireotide acutely elevated plasma glucose, whereas single-dose s.c. octreotide had no or a small hypoglycemic effect. Glucose elevation with s.c. pasireotide was transient with tachyphylaxis after repeated or continuous administration. Pasireotide and octreotide caused similar inhibitory effects on insulin secretion, whereas pasireotide had a weaker inhibitory effect on glucagon secretion than octreotide. Continuous infusion of pasireotide or injection of pasireotide long-acting release (LAR) resulted in only small and transient elevations of plasma glucose. Based on these results, and differences in the sstr binding affinity of pasireotide vs octreotide, it was hypothesized that the sstr(5) vs sstr(2) receptor activation ratio is the main driver of hyperglycemia after pasireotide. The results also suggest that stronger activation of sstr(2) may counteract the hyperglycemic effect. Indeed, co-administration of octreotide, which has a high affinity for sstr(2), with a hyperglycemic dose of pasireotide did not cause significant changes in plasma glucose levels. In conclusion, although pasireotide and octreotide inhibited insulin to a similar degree, only pasireotide administration was associated with hyperglycemia. The strong glucagon inhibitory effect exhibited by octreotide but not pasireotide may explain this observation. The lack of hyperglycemia during co-administration of pasireotide and octreotide may be explained by the greater activation of sstr(2) compared with pasireotide alone, causing the insulin-glucagon balance to shift within the normoglycemic range. Extrapolation of these data to humans must account for species differences in islet cell sstr expression.

Context-specific α-to-β-cell reprogramming by forced Pdx1 expression

Using single transcription factors to reprogram cells could produce important insights into the epigenetic mechanisms that direct normal differentiation, or counter inappropriate plasticity, or even provide new ways of manipulating normal ontogeny in vitro to control lineage diversification and differentiation. We enforced Pdx1 expression from the Neurogenin-3-expressing endocrine commitment point onward and found during the embryonic period a minor increased β-cell allocation with accompanying reduced α-cell numbers. More surprisingly, almost all remaining Pdx1-containing glucagon/Arx-producing cells underwent a fairly rapid conversion at postnatal stages, through glucagon-insulin double positivity, to a state indistinguishable from normal β cells, resulting in complete α-cell absence. This α-to-β conversion was not caused by activating Pdx1 in the later glucagon-expressing state. Our findings reveal that Pdx1 can work single-handedly as a potent context-dependent autonomous reprogramming agent, and suggest a postnatal differentiation evaluation stage involved in normal endocrine maturation.