Insulin Glucagon Research Articles

Computational techniques to monitoring fractional order type-1 diabetes mellitus model for feedback design of artificial pancreas

Background and objectives:In this paper, we developed a significant class of control issues regulated by nonlinear fractal order systems with input and output signals, our goal is to design a direct transcription method with impulsive instant order. Recent advances in the artificial pancreas system provide an emerging treatment option for type 1 diabetes. The performance of the blood glucose regulation directly relies on the accuracy of the glucose-insulin modeling. This work leads to the monitoring and assessment of comprehensive type-1 diabetes mellitus for controller design of artificial panaceas for the precision of the glucose-insulin glucagon in finite time with Caputo fractional approach for three primary subsystems. Methods:For the proposed model, we admire the qualitative analysis with equilibrium points lying in the feasible region. Model satisfied the biological feasibility with the Lipschitz criteria and linear growth is examined, considering positive solutions, boundedness and uniqueness at equilibrium points with Leray–Schauder results under time scale ideas. Within each subsystem, the virtual control input laws are derived by the application of input to state theorems and Ulam Hyers Rassias. Results:Chaotic Relation of Glucose insulin glucagon compartmental in the feasible region and stable in finite time interval monitoring is derived through simulations that are stable and bounded in the feasible regions. Additionally, as blood glucose is the only measurable state variable, the unscented power-law kernel estimator appropriately takes into account the significant problem of estimating inaccessible state variables that are bound to significant values for the glucose-insulin system. The comparative results on the simulated patients suggest that the suggested controller strategy performs remarkably better than the compared methods. Conclusion:In the model under investigation, parametric uncertainties are identified since the glucose, insulin, and glucagon system’s parameters are accurately measured numerically at different fractional order values. In terms of algorithm resilience and Caputo tracking in the presence of glucagon and insulin intake disturbance to maintain the glucose level. A comprehensive analysis of numerous difficult test issues is conducted in order to offer a thorough justification of the planned strategy to control the type 1 diabetes mellitus with designed the artificial pancreas.

Insulin:Glucagon Bipolar Axis in Obesity With a Glimpse Into Its Association With Insulin Resistance in Different Glucose Tolerance States.

Dysregulation of insulin and glucagon secretion alters the normal insulin:glucagon ratio (IGR) in type 2 diabetes mellitus, obesity, and metabolic syndrome. This study explores the scope of construing the role of these two diametrically opposing hormones on the glucose level not just in obesity but in different glucose tolerance states by looking at the hormone levels and at the insulin glucagon bipolar axis itself. This is an analytical cross-sectional study of 60 healthy adults consisting of an equal number of adults who are lean and adults who are obese. It was conducted at North Eastern Indira Gandhi Regional Institute of Health and Medical Sciences (NEIGRIHMS), located in Shillong City, Meghalaya, India. Fasting glucose, insulin, glucagon, and lipids were estimated. Postprandial estimation of glucose was done two hours after oral administration of 75 grams of glucose solution. The study demonstrated a state of hyperinsulinemia and hyperglucagonemia prevailing in obesity and all sub-categories of the group of persons who are obese. The study showed a higher fasting IGRin the group consisting of adults who were obese (with a mean of 4.11) when compared with the group of adults who are lean (with a mean of 2.24). Fasting IGRwas seen to increase with increasing levels of insulin resistance and increasing impairment in glucose tolerance. IGR showed a positive correlation with the homeostatic model assessment for insulin resistance (HOMA-IR) in the impaired fasting glucose (IFG) category and strongly in the impaired glucose tolerance (IGT) category. Hyperglucagonemia in the group of adult persons who are obese indicates a decreased sensitivity of alpha cells to insulin failing insulin to adequately suppress the secretion of glucagon. The study also demonstrated a positive correlation between IGR and HOMA-IR in obesity and all glucose tolerance states of the group of adults who are obese. It is telltale that the sturdier the insulin resistance, the higher the IGR.

Analysis and dynamical structure of glucose insulin glucagon system with Mittage-Leffler kernel for type I diabetes mellitus

In this paper, we propose a fractional-order mathematical model to explain the role of glucagon in maintaining the glucose level in the human body by using a generalised form of a fractal fractional operator. The existence, boundedness, and positivity of the results are constructed by fixed point theory and the Lipschitz condition for the biological feasibility of the system. Also, global stability analysis with Lyapunov’s first derivative functions is treated. Numerical simulations for fractional-order systems are derived with the help of Lagrange interpolation under the Mittage-Leffler kernel. Results are derived for normal and type 1 diabetes at different initial conditions, which support the theoretical observations. These results play an important role in the glucose-insulin-glucagon system in the sense of a closed-loop design, which is helpful for the development of artificial pancreas to control diabetes in society.

Maternal nutrient metabolism in the liver during pregnancy.

The liver plays pivotal roles in nutrient metabolism, and correct hepatic adaptations are required in maternal nutrient metabolism during pregnancy. In this review, hepatic nutrient metabolism, including glucose metabolism, lipid and cholesterol metabolism, and protein and amino acid metabolism, is first addressed. In addition, recent progress on maternal hepatic adaptations in nutrient metabolism during pregnancy is discussed. Finally, the factors that regulate hepatic nutrient metabolism during pregnancy are highlighted, and the factors include follicle-stimulating hormone, estrogen, progesterone, insulin-like growth factor 1, prostaglandins fibroblast growth factor 21, serotonin, growth hormone, adrenocorticotropic hormone, prolactin, thyroid stimulating hormone, melatonin, adrenal hormone, leptin, glucagon-like peptide-1, insulin glucagon and thyroid hormone. Our vision is that more attention should be paid to liver nutrient metabolism during pregnancy, which will be helpful for utilizing nutrient appropriately and efficiently, and avoiding liver diseases during pregnancy.

The Insulin: Glucagon Ratio and Obesity.

This communication discusses the physiology and pathology of the insulin glucagon ratio, with respect to obesity. Though high insulin levels are associated with obesity in this manuscript the authors specifically highlight its role in the causation and clinical management of obesity. It suggests that the term insulin glucagon ratio be used in preference to glucagon insulin ratio, and shares insights which may be helpful in informing future research.

The role of pancreas to improve hyperglycemia in STZ-induced diabetic rats by thiamine disulfide

BackgroundThe present study investigated the effect of thiamine disulfide (TD) on the pancreas in terms of hyperglycemia improvement and insulin sensitivity increase in diabetic male rats. We also aimed to study the function of Pdx1 (pancreatic and duodenal homeobox 1) and Glut2 (glucose transporter 2) genes in pancreatic tissue.MethodsType 1 diabetes was induced through injection of 60 mg/kg streptozotocin (STZ). The diabetic rats were divided into four groups, namely diabetic control (DC), diabetic treated with thiamine disulfide (D-TD), diabetic treated with insulin (D-insulin), and diabetic treated with TD and insulin (D-insulin+TD). The non-diabetic (NDC) and diabetic groups received a normal diet (14 weeks). Blood glucose level and body weight were measured weekly; insulin tolerance test (ITT) and glucagon tolerance test (GTT) were performed in the last month of the study. The level of serum insulin and glucagon were measured monthly and a hyperglycemic clamp (Insulin Infusion rate (IIR)) was done for all the groups. Pancreas tissue was isolated so that Pdx1and Glut2 genes expression could be measured.ResultsWe observed that TD therapy decreased blood glucose level, ITT, and serum glucagon levels in comparison with those of the DC group; it also increased serum insulin levels, IIR, and expression of Pdx1 and Glut2 genes in comparison with those of the DC group.ConclusionAdministration of TD could improve hyperglycemia in type 1 diabetic animals through improved pancreas function. Therefore, not only does TD have a significant effect on controlling and reducing hyperglycemia in diabetes, but it also has the potential to decrease the dose of insulin administration.

153-OR: Ventromedial Hypothalamic Nucleus Controls Glucose Metabolism through Adipose Tissue Lipolysis

The central nervous system (CNS) coordinates metabolic target organ function to optimize blood glucose levels, while dysregulation of this system leads to impaired glycemia. Attempts to improve glucose control through CNS targeting are hindered by a incomplete understanding of the specific neuronal populations involved and how these cells coordinate peripheral metabolic target organ function. We found that cholecystokinin b receptor-expressing neurons of the ventromedial nucleus of the hypothalamus (VMN; VMNCCKBR neurons) mediate glucose mobilization during counter-regulatory responses to hypoglycemia and regulate glucose levels in normal and diabetic mice. Silencing VMNCCKBR neurons with tetanus toxin (CCKBRTT) attenuates hyperglycemia in ob/ob mice and decreases baseline blood glucose by suppressing hepatic gluconeogenesis despite decreased insulin and elevated glucagon. CCKBRTT mice have elevated hepatic gluconeogenic enzyme expression and normal glycemic responses to exogenous gluconeogenic substrates, suggesting that silencing VMNCCKBR neurons decreases blood glucose through impaired gluconeogenic substrate mobilization. To determine which gluconeogenic substrates contribute to VMNCCKBR-neuron mediated glucose production, we expressed channel rhodopsin in VMNCCKBR neurons to optogenetically activate VMNCCKBR neurons in freely moving mice. In addition to elevating plasma glucose, optogenetic activation resulted in a β3-adrenergic receptor-dependent increase in plasma ketones and glycerol, suggesting that VMNCCKBR neurons increase lipolysis though SNS innervation of white adipose tissue (WAT) . Consistent with this observation, CCKBRTT mice exhibited decreased fasting plasma glycerol and in vivo lipolysis, while β3-agonist treatment elevated these appropriately. Hence, VMNCCKBR neuron-mediated SNS outflow to WAT promotes lipolysis to provide gluconeogenic substrates and support baseline blood glucose in mice. Disclosure A.Affinati: Other Relationship; Novo Nordisk A/S. J.Flak: Research Support; Eli Lilly and Company. N.Kodur: None. A.Hashsham: None. A.J.Tomlinson: None. N.Bozadjieva kramer: None. C.Li: Employee; Novo Nordisk. M.G.Myers: Advisory Panel; Regeneron Pharmaceuticals Inc., Research Support; AstraZeneca, Novo Nordisk. Funding National Institutes of Health (F32DK122660)

Dapagliflozin Impairs the Suppression of Endogenous Glucose Production in Type 2 Diabetes Following Oral Glucose.

To examine the effect of SGLT2 inhibitors (SGLT2i) on endogenous glucose production (EGP) in patients with type 2 diabetes after an oral glucose load. Forty-eight patients with type 2 diabetes received an 8-h [3-3H]-glucose infusion (protocol I) to assess EGP response to: 1) dapagliflozin (DAPA), 10 mg; 2) exenatide (EXE), 5 μg s.c.; 3) DAPA/EXE; and 4) placebo (PCB). After 2 weeks (protocol II), patients were restudied with a 5-h double-tracer (i.v. [3-3H]-glucose and oral [1-14C]-glucose) oral glucose tolerance test (OGTT) preceded by PCB, DAPA, EXE, or DAPA/EXE. Protocol I: EGP decreased (P < 0.01) with PCB (2.16 ± 0.15 to 1.57 ± 0.08 mg/kg/min) and EXE (2.13 ± 0.16 to 1.58 ± 0.03) and remained unchanged (P = NS) with DAPA (2.04 ± 0.17 vs. 1.94 ± 0.18) and DAPA/EXE (2.13 ± 0.10 vs. 2.09 ± 0.03). During OGTT, EGP decreased (P < 0.01) with PCB (2.30 ± 0.05 to. 1.45 ± 0.06 mg/kg/min) and EXE (2.53 ± 0.08 to 1.36 ± 0.06); with DAPA (2.20 ± 0.04 vs. 1.71 ± 0.07) and DAPA/EXE (2.48 ± 0.05 vs. 1.64 ± 0.07), the decrease in EGP was attenuated (both P < 0.05). During OGTT, the insulin/glucagon (INS/GCN) ratio increased in PCB (0.26 ± 0.03 vs. 0.71 ± 0.06 μU/mL per pg/mL), whereas in DAPA (0.26 ± 0.02 to 0.50 ± 0.04), the increase was blunted (P < 0.05). In EXE, INS/GCN increased significantly (0.32 ± 0.03 to 1.31 ± 0.08) and was attenuated in DAPA/EXE (0.32 ± 0.03 vs. 0.78 ± 0.08) (P < 0.01). These findings provide novel evidence that the increase in EGP induced by SGLT2i is present during an oral glucose load. The fact that stimulation of EGP occurs despite elevated plasma insulin and glucagon suggests that additional factors must be involved.

Interrelationship between 2019-nCov receptor DPP4 and diabetes mellitus targets based on protein interaction network

Patients with diabetes are more likely to be infected with Coronavirus disease 2019 (COVID-19), and the risk of death is significantly higher than ordinary patients. Dipeptidyl peptidase-4 (DPP4) is one of the functional receptor of human coronavirus. Exploring the relationship between diabetes mellitus targets and DPP4 is particularly important for the management of patients with diabetes and COVID-19. We intend to study the protein interaction through the protein interaction network in order to find a new clue for the management of patients with diabetes with COVID-19. Diabetes mellitus targets were obtained from GeneCards database. Targets with a relevance score exceeding 20 were included, and DPP4 protein was added manually. The initial protein interaction network was obtained through String. The targets directly related to DPP4 were selected as the final analysis targets. Importing them into String again to obtain the protein interaction network. Module identification, gene ontology (GO) analysis and Kyoto encyclopedia of genes and genomes (KEGG) pathway analysis were carried out respectively. The impact of DPP4 on the whole network was analyzed by scoring the module where it located. 43 DPP4-related proteins were finally selected from the diabetes mellitus targets and three functional modules were found by the cluster analysis. Module 1 was involved in insulin secretion and glucagon signaling pathway, module 2 and module 3 were involved in signaling receptor binding. The scoring results showed that LEP and apoB in module 1 were the highest, and the scores of INS, IL6 and ALB of cross module associated proteins of module 1 were the highest. DPP4 is widely associated with key proteins in diabetes mellitus. COVID-19 may affect DPP4 in patients with diabetes mellitus, leading to high mortality of diabetes mellitus combined with COVID-19. DPP4 inhibitors and IL-6 antagonists can be considered to reduce the effect of COVID-19 infection on patients with diabetes.

Abstract MP227: Single Cell RNA Sequencing Analysis Reveals Insulin Signaling Defects In Cardiomyocytes Derived From A Novel Mouse Model Of Heart Failure With Preserved Ejection Fraction

Heart failure with preserved ejection fraction (HFpEF) is an emerging form of heart failure worldwide with no effective therapies in contrast with heart failure with reserved ejection fraction (HFrEF). To simulate multiple risk-factors associated with HFpEF in clinic, we developed a HFpEF mouse model by introducing cardiac hypertrophy with transverse aortic constriction (TAC) in ObOb ( Lep ob/ob ) mice, which has intrinsic systemic metabolic dysfunctions including obesity and insulin resistance. We first validated pathological changes in diastolic but not systolic parameters in the Ob-TAC vs. Ob-sham mice up to 10 weeks post-TAC by echocardiography. To evaluate the global transcriptome change in difference cell types, we conducted single nuclei RNA sequencing (snRNA-seq) from whole hearts of lean mice (c57), ObOb, and Ob-TAC mice (male only). 10x genomic 3’ GEM kit was used to generate the cDNA library and sequencing was done by Novaseq SP platform. A total of 13k nuclei were recovered from QC, nFeature RNA (&amp;lt 2500) and mitochondrial gene (&amp;lt 5%) filtering. By UMAP dimension reduction analysis, we annotated major cardiac cell types in the integrated snRNA-seq dataset, including 3 clusters of Cardiomyocytes (CMs). By pathway analysis of the differentially expressed genes in each CM clusters, we found that insulin resistance and glucagon pathway were enriched among the up regulated genes in CMs in HFpEF vs. lean control, while cell migration, signal transduction including insulin substrates were down regulated. Thus, we hypothesized that the altered crosstalk between glucagon and insulin signaling might contribute to the development of HFpEF in this mouse modal. This hypothesis was validated in a proof-of-concept study showing significant improvement of HFpEF features by inhibiting the glucagon receptors post-TAC with injection of a glucagon receptor antagonist.

Modeling and simulation of glucose insulin glucagon algorithm for artificial pancreas to control the diabetes mellitus

Modeling and simulation of glucose insulin glucagon algorithm for artificial pancreas to control the diabetes mellitus

Genome-wide identification and functional prediction of long non-coding RNAs in Sprague-Dawley rats during heat stress

BackgroundHeat stress (HS) is a major stress event in the life of an animal, with detrimental upshots in production and health. Long-non-coding RNAs (lncRNAs) play an important role in many biological processes by transcriptional regulation. However, no research has been reported on the characterization and functionality of lncRNAs in heat-stressed rats.ResultsWe studied expression levels of lncRNAs in rats during HS, using strand-specific RNA sequencing. Six rats, three in each of Control (22 ± 1 °C) and H120 (42 °C for 120 min) experimental groups, were used to screen for lncRNAs in their liver and adrenal glands. Totally, 4498 and 7627 putative lncRNAs were identified in liver and adrenal glands of the Control and H120 groups, respectively. The majority of lncRNAs were relatively shorter and contained fewer exons than protein-coding transcripts. In total, 482 (174 up-regulated and 308 down-regulated) and 271 (126 up-regulated and 145 down-regulated) differentially-expressed lncRNAs (DElncRNAs, P < 0.05) were identified in the liver and adrenal glands of the Control and H120 groups, respectively. Furthermore, 1274, 121, and 73 target differentially-expressed genes (DEGs) in the liver were predicted to interact with DElncRNAs based on trans−/cis- and sequence similarity regulatory modes. Functional annotation analyses indicated that these DEGs were mostly significantly enriched in insulin signalling, myeloid leukaemia, and glucagon signalling pathways. Similarly, 437, 73 and 41 target DEGs in the adrenal glands were mostly significantly enriched in the cell cycle (trans-prediction) and lysosome pathways (cis-prediction). The DElncRNAs interacting with DEGs that encode heat shock proteins (HSPs) may play an important role in HS response, which include Hsf4, Dnaja1, Dnajb4, Hsph1 and Hspb1 in the liver, and Dnajb13 and Hspb8 in the adrenal glands. The strand-specific RNA sequencing findings were also further verified through RT-qPCR.ConclusionsThis study is the first to provide a detailed characterization and functional analysis of expression levels of lncRNAs in liver and adrenal glands of heat-stressed rats, which provides basis for further studies on the biological functions of lncRNAs under heat stress in rats and other mammalian species.

Microencapsulation of cellular aggregates composed of differentiated insulin and glucagon-producing cells from human mesenchymal stem cells derived from adipose tissue

BackgroundIn type I diabetes mellitus (T1DM) pancreatic β cells are destroyed. Treatment entails exogenous insulin administration and strict diet control, yet optimal glycemic control is hardly attainable. Islet transplant could be an alternative in patients with poor glycemic control, but inefficient islet purification and autoimmune response of patients is still a challenge. For these reasons, it is necessary to explore new cellular sources and immunological isolation methods oriented to develop T1DM cell-based therapies.AimsWe postulate human adipose-derived stem cell (hASC) as an adequate source to generate pancreatic islet cells in vitro, and to produce islet-like structures. Furthermore, we propose microencapsulation of these aggregates as an immunological isolation strategy.MethodshASC obtained from lipoaspirated fat tissue from human donors were differentiated in vitro to insulin (Ins) and glucagon (Gcg) producing cells. Then, insulin producing cells (IPC) and glucagon producing cells (GPC) were cocultured in low adhesion conditions to form cellular aggregates, and later encapsulated in a sodium alginate polymer. Expression of pancreatic lineage markers and secretion of insulin or glucagon in vitro were analyzed.ResultsThe results show that multipotent hASC efficiently differentiate to IPC and GPC, and express pancreatic markers, including insulin or glucagon hormones which they secrete upon stimulation (fivefold for insulin in IPC, and fourfold for glucagon, compared to undifferentiated cells). In turn, calculation of the Feret diameter and area of cellular aggregates revealed mean diameters of ~ 80 µm, and 65% of the aggregates reached 4000 µm2 at 72 h of formation. IPC/GPC aggregates were then microencapsulated in sodium-alginate polymer microgels, which were found to be more stable when stabilized with Ba2+, yielding average diameters of ~ 300 µm. Interestingly, Ba2+-microencapsulated aggregates respond to high external glucose with insulin secretion.ConclusionsThe IPC/GPC differentiation process from hASC, followed by the generation of cellular aggregates that are later microencapsulated, could represent a possible treatment for T1DM.

1902-P: Insulin Pulses Do Not Inhibit Glucagon Secretion in Nondiabetic Humans

Type 2 diabetes (T2DM) is characterized by defects in insulin secretion and glucagon suppression. It has been assumed that defective glucagon secretion arises due to impaired insulin secretion. Indeed, prior work suggests that pulsatile insulin secretion has an inverse relationship with post-prandial glucagon secretion. However, more recent data suggest that dysregulation of glucagon secretion in prediabetes occurs early, and independently, of changes in insulin secretion. During a series of experiments examining the mechanisms underlying prediabetes, we studied 29 nondiabetic subjects (age = 44 ± 2, BMI 28 ± 1 Kg/m2). Hepatic vein catheterization allowed sampling of insulin and glucagon at 2 minute intervals during fasting and during a hyperglycemic clamp (150mg/dL). Mean insulin concentrations rose from fasting (33 ± 1 vs. 144 ± 2 pmol/L, p&amp;lt;0.01) while glucagon was suppressed (96 ± 1 vs. 62 ± 1 ng/L, p&amp;lt;0.01) during the clamp. A cross-correlation analysis of the two hormones showed, on average, a small in-phase coordination between insulin and glucagon pulses during fasting, which inverted during hyperglycemia (0.2 ± 0.1 vs. -0.4 ± 0.1, p&amp;lt;0.01). Subsequently, Cross-Approximate Entropy (Cross-ApEn), a technique for comparing synchronicity between two time series, was used to evaluate their interaction. This showed a moderate level of synchronicity, unaffected by glucose concentrations, whether calculated using glucagon as the template to assess pattern reproducibility in insulin concentration (0.78 ± 0.03 vs. 0.76 ± 0.03, fasting vs. hyperglycemia), or when using insulin as the template for the glucagon pattern (0.78 ± 0.02 vs. 0.76 ± 0.03, fasting vs. hyperglycemia). The values of Cross-ApEn did not differ between the two scenarios, suggesting the interaction between the two hormones is not driven by either. Overall these data suggest that, on a minute-to-minute basis, direct control and secretion of glucagon is not mediated (or restrained) by insulin. Disclosure M.C. Laurenti: None. C. Dalla Man: Research Support; Self; Sanofi-Aventis Deutschland GmbH. R.T. Varghese: None. R.A. Rizza: None. A. Matveyenko: None. C. Cobelli: None. A. Vella: Advisory Panel; Self; vTv Therapeutics, Zealand Pharma A/S. Research Support; Self; Novo Nordisk A/S, Xeris Pharmaceuticals, Inc. Funding National Institutes of Health (DK78646, DK116231)

147-OR: Long-Term Effect of GLP-1 on Pancreas Endocrine Function after Gastric Bypass in Individuals with and without Diabetes Remission

The contribution of GLP-1 on glucose control after gastric bypass (GBP) is not fully elucidated. Hypotheses: The improvement in β-cell glucose sensitivity (BCGS) to oral glucose after GBP is GLP-1 mediated, weight loss independent, and varies according to diabetes (T2D) remission status; The administration of exendin 9-39 (EX9), a GLP-1 receptor blocker, has minimal effect on blood glucose. Methods: Patients with T2D (n=29) underwent a 75 g OGTT prior to and at 3, 12 and 24 months (M) after GBP. Glucose, insulin secretion rates (ISR), BCGS, and glucagon were measured with and without EX9. The cohort was retrospectively divided into 3 groups based on T2D remission status determined at the latest study time point (24 or 12M): remitters (REM, n=5), persistent T2D (P-T2D, n=8), impaired (IGT, n=16). Results: Prior to GBP, patients were 42.9±8.3y old, had a BMI of 42.4±4.6 kg/m2, 7.7±7.3 y known T2D duration, an HbA1c of 7.8±1.1% (35% on insulin) and an HOMA-IR of 11.5±5.8. Both magnitude and temporal increases in BCGS varied according to remission status: greater (up to 6.5 fold, p&amp;lt;0.03) and sustained in REM, variable in IGT (∼3 fold, p&amp;lt;0.01), minimal and only transient (3M, p=0.014) in P-T2D. These differences were not explained by weight-loss since it did not differ between the 3 groups at any time. EX9 reversed the effect of GBP on ISR at 3, 12 and 24M (p&amp;lt;0.003); it further enhanced the rise in post-prandial glucagon, but this effect was only significant at 3M (p=0.005). Both effects varied in magnitude overtime and by remission status. Glucose improved after GBP, as expected; EX9 decreased glucose levels at 3M in the whole cohort (p&amp;lt;0.001), but had no effect on glucose at 12 and 24M. EX9 increased significantly, albeit minimally, glucose at 120 and/or 180 minutes during the OGTT in REM and IGT, but not in P-T2D. Conclusions: Our data suggest that the effect of endogenous GLP-1 on pancreatic endocrine function and glucose varies with time and according to remission status after GBP. Disclosure M.A. Prasad: None. A. Shah: None. V.M. Mark: None. N. Nair: None. J.J. Holst: Advisory Panel; Self; AstraZeneca, Merck Sharp &amp; Dohme Corp., Novo Nordisk A/S, Zealand Pharma A/S. Other Relationship; Spouse/Partner; Antag Therapeutics. Funding National Institutes of Health (R01DK67561, DK007559, P30DK26687, UL1RR024156, UL1TR000040, F32DK113747)

Clinical observation of linagliptin combined with insulin in the treatment of fragility diabetes complicated with early diabetic nephropathy

Objective To evaluate the clinical effect of linagliptin combined with insulin in the treatment of fragile diabetes complicated with early diabetic nephropathy. Methods From January 2014 to May 2017, 98 patients with fragile diabetes complicated with early diabetic nephropathy were divided into two groups according to 1∶1 randomized, double-blind group. On the basis of insulin and benazepril, they were divided into oral linagliptin group and oral placebo control group. The course of treatment was 12 weeks. General data of age, sex, course of disease, height, weight, systolic and diastolic blood pressure, triglyceride, total cholesterol, blood urea nitrogen, cereatinine, uric acid and microalbuminuria were collected. After the subjects were enrolled in the group, self-blood glucose monitoring was performed to record their blood glucose control and fluctuation. The patients were followed up at baseline, 4, 8 and 12 weeks after treatment. Meanwhile, the changes of insulin dosage, blood sugar, serum C-peptide, glucagon, GLP-1, GIP and microalbuminuria levels were collected before and after treatment. Results After 12 weeks of treatment, the average blood sugar, FBG and PPG in the linagliptin group were lower than those before treatment and after treatment in the control group (P 0.05). The levels of glucagon and GIP in the linagliptin group 30 minutes after meal were lower than those before and after treatment(P<0.01), while the levels of GLP-1 (60 minutes) were higher than those before treatment and in the control group(P<0.01). Conclusions Combination of linagliptin and insulin in the treatment of fragile diabetes complicated with early diabetic nephropathy can achieve the target of HbA1c, decrease the fluctuation of blood sugar, decrease the dosage of insulin and the occurrence of hypoglycemia, without increasing risk of renal impairment. Key words: Diabetes Mellitus; Diabetic Nephropathies; Linagliptin; Insulin

1077-P: Treatment of Post-pancreatectomy Diabetes in Individuals with Congenital Hyperinsulinism Using a Bihormonal Bionic Pancreas

Congenital Hyperinsulinism (HI) is a disorder of beta-cell function that results in severe hypoglycemia. Near-total pancreatectomy (Ppx) is necessary for intractable hypoglycemia in the most severe cases, which results in diabetes later in life. The evolution of diabetes after Ppx is characterized by marked hypo- and hyper-glycemia due to residual dysregulated insulin secretion and glucagon deficiency. We aim to evaluate the safety and efficacy of a bihormonal bionic pancreas (BHBP) in individuals with HI and post-Ppx diabetes. Autonomously adaptive dosing algorithms in the BHBP use data from an integrated continuous glucose monitor (CGM) to control subcutaneous delivery of insulin and glucagon. Our hypothesis is that the BHBP will result in improved glycemic control compared to conventional insulin pump (CIP) therapy. This is an open-label, random-order, crossover, pilot study. Subjects with HI and post-Ppx diabetes are randomly assigned to BHBP therapy or CIP therapy during a 4-day inpatient stay, followed by the opposite intervention at least 1 week later. The BHBP was initialized with only the subject’s body weight. The coprimary outcomes are mean glucose and time with CGM glucose &amp;lt; 60 mg/dL analyzed over days 2-4. Seven subjects age 7-25 years (4 F) with mean A1C of 7.5% (SD 0.57) have completed the study to date. Mean CGM glucose was 148 mg/dL (SD 14) during the BHBP period vs. 156 mg/dL (SD 28) during the CIP period. All subjects had mean glucose during their BHBP period at or below 169 mg/dL (corresponding to A1C of 7.5%), whereas only 57% of subjects met this goal during their CIP period. Mean time with CGM glucose &amp;lt; 60 mg/dL was 0.07% (SD 0.60%) during the BHBP period vs. 1.71% (SD 3.48) during the CIP period. The BHBP was well tolerated. Relative to CIP therapy, the BHBP was able to produce, with greater ease of use, comparable, if not superior, results in terms of mean glucose and reduced frequency of hypoglycemia in individuals with HI and post-Ppx diabetes. Disclosure A. Rayannavar: None. L.M. Mitteer: None. K. Lord: None. C.P. Hawkes: None. C.A. Balliro: None. F. El-Khatib: Employee; Self; Beta Bionics. Stock/Shareholder; Self; Beta Bionics. E. Damiano: Advisory Panel; Self; Novo Nordisk A/S. Board Member; Self; Beta Bionics. Employee; Self; Beta Bionics. Stock/Shareholder; Self; Beta Bionics. Stock/Shareholder; Spouse/Partner; Beta Bionics. Other Relationship; Self; Ascensia Diabetes Care, Senseonics. S.J. Russell: Advisory Panel; Self; Companion Medical, Unomedical a/s. Consultant; Self; Flexion Therapeutics. Research Support; Self; Beta Bionics, MITRE Corporation, Novo Nordisk A/S, Zealand Pharma A/S. Other Relationship; Self; ADOCIA, Ascensia Diabetes Care, Ascensia Diabetes Care, Lilly Diabetes, Roche Diabetes Care, Senseonics. D. De Leon: Consultant; Self; Crinetics, Novartis Pharmaceuticals Corporation, ProSciento, Soleno Therapeutics, Zealand Pharma A/S. Employee; Spouse/Partner; Merck &amp; Co., Inc. Research Support; Self; Crinetics, Dexcom, Inc., Zealand Pharma A/S. Stock/Shareholder; Self; Merck &amp; Co., Inc. Funding Zealand Pharma A/S; Dexcom, Inc.; University of Pennsylvania; Children's Hospital of Philadelphia Women's Committee; National Institutes of Health (T32DK06368-14 to A.R.); Pediatric Endocrine Society

1831-P: Delayed Glucagon Suppression Contributes to Postprandial Hyperglycemia Independently of the Degree of Insulin Secretion

Type 2 diabetes (T2DM) is characterized by impaired postprandial insulin secretion and glucagon suppression. Recent work suggests that α-cell dysfunction is independent of β-cell dysfunction. The effect of diabetes-associated variation in TCF7L2 on α-cell function also suggests a direct role in the pathogenesis of T2DM. To quantify the interaction between a lack of glucagon suppression with intact, mildly or moderately impaired insulin secretion we studied 45 nondiabetic subjects with and without suppressed glucagon. On both occasions, an intravenous glucose infusion mimicking the systemic appearance of 50g oral glucose was administered in the presence of a pancreatic clamp. Glucagon was infused at a rate of 0.65ng/kg/min, starting at 0 min or 120 min (non-suppressed vs. suppressed respectively). In one group (100%) a nondiabetic insulin profile was infused; another group received 80% of this profile and the third group received 60% of the insulin infused in the first group. We observed that a lack of glucagon suppression increased peak (p &amp;lt; 0.05) and area above basal (AAB) glucose (p &amp;lt; 0.02) in all groups (1.5 ± 0.1 vs. 1.1 ± 0.1; 1.6 ± 0.1 vs. 1.1 ± 0.1; 1.5 ± 0.1 vs.1.3 ± 0.1 Mol per 5hr, 100%, 80%, 60% respectively). These increases were explained by delayed suppression of endogenous glucose production (EGP) so that EGP at 120 minutes was higher (p &amp;lt; 0.05) in the presence of non-suppressed glucagon (6.6 ± 1.0 vs. 4.2 ± 0.6; 7.2 ± 0.8 vs. 5.1 ± 0.5; 7.7 ± 0.8 vs. 5.9 ± 0.6 μmol/kg/min, 100%, 80%, 60% respectively) as was integrated EGP (p &amp;lt; 0.05) over the postprandial period (-1.9 ± 0.4 vs. -2.1 ± 0.1; -1.8 ± 0.1 vs. -1.9 ± 0.2; -1.6 ± 0.3 vs. -1.8 ± 0.1 mmol/kg per 5hr, 100%, 80%, 60% respectively). These data indicate that impaired postprandial glucagon suppression contributes to postprandial hyperglycemia through increased EGP even when insulin secretion is intact as can occur early in prediabetes. These effects are exacerbated by increasing degrees of insulin deficiency. Disclosure J. Adams: None. M.C. Laurenti: Employee; Self; GlySens Incorporated. R.A. Rizza: Advisory Panel; Self; Lilly Diabetes, Metavention, Novo Nordisk A/S, vTv Therapeutics. A.M. Egan: None. C. Cobelli: None. C. Dalla Man: None. A. Vella: Advisory Panel; Self; vTv Therapeutics. Research Support; Self; Novo Nordisk Inc. Funding National Institutes of Health

1878-P: Glucagon Is neither Necessary nor Sufficient for Ketosis in Mice

The current consensus mechanism for hepatic ketogenesis posits a key role for islet hormones, with insulin inhibiting and glucagon stimulating formation of ketone bodies. In this model the action of glucagon in the presence of low portal insulin concentrations causes ketosis. Sodium-glucose co-transporter 2 inhibitors (SGLT2i) are effective for lowering glucose in diabetic patients, and cause a relative insulinopenia. These agents have been described to increase ketone production, and have been associated with cases of diabetic ketoacidosis. SGLT2i have been recently reported to stimulate islet α-cells, suggesting the hypothesis that SGLT2i-induced glucagon secretion drives ketogenesis. To test this hypothesis, mice were given the SGLT2i dapagliflozin (dapa) in the presence or absence of glucagon signaling. Fasting-induced ketosis was used as a positive control. In both dapa-treated mice and 16 hour fasted mice, blood glucose decreased to the 4-5 mM range, β-OHB increased 2-3 fold, and NEFA rose 30-50%. Fasting had minimal effects on plasma glucagon, but dapa increased glucagon concentrations, albeit at a delayed rate compared to changes in glycemia, β-OHB, or NEFAs. Interruption of glucagon signaling with either: 1) a glucagon receptor antagonist (GRA); or 2) mice with a deletion of the proGlucagon gene had no effect on the development of ketosis in response to dapa or fasting, indicating that glucagon is not necessary for ketosis in these conditions. To test its sufficiency, glucagon (20µg/kg) was given to fed mice, 16 hour fasted mice, dapa-treated mice, and mice with insulin receptor blockade (IRB). Fasting, dapa and IRB all increased β-OHB significantly but glucagon did not add to this. In contrast, epinephrine significantly elevated ketone levels under these conditions. These findings indicate that the current model of the regulation of ketogenesis needs to be reconsidered, and that in mice glucagon does not have a significant role in this process. Disclosure M. Capozzi: None. R. Coch: None. J.B. Wait: None. J.J. Koech: None. J. Campbell: Research Support; Self; Eli Lilly and Company. Speaker's Bureau; Self; Merck Sharp &amp; Dohme Corp. D.A. D'Alessio: Advisory Panel; Self; Eli Lilly and Company. Research Support; Self; Eli Lilly and Company, Merck &amp; Co., Inc. Funding National Institutes of Health (F32-DK116542)

A linear control of composite model for glucose insulin glucagon pump

Abstract Presently Type 1 diabetes is global issue and challenges for diabetes public for healthy life. Fully automatic artificial pancreas is well solution for diabetic patients to avoid the hyperglycemia/hypoglycemia as it provided the insulin/glucose when needed. A composite model of Glucagon-Glucose Dynamics is treated for type 1 diabetes mellitus to check the linear controllability and observability of the model and the stability analysis by using Lyapunov function. Two cases are discussed in system according to the input. For case I, Insulin as the input only and glucose as an output and in case II insulin and glucagon as an input and glucose as output only. A control system can only be used in the form of closed-loop control to stabilize the system. This may be show vital part in the progress of fully automatic artificial pancreas and stabilize the control loop system for the Glucose Insulin Glucagon pump.