Increase In Glucose Infusion Rate Research Articles

The incidence of and risk factors for hyperglycemia and hypoglycemia in preterm infants receiving early-aggressive parenteral nutrition

IntroductionOptimizing nutritional support helps prevent extra uterine growth restriction and adverse long-term outcomes in preterm infants. ObjectivesThis study aimed to analyze the incidence of and risk factors for hyperglycemia and hypoglycemia in preterm infants receiving early-aggressive parenteral nutrition (PN). MethodsThis prospective observational study included preterm infants receiving PN at the Neonatal Intensive Care Unit of Dr. Soetomo General Hospital between April 2018 and May 2019. Potential risk factors analyzed included asphyxia, sepsis, respiratory distress syndrome, multiple congenital anomalies, mortality, necrotizing enterocolitis, retinopathy of prematurity, the postoperative period, inotropic administration, glucose infusion rate (GIR) > 10–12 mg/kg/min, GIR 4–<5.5 mg/kg/min, and increase in GIR <1 mg/kg/min. ResultsOf the 105 preterm infants included, hyperglycemia and hypoglycemia were found in 14 (13.3%) and 26 (24.8%) infants, respectively, with most incidents occurring in the first week (hyperglycemia: 85.7%; hypoglycemia: 88.5%). Sepsis was an independent risk factor for hyperglycemia (odds ratio [OR]: 8.743, 95% confidence interval [CI]: 2.392–31.959; P = 0.001). Hypoglycemia independent risk factors included the postoperative period (OR: 4.425, 95% CI: 1.218–16.073; P = 0.024) and use of GIR 4–<5.5 mg/kg/min (OR: 2.950, 95% CI: 1.035–8.405; P = 0.043). ConclusionHyperglycemia and hypoglycemia can occur in preterm infants receiving early-aggressive PN; most cases occur within the first week of life. Hypoglycemia correlated with low glucose intake, and hyperglycemia correlated with sepsis. Monitoring blood glucose levels in preterm infants receiving PN, especially in the first weeks of life, may decrease morbidity associated with hyperglycemia or hypoglycemia.

1559-P: Glucagon Receptor–Mediated Improvements in Glycemia Are Dependent on Agonist Pharmacodynamics

Glucagon is considered the main glucose counter-regulatory hormone to insulin. Although, chronic glucagon receptor (GCGR) agonism induces hyperglycemia and glucose intolerance, it also improves insulin secretion and action. Surprisingly, we found chronic treatment with the selective, long-acting GCGR agonist, IUB288, improves ad libitum glycemia and glucose tolerance 4h after treatment. These glycemic improvements were associated with enhanced AKT phosphorylation, despite control-like insulin levels. We next tested if these results could be replicated with a short acting GCGR agonist. IUB94 displays improved aqueous solubility but maintains the short half-life and potency of native glucagon. 4h glucose excursion was monitored in lean mice after injection of IUB288, IUB94, or vehicle. We observed a transient rise in blood glucose (BG) 15min after either IUB288 or IUB94 compared to vehicle. Intriguingly, IUB288-treated mice exhibited improved BG from 120-240min, while BG in IUB94-treated mice was similar to vehicle controls. These data suggest that acute BG regulation is agonist-dependent yet, it remains unclear if pharmacodynamics or some inherent difference in potency is influencing the 4h BG. We next treated lean mice for 4d with vehicle or IUB288, measuring ad libitum glycemia over the final 24h period. IUB288-treated mice displayed improved glycemia 4h after the last injection and hyperglycemia after 12h, compared to vehicle-treated controls, suggesting chronic GCGR agonism is not exclusively hyperglycemic. Surprisingly, 4d IUB288 treatment in diet-induced obese (DIO) mice reduced ad libitum glycemia for a longer duration than observed in chow IUB288-treated mice. IUB288 treatment also increased glucose infusion rate, suppression of endogenous glucose production, and AKT phosphorylation during hyperinsulinemic-euglycemic clamps. These data provide insight into the potential therapeutic use of sustained-acting GCGR agonists against diabetes and obesity. Disclosure S.Nason: None. T.Kim: None. J.Antipenko: None. B.Yang: None. R.Dimarchi: None. K.M.Habegger: Consultant; Glyscend Inc., Research Support; Eli Lilly and Company, Novo Nordisk, Glyscend Inc., Stock/Shareholder; Glyscend Inc. Funding National Institutes of Health

Probing the mechanism of reduced in vivo potency of insulin detemir

ABSTRACT Background Insulin detemir (IDet) is an insulin analog used to treat diabetes. IDet shows full efficacy but reduced potency compared to human insulin (HI) in both man and rat. In contrast, in pigs and dogs, IDet appears to have full in vivo potency. Non-receptor mediated degradation (NRMD) has previously been suggested as an explanation for the low potency of IDet, but this hypothesis has not been investigated further until now. Bacitracin is a nonspecific protease inhibitor which we hypothesized could inhibit NRMD of IDet in rats. Research design and methods Healthy male rats instrumented with permanent catheters underwent euglycemic clamp during constant infusion of either HI or IDet at effect-matched doses with co-infusion of vehicle or bacitracin. Results Plasma concentrations of IDet increased significantly (p < 0.005) during bacitracin compared to vehicle co-infusion and the concomitant increase in glucose infusion rate (GIR, p < 0.001) required to maintain euglycemic clamp indicates that the IDet rescued from NRMD indeed was active. No significant differences were detected with co-infusions of HI with either bacitracin or vehicle. Conclusions A large proportion of NRMD of IDet which can be inhibited by bacitracin may partly explain the reduced potency of IDet observed in rats and likely also in man.

The influence of exercise training versus intensive insulin therapy on insulin resistance development in type 1 diabetes

The etiology of insulin resistance (IR) in Type 1 Diabetes (T1D) is unclear; however, intramyocellular lipids (IMCL) are likely contributors. While exercise lessens IR and IMCL content; T1D patients elevate glycemia to offset exercise-induced hypoglycemic risk. The preferred treatment for T1D patients is tight glucose management through intensive insulin therapy (IIT); however, IIT is accompanied with a sedentary lifestyle. The purpose of this study was to examine IR development and IMCL in combined exercise (DARE; aerobic/resistance) and IIT-treated T1D animals. 76 rats were divided into control sedentary (C), diabetic sedentary (CD), diabetes sedentary intensive insulin therapy (DIT) and DARE groups. Following streptozotocin (STZ), glycemia was maintained at either 9-15 mM (CD, DARE) or 5-9 mM (DIT) using insulin. DARE alternated between running and weighted climbing for 12 weeks. Results demonstrate that DARE exhibited reduced onset of IR compared with C, DIT and CD, indicated by increased glucose infusion rate (hyperinsulinemic-euglycemic-clamp). A shift in lipid metabolism was evident whereby diacylglycerol was elevated in DIT compared to DARE, while triacylglycerol was elevated in DARE. These findings indicate enhanced IMCL metabolism and the sequestration of fat as neutral triacylglycerol leads to reduced IR in DARE. In contrast, IIT and sedentary behavior leads to diacylglycerol accumulation and IR.

Hepatic mTORC2 Signaling Facilitates Acute Glucagon Receptor Enhancement of Insulin-Stimulated Glucose Homeostasis in Mice.

Long-term glucagon receptor (GCGR) agonism is associated with hyperglycemia and glucose intolerance, while acute GCGR agonism enhances whole-body insulin sensitivity and hepatic AKTSer473 phosphorylation. These divergent effects establish a critical gap in knowledge surrounding GCGR action. mTOR complex 2 (mTORC2) is composed of seven proteins, including RICTOR, which dictates substrate binding and allows for targeting of AKTSer473. We used a liver-specific Rictor knockout mouse (RictorΔLiver) to investigate whether mTORC2 is necessary for insulin receptor (INSR) and GCGR cross talk. RictorΔLiver mice were characterized by impaired AKT signaling and glucose intolerance. Intriguingly, RictorΔLiver mice were also resistant to GCGR-stimulated hyperglycemia. Consistent with our prior report, GCGR agonism increased glucose infusion rate and suppressed hepatic glucose production during hyperinsulinemic-euglycemic clamp of control animals. However, these benefits to insulin sensitivity were ablated in RictorΔLiver mice. We observed diminished AKTSer473 and GSK3α/βSer21/9 phosphorylation in RictorΔLiver mice, whereas phosphorylation of AKTThr308 was unaltered in livers from clamped mice. These signaling effects were replicated in primary hepatocytes isolated from RictorΔLiver and littermate control mice, confirming cell-autonomous cross talk between GCGR and INSR pathways. In summary, our study reveals the necessity of RICTOR, and thus mTORC2, in GCGR-mediated enhancement of liver and whole-body insulin action.

230-OR: Hepatic TORC2 Signaling Facilitates Glucagon-Receptor Enhancement of Insulin-Stimulated Glucose Homeostasis in Mice

Long term glucagon receptor (GCGR) agonism is associated with hyperglycemia and glucose intolerance, while acute GCGR agonism enhances whole-body insulin sensitivity and hepatic AKTSer473 phosphorylation. These divergent effects establish a critical gap in knowledge surrounding GCGR action. mTOR Complex 2 (mTORC2) is composed of seven proteins, including RICTOR, which dictates substrate binding and allows for targeting of AKTSer473. We utilized a liver specific Rictor knockout mouse (RictorΔLiver) to investigate whether mTORC2 is necessary for insulin-receptor (INSR) and GCGR crosstalk. RictorΔLiver mice were characterized by impaired Akt signaling and glucose intolerance. Intriguingly, RictorΔLiver mice were also resistant to GCGR-stimulated hyperglycemia. Consistent with our prior report, GCGR agonism increased glucose infusion rate and suppressed hepatic glucose production during hyperinsulinemic-euglycemic clamp of control animals. However, these benefits to insulin sensitivity were ablated in RictorΔLiver mice. We observed diminished AKTSer473 and GSK3α/β Ser21/9 phosphorylation in RictorΔLiver mice, whereas phosphorylation of AKTThr3was unaltered in livers from clamped mice. These signaling effects were replicated in primary hepatocytes isolated from RictorΔLiver and littermate control mice, confirming cell autonomous crosstalk between GCGR and INSR pathways. In summary, our study reveals the necessity of RICTOR, and thus mTORC2, in GCGR-mediated enhancement of liver and whole-body insulin action. Disclosure T.Kim: None. S.Nason: None. J.P.Antipenko: None. B.Finan: Employee; Novo Nordisk. A.Shalev: None. R.Dimarchi: None. K.M.Habegger: Consultant; Glyscend Inc., Research Support; Eli Lilly and Company, Novo Nordisk, Stock/Shareholder; Glyscend Inc. Funding 1R01DK112934P30DK079626

197-OR: Glucagon Receptor Agonism Stimulates Time-Dependent Glycemic Regulation

Historically, glucagon is proposed to be a key factor in the development of diabetes. However, we demonstrated that while chronic glucagon receptor (GCGR) agonism induces hyperglycemia and glucose intolerance, it also improves insulin secretion and insulin action. These paradoxical actions suggest the mechanisms regulating GCGR-mediated glucose metabolism have yet to be fully elucidated. Glucose metabolism and glucagon-stimulated glucose production are both regulated in a circadian manner. Thus, we hypothesized that chronic GCGR signaling regulates glycemia in a time-of-day dependent manner. We treated lean mice for 4d with vehicle or the GCGR agonist IUB288 administered either during the early (ZT 3) or late (ZT9) light period. Ad libitum glycemia was assessed every 4h over a 24h period after the last injection. Independent of the time injected, IUB288-treated mice displayed improved glycemia 4h after the last injection and hyperglycemia after 12h, compared to vehicle-treated controls. This suggests that chronic GCGR agonism is not exclusively hyperglycemic and variations in GCGR-stimulated glycemia are dependent on the time after treatment, rather than the time of day. Interestingly, ad libitum insulin levels were no different between IUB288 and vehicle-treated mice, suggesting differences in insulin sensitivity. Surprisingly, 4d IUB288 treatment in diet-induced obese (DIO) mice reduced ad libitum glycemia for a greater duration than chow IUB288-treated mice. We used hyperinsulinemic-euglycemic clamps to further dissect the mechanisms of these benefits. In DIO mice, IUB288 treatment increased glucose infusion rate, suppression of endogenous glucose production, and phosphorylation of AKT (S473 and T308) . Together, these data increase our understanding of GCGR pharmacology and its therapeutic role in diabetes and obesity treatment. Disclosure S.Nason: None. T.Kim: None. J.P.Antipenko: None. B.Finan: Employee; Novo Nordisk. R.Dimarchi: None. K.M.Habegger: Consultant; Glyscend Inc., Research Support; Eli Lilly and Company, Novo Nordisk, Stock/Shareholder; Glyscend Inc. Funding T32 AI007051

Improving skeletal muscle insulin sensitivity via beta2 -agonist administration: a promising strategy to counteract metabolic disease and muscle loss.

Improving skeletal muscle insulin sensitivity via beta2 -agonist administration: a promising strategy to counteract metabolic disease and muscle loss.

171-OR: Dopaminergic Signaling in the Ventral Tegmental Area of the Brain Mediates the Impaired Sympathoadrenal Response to Hypoglycemia

The mechanism by which recurrent hypoglycemia (RH) impairs the sympathoadrenal response to hypoglycemia remains unknown. To explore altered brain dopaminergic signaling as a mechanism, 10 weeks old rats were randomized to 3 days: 1) recurrent saline (RS), 2) insulin (2-1.2 U/kg, sc) induced RH (25-50 mg/dl), or 3) RH + antecedent dopamine receptor antagonist metoclopramide (MET, 3 mg/kg, ip). qPCR of brain biopsies demonstrated RH downregulated dopaminergic signaling, noted by decreased expression of dopamine D2 receptor (Drd2, 52%*) and increased dopamine transporter (DAT, ~1.9-fold*) in the ventral tegmental area (VTA); an effect prevented by MET (Figure 1A). To test whether recurrent dopamine activation in the VTA is sufficient to impair the sympathoadrenal response to hypoglycemia, a second rat cohort was randomized to 3-day recurrent VTA infusion of: 1) aCSF (control), or 2) Drd2 agonist bromocriptine (Bromo; 5 µg/d). During hyperinsulinemic (20 mU/kg/min) hypoglycemic (∼45 mg/dl) clamps, recurrent Bromo resulted in an increased glucose infusion rate (1.7-fold*) and blunted epinephrine response (~50%*, Figure 1B). These results demonstrate that blunted dopaminergic signaling in the VTA induced by RH contributes to the impaired sympathoadrenal response, which may be associated with recurrent brain dopaminergic activation. *p<0.05.View largeDownload slideView largeDownload slide DisclosureR. Agrawal: None. S. Sharma: None. S. Fisher: None. FundingNational Institutes of Health (R01NS070235-01A1, R01DK118082)

Piperine protects against pancreatic β-cell dysfunction by alleviating macrophage inflammation in obese mice

AimsPiperine, the major pharmacological ingredient of pepper, can delay the procession of “obesity to diabetes”. However, the underlying mechanism remains unclear. This study aims to investigate whether piperine protects against β-cell dysfunction by inhibiting macrophage accumulation and M1-like polarization. Materials and methodsPre-diabetic model was induced by feeding 60% high-fat diet (HFD) in C57BL/6C mice, piperine (15 or 30 mg/kg/day) and rosiglitazone (4 mg/kg/day) were given orally for 8 weeks. Oral glucose tolerance test (OGTT), insulin tolerance test (ITT), fasting blood glucose (FBG), total cholesterol (TC) and triglyceride (TG) were used to assay the disorder of glycolipid metabolism. Serum levels of cytokines and insulin were measured by Elisa. Hyperglycemic clamp assay was carried out to evaluate β-cell function. RT-PCR, immunofluorescence and western blot were used to detect the expression of biomarkers associated with macrophage polarization and β-cell dedifferentiation. Key findingsPiperine protected against β-cell dysfunction, indicated by the improvement of hyperinsulinemia, OGTT and increased glucose infusion rate (GIR). Piperine dramatically reduced the serum levels of lipopolysaccharide (LPS), interleukin-1β (IL-1β) and Galectin-3 (Gal-3), suppressed the expression of M1-like cytokines (CD11c, IL-1β and Gal-3) in epididymal adipose tissues and islets. Furthermore, piperine partially reversed the down-regulation of Pdx1, inhibited the up-regulation of ALDH1A3 in β-cell, and these effects were closely related to the mTOR/S6/4E-BP1 signal pathway. SignificancePiperine markedly ameliorates the dedifferentiation and dysfunction of β-cell by inhibiting the accumulation and M1-like polarization of macrophages in visceral adipose tissues and islets.

Histone deacetylase 3-selective inhibitor RGFP966 ameliorates impaired glucose tolerance through β-cell protection

The potential therapeutic effect of histone deacetylase 3 (HDAC3) pharmacologic inhibition on diabetes has been focused recently. RGFP966, as a highly-selective HDAC3 inhibitor, its possible roles and underlying mechanism in the treatment of diabetes needs to be clarified. In this study, low-dose streptozotocin (STZ)-induced pre-diabetic mice were used to test the regulatory ability of RGFP966 in blood glucose and insulin. We isolated the islets both from normal C57BL/6 J mice and KKAy mice with spontaneous type 2 diabetes to determine the potency of RGFP966 on glucose-stimulated insulin secretion. NIT-1 pancreatic β-cells induced by sodium palmitate (PA) were applied to identify the protective effects of RGFP966 against β-cell apoptosis. The results showed that administration of RGFP966 in the pre-diabetic mice not only significantly reduced hyperglycemia, promoted phase I insulin secretion, improved morphology of islets, but also increased glucose infusion rate (GIR) during hyperglycemic clamp test. When treated in vitro, RGFP966 enhanced insulin secretion and synthesis in islets of normal C57BL/6J mice and diabetic KKAy mice. In addition, it partially attenuated PA-induced apoptosis in NIT-1 cells. Therefore, our research suggests that RGFP966, probably through selective inhibition of HDAC3, might serve as a novel potential preventive and therapeutic candidate for diabetes.

1898-P: Colonic Short-Chain Fatty Acids Lower Endogenous Glucose Production

Hyperglycemia is a hallmark characteristic of diabetes, resulting in elevated blood glucose levels, due in part to a chronic elevation in endogenous hepatic glucose production (GP). Recent work has highlighted the gut microbiota as a salient contributor to energy and glucose homeostasis. One potential mechanism may be through increased short-chain fatty acid (SCFA) signaling mechanisms. SCFAs are bacterial breakdown products of nondigestible dietary fibers, occurring mainly in the colon, and have been shown to improve glucose homeostasis. Interestingly, recent work has highlighted that ingested nutrients can activate small intestinal nutrient-sensing mechanisms to lower hepatic glucose production via a neuronal gut-brain-liver axis mediated via gut peptide signaling. However, no one has directly tested whether colonic SCFAs can regulate GP via a similar colonic neuronal mechanism. To test this, we directly infused SCFAs (acetate, propionate, butyrate; 10mM or 100mM) into the colon during a pancreatic euglycemic clamp, the gold standard for measuring endogenous glucose production and uptake, in high-fat diet (HFD) fed rats that we previously found to have diminished levels of SCFAs in the large intestine. Administration of either acetate, propionate or butyrate (10mM or 100mM) directly into the colon of HFD-fed rats resulted in an increased glucose infusion rate needed to maintain euglycemia, which was due to a significant decrease in endogenous GP compared to saline infusion. Furthermore, we found that this was mediated via GLP-1 receptor signaling, as co-administration of exendin-9 with either SCFA (10mM) abolished the GP-lowering effect. Additionally, portal levels of GLP-1 were significantly increased at the end of the pancreatic clamp in rats receiving infusion of acetate, butyrate, or propionate compared to saline. Taken together, this work demonstrates that colonic SCFAs can activate a GLP-1 receptor mediated pathway in the colon to lower endogenous GP. Disclosure A.I.L. Lane: None. S.N. Weninger: None. F. Duca: None. Funding National Institutes of Health (R01DK121804)

Chronic treatment of JTP‐109192, a novel G‐protein coupled receptor 119 agonist, improves metabolic abnormalities in Zucker Fatty rats

G-protein coupled receptor 119 (GPR119) expression in pancreatic β-cells and intestinal L cells is a potential therapeutic target for treating type 2 diabetes. A natural GPR119 agonist oleoylethanolamide is well known to enhance a glucose-stimulated insulin secretion (GSIS) and glucagon-like peptide-1 (GLP-1) secretion by elevating intracellular cAMP levels. In the present study, a glucose lowering effect of the GPR119 agonist, JTP-109192 leading to improvement of insulin sensitivity was examined in Zucker Fatty (ZF) rats. We investigated the in vitro effects of JTP-109192 on GSIS in the rat pancreatic β-cell line (INS1E) cells and on GLP-1 secretion in the murine enteroendocrine cell line (GLUTag) cells. We also investigated the effect of JTP-109192 on GSIS in Sprague-Dawley (SD) rats with single administration and its effect on glucose metabolism in ZF rats with repeated administration once daily for about 6weeks. After repeated administration, the hyperinsulinaemic euglycaemic glucose clamp test was performed to evaluate insulin sensitivity. JTP-109192 increased intracellular cAMP levels (EC50 value: 3.6nmol/L) and enhanced GSIS in the INS1E cells and GLP-1 secretion in GLUTag cells. In SD rats, a single administration of JTP-109192 enhanced GSIS at high blood glucose levels. The repeated administrations in ZF rats improved glucose metabolism without lack of drug efficacy (tachyphylaxis) and increased glucose infusion rates due to improvement of insulin sensitivity.

165-OR: The Mechanisms by Which Adiponectin Reverses Insulin Resistance in High-Fat Diet Fed Mice

Adiponectin has emerged as an antidiabetic adipokine, and a potential therapy to treat type 2 diabetes. However, the mechanism by which adiponectin improves insulin sensitivity remains unclear. To address this question, we examined the effects of a 2-week continuous infusion of globular adiponectin (gAcrp30) or saline (CON) on glucose and lipid metabolism in a high fat diet fed (HFD) mouse model. Whole-body and tissue-specific insulin action was assessed by a hyperinsulinemic-euglycemic clamp (HEC). gAcrp30-treated mice displayed reduced fasting plasma glucose and insulin concentrations (both P&amp;lt;0.05 vs. CON) and increased glucose infusion rate (14 vs. 22 mg/(kg-min), P&amp;lt;0.001) during the HEC reflecting increased whole-body insulin-sensitivity. Increased insulin sensitivity could be attributed to reduced endogenous glucose production (16.7 vs.14.2 mg/(kg-min), P&amp;lt;0.05), increased glucose uptake in muscle (191 vs. 285 nmol/(kg-min), p=0.006) and adipose tissues (BAT: 112 vs. 217, WAT: 11 vs. 22 nmol/(kg-min), both P&amp;lt;0.05) during the HEC. These improvements in liver and muscle insulin sensitivity were associated with ∼50% reductions in liver and muscle triglyceride (TAG) and ∼40% diacylglycerol (DAG) (both P&amp;lt;0.01 vs. CON) content but no changes in hepatic ceramide content. Reduced tissue TAG/DAG content occurred independent of changes in WAT lipolysis, hepatic AMPK activation, ACC phosphorylation or mitochondrial oxidation. Reduced tissue DAG content was associated with decreased PKCε activation in liver and PKCθ activation in muscle and increased insulin signaling in liver, muscle and white adipose tissue. Conclusion: Taken together these data support the hypothesis that adiponectin improves insulin sensitivity in liver and muscle of HFD fed mice by reducing ectopic lipid (DAG) content in these tissues leading to decreased nPKC activity and increased insulin signaling, and contrary to prior studies, is independent of changes in hepatic ceramide content. Disclosure X. Li: None. D. Zhang: None. R.J. Perry: Research Support; Self; AstraZeneca. D.F. Vatner: None. L. Goedeke: None. Y. Zhang: None. G.I. Shulman: Advisory Panel; Self; AstraZeneca, Janssen Research &amp; Development, Merck &amp; Co., Inc. Advisory Panel; Spouse/Partner; Merck &amp; Co., Inc. Board Member; Self; Novo Nordisk A/S. Consultant; Self; Aegerion Pharmaceuticals, IMetabolic BioPharma Corporation, Longitude Capital, Nimbus Discovery, Inc., Staten Biotechnology B.V. Funding American Heart Association (19PRE34380268); National Institutes of Health (R01DK116774)

Impact of Brain Fatty Acid Signaling on Peripheral Insulin Action in Mice.

Glucose homeostasis and energy balance are under control by peripheral and brain processes. Especially insulin signaling in the brain seems to impact whole body glucose homeostasis and interacts with fatty acid signaling. In humans circulating saturated fatty acids are negatively associated with brain insulin action while animal studies suggest both positive and negative interactions of fatty acids and insulin brain action. This apparent discrepancy might reflect a difference between acute and chronic fatty acid signaling. To address this question we investigated the acute effect of an intracerebroventricular palmitic acid administration on peripheral glucose homeostasis. We developed and implemented a method for simultaneous monitoring of brain activity and peripheral insulin action in freely moving mice by combining radiotelemetry electrocorticography (ECoG) and euglycemic-hyperinsulinemic clamps. This method allowed gaining insight in the early kinetics of brain fatty acid signaling and its contemporaneous effect on liver function in vivo, which, to our knowledge, has not been assessed so far in mice. Insulin-induced brain activity in the theta and beta band was decreased by acute intracerebroventricular application of palmitic acid. Peripherally it amplified insulin action as demonstrated by a significant inhibition of endogenous glucose production and increased glucose infusion rate. Moreover, our results further revealed that the brain effect of peripheral insulin is modulated by palmitic acid load in the brain. These findings suggest that insulin action is amplified in the periphery and attenuated in the brain by acute palmitic acid application. Thus, our results indicate that acute palmitic acid signaling in the brain may be different from chronic effects.

The combination of luteolin and l-theanine improved Alzheimer disease–like symptoms by potentiating hippocampal insulin signaling and decreasing neuroinflammation and norepinephrine degradation in amyloid-β–infused rats

Luteolin and l-theanine have anti-inflammatory, antioxidant, and possible antidiabetic activities, and they may synergistically protect against dementia. Here, we hypothesized that a combination of luteolin and l-theanine would synergistically act to improve memory function and glucose disturbances in rats infused with amyloid-β, and the mechanisms underlying these actions were investigated. Rats that received an amyloid-β(25-35) infusion into the CA1 region of the hippocampus were fed dextrin (AD-CON), 0.1% luteolin (AD-Lut), 0.2% l-theanine (AD-Thea), or both 0.05% luteolin and 0.1% l-theanine (AD-LuTh) in conjunction with a high-fat diet over 8 weeks. AD-LuTh improved memory function, as determined by water maze and passive avoidance tests, by potentiating the hippocampal insulin signaling and reducing inflammation: Luteolin mainly potentiated insulin signaling via the pAkt➔pGSK➔pTau pathway, and l-theanine primarily reduced tumor necrosis factor-α. In the metabolomics analysis of the hippocampus lysates, the concentration of proline, phenylpyruvic acid, and normetanephrine decreased in the AD-LuTh compared to AD-CON. Norepinephrine contents were lower in the AD-CON than non-AD rats with a high fat diet with 0.2% dextrin, whereas AD-Thea and AD-LuTh inhibited the decrease. Both the AD-Lut and AD-LuTh increased glucose infusion rates and decreased hepatic glucose output under basal and hyperinsulinemic conditions, indicating improved whole-body and hepatic insulin sensitivity. Disturbances in glucose-stimulated insulin secretion during hyperglycemic clamp were most effectively corrected by the AD-Lut and AD-LuTh treatments. In conclusion, the hypothesis of the study was accepted. The combination of luteolin and l-theanine prevented Alzheimer disease–like symptom, possibly by improving hippocampal insulin signaling, norepinephrine metabolisms, and decreasing neuroinflammation. The combination of luteolin and l-theanine may be a useful therapeutic option for preventing and/or delaying the progression of memory dysfunction.

Insulin regulates GLUT4 in the ventromedial hypothalamus to restore the sympathoadrenal response to hypoglycemia in diabetic rats.

It is proposed that the impaired counterregulatory response (CRR) to hypoglycemia in insulin-deficient diabetes may be due to chronic brain insulin deficiency. To test this hypothesis, streptozotocin-induced diabetic Sprague-Dawley rats were infused with insulin (3 mU/day) or artificial cerebrospinal fluid (aCSF) bilaterally into the ventromedial hypothalamus (VMH) for 2 wk and compared with nondiabetic rats. Rats underwent hyperinsulinemic (50 mU·kg-1·min-1)-hypoglycemic (~45 mg/dl) clamps. Diabetic rats demonstrated an impaired CRR to hypoglycemia, noted by a high glucose infusion rate and blunted epinephrine and glucagon responses. The defective sympathoadrenal response was restored by chronic infusion of insulin into the VMH. Diabetic rats had decreased VMH Akt phosphorylation and decreased VMH glucose transporter 4 (GLUT4) content, which was also restored by chronic infusion of insulin into the VMH. Separate experiments in nondiabetic rats in which GLUT4 translocation into the VMH was inhibited with an infusion of indinavir were notable for an impaired CRR to hypoglycemia, indicated by increased glucose infusion rate and diminished epinephrine and glucagon responses. Results suggest that, in this model of diabetes, VMH insulin deficiency impairs the sympathoadrenal response to hypoglycemia and that chronic infusion of insulin into the VMH is sufficient to normalize the sympathoadrenal response to hypoglycemia via restoration of GLUT4 expression in the VMH.

Hepatic Glucagon Receptor Signaling Enhances Insulin-Stimulated Glucose Disposal in Rodents.

Glucagon receptor (GCGR) agonists cause hyperglycemia but also weight loss. However, GCG-like peptide 1 receptor (GLP1R)/GCGR mixed agonists do not exhibit the diabetogenic effects often attributed to GCGR activity. Thus, we sought to investigate the effect of glucagon agonism on insulin action and glucose homeostasis. Acute GCGR agonism induced immediate hyperglycemia, followed by improved glucose tolerance and enhanced glucose-stimulated insulin secretion. Moreover, acute GCGR agonism improved insulin tolerance in a dose-dependent manner in both lean and obese mice. Improved insulin tolerance was independent of GLP1R, FGF21, and hepatic glycogenolysis. Moreover, we observed increased glucose infusion rate, disposal, uptake, and suppressed endogenous glucose production during euglycemic clamps. Mice treated with insulin and GCGR agonist had enhanced phosphorylation of hepatic AKT at Ser473; this effect was reproduced in isolated mouse primary hepatocytes and resulted in increased AKT kinase activity. These data reveal that GCGR agonism enhances glucose tolerance, in part, by augmenting insulin action, with implications for the use of GCGR agonism in therapeutic strategies for diabetes.

Correlation of maternal A1c with glucose infusion rate requirements in the newborn.

Fetal hyperinsulinemia and neonatal hyperglycemia are complications of poor maternal glycemic control and may result in increased glucose infusion rate (GIR) requirements in infants of diabetic mothers (IDMs). The objectives of this study were to correlate maternal A1c levels with GIR requirements in IDMs, establish an A1c threshold predictive for GIR requirements, and identify associations between A1c levels and complications in IDMs. A retrospective review of paired maternal A1c values and GIR requirements of IDMs were compared via logistic regression analysis. A likelihood ratio was calculated to correlate A1c levels with GIR requirements, and identify a maternal A1c threshold. Increasing A1c values were significantly correlated with GIR≥5 mg/kg/min (OR, 1.37; 95% CI 1.04-1.79, p = 0.021). Macrosomia was the most frequent complication (OR, 1.31; 95% CI 1.04-1.67, p = 0.022) and A1c > 6.8% was predictive for increased GIR requirements. Increased A1c values were significantly associated with GIR requirements≥5 mg/kg/min. Increased maternal A1c is significantly associated with complications in newborns, specifically macrosomia. A maternal A1c of 6.8% was identified as a threshold predictive of increased GIR requirements.

Effect of magnesium sulfate administration to improve insulin resistance in type 2 diabetes animal model: using the hyperinsulinemic-euglycemic clamp technique.

This study attempted to elucidate the possible mechanism of magnesium sulfate (MgSO4 ) administration on reducing insulin resistance in type 2 diabetic rats. Fifty Wistar rats were divided into five groups: NDC was fed the normal diet, CD received high-fat diet with 35mg/kg of streptozotocin, CD-Mg animals received MgSO4 via drinking water, CD-Ins1, and CD-Ins2 animals treated with low or high dose of insulin. Body weight and blood glucose levels were measured weekly. Intraperitoneal glucose tolerance test (IPGTT), insulin tolerance test, and metabolic cage assessment were performed monthly. After 12weeks, the hyperinsulinemic-euglycemic clamp was performed for all animals and blood sample was taken to measure glycated hemoglobin (HbA1c), plasma insulin, glucagon, calcium, and magnesium levels. Liver and gastrocnemius muscle were isolated to measure glucagon receptor (GR), Glucose 6 phosphatase (G6Pase), Phosphoenolpyruvate carboxykinase (Pepck) and Glucose transporter 4 (Glut4) genes expression and GLUT4 protein translocation into the cell membrane. Consuming of high-fat diet generated insulin-resistant rats. Magnesium or insulin therapy altered insulin resistance, blood glucose, IPGTT, gluconeogenesis pathway, GR, body weight, the percentage of body fat, and HbA1C in diabetic rats. Administrations of MgSO4 or insulin in Type 2 diabetes mellitus animals increase GLUT4 gene and protein expression. Mg could improve glucose tolerance via stimulation of Glut4 gene expression and translocation and also suppression of the gluconeogenesis pathway and GR gene expression. Mg also increased glucose infusion rate and displayed beneficial effects in the treatment of glucose metabolism and improved insulin resistance.