Higher Glucose Infusion Rate Research Articles

Role of human Kallistatin in glucose and energy homeostasis in mice

ObjectiveKallistatin (KST), also known as SERPIN A4, is a circulating, broadly acting human plasma protein with pleiotropic properties. Clinical studies in humans revealed reduced KST levels in obesity. The exact role of KST in glucose and energy homeostasis in the setting of insulin resistance and type 2 diabetes is currently unknown. MethodsKallistatin mRNA expression in human subcutaneous white adipose tissue (sWAT) of 47 people with overweight to obesity of the clinical trial “Comparison of Low Fat and Low Carbohydrate Diets With Respect to Weight Loss and Metabolic Effects (B-SMART)” was measured. Moreover, we studied transgenic mice systemically overexpressing human KST (hKST-TG) and wild type littermate control mice (WT) under normal chow (NCD) and high-fat diet (HFD) conditions. ResultsIn sWAT of people with overweight to obesity, KST mRNA increased after diet-induced weight loss. On NCD, we did not observe differences between hKST-TG and WT mice. Under HFD conditions, body weight, body fat and liver fat content did not differ between genotypes. Yet, during intraperitoneal glucose tolerance tests (ipGTT) insulin excursions and HOMA-IR were lower in hKST-TG (4.42 ± 0.87 AU, WT vs. 2.20 ± 0.27 AU, hKST-TG, p < 0.05). Hyperinsulinemic euglycemic clamp studies with tracer-labeled glucose infusion confirmed improved insulin sensitivity by higher glucose infusion rates in hKST-TG mice (31.5 ± 1.78 mg/kg/min, hKST-TG vs. 18.1 ± 1.67 mg/kg/min, WT, p < 0.05). Improved insulin sensitivity was driven by reduced hepatic insulin resistance (clamp hepatic glucose output: 7.7 ± 1.9 mg/kg/min, hKST-TG vs 12.2 ± 0.8 mg/kg/min, WT, p < 0.05), providing evidence for direct insulin sensitizing effects of KST for the first time. Insulin sensitivity was differentially affected in skeletal muscle and adipose tissue. Mechanistically, we observed reduced Wnt signaling in the liver but not in skeletal muscle, which may explain the effect. ConclusionsKST expression increases after weight loss in sWAT from people with obesity. Furthermore, human KST ameliorates diet-induced hepatic insulin resistance in mice, while differentially affecting skeletal muscle and adipose tissue insulin sensitivity. Thus, KST may be an interesting, yet challenging, therapeutic target for patients with obesity and insulin resistance.

OR12-04 LEAP2 Deletion Does Not Counteract The Effects Of Ghrelin Deletion During Insulin-Induced-Hypoglycemia

Abstract Disclosure: K. Shankar: None. S. Varshney: None. D. Gupta: None. O. Singh: None. S.B. Ogden: None. S. Osborne-Lawrence: None. N.P. Metzger: None. C.P. Richard: None. J.M. Zigman: Grant Recipient; Self; Novo Nordisk. Objective: The hormones ghrelin and LEAP2 both are endogenous ligands for the growth hormone secretagogue receptor (GHSR). Whereas ghrelin activates GHSR, LEAP2 blocks ghrelin from activating GHSR and also inhibits GHSR constitutive activity. It is via GHSR that the glucoregulatory actions of ghrelin and LEAP2 are mediated. These glucoregulatory actions are highlighted by the findings of severe hypoglycemia in ghrelin-KO mice and LEAP2-overexpressing mice when they are submitted to an acute-on-chronic caloric restriction protocol. Also, recently, our group showed that ghrelin-KO mice require a much higher glucose infusion rate (GIR) and exhibit markedly reduced elevation of counterregulatory hormones when submitted to a hyperinsulinemic-hypoglycemic clamp. In the current study, we investigated the potential of LEAP2 to protect against insulin-induced-hypoglycemia and counteract the effects of ghrelin deletion during the hypoglycemic clamp. Methods: Eight-ten week-old male wild-type (WT), Ghrelin-KO, LEAP2-KO, and LEAP2/Ghrelin-doubleKO (lacking both ghrelin and LEAP2 ) littermates were used for this study (n=7-10 per genotype). Mice were implanted with a right jugular vein catheter. Five days later, hyperinsulinemic-hypoglycemic clamps were performed in conscious, unrestrained mice. A low dose of insulin was infused at 4 mU/kg/min i.v. over 2 hr. A 20% glucose solution was simultaneously infused at a variable rate to achieve hypoglycemia (35–45 mg/dL) during the final 30 min. Blood glucose was measured via tail nicks every 5 min. Results: We were able to achieve the target hypoglycemic range in all four genotypes using this protocol. As compared to WT mice, Ghrelin-KO mice required markedly elevated (∼110% higher) GIRs (10±4 mg/kg/min in WT vs. 22±2 mg/kg/min in Ghrelin-KO mice; p=0.03) by the end of the 2-hr clamp. The GIRs required by LEAP2-KO mice were equivalent to those of WT mice (7±2 mg/kg/min in LEAP2-KO; p=n.s.). Furthermore, although during the first 60 min of the clamp, LEAP2/Ghrelin-doubleKO mice exhibited slightly lower blood glucose levels than the other genotypes and during the middle 60 min of the clamp, they required higher GIRs than the other genotypes, by the end of the 2-hr clamp, their GIRs were similar to Ghrelin-KO mice (25±3 mg/Kg/min in Ghrelin/LEAP2-doubleKO mice, p=n.s.). Conclusions: These data suggest a complex effect of LEAP2 on blood glucose. Alone, LEAP2 deletion does not impact insulin sensitivity. When coupled with ghrelin deletion, LEAP2 deletion lowers fasting blood glucose and causes greater insulin sensitivity early on during the hyperinsulinemic-hypoglycemic clamp. By the end of the clamp, this effect of LEAP2 deletion when coupled to ghrelin deletion is gone. Altogether, these results suggest that LEAP2 deletion does not counteract the effects of ghrelin deletion during insulin-induced hypoglycemia. Presentation: Friday, June 16, 2023

1554-P: Carnosic Acid Protects against Short-Term Lipid-Infusion–Induced Glucose Intolerance in Mice

Background: Obesity and type 2 diabetes (T2D) are associated with elevated plasma free fatty acids (FFA). In vivo exposure to FFAs, such as palmitate, by lipid infusion results in insulin resistance as observed in obesity and T2D. In recent years, compounds found in herbs and plants have attracted attention for prevention and treatment of insulin resistance and T2D. In recent studies by our group, carnosic acid (CA), found in rosemary, increased glucose uptake and attenuated the FFA (palmitate)-induced insulin resistance in muscle cells and adipocytes. In addition, CA caused a robust activation of AMP-activated protein kinase (AMPK). Our present study aimed to examine the effects of CA in short-term FFA-induced glucose intolerance in mice. Material and Methods: C57Bl/6J mice were cannulated in their jugular veins and infused for 48h with ethylpalmitate (EtP, nontoxic method of elevating circulating palmitate because of hydrolysis to palmitate and ethanol by plasma esterases), mimicking elevated FFA levels seen in obesity. In addition, a group of mice were infused with EtP plus 50 mg/kg CA for 48h. Ethanol vehicle with or without CA were two additional control groups. At the end of the infusions, the mice were subjected to a 2 hr hyperglycemic clamp (20 mM glucose) and the glucose infusion rate was measured to assess glucose tolerance. Results: Preliminary data revealed that mice infused with EtP and CA had a higher glucose infusion rate (GIR; mg/kg*min) (66.5±10, mean±SEM) than mice infused with EtP alone (22.7±10). The EtP and CA was comparable to the GIR of ethanol vehicle infused mice (73±9). Future Directions: Further analysis of collected plasma and tissue will be used to assess insulin resistance and beta cell function in vivo and to elucidate the mechanisms of CA alleviation of FFA-induced insulin resistance. Conclusions: Our data indicate that CA has the potential to counteract FFA-induced glucose intolerance in mice. Disclosure N.Tsakiridis: None. F.Vlavcheski: None. E.Tsiani: None. A.Giacca: None.

A case of diazoxide unresponsive congenital hyperinsulinemic hypoglycemia with missense mutation in ABCC8 gene

Hypersecretion of insulin by pancreatic ß-cells causes hypoglycemia called congenital hyperinsulinism (CHI). It can inhibit brain development in infants. It is associated with mutations in the ABCC8 or KCNJ11 genes encoding for the SUR1 and KIR 6 (subunits of the ATP-sensitive potassium (KATP channel) a rare genetic disorder. It has an incidence rate of 1 in 50,000 in general populations and 1 in 2000 in areas with a higher rate of consanguinity. Here, we report a case of hyperinsulinemic hypoglycemia with ABCC8 gene mutation in a late preterm female infant who developed late-onset hypoglycemia. The infant developed hypoglycemic seizures on day 3 of life and her metabolic workup revealed hyperinsulinemia. A high glucose infusion rate and enteral feeding could not maintain the infant's serum glucose level. PET scan showed no abnormal somatostatin receptor avid lesion in pancreatic parenchyma. Hence genetic workup was done which showed a missense mutation in the ABCC8 gene which was c.4154C&gt;G/p.Ser1385Cys. Over 9 months of follow-up, the infant is treated with octreotide and diazoxide, hasn't had any hypoglycemic events and has normal growth and psychomotor development for her age.

Effects of pregnancy and electroacupuncture on pancreatic beta cell mass in rats with diet-induced obesity

We previously demonstrated that repeated electroacupuncture (EA) throughout pregnancy improves insulin sensitivity (reflected by higher glucose infusion rates during a hyperinsulinemic-euglyemic clamp; Figure 1A) in a high fat/sucrose (HFS) diet-induced rat model of maternal obesity. Compared to non-obese, non-pregnant controls (Con group), pancreatic weight (Figure 1B) was unaffected by diet (HFS group) but increased 24% in HFS-exposed pregnancy (HFS-P group); EA abolished this effect (HFS-P+EA group).

The Effects of Acute High‐Intensity Interval Exercise and Hyperinsulinemic‐Euglycemic Clamp on Osteoglycin Levels in Young and Middle‐Aged Men

Osteoglycin (OGN) is a leucine-rich proteoglycan that has been implicated in the regulation of glucose in animal models. However, its relationship with glucose control in humans is unclear. We examined the effect of high-intensity interval exercise (HIIE) and hyperinsulinemic-euglycemic clamp on circulating levels of OGN as well as whether circulating OGN levels are associated with markers of glycemic control and cardio-metabolic health. Serum was analyzed for OGN (ELISA) levels from 9 middle-aged obese men (58.1 ± 2.2 years, body mass index [BMI]=33.1 ± 1.4kg∙m-2, mean ± SEM) and 9 young men (27.8 ± 1.6 years, BMI=24.4 ± 0.08 kg∙m-2) who previously completed a study involving a euglycemic-hyperinsulinemic clamp at rest and after HIIE (4x4 minutes cycling at approximately 95% peak heart rate (HRpeak), interspersed with 2 minutes of active recovery). Blood pressure, body composition (dual-energy X-ray absorptiometry), and insulin sensitivity (hyperinsulinemic-euglycemic clamp) were assessed. Serum OGN was higher in the young cohort compared with the middle-aged cohort (65.2 ± 10.1ng/mL versus 36.5 ± 4. 5 ng/mL, p ≤ 0.05). Serum OGN was unaffected by acute HIIE but decreased after the insulin clamp compared with baseline (~-27%, p=0.01), post-exercise (~-35%, p=0.01), and pre-clamp (~-32%, p=0.02) time points, irrespective of age. At baseline, lower circulating OGN levels were associated with increased age, BMI, and fat mass, whereas higher OGN levels were related to lower fasting glucose. Higher OGN levels were associated with a higher glucose infusion rate. Exercise had a limited effect on circulating OGN. The mechanisms by which OGN affects glucose regulation should be explored in the future. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

1329-P: A RIPK2 Inhibitor Protects against Saturated-Fat–Induced Glucose Intolerance in Mice

Background: Obesity and type 2 diabetes (T2D) are associated with chronic low-grade inflammation. Elevated free fatty acids (FFAs) , as seen in obesity and T2D, can act as damage associated molecular patterns (DAMPs) activating the innate immune system. Recent studies have identified nucleotide binding oligomerization domain 1 (NOD1) , an intracellular pattern recognition receptor, can be activated by saturated fatty acids (sFA) . NOD1 activates inflammatory kinase RIPK2, leading to increased cytokine production by the innate immune system. Our study aimed to determine whether wild type mice treated with GSK583, a RIPK2 inhibitor, are protected against FFA-induced glucose intolerance. Material and Methods: C57Bl/6J mice were surgically cannulated in their jugular veins and were infused with ethylpalmitate (EtP) for 48h, which results in increased plasma palmitate levels and mimics the elevated FFA levels seen in vivo. Furthermore, mice were also infused with EtP and GSK583 for 48h. After infusion, the mice were subjected to a hyperglycemic clamp and the glucose infusion rate was measured to assess glucose tolerance that under hyperglycemic clamp conditions, is mainly determined by the beta cell ability to compensate for FFA-induced insulin resistance. Results: Preliminary data revealed that mice infused with EtP and GSK583 had a higher glucose infusion rate (GIR; mg/kgmin) (83+20, mean+SEM) than mice infused with EtP alone (57+4) . The EtP and GSK583 was comparable to the GIR of control (EtP vehicle infused) mice (84+7) . Conclusions: Our data indicate that pharmacological inhibition of NOD1 signaling protects against FFA-induced glucose intolerance in mice. Targeting NOD1 may be an effective strategy for treating beta cell dysfunction in T2D. Disclosure N.Tsakiridis: None. A.Ivovic: None. S.Rahman: None. Y.Tan: None. A.Giacca: None.

A Term Neonate with Multiorgan Dysfunction, Severe Metabolic Acidosis, and Hyperkalemia.

A Term Neonate with Multiorgan Dysfunction, Severe Metabolic Acidosis, and Hyperkalemia.

A Case of Persistent Hypoglycemia with Disorder of Sex Development

A Case of Persistent Hypoglycemia with Disorder of Sex Development

P-48: Temporary Use of High Glucose Infusion Rate and Lipid Minimization to Treat Pediatric Intestinal Failure Patients Severely Malnourished and Cholestatic

P-48: Temporary Use of High Glucose Infusion Rate and Lipid Minimization to Treat Pediatric Intestinal Failure Patients Severely Malnourished and Cholestatic

79-LB: Pharmacokinetics and Pharmacodynamics of Avexitide (Exendin 9-39) in Neonates and Infants with Congenital Hyperinsulinism

Congenital hyperinsulinism (HI) is an ultra-rare pediatric disease with high unmet medical need. Avexitide, a first-in-class GLP-1 receptor antagonist, has been shown to reduce hyperinsulinemic hypoglycemia in children and adolescents with HI. Among neonates, maintenance of euglycemia often depends on high glucose infusion rates (GIR) by central lines. Those whose GIR exceeds 10 mg/kg/min frequently require subtotal pancreatectomy, leading to prolonged hospitalization, life-threatening complications, and induction of insulin-dependent diabetes. In this Phase 2 trial, 13 neonates and infants ages 11 days to 5 months with diazoxide-unresponsive HI were randomized to single ascending doses of avexitide and placebo by continuous IV infusion for up to 12 hours on two days in crossover design. Plasma glucose was monitored with GIR adjusted to maintain euglycemia. The primary endpoint was GIR. Relationships between avexitide exposure and absolute difference in GIR during avexitide vs. placebo were evaluated. A pharmacokinetic (PK) simulation of avexitide following subcutaneous (SC) injection in neonates was performed based on a modified PopPK model previously established with inclusion of weight-based allometric scaling. Relative to placebo, avexitide significantly reduced GIR when evaluated across dose levels (p=0.0087) with dose-dependent improvements observed. On average, avexitide infused at 100, 200 and 1000 pmol/kg/min demonstrated 1.3 (15%), 2.9 (24%), and 4.3 (56%) mg/kg/min reductions in GIR relative to placebo and entirely abolished glucose requirements in 50% of patients at the top dose. PK/PD analysis demonstrated an exposure-response relationship best described by an Emax model. PK simulation indicated that avexitide dosed by SC injection may achieve adequate steady-state exposure to lower GIR requirements. Subcutaneous avexitide may represent a promising therapeutic approach for treatment of neonates and infants with HI. Disclosure C. Craig: Consultant; Self; Eiger BioPharmaceuticals. D. D. De leon: Advisory Panel; Self; Zealand Pharma A/S, Consultant; Self; Hanmi Pharmaceutical, Heptares Therapeutics, Poxel SA, Soleno Therapeutics, Inc., Employee; Spouse/Partner; Merck &amp; Co., Inc., Research Support; Self; Crinetics Pharmaceuticals, Tiburio, Zealand Pharma A/S. Funding National Institute of Diabetes and Digestive and Kidney Diseases (1R56DK083670); Clifford and Katherine Goldsmith Foundation; National Center for Research Resources (UL1RR024134); Eiger BioPharmaceuticals

Neonatal congenital hyperinsulinism in Indonesia

Congenital hyperinsulinism (CHI) is resulted from dysregulated insulin secretion from hyperplastic and hyperactive but apparently normally structured β-cells islet. Principal management is maintaining normal blood glucose level by giving high GIR and pharmacological therapy. Surgery is chosen when CHI is unresponsive to pharmacological treatment. A 3-days-old girl was admitted to Sanglah Hospital, with a complaint of lethargic, refused to drink, seizure, weak tonus. The patient had a very low blood glucose level, normal lactate level, normal blood pH, high fasting insulin and C-Peptide level, normal cortisol, normal growth hormone, normal TSHs, and FT4 level, no ketonuria, no glucosuria, and no proteinuria. An abdominal CT scan showed diffuse dilatation of the caput, corpus, and tail of the pancreas without pancreatic duct dilatation. The patient was treated with Hydrocortisone, Octreotide, Nifedipine, and a high glucose infusion rate. The patient was undergone subtotal pancreatectomy and only remained 22% from the previous size. Histopathologic examination revealed serous acini zymogenic cells that were arranged in lobules, hyperplastic of the Langerhans islands, and cell within Langerhans islands. Post-surgery condition, she had controlled blood glucose, good drink tolerance, without a recurrent seizure. CHI is a rare disease and differential diagnosis of persistent hypoglycemia in the infant. Comprehensive and multidisciplinary management is required for a better outcome.

Ghrelin Protects Against Insulin-Induced Hypoglycemia in a Mouse Model of Type 1 Diabetes Mellitus

Insulin-induced hypoglycemia is a major limiting factor in maintaining optimal blood glucose in patients with type 1 diabetes and advanced type 2 diabetes. Luckily, a counterregulatory response (1) system exists to help minimize and reverse hypoglycemia, although more studies are needed to better characterize its components. Recently, we showed that the hormone ghrelin is permissive for the normal CRR to insulin-induced hypoglycemia when assessed in mice without diabetes. Here, we tested the hypothesis that ghrelin also is protective against insulin-induced hypoglycemia in the streptozotocin (2) mouse model of type 1 diabetes. STZ-treated ghrelin-knockout (KO) (3) mice as well as STZ-treated wild-type (WT) littermates were subjected to a low-dose hyperinsulinemic-hypoglycemic clamp procedure. The STZ-treated ghrelin-KO mice required a much higher glucose infusion rate than the STZ-treated WT mice. Also, the STZ-treated ghrelin-KO mice exhibited attenuated plasma epinephrine and norepinephrine responses to the insulin-induced hypoglycemia. Taken together, our data suggest that without ghrelin, STZ-treated mice modeling type 1 diabetes are unable to mount the usual CRR to insulin-induced hypoglycemia.

A Novel HNF4A Mutation Causing Three Phenotypic Forms of Glucose Dysregulation in a Family

Maturity-onset diabetes of the young (MODY) classically describes dominantly inherited forms of monogenic diabetes diagnosed before 25 years of age due to pancreatic β-cell dysfunction. In contrast, mutations in certain MODY genes can also present with transient or persistent hyperinsulinemic hypoglycemia in newborn infants, reflecting instead β-cell dysregulation. Of the MODY genes described to date, only hepatocyte nuclear factor-4-alpha (HNF4A; MODY1) and hepatocyte nuclear factor-1-alpha (HNF1A; MODY3) mutations may result in a biphasic phenotype of hypoglycemia in early life and hyperglycemia in later life. We report a family with a novel HNF4A mutation with diverse phenotypic presentations of glucose dysregulation. The proband was a term, appropriate-for-gestational age male infant with symptomatic hypoglycemia on day 3 of life needing high glucose infusion rate to maintain normoglycemia. He was born to a non-obese and non-diabetic mother. Glucose regulation was optimized using diazoxide upon confirmation of hyperinsulinism. Cascade genetic screening identified the same mutation in his father and elder sister, but mother was negative. Father was diagnosed with Type 1 diabetes at 15 years of age that required insulin therapy. Proband's elder sister, born at term appropriate for gestational age, presented with transient neonatal hypoglycemia needing parenteral glucose infusion for a week followed by spontaneous resolution. The paternal grandparents were negative for this mutation, confirming a paternal de novo mutation and autosomal dominant inheritance in this family. This pedigree suggests that the presence of early-onset paternal diabetes should prompt molecular testing in infants presenting in the newborn period with diazoxide-responsive hyperinsulinemic hypoglycemia, even in the absence of maternal diabetes and macrosomia.

Glucose Levels during the First 24 Hours following Perinatal Hypoxia.

Hypoglycemia is a significant risk factor for perinatal brain injury and adverse outcomes, particularly in infants requiring resuscitation following hypoxic ischemic (HI) insult. We aimed to study blood glucose (BG) levels in physiologically stressed infants in the presence or absence of epinephrine (Epi) administration at resuscitation in the first 24 hours after birth. A retrospective chart review of all infants with heart rate (HR) < 100/min at 1 minute requiring positive pressure ventilation (PPV) at birth was performed. Infants were classified into two groups as follows: (1) PPV group: infants' HR improved with PPV only at resuscitation, and Epi group: infants received Epi at resuscitation for persistent bradycardia. Serial measurements of BG levels collected and glucose infusion rate (GIR) calculated at 24 hours. By design, infants in the Epi group had lower cord pH and higher base deficit. BG was significantly lower overtime in premature infants ≤32 weeks of gestation in the Epi group. The BG was markedly higher in near-term and term infants in the Epi group compared with the PPV group. Hypoglycemia was more common despite administration of higher GIR in premature infants ≤32 weeks of gestation. In the presence of physiological stress, premature infants are more at risk for hypoglycemia than term infants.

385-P: Blocking the Nicotinic Receptors of the Parasympathetic Nervous System Prevents Severe Hypoglycemia-Induced Fatal Cardiac Arrhythmias in Rats

In response to hypoglycemia, excessive stimulation of the parasympathetic nervous system (PNS) may induce bradycardia and fatal heart block. Since signaling via nicotinic receptors mediates the PNS response, it was hypothesized that these receptors may mediate hypoglycemia-induced cardiac arrhythmias. To test this hypothesis, mecamylamine (a nicotinic receptor antagonist; 7.5 mg/kg, n = 17) or saline (control; n = 20) was infused intravenously in Sprague Dawley rats during insulin-induced (0.2mU/kg/min) severe hypoglycemic (10-15 mg/dl) clamps for 3 hours with electrocardiogram recordings. Compared to controls, mecamylamine-treated rats required a 3-fold higher glucose infusion rate during severe hypoglycemia, consistent with lower peak epinephrine levels (5698±557 vs. 2418±396 pg/ml; p &amp;lt; 0.001). In control rats, hypoglycemia led to 2nd degree heart block (1.8±1.7/min), 3rd degree heart block (32%), and mortality (25%). However, mecamylamine treatment completely prevented 2nd and 3rd degree heart block resulting in 100% survival (*p &amp;lt; 0.05). In summary, blocking nicotinic receptors prevents cardiac arrhythmias and mortality during severe hypoglycemia. Clinically, targeting the parasympathetic nervous system could be a logical approach to prevent sudden death in people with insulin-treated diabetes at risk for hypoglycemia. Disclosure C.M. Reno: None. J. Bayles: None. Y. Huang: None. M.B. Oxspring: None. S. Fisher: None. Funding National Institutes of Health; National Institute of Diabetes and Digestive and Kidney Diseases; JDRF

Thoracic epidural anaesthesia reduces insulin resistance and inflammatory response in experimental acute pancreatitis

Aims: The activity of the sympathetic nervous system (SNS) is crucial at an early stage in the development of an inflammatory reaction. A study of metabolic events globally and locally in the early phase of acute pancreatitis (AP), implying hampered SNS activity, is lacking.We hypothesized that thoracic epidural anaesthesia (TEA) modulates the inflammatory response and alleviates the severity of AP in pigs.Material and methods: The taurocholate (TC) group (n = 8) had only TC AP. The TC + TEA group (n = 8) had AP and TEA. A control group (n = 8) underwent all the preparations, without having AP or TEA. Metabolic changes in the pancreas were evaluated by microdialysis and by histopathological examination.Results: The relative increase in serum lipase concentrations was more pronounced in the TC group than in TC + TEA and control groups. A decrease in relative tissue oxygen tension (PtiO2) levels occurred one hour later in the TC + TEA group than in the TC group. The maintenance of normoglycaemia in the TC group required a higher glucose infusion rate than in the TC + TEA group. The relative decrease in serum insulin concentrations was most pronounced in the TC + TEA group.Conclusion: TEA attenuates the development of AP, as indicated by changes observed in haemodynamic parameters and by the easier maintenance of glucose homeostasis. Further, TEA was associated with attenuated insulin resistance and fewer local pathophysiological events.

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.

The time lag prior to the rise in glucose requirements to maintain stable glycaemia during moderate exercise in a fasted insulinaemic state is of short duration and unaffected by the level at which glycaemia is maintained in Type 1 diabetes.

To determine the duration of the low hypoglycaemia risk period after the start of moderate-intensity exercise performed under basal insulinaemic conditions and whether this period is affected by the level at which glycaemia is maintained under these conditions. This was a prospective, randomized counterbalanced study. Eight participants with Type 1 diabetes (mean ± sd age 21.5 ± 4.0 years) underwent either a euglycaemic (5-6 mmol/l) or hyperglycaemic clamp (9-10 mmol/l) on separate days and were infused with insulin at basal rates and [6,6-2 H]glucose while cycling for 40 min at 50% maximum oxygen consumption rate. The main outcome measures were the glucose infusion rates required to maintain stable glycaemia and glucoregulatory hormone levels, and rates of glucose appearance and disappearance. During the first 20 min of exercise, the glucose infusion rate did not increase significantly, irrespective of the level at which glycaemia was maintained, but increased acutely between 20 and 25 min under both conditions. Maintaining higher glycaemia resulted in higher glucose infusion rate during, but not early post-exercise. With the exception of epinephrine, the glucoregulatory hormone levels and rates of glucose appearance and disappearance were similar between conditions. Irrespective of the levels at which glycaemia is maintained, there is a 20-min low exogenous glucose demand period during which the exogenous glucose requirements to maintain stable glycaemia do not increase during moderate exercise performed at basal insulin level.

Differential Impacts of Insulin Analogs Lispro and Glulisine on Glucose and Lipid Homeostasis during Hyperinsulinemic Euglycemic Clamp in Streptozotocin-Induced Diabetic Rats

In addition to their benefits on glycemia, the specific actions of insulin analogs on glucose and lipid metabolism should be depicted. Here we analyzed the effects of Lispro (LIS) and Glulisine (GLU) insulin-analogs in diabetic rats. Diabetes was induced in Wistar male rats following an i.v. injection of streptozotocin (STZ) at 60mg/kg. Conscious rats underwent a 2-hour hyperinsulinemic (LIS or GLU at 0.8U/kg/h) euglycemic clamp with a constant infusion of 3H-glucose (4µCi/kg/min), with n=8 rats per each group. Glycemia was monitored continuously to adjust glucose infusion rate (GIR) to maintain euglycemia during the LIS or GLU perfusion. Blood, muscle and liver samples were collected for biochemical and radioactivity analysis. Compared to GLU, mean GIR was 51% higher in LIS treated rats (LIS: 18 +/- 1mg/kg/min, GLU: 12 +/- 1 mg/kg/min, p&amp;lt;0.01). Importantly, the higher GIR observed with LIS was associated with a strong inhibition of hepatic glucose production, which remained elevated in rats treated with GLU (LIS: 0.4 +/- 0.9mg/kg/min, GLU: 6.4 +/-1.6 mg/kg/min, p&amp;lt;0.01). Whole body glycolysis, glycogen, as well as liver and muscle glycogen synthesis rates remain similar between groups. Compared with LIS, rats treated with GLU showed a better reduction in plasma free fatty acids and glycerol levels during the clamp experiment, with a 50% and 139% lower plasma free fatty acids and glycerol area under the curve (p&amp;lt;0.and p&amp;lt;0.01 vs. LIS, respectively). 3H-glucose incorporation in muscle and liver lipid stores was not different, indicating that lipolysis rather than lipogenesis was differentially impacted. In conclusion, hyperinsulinemic euglycemic clamps in STZ rats enabled to detect a strong inhibition of hepatic glucose production by LIS, while GLU better suppresses lipolysis. Our experimental setting should help to differentiate other insulin analogs and dissect their mechanisms of action. Disclosure F. Briand: Employee; Self; Physiogenex S.A.S.. Stock/Shareholder; Self; Physiogenex S.A.S. E. Brousseau: Employee; Self; Physiogenex S.A.S. R. Burcelin: Stock/Shareholder; Self; Physiogenex S.A.S. T. Sulpice: Employee; Self; Physiogenex S.A.S.. Stock/Shareholder; Self; Physiogenex S.A.S..