Maintenance Of Euglycemia Research Articles

A Retrospective Cohort Analysis of Two Computerized Insulin Infusion Protocols.

The primary objective of this analysis was to compare the safety and efficacy of a novel computerized insulin infusion protocol (CIIP), the Lalani Insulin Infusion Protocol (LIIP), with an established CIIP, Glucommander. We conducted a 10-month retrospective analysis of 778 patients in whom LIIP was used (August 18, 2020 to June 25, 2021) at six HonorHealth Hospitals in the Phoenix metropolitan area. These data were compared with Glucommander that was used at those same hospitals from January 1, 2018 to August 17, 2020, n = 4700. Primary end points of the project included average time to euglycemia and average time in hyperglycemia (>180 mg/dL) and hypoglycemia (<70 mg/dL). Additional subgroup analysis was done to evaluate CIIP performance in patients in whom maintenance of euglycemia was more challenging. The LIIP had a faster time to euglycemia (191 vs 222 minutes, P < .001) and similar time in hypoglycemia (2.79 vs 2.76 minutes, P = .50) for all patients, when compared with Glucommander. Similar observations were made for the following subgroups: diabetic ketoacidosis/hyperosmolar hyperglycemic state (DKA/HHS) patients, COVID-19 patients, patients on steroids, patients with ≥60 glomerular filtration rate (GFR), patients with renal insufficiency, and patients with sepsis. The LIIP is a safe and effective CIIP in managing intravenous insulin infusion rates. Utilization of LIIP resulted in reduced time to euglycemia, P < .001, when compared with Glucommander and did not cause increased hypoglycemia during the project period. Contributing factors to the success of LIIP may include improved clinical workflow, learnability and ease of use, compatibility with the Epic electronic health record (EHR), and its unique, dynamic and adaptive algorithm.

P.159: Investigating the Role of Cathepsin L in Islet Graft Rejection

Type 1 diabetes (T1D) is a T cell-mediated autoimmune disorder in which beta-cell specific destruction leads to life-long exogenous insulin dependence. While islet transplantation can restore euglycemia in these patients, both allogeneic and autoimmune rejection of the islet graft pose challenges limiting graft longevity. CD4+ T cells play a major role in driving T1D autoimmune development and islet graft rejection. Recent discovery of hybrid insulin peptides (HIPs), a fusion of insulin peptides with other beta-cell granule containing peptides, were found to be cognate autoantigens for autoreactive CD4+ T cells in mouse models and in patients with T1D. HIPs are formed within the beta-cell during crinophagy, a process of protein degradation or turnover where insulin granules fuse with lysosomes. By reducing the formation of HIPs, autoimmune-mediated islet graft rejection may be delayed. Cathepsin L (CatL) is a lysosomal endopeptidase enzyme involved in protein degradation and is implicated in the generation of HIPs. Non-Obese Diabetic (NOD) mice lacking CatL (NOD.CatL-/-) exhibited a delay in spontaneous T1D development. Immunophenotyping of islet-infiltrating immune cells from NOD.CatL-/- mice displayed reductions in effector CD4+ T cells and tetramer-specific autoreactive BDC-2.5, BDC-6.9, and insulin T cells compared to NOD mice. We hypothesize that islets deficient in CatL will delay immune-mediated rejection due to the absence of antigenic HIPs following transplantation. CatL-deficient islets may improve islet graft survival due to reduced release of antigenic peptides and passenger CD4+ T cells when transplanted into recipient mice. Isolated islets (250 islets/recipient) from NOD.CatL-/-, NOD.CatL+/-, or NOD.Rag mice, were transplanted under the kidney capsule of streptozotocin-treated and spontaneously diabetic NOD mice and monitored for restoration and maintenance of euglycemia. Both NOD.CatL-/- and NOD.CatL+/- islets restored euglycemia similarly as NOD.Rag islets. Future studies will investigate the impact of CatL-deficiency on long-term graft survival and effects on immune cell infiltration and activation. This work was supported by an NIH/NIDDK R01 award (DK099550), JDRF award SRA-2016-270-S-B, JDRF award 2-SRA-2019-692-S-B, NIH/NIDDK R01 award (DK126456), NIH/NIDDK R01 award (DK127497), NIH/NIGMS (T32GM008111) Cell, Molecular, and Developmental Biology T32 training grant.

A hospital based research to determine the incidence and severity of vitamin d insufficiency in people with type 2 diabetes

Aims: The aim of the study to assess the prevalence and severity of vitamin D deficiency in type 2 DM. Material and methods: A 5 months case-control study was carried out at Dhawan Hospital in Ludhiana, Punjab, India, at the request of the researchers. A total of 240 volunteers participated in the study, with 120 type 2 diabetes patients serving as case participants (Group A) and 120 healthy volunteers serving as control participants (Group B). Laboratory testing on a regular basis CBC, FBS, RBS, PP2BS, haemoglobin A1C, blood urea, serum creatinine, lipid profile, urine albumin, and Vitamin D3 levels were all measured using conventional techniques at the institute's central laboratory, according to the guidelines. Results: When comparing groups A and B, the mean age of group A (case) was 51.42 9.25 years, while the mean age of group B (control) was 50.12 10.18 years. The prevalence of low vitamin D levels in the healthy population was just 19.2 percent, while the prevalence in the diabetic population was 84.2 percent. Vitamin D levels were found to be sufficient, insufficient, and deficient in 18.51 percent, 61.11 percent, and 16.67 percent, respectively, in patients with controlled diabetes according to HbA1C criteria, but only 10.60 percent, 68.18 percent, and 24.24 percent in patients with uncontrolled diabetes, according to the same criteria. In contrast to diabetic patients with managed condition, a higher proportion of diabetic patients with uncontrolled state (24.24 percent) had overt vitamin D insufficiency (16.67 percent). There is a statistically significant relationship between the maintenance of euglycemia and the degree of Vitamin D deficiency in diabetic patients, as shown by a p value less than 0.05. Conclusion: All patients with type-2 diabetes should have their vitamin D levels checked, and those who are found to have insufficiency or shortage of vitamin D should be prescribed vitamin D supplements. In order to avoid vitamin D insufficiency, it is also necessary to maintain tight control over one's diabetic condition.

A triple-blinded crossover study to evaluate the short-term safety of sweet manioc starch for the treatment of glycogen storage disease type Ia

BackgroundGlycogen storage disease type 1a (GSD Ia) is characterized by severe fasting hypoglycemia. The clinical management includes the administration of uncooked cornstarch (UCCS). Although such a diet approach is effective in achieving euglycemia, its impact on the quality of life of patients should be considered. In vitro analyses suggest a longer release of glucose when using sweet manioc starch (SMS).MethodsWe compared the efficacy and safety of the administration of SMS and UCCS during a short-fasting challenge in patients with GSD Ia in a randomized, triple-blind, phase I/II, cross-over study. GSD Ia patients aged ≥ 16 years and treated with UCCS were enrolled. Participants were hospitalized for two consecutive nights, receiving UCCS or SMS in each night. After the administration of the starches, glucose, lactate and insulin levels were measured in 1-h interval throughout the hospitalization period. The procedures were interrupted after 10 h of fasting or in a hypoglycemic episode (< 3.88 mmol/L).ResultsEleven individuals (mean age: 21.6 ± 4.3 years; all presenting body mass index > 25 kg/m2) participated in the study. The average fasting period was 8.2 ± 2.0 h for SMS and 7.7 ± 2.3 h for UCCS (p = 0.04). SMS maintained euglycemia for a greater period over UCCS. Increased lactate concentrations were detected even in absence of hypoglycemia, not being influenced by the different starches investigated (p = 0.17). No significant difference was found in total cholesterol, HDL, triglycerides and uric acid levels in both arms. None of the patients showed severe adverse events.ConclusionsSMS appears to be non-inferior to UCCS in the maintenance of euglycemia, thus emerging as a promising alternative to the treatment of GSD Ia.

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

Selective Somatostatin 5 (SST5) and Somatostatin 2 (SST2) Nonpeptide Agonists Potently Suppress Glucose- and Tolbutamide-Stimulated Dynamic Insulin Secretion From Isolated Human Islets

Congenital hyperinsulinism (HI) is the most common cause of persistent hypoglycemia in newborns and infants and arises from dysregulated insulin secretion. Rapid recognition and treatment are vital to prevent seizures, permanent developmental delays, coma, or even death. Very few medical options exist to treat congenital HI patients: the KATP channel activator diazoxide, the injectable somatostatin receptor peptide agonists octreotide and lanreotide, or chronic glucose infusions. However, side effects and/or limited efficacy render these therapies inadequate for many patients.Somatostatin is a 14-amino acid peptide hormone with a broad spectrum of biological actions, which are regulated through five somatostatin receptor subtypes (SST1-SST5). Somatostatin’s common physiological role is to down-regulate secretion of other hormones in various tissues. Its role in the maintenance of euglycemia is to regulate insulin and glucagon secretion from pancreatic β- and α-cells, respectively. Somatostatin regulates insulin secretion by decreasing the intracellular levels of cAMP, inhibition of voltage-gated calcium channels (VGCC), activation of the G protein-activated inward rectifier K+ channel (GIRK), and direct inhibition of insulin exocytosis.Several studies have evaluated the effect of somatostatin, somatostatin peptide analogs, and a limited number of nonpeptide somatostatin receptor agonists on insulin secretion in static assays using isolated human islets. However, the lack of highly selective agonists has made the interpretation of the contribution of SST receptor sub-types difficult to discern. Our programs for the treatment of hyperinsulinism, acromegaly, and other indications have led to the development of selective nonpeptide SST2, SST3, SST4, and SST5 agonists, possessing EC50s < 1 nM in cell-based assays of receptor activation and selectivity > 130 times over the other members of the family. The ability of these selective nonpeptide agonists to regulate glucose- and tolbutamide-stimulated dynamic insulin secretion from human islets was evaluated using a perifusion system (Biorep, FL).We found that selective SST2 and SST5 agonists potently suppressed dynamic insulin secretion in contrast to SST3 or SST4 selective agonists. Importantly, SST5 agonists were shown to have a greater effect than selective SST2 agonists or diazoxide, demonstrating their potential utility in human conditions such as congenital HI. In addition, SST5 activation is also known to have a smaller effect on glucagon secretion and is also less prone to agonist-driven desensitization than SST2 activation. Taken together, these studies support our program to identify, characterize, and develop potent, nonpeptide, orally-bioavailable, selective SST5 agonists with appropriate pharmaceutical and safety characteristics for the treatment of congenital HI.

Managing Patients with Insulin Pumps and Continuous Glucose Monitors in the Hospital: to Wear or Not to Wear.

Purpose of ReviewAs the prevalence of diabetes mellitus in the USA continues to rise, so does the popularity of diabetes management devices such as continuous glucose monitors (CGMs) and insulin pumps. The use of this technology has been shown to improve outpatient glycemic outcomes and quality of life and oftentimes may be continued in the hospital setting. Our aim is to review the current guidelines and available evidence on the continuation of insulin pumps and CGMs in the inpatient setting.Recent FindingsPatients with diabetes are at higher risk for hospitalizations and complications due to hyper- or hypoglycemia, metabolic co-morbidities, or as seen recently, more severe illness from infections such as SARS-CoV-2. The maintenance of euglycemia is important to decrease both morbidity and mortality in the hospital setting. There is consensus among experts and medical societies that inpatient use of diabetes technology in carefully selected patients with proper institutional protocols is safe and can improve inpatient glycemic outcomes and reduce hypoglycemia. During the COVID-19 pandemic, CGMs played a vital role in managing hyperglycemia in some hospitalized patients.SummaryInsulin pumps and CGMs have the potential to transform glycemic management in hospitalized patients. In order for institutions to safely and effectively incorporate these technologies on their inpatient units, hospital-based providers will need to be able to understand how to manage and utilize these devices in their practice in conjunction with diabetes experts.

To determine the prevalence and severity of vitamin D deficiency and its association with hyperglycaemia in type 2 DM

Aims: The aim of the study to assess the prevalence and severity of vitamin D deficiency in type 2 DM as well as to record the effect of hyperglycaemia on serum vitamin D level. Material and methods: A case-control study was conducted in the Department of General Medicine, Metro Hospital and Cancer Research Centre, Jabalpur, MP, India from December 2017 to November 2019. Total 240 participants were include in the study out of which 120 healthy people were include as case (Group A) and 120 type 2 diabetic patients as controls (Group B). Routine laboratory Investigations like CBC, FBS, RBS, PP2BS, HbA1C, blood urea, serum creatinine, lipid profile, urine albumin and Vitamin D3 levels were done by standard methods in central laboratory of Institute. Results: Prevalence of low vitamin D level in healthy population was only 23.33% in my study, while prevalence was 85.83% in Diabetic group. Among diabetic patients having abnormal Vitamin D level, majority (65%) were having insufficiency, only 20.83% were having over vitamin D deficiency in Diabetic patients. In patients with controlled diabetes as per HbA1C criteria, the prevalence of sufficient, Insufficient and Deficient Vitamin D was 18.51%, 61.11% and 16.67% respectively, where in patients with uncontrolled diabetes it was 10.60%, 68.18% and 24.24% respectively. More number of diabetic patients with uncontrolled status (24.24%) was having overt vitamin D deficiency in comparison to controlled status (16.67%). There is a significant association between the maintenance of euglycemia and severity of Vitamin D level in diabetic patients, as the p value is less than 0.05. Hypertension was most common co-morbidity found in diabetic group (18.33%) followed by Ischemic Heart Disease (5.83%). Conclusion: control of diabetic status is mandatory in order to prevent vitamin D deficiency.

MON-189 Glycemic Control and the Presence of Complications in Glycogen Storage Disease Type I: Results from the Swiss Registry

Background: Regular carbohydrate intake to avoid hypoglycemia is the mainstay of dietary treatment in glycogen storage disease type I (GSDI). The aim of this study was to evaluate the quality of dietary treatment and glycemic control in a cohort of GSDI patients, in relation to the presence of typical long-term complications. Methods: Data of 25 patients (22 GSD subtype Ia and 3 GSDIb, median age 20y) from the Swiss hepatic glycogen storage disease registry was analyzed cross-sectionally. Frequency and type of hypoglycemia symptoms were assessed prospectively using a structured questionnaire. Continuous glucose monitoring (CGMS) was performed as part of usual clinical care to assess glycemic control in 14 patients. Results: Although maintenance of euglycemia is the primary goal of dietary treatment, few patients (n=3, 13%) performed capillary blood glucose measurements regularly. Symptoms of hypoglycemia were present in 13 patients (57 %), but CGMS revealed periods of low glucose (<4mmol/l) in all patients, irrespective of the presence of symptoms. GSDIa patients with liver adenomas (n=9, 41%) showed a higher frequency and area under the curve (AUC) of low blood glucose than patients without adenomas (frequency 2.7±0.8 vs. 1.5±0.7 per day, AUC 0.11±0.08 vs. 0.03±0.02 mmol/l/d, p<0.05). The presence of microalbuminuria was also related to the frequency of low blood glucose. Z-Scores of bone density correlated negatively with lactate levels. Conclusion: The quality of glucose control is related to the presence of typical long-term complications in GSDI. Many patients experience episodes of asymptomatic low blood glucose. Regular assessment of glucose control is an essential element to evaluate the quality of treatment, and increasing the frequency of glucose self-monitoring remains an important goal of patient education and motivation. CGMS devices may support patients to optimize dietary therapy in everyday life.

111 - Insulin Treatment is Associated with Increased Cardiorenal Fibrosis Despite Maintaining Euglycemia in Experimental Diabetic Cardiomyopathy

Introduction: There is a high prevalence of diabetic cardiomyopathy among diabetics, characterized by diastolic dysfunction independent of coronary artery disease and hypertension, which is thought to be related to metabolic derangements and protein alterations. Diabetes mellitus (DM) is associated with cardiorenal fibrosis and heart failure, but the effects of insulin treatment on this pathophysiologic process is undefined. Our objective is to determine the cellular effects of insulin treatment on cardiorenal fibrosis in DM. Methods: Three groups of male Wistar rats (n = 9 to 15 per group): 1) Normal control; 2) Diabetic (DM) control; 3) Insulin-treated DM rats; were used. One dose of streptozotocin was administered to induce DM. Two months after induction of DM, Alzet pumps filled with insulin (11.5 u/kg/day) or saline as a sham control were serially implanted subcutaneously every 14 days over the course of 1 month. Cardiac structure and function was assessed by echocardiography. Neurohormones were measured by radioimmunoassay. Cardiac and renal tissue was collected upon animal sacrifice, and fibrosis was determined by picrosirius red and trichrome staining. Results: The development of diabetes was confirmed by glucose measurements: normal control 110 ± 3, DM control 435 ± 20, insulin-treated DM 108 ± 15 mg/dL (P < .01). There was a reduction in LV ejection fraction when normal control is compared to DM and insulin-treated DM groups (80.5 ± 1.6 versus 76.7 ± 1.7 and 77.4 ± 1.4%, P < .05). Echocardiography showed that LV diameter is greater for the DM and insulin-treated DM groups compared to normal controls (8.5 ± 0.3 and 8.0 ± 0.2 versus 6.2 ± 0.2 mm, P < .01). Histological analyses by picrosirius staining revealed that insulin-treated DM had an increase in LV interstitial fibrosis (3.6 ± 0.4 vs 1.8 ± 0.2 %, P < .01) and kidney cortex fibrosis (3.4 ± 0.3 vs 1.8 ± 0.2%, P < .01) versus DM group, both greater as compared to normal controls (P < .01). Furthermore, there was no difference in 24 hour urine protein excretion between insulin-treated DM and DM groups (P = .76), both increased as compare to normal controls (1.9 ± 0.2 vs 1.7 ± 0.2 vs 0.8 ± 0.1 mg/min, P < .01). Plasma cGMP was the lowest in the insulin-treated DM group vs DM vs normal controls (2.3 ± 0.2 vs 10.4 ± 1.3 vs 4.9 ± 0.9 pmol/ml, P < .05). Conclusion: The results demonstrated that despite the maintenance of euglycemia with insulin, there was an increase in cardiorenal fibrosis associated with attenuated plasma cGMP level in experimental model of DM. There is a need for glycemic agents that may have beneficial effects in cardiorenal fibrosis associated with diabetic cardiomyopathy.

Hyperglycemia in transported neonates: A tertiary care experience

Introduction: Hyperglycemia is common in low birth weight and sick neonates which affect them adversely due to hyperosmolarity. As these neonates need often referral to higher setup, maintenance of euglycemia during transport should be emphasized. Objective: To know the prevalence of hyperglycemia on admission among outborn neonates and analyze the association of different transport variables and other clinical parameters with it. Methods: An observational, analytical, and cross-sectional study was designed and conducted on outborn neonates, enrolled by simple consecutive sampling from November 2014 to October 2016. All data were analyzed using SPSS version 24 and Microsoft Excel version 16 software. Results: Out of 394 outborn neonates, 33.75% were hyperglycemic. 76.4% newborns were transported by ambulance, 94.9% were stabilized before referral, 61.2% had accompanying paramedics, 86.5% neonates given intravenous fluid (IVF) during transport, 61.4% transported by moderately equipped, and 38.6% by poorly equipped vehicle. Admission hyperglycemia was significantly associated with variables such as gestational age, birth asphyxia, type of transport vehicle, duration of transport, IVF during transport, hypoxic ischemic encephalopathy, and neonatal jaundice with p&lt;0.05. Logistic regression model taking variable which shows a strong association, we can predict 70.3% time correctly the hyperglycemia on admission. Conclusion: Prevalence of hyperglycemia found to be quite common in referred neonates. Although there is quite improvement in neonatal transport due to the implementation of various government transport schemes for patients, specialized neonatal transport service with accompanied skill personnel and care during transport is a long way to go.

Regulation of intestinal SGLT1 by catestatin in hyperleptinemic type 2 diabetic mice

The small intestine is the major site for nutrient absorption that is critical in maintenance of euglycemia. Leptin, a key hormone involved in energy homeostasis, directly affects nutrient transport across the intestinal epithelium. Catestatin (CST), a 21-amino acid peptide derived from proprotein chromogranin A, has been shown to modulate leptin signaling. Therefore, we reasoned that leptin and CST could modulate intestinal Na+-glucose transporter 1 (SGLT1) expression in the context of obesity and diabetes. We found that hyperleptinemic db/db mice exhibit increased mucosal mass, associated with an enhanced proliferative response and decreased apoptosis in intestinal crypts, a finding absent in leptin-deficient ob/ob mice. Intestinal SGLT1 abundance was significantly decreased in hyperleptinemic but not leptin-deficient mice, indicating leptin regulation of SGLT1 expression. Phlorizin, a SGLT1/2 inhibitor, was without effect in an oral glucose tolerance test in db/db mice. The alterations in architecture and SGLT1 abundance were not accompanied by changes in the localization of intestinal alkaline phosphatase, indicating intact differentiation. Treatment of db/db mice with CST restored intestinal SGLT1 abundance and intestinal turnover, suggesting a cross-talk between leptin and CST, without affecting plasma leptin levels. Consistent with this hypothesis, we identified structural homology between CST and the AB-loop of leptin and protein–protein docking revealed binding of CST and leptin with the Ig-like binding site-III of the leptin receptor. In summary, downregulation of SGLT1 in an obese type 2 diabetic mouse model with hyperleptinemia is presumably mediated via the short form of the leptin receptor and reduces overt hyperglycemia.

Clinical characteristics and long-term outcome of Taiwanese children with congenital hyperinsulinism.

Congenital hyperinsulinism (CHI) is a rare condition causing severe hypoglycemia in neonates and infants due to dysregulation of insulin secretion. This study aimed to review 20 years' experience in the management of Taiwanese children with CHI. Between 1990 and 2010, children diagnosed with CHI and followed up at the Pediatric Endocrine Clinic of the National Taiwan University Hospital were enrolled. Their medical records were thoroughly reviewed. In total, 13 patients (8 boys and 5 girls) were enrolled, including six patients with onset of hypoglycemia within 1 month of age and seven patients at 4.0±2.1 months of age. The birth weight standard deviation scores of these two age groups were 4.6±1.8 and 1.4±1.3 standard deviation score, respectively (p<0.01). Initial intravenous glucose infusion at rates of 22.9±5.3mg/kg/min and 13.4±5.6mg/kg/min, respectively, were mandatory to maintain euglycemia in these two groups (p<0.05). All received pancreatectomy after failure of initial medical treatment. Twelve patients were followed up for a period of 2.5-19.8 years. Eight of them remained euglycemic without any medication and three patients developed diabetes mellitus. Seven of the nine patients who underwent intelligence evaluation had normal mental outcomes. Mental retardation of two patients was too severe to be evaluated. All four patients with mental retardation had a delay in the maintenance of euglycemia, and three of them also had seizure disorder. The age at onset of hypoglycemia reflects the severity of CHI. Early diagnosis and appropriate treatment are important for favorable mental outcomes.

GENDER SPECIFIC DIFFERENCES IN A NEW APOE-/-:INS2+/AKITA MOUSE MODEL OF HYPERGLYCEMIA-INDUCED ATHEROSCLEROSIS

PURPOSE: People with diabetesmellitus have a 2 to 4-fold increased risk of cardiovascular disease (CVD). Despite a vast amount of research, the underlying mechanisms that predispose individuals with diabetes to the development of CVD are unclear. Thus, to further our understanding of how diabetes promotes CVD and to begin to delineate how gender may influence pathogenesis, we have established, characterized and manipulated a new model of hyperglycemia-induced atherosclerosis: the apoE:Ins2 mouse. METHODS: Ins2 is anautosomaldominantmutation(C96Y)that induces juvenile-onset hyperglycemia in the absence of obesity. Ins2 Akita male mice were crossed to apoE female mice, which spontaneously develop atherosclerosis. At 5 weeks of age, male/female apoE:Ins2 mice were castrated/ovariectomized and fed a standard chow diet until the 25 weeks of age whenmice were euthanized and organs were harvested. Metabolic parameters and atherosclerotic developmentweremonitored and analyzed through the whole study. RESULTS: Male apoE:Ins2 developed persistent hyperglycemia. At 25 weeks of age, lesions from hyperglycemic mice were 3-4 times larger, with significantly larger necrotic cores, and presented calcifiedregions,comparedtonormoglycemicapoEmales.Castrated maleapoE:Ins2miceshowedareductioninbloodglucoselevels which correlated to a lack of testosterone, an improvement of several metabolic parameters, and a partial amelioration of atherosclerosis. Female apoE:Ins2 presented transient hyperglycemia that normalized by 15 weeks of age. Despite the transient hyperglycemia, larger atherosclerotic lesions were observed at 15 weeks of age compared to apoE females. Ovariectomized female apoE:Ins2 Akita mice presented chronic hyperglycemia and accelerated atherosclerosis relatively similar to male apoE:Ins2 mice. Estradiol levels were compensated in all ovariectomized mice suggesting a role for progesterone in the maintenance of euglycemia. CONCLUSION: We have developed gender-specific models of chronic and transient hyperglycemia-induced atherosclerosis. In both genders, sexual hormones impacted atherosclerosis through at least 3 mechanisms: i) the effect on insulin secretion and its regulation of the glucose levels, ii) the effect on lipid metabolism and the bioavailability of atherogenic lipoprotein particles, and iii) the protective effect directly exerted on the vasculature. CDA

Dietary management in glycogen storage disease type III: what is the evidence?

In childhood, GSD type III causes relatively severe fasting intolerance, classically associated with ketotic hypoglycaemia. During follow up, history of (documented) hypoglycaemia, clinical parameters (growth, liver size, motor development, neuromuscular parameters), laboratory parameters (glucose, lactate, ALAT, cholesterol, triglycerides, creatine kinase and ketones) and cardiac parameters all need to be integrated in order to titrate dietary management, for which age-dependent requirements need to be taken into account. Evidence from case studies and small cohort studies in both children and adults with GSD III demonstrate that prevention of hypoglycaemia and maintenance of euglycemia is not sufficient to prevent complications. Moreover, over-treatment with carbohydrates may even be harmful. The ageing cohort of GSD III patients, including the non-traditional clinical presentations in adulthood, raises ‬‬‬new questions.

Resveratrol Prevents Hypertension and Cardiac Hypertrophy in Hypertensive Rodents

s / Can J Diabetes 37 (2013) S13eS84 S23 and unacylated ghrelin (UAG). Acylation is mediated by ghrelin Oacyltransferase (GOAT). Maintenance of euglycemia during calorie restriction (CR) in pregnancy is key for optimal outcome. Hypothesis: Upregulation of GOAT/ghrelin, increased AG and GH concentrations are part of the hormonal response to hypoglycemia during CR. Methods: Wild-type (WT) and GOAT-KO (KO), pregnant (P) and non-pregnant (NP) mice were freely fed (FF) or submitted to 50% CR for 7 days. In P mice, CR occurred between days 11 to 18 (1⁄4 sacrifice) of pregnancy. Blood glucose (BG), plasma AG, UAG and GH were measured by EIA and GOAT/ghrelin expression by RT-PCR. Results (Table 1): 1. In WT mice, CR did not affect BG in NP mice but caused lower BG in P mice. This was associated with higher AG and GH (from placenta) concentrations and lower stomach GOAT and ghrelin mRNA. 2. In KO mice, where plasma AG is by definition absent, CR caused severe hypoglycemia (causing systematic P termination) in P mice and lower BG in NP mice. The latter was associated with higher UAG and lower stomach ghrelin mRNA. Conclusion: 1. GOAT-KO mice are more prone to hypoglycemia, suggesting a role for AG that is independent from GH secretion; 2. The AG increase during CR not due to increased stomach production but likely decreased degradation. 3. AG is not necessary for GH production (by the placenta) in P mice.

UCP2 Regulates the Glucagon Response to Fasting and Starvation

Glucagon is important for maintaining euglycemia during fasting/starvation, and abnormal glucagon secretion is associated with type 1 and type 2 diabetes; however, the mechanisms of hypoglycemia-induced glucagon secretion are poorly understood. We previously demonstrated that global deletion of mitochondrial uncoupling protein 2 (UCP2−/−) in mice impaired glucagon secretion from isolated islets. Therefore, UCP2 may contribute to the regulation of hypoglycemia-induced glucagon secretion, which is supported by our current finding that UCP2 expression is increased in nutrient-deprived murine and human islets. Further to this, we created α-cell–specific UCP2 knockout (UCP2AKO) mice, which we used to demonstrate that blood glucose recovery in response to hypoglycemia is impaired owing to attenuated glucagon secretion. UCP2-deleted α-cells have higher levels of intracellular reactive oxygen species (ROS) due to enhanced mitochondrial coupling, which translated into defective stimulus/secretion coupling. The effects of UCP2 deletion were mimicked by the UCP2 inhibitor genipin on both murine and human islets and also by application of exogenous ROS, confirming that changes in oxidative status and electrical activity directly reduce glucagon secretion. Therefore, α-cell UCP2 deletion perturbs the fasting/hypoglycemic glucagon response and shows that UCP2 is necessary for normal α-cell glucose sensing and the maintenance of euglycemia.

Investigation of the mechanisms contributing to the compensatory increase in insulin secretion during dexamethasone-induced insulin resistance in rhesus macaques

Dexamethasone has well-described effects to induce insulin resistance and increase insulin secretion. Herein, we examined potential contributors to the effect of dexamethasone to increase insulin secretion in rhesus macaques. Six male rhesus macaques received daily injections of either saline or dexamethasone (0.25 mg/kg i.m. for 7 days) in random order with 3 weeks between treatments. At the end of the treatment period, animals were fasted overnight and underwent a feeding study the next day, during which blood samples were taken before and for 60 min after a meal in order to assess islet hormone and incretin secretion. Dexamethasone induced marked increases in fasting plasma insulin, glucagon, leptin, and adiponectin concentrations (P<0.05). Surprisingly, the glycemic response after meal ingestion was decreased twofold during dexamethasone treatment (P<0.05). Dexamethasone-treated animals exhibited a significant increase in both insulin and glucose-dependent insulinotropic polypeptide (GIP) secretion during the feeding study (P<0.05). However, glucagon-like peptide-1 secretion was significantly lower in dexamethasone-treated animals compared with controls (P<0.01). Fasting and meal-stimulated pancreatic polypeptide concentrations (an index of the parasympathetic input to the islet) did not differ between saline and dexamethasone treatments. However, the proinsulin:insulin ratio was decreased throughout the feeding study with dexamethasone treatment suggesting an improvement of β-cell function (P<0.05). In conclusion, the maintenance of euglycemia and reduction of postprandial glycemia with short-term dexamethasone treatment appears to be due to the marked elevations of fasting and meal-stimulated insulin secretion. Furthermore, increases in postprandial GIP secretion with dexamethasone treatment appear to contribute to the effect of dexamethasone treatment to increase insulin secretion.

Long-term Correction of Very Long-chain Acyl-CoA Dehydrogenase Deficiency in Mice Using AAV9 Gene Therapy

Very long-chain acyl-coA dehydrogenase (VLCAD) is the rate-limiting step in mitochondrial fatty acid oxidation. VLCAD-deficient mice and patients clinical symptoms stem from not only an energy deficiency but also long-chain metabolite accumulations. VLCAD-deficient mice were treated systemically with 1 × 1012 vector genomes of recombinant adeno-associated virus 9 (rAAV9)-VLCAD. Biochemical correction was observed in vector-treated mice beginning 2 weeks postinjection, as characterized by a significant drop in long-chain fatty acyl accumulates in whole blood after an overnight fast. Changes persisted through the termination point around 20 weeks postinjection. Magnetic resonance spectroscopy (MRS) and tandem mass spectrometry (MS/MS) revealed normalization of intramuscular lipids in treated animals. Correction was not observed in liver tissue extracts, but cardiac muscle extracts showed significant reduction of long-chain metabolites. Disease-specific phenotypes were characterized, including thermoregulation and maintenance of euglycemia after a fasting cold challenge. Internal body temperatures of untreated VLCAD−/− mice dropped below 20 °C and the mice became lethargic, requiring euthanasia. In contrast, all rAAV9-treated VLCAD−/− mice and the wild-type controls maintained body temperatures. rAAV9-treated VLCAD−/− mice maintained euglycemia, whereas untreated VLCAD−/− mice suffered hypoglycemia following a fasting cold challenge. These promising results suggest rAAV9 gene therapy as a potential treatment for VLCAD deficiency in humans.

Perioperative Glucose Control in Neurosurgical Patients

Many neurosurgery patients may have unrecognized diabetes or may develop stress-related hyperglycemia in the perioperative period. Diabetes patients have a higher perioperative risk of complications and have longer hospital stays than individuals without diabetes. Maintenance of euglycemia using intensive insulin therapy (IIT) continues to be investigated as a therapeutic tool to decrease morbidity and mortality associated with derangements in glucose metabolism due to surgery. Suboptimal perioperative glucose control may contribute to increased morbidity, mortality, and aggravate concomitant illnesses. The challenge is to minimize the effects of metabolic derangements on surgical outcomes, reduce blood glucose excursions, and prevent hypoglycemia. Differences in cerebral versus systemic glucose metabolism, time course of cerebral response to injury, and heterogeneity of pathophysiology in the neurosurgical patient populations are important to consider in evaluating the risks and benefits of IIT. While extremes of glucose levels are to be avoided, there are little data to support an optimal blood glucose level or recommend a specific use of IIT for euglycemia maintenance in the perioperative management of neurosurgical patients. Individualized treatment should be based on the local level of blood glucose control, outpatient treatment regimen, presence of complications, nature of the surgical procedure, and type of anesthesia administered.