Oral Glucose Ingestion Research Articles

Neonatal hypoglycemia: A review with focus on practical challenges and recent updates on management

At birth, a neonate undergoes a transition from the continuous maternal supply of glucose to a variable and intermittent oral glucose intake, which is regulated by the interplay of hormones and metabolic enzyme induction. Because low plasma glucose concentrations are common in the neonatal period, it may be difficult to identify those who have pathologic hypoglycemia. Hence, it is important to formally evaluate such babies by drawing critical samples. Here, we present two cases of neonatal hypoglycemia where the presentation had some similarities, but the comprehensive evaluation revealed a varied etiological spectrum necessitating lifelong management. Through these case studies, authors discuss practical challenges in the diagnosis, management, and follow-up of neonates with endocrine causes of hypoglycemia.

Glucose ingestion does not lower testosterone concentrations in men on testosterone therapy.

Oral calorie intake causes an acute and transient decline in serum testosterone concentrations. It is not known whether this decline occurs in men on testosterone therapy. In this study, we evaluated the change in testosterone concentrations following oral glucose ingestion in hypogonadal men before and after treatment with testosterone therapy. This is a secondary analysis of samples previously collected from a study of hypogonadal men with type 2 diabetes who received testosterone therapy. Study participants (n = 14) ingested 75 grams of oral glucose, and blood samples were collected over 2 h. The test was repeated after 23 weeks of intramuscular testosterone therapy. The mean age and body mass index of study volunteers were 53 ± 8 years and 38 ± 7 kg/m2, respectively. Following glucose intake, testosterone concentrations fell significantly prior to testosterone therapy (week 0, p = 0.04). The nadir of testosterone concentration was at 1 h, followed by recovery to baseline by 2 h. In contrast, there was no change in testosterone concentrations at week 23. The change in serum testosterone concentrations at 60 min was significantly more at week 0 than week 23 (-11 ± 10% vs 0 ± 16%, p = 0.05). We conclude that oral glucose intake has no impact on testosterone concentrations in men on testosterone therapy. Endocrinology societies should consider clarifying in their recommendations that fasting testosterone concentrations are required for the diagnosis of hypogonadism, but not for monitoring testosterone therapy.

Salivary testosterone changes during oral glucose tolerance tests in overweight and obese men - postprandial or circadian variation?

Serum total testosterone (T) decreases postprandially. Postprandial salivary testosterone (SalT) responses, however, have not been studied. We report on the effect of glucose ingestion on fasting SalT concentrations. To investigate the effect of oral glucose ingestion on fasting SalT. Salivary and blood samples were collected between 09.00 and 09.30 and two hours after a 75g oral glucose load in 32 men with mean (standard deviation) age of 52 (5.7) years and body mass index of 32.6 (5.56) kg/m2. Free T and bioavailable testosterone (BAT) were calculated using the Vermeulen equation. Two hours following oral glucose, there was a decrease in fasting mean (standard deviation) SalT [178.2 (56.6) vs 146.0 (42.2) pmol/L; p = 0.0003], serum cortisol [332 (105.0) vs 239 (75.3) nmol/L; p = <0.0001], prolactin [193 (75.0) vs 127 (55.9) mIU/L; p = <0.0001] and TSH [1.60 (0.801) vs 1.16 (0.584) mIU/L; p = <0.0001]. Plasma glucose increased [6.2 (0.72) vs 8.1 (3.71) mmol/L; p = 0.0029]. Serum total T, SHBG, albumin, Free T, BAT, gonadotrophins and FT4 remained unchanged. SalT decreased postprandially. A concomitant decrease in serum cortisol, prolactin and TSH reflecting diurnal variation offers an alternative explanation for the decrease in SalT independent of food consumption. Further studies are required to determine whether morning temporal changes in SalT are related to food consumption or circadian rhythm or both.

Targeted Metabolic Profiling of Plasma in Lean and Obese Individuals during Oral Glucose Ingestion

Obesity has long been associated with metabolic inflexibility and insulin resistance. The purpose of this study was to determine 1) if the plasma metabolite/lipid profile was altered during an oral glucose tolerance test (OGTT) with obesity and 2) whether changes in plasma metabolites/lipids were related to insulin sensitivity or metabolic flexibility. Fourteen (7M/7F), young, lean (BMI: 21.9 ± 1.8 kg/m2) and fourteen (7M/7F) young, obese (BMI: 40.6 ± 5.4 kg/m2) individuals underwent a 2-hour OGTT with plasma samples obtained at baseline, 45 min and 120 min. Plasma was immediately stored at -80°C for subsequent targeted metabolomics (Biocrates MxP® Quant 500, Biocrates Life Sciences AG, Innsbruck, Austria). A 2 (body composition group) x 3 (time point) ANOVA was performed for each sex, with the false discovery rate (FDR q-value &lt;0.10) used to account for multiple testing. Of the 73 small molecule metabolites tested, 2 (Glucose and Glutamate) differed between lean and obese females, and 34 metabolites (including 10 amino acids, 9 amino acid related, 5 bile acids, 2 biogenic amines and 2 carboxylic acids) changed with time in females. Of the 427 plasma lipid species tested, 79 (primarily triglycerides, TG) differed between lean and obese females, and 134 (primarily fatty acids and TG) changed with time. In males, 45 metabolites (similar to females) and 5 lipid species (Fatty acids only) changed with time. When examining the change in all plasma metabolites/lipid species from baseline to 120 min, the change in 9 TGs, 1 dihexosylceramide, as well as glycolithocholic acid sulfate (bile acid) were related to insulin sensitivity (Matsuda Index). Metabolic flexibility (change in respiratory exchange ratio from baseline to 120 min) was related to the change in 4 lysophosphatidylcholines, 3 TG, 2 acylcarnitines, 2 diglycerides, 3-Indoleacetic acid and glutamate. American Heart Association Grant: 18AIREA33960404. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Effect of 0.5% Oral Intake of Glucose on Tear Production

Objective: To determine, how 0.5% oral glucose consumption affects the formation of tears Methodology: After ethical approval, this cross-sectional study involved 176 non-glycemic individuals (103 males and 73 females) with an average age of 23.7±2.70 years. Participants with normal body mass index (BMI) were included in the study, with an average BMI of 22.42kg/m2. After informed consent, tear production was measured at fasting and thirty, ninety and two hours minutes after intake of 0.5% glucose. Data was entered and analyzed in SPSS. RESULTS: The mean tear production at fasting was found to be 13.88±5.18mm. After 30 minutes of oral intake of 0.5% glucose, the mean tear production remained at 13.88±5.18mm. However, after 60 minutes of oral intake of 0.5%glucose, the mean tear production decreased to 12.96±5.196mm. After 90 minutes of glucose intake, the mean tear production increased to 13.58±5.03mm, and after 120 minutes, it further increased to 15.54±5.09mm. Statistical analysis revealed significant differences in tear production after 30, 60, and 90 minutes of oral intake of 0.5%glucose. However, after 90 minutes, the difference in tear production became insignificant.

Glucose intake is influencing the concentration of AD‐related plasma biomarkers in healthy adults

AbstractBackgroundBlood biomarker analyses are seen as a great aid to early diagnose and confirm underlying Alzheimer’s disease (AD) pathology. Developing evidence suggests that certain confounders need to be considered which may affect the reliability of biomarker results, e.g., chronic kidney disease. However, little is known with respect to potential confounding effects of energy/nutrient intake on these biomarkers. Thus, we aim to study the short‐term effects of oral glucose intake in healthy, obese adults.Method111 participants (60±7y, BMI 31±4kg/m2, 47 males) ingested 300ml of a glucose syrup (75g glucose, Accu‐Chek, Roche). Neurofilament light, glial fibrillary acidic protein [GFAP], amyloid‐β 42/40 ratio, phosphorylated tau ([p‐tau] 181 and p‐tau 231) were measured in fasting (0 minutes) and postprandial blood samples collected 15, 30, 45, 60, 120 and 180 minutes after ingestion of the glucose syrup using ultra‐sensitive Single molecule array assays. Additionally, a fasting (control) group (n = 26) was followed over the same time period. Statistical analysis was done using polynomial spline of degree 3 to test for differences in parameter progression over time within and between groups.ResultIn both groups, all biomarkers changed significantly over time (glucose group: all p&lt;0.0001, fasting group all p&lt;0.05) compared to baseline (0 minutes). The changes to baseline in GFAP were significantly different after glucose ingestion compared to the fasting state (p&lt;0.0001). The GFAP level decreased in the early postprandial phase (until 60 minutes) and subsequently increased in the late postprandial phase.ConclusionOur results suggest that plasma biomarkers for AD‐related pathologies are influenced by the individual nutritional status (prolonged fasting, postprandial situation). This should be considered when using AD‐related biomarkers for screening and diagnostic purposes.

Comparative analysis of glucose and fructose tolerance in two marine fishes: effects on insulin secretion and acute hypoxia tolerance

Carbohydrates are a common and economical energy source in animal feeds. However, most fish show a persistent postprandial hyperglycemia after intake of a high-carbohydrate diet. Unfortunately, the mechanism of glucose metabolism in fish is still unclear. In the present study, tiger puffer (Takifugu rubripes) and turbot (Scophthalmus maximus) were intraperitoneally injected or orally administered with glucose or fructose (500 mg/kg body weight) to evaluate the ability of fish to utilize carbohydrates. Afterwards, serum glucose, fructose, pyruvate, insulin levels, and acute hypoxia tolerance were measured. Our results showed increased serum glucose level and then decreased post intraperitoneal injection with glucose, and reached a peak after 0.5 hours in turbot and 1 hour in tiger puffer. Tiger puffer had significantly lower liver glycogen, serum glucose, fructose, pyruvate, and insulin contents than turbot. Glucose and fructose only induced insulin secretion in turbot, but did not change serum insulin level in tiger puffer. Glucose was a stronger stimulator of insulin than fructose in the two marine species. Both intraperitoneal injection and oral fructose intake increased serum glucose level, while intraperitoneal or oral glucose also increased serum fructose level. Intraperitoneal injection of glucose promoted absorption and utilization of glucose in the blood more effectively than oral glucose intake. In addition, turbot and tiger puffer were intolerant to acute hypoxia, whereas supplementation with glucose or fructose improved hypoxia tolerance in the two marine fishes by activating anaerobic glycolysis. Taken together, our results provide important scientific information for understanding the mechanism for glucose and fructose utilization and improving hypoxia tolerance in fish.

Factors Influencing Glucose Response to Exercise Following Oral Glucose Load

PURPOSE: Exercise can reduce postprandial hyperglycemia by increasing contraction-mediated glucose uptake in skeletal muscles. However, postprandial exercise does not always have similar effects in all patients. This study aimed to analyze the factors influencing glucose response to exercise following oral glucose load.METHODS: We enrolled 169 adults with impaired glucose tolerance (IGT, n = 64) and type 2 diabetes (T2D, n = 105). We measured fingertip capillary blood glucose level at 30-minute intervals over 2-hour after the 75-g oral glucose ingestion. In addition, a single bout of moderate-intensity aerobic exercise was conducted at 30 minutes after 75-g oral glucose ingestion. We also measured glycated hemoglobin (HbA1c), insulin, insulin resistance (HOMA-IR), β-cell function (HOMA-β), physical activity level questionnaire and anthropometrics.RESULTS: There was a significant difference in glucose concentration between the IGT and T2D groups (&lt;i&gt;p&lt;/i&gt; &lt;.001). Additionally, we found that patients with short diabetes duration (≤1 year) had significantly more decrease in glucose concentration than long diabetes duration (≥10 years) (&lt;i&gt;p&lt;/i&gt; &lt;.001). A regression analysis showed that waist circumference, visceral fat area, fasting glucose, HbA1c, and HOMA-IR affected glucose response to exercise following oral glucose load in patients with T2D.CONCLUSIONS: Higher volumes of exercise following an oral glucose load may be necessary for individuals with Type 2 Diabetes (T2D) who have a longer disease duration, larger waist circumference, increased visceral fat area, higher HbA1c levels, and elevated HOMA-IR values in order to prevent hyperglycemia.

Increased Insulin Secretion and Glucose Effectiveness in Obese Patients with Type 2 Diabetes following Bariatric Surgery.

β-cell dysfunction and insulin resistance are the main mechanisms causing glucose intolerance in type 2 diabetes (T2D). Bariatric surgeries, i.e., sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB), are procedures both known to induce weight loss, increase insulin action, and enhance β-cell function, but hepatic insulin extraction and glucose effectiveness may also play a role. To determine the contribution of these regulators on glucose tolerance after bariatric surgery, an oral glucose tolerance test (OGTT) was performed before and 2 months after surgery in 9 RYGB and 7 SG subjects. Eight healthy subjects served as metabolic controls. Plasma glucose, insulin, C-peptide, GLP-1, and GIP were measured during each OGTT. Insulin sensitivity and secretion, glucose effectiveness, and glucose rate of appearance were determined via oral minimal models. RYGB and SG resulted in similar weight reductions (13%, RYGB (p < 0.01); 14%, SG (p < 0.05)). Two months after surgery, insulin secretion (p < 0.05) and glucose effectiveness both improved equally in the two groups (11%, RYGB (p < 0.01); 8%, SG (p > 0.05)), whereas insulin sensitivity remained virtually unaltered. Bariatric surgery resulted in a comparable increase in the GLP-1 response during the OGTT, whereas GIP concentrations remained unaltered. Following surgery, oral glucose intake resulted in a comparable increase in hepatic insulin extraction, the response in both RYGB and SG patients significantly exceeding the response observed in the control subjects. These results demonstrate that the early improvement in glucose tolerance in obese T2D after RYGB and SG surgeries is attributable mainly to increased insulin secretion and glucose effectiveness, while insulin sensitivity seems to play only a minor role. This trial is registered with NCT02713555.

Differential effect of gastric bypass versus sleeve gastrectomy on insulinotropic action of endogenous incretins.

Prandial hyperinsulinemia after Roux-en-Y gastric bypass surgery (GB), and to lesser degree after sleeve gastrectomy (SG), has been attributed to rapid glucose flux from the gut and increased insulinotropic gut hormones. However, β-cell sensitivity to exogenous incretin is reduced after GB. This study examines the effect of GB versus SG on prandial glycemia and β-cell response to increasing concentrations of endogenous incretins. Glucose kinetics, insulin secretion rate (ISR), and incretin responses to 50-g oral glucose ingestion were compared between ten nondiabetic participants with GB versus nine matched individuals with SG and seven nonoperated normal glucose tolerant control individuals (CN) with and without administration of 200 mg ofsitagliptin. Fasting glucose and hormonal levels were similar among three groups. Increasing plasma concentrations of endogenous incretins by two- to three-fold diminished prandial glycemia and increased β-cell secretion in all three groups (p < 0.05), but insulin secretion per insulin sensitivity (i.e., disposition index) was increased only in GB (p < 0.05 for interaction). However, plot of the slope of ISR (from premeal to peak values) versus plasma glucagon-like peptide-1 concentration was smaller after GB compared with SG and CN. After GB, increasing incretin activity augments prandial β-cell response whereas the β-cell sensitivity to increasing plasma concentrations of endogenous incretin is diminished.

SAT142 Utilization Of Continuous Glucose Monitoring In Diagnosis And Management Of Insulinoma

Abstract Disclosure: V. Phan: None. P. kretschmer: None. A.G. Pittas: None. Background: Insulinoma is a rare condition that can cause life-threatening hypoglycemia. Its diagnosis and management are challenging due to the requirement of a prolonged fasting test and frequent blood glucose testing. Continuous glucose monitoring (CGM) is widely available in diabetes management; however, its usage in people without diabetes is limited due to lack of evidence. Here, we report an acutely ill patient where we used professional CGM to streamline and expedite the diagnosis of insulinoma, and personal CGM to titrate medical management with diazoxide. Clinical Case: An 81-year-old woman with complex past medical history was admitted for chest pain and shortness of breath, found to have non-ST-elevation myocardial infarction. During inpatient work up, she experienced several hypoglycemia episodes that resolved with oral glucose intake. She had a history of recurrent hypoglycemia and prior MRI showing pancreatic tumor; however, outside records did not reveal biochemical work-up for insulinoma. Her symptoms were unpredictable, so a professional CGM (Freestyle Libre) was placed. CGM data revealed persistent nocturnal hypoglycemia, and occasional postprandial hypoglycemia. Patient-recorded symptoms were present in less than half of the hypoglycemic periods detected by CGM, indicating hypoglycemia unawareness. Given her acute cardiac condition and knowing her nocturnal hypoglycemia pattern from CGM, we performed a modified 72-hour fasting test that started at midnight and was able to capture a hypoglycemia episode within only 2.5 hours of initiation. Her plasma glucose was 57 mg/dL, insulin was 13 uIU/mL, C-peptide was 1.33 uIU/mL, and proinsulin was 9.5 pmol/L. She had a negative screen for sulfonylurea and there was no evidence of antibodies to insulin, suggesting a diagnosis of insulinoma. While awaiting localization studies, the patient was started on diazoxide. We used the personal CGM connected to our clinic portal to monitor glycemia at home and titrate diazoxide dose and frequency. CGM data showed nocturnal hypoglycemia and minimal daytime hypoglycemia, therefore, we recommended diazoxide only at bedtime to minimize daytime side effects and hyperglycemia. On one occasion, the patient was on as short course of prednisone which typically causes hyperglycemia during the day and hypoglycemia in early morning. CGM allowed us to monitor patterns of steroid-induced hyperglycemia, and we moved the prednisone dose to bedtime which resulted in euglycemia overnight. Conclusion: CGM can be a valuable tool in diagnosing and managing people with insulinomas. The CGM provides information about hypoglycemia frequency and pattern. It also helps detect hypoglycemia unawareness. With CGM, we can choose the right timing for 72-hour fasting test to minimize the length of the procedure. As outpatient, CGM also makes monitoring response to diazoxide a seamless process. Presentation: Saturday, June 17, 2023

Assessment of the incretin effect in healthy subjects: concordance between clamp and OGTT methods.

The incretin effect describes the insulin response to nutrient ingestion that exceeds the response to glycemia per se. It is mediated by gastrointestinal factors and is necessary to maintain postprandial glucose homeostasis. The incretin effect results in a more than twofold increase of the insulin response to a meal in healthy people and two different techniques have been used in the past to measure its magnitude. Most studies employ an OGTT on 1 day, followed by a matching glucose infusion on a separate day. Another study design employs a hyperglycemic glucose clamp that is maintained after oral ingestion of glucose. Both protocols allow quantification of the incretin effect by comparing the insulin response to an identical glycemic stimulus. Here we performed a within-subject comparison of both techniques to quantify the incretin effect and suggest different calculation methods to interpret the results derived from the clamp experiment in a cohort of healthy young adults (n = 10, age 33 ± 4 yr). All subjects participated on four different study days: 1) OGTT, 2) isoglycemic glucose infusion (Iso-IV), 3) hyperglycemic clamp with oral glucose ingestion (clamp-OGTT), and 4) hyperglycemic clamp (clamp). With the classic OGTT/Iso-IV method, the insulin response to glucose ingestion increased more than twofold and was 60 ± 6% and 49 ± 5% for insulin and c-peptide. Different estimates of the incretin effect based on the clamp method ranged from 58% to 79% for insulin and 38% to 61% for c-peptide, both significantly higher than values derived from the OGTT/isoglycemic infusion method. However, when the effect of continuous hyperglycemia on insulin secretion was accounted for, using extrapolation from early time points of the clamp, good agreement was noted between the two methods. Based on these results, both techniques seem to be equally suited to measure the incretin effect and should be employed according to the scientific questions, experimental contingencies, and investigator experience.NEW & NOTEWORTHY This proof-of-concept study shows that the incretin effect can be reliably assessed by two different methods with similar quantitative results. A single-day hyperglycemic clamp with oral glucose ingestion allows the determination of the incretin effect with fewer study days and less day-to-day variability.

Clinical evaluation of a decision support system for glucose infusion in hypoglycaemic clamp experiments.

To provide a preliminary evaluation of the accuracy and safety of Gluclas decision support system suggestions in a hypoglycaemic clamp study. This analysis was performed using data from 32 participants (four groups with different glucose-insulin regulation: post Roux-en-Y gastric bypass with and without postprandial hypoglycaemia syndrome, postsleeve gastrectomy and non-operated controls) undergoing Gluclas-assisted hypoglycaemic clamps (target: 2.5 mmol/L for 20 minutes at 150 minutes after oral glucose ingestion). Gluclas provided glucose infusion rate suggestions upon manual entry of blood glucose values (every 5 minutes), which were either followed or overruled by investigators after critical review. Accuracy and safety were evaluated by mean absolute error (MAE), mean absolute percentage error (MAPE), average glucose level, coefficient of variation (CV) and minimal glucose level during the 20-minute hypoglycaemic period. Investigators accepted 84% of suggestions, with a mean deviation of 30.33 mg/min. During the hypoglycaemic period, the MAE was 0.16 (0.12-0.24) (median [interquartile range]) mmol/L and the MAPE was 6.12% (4.80%-9.29%). CV was 4.90% (3.58%-7.27%), with 5% considered the threshold for sufficient quality. The minimal glucose level was 2.40 (2.30-2.50) mmol/L. Gluclas achieved sufficiently high accuracy with minimal safety risks in a population with differences in glucose-insulin dynamics, underscoring its applicability to various patient groups.

Sugar signals from oral glucose transporters elicit cephalic-phase insulin release in mice

Cephalic-phase insulin release (CPIR) occurs before blood glucose increases after a meal. Although glucose is the most plausible cue to induce CPIR, peripheral sensory systems involved are not fully elucidated. We therefore examined roles of sweet sensing by a T1R3-dependent taste receptor and sugar sensing by oral glucose transporters in the oropharyngeal region in inducing CPIR. Spontaneous oral ingestion of glucose significantly increased plasma insulin 5 min later in wild-type (C57BL/6) and T1R3-knockout mice, but intragastric infusion did not. Oral treatment of glucose transporter inhibitors phlorizin and phloretin significantly reduced CPIR after spontaneous oral ingestion. In addition, a rapid increase in plasma insulin was significantly smaller in WT mice with spontaneous oral ingestion of nonmetabolizable glucose analog than in WT mice with spontaneous oral ingestion of glucose. Taken together, the T1R3-dependent receptor is not required for CPIR, but oral glucose transporters greatly contribute to induction of CPIR by sugars.

Robust increase in glucagon secretion after oral protein intake, but not after glucose or lipid intake in Japanese people without diabetes.

Few studies in Asian populations have analyzed how glucagon secretion is affected by ingested glucose, proteins or lipids, individually. To investigate the fluctuations of glucagon secretion after the intake of each of these nutrients, 10 healthy volunteers underwent oral loading tests using each of glucose, proteins and lipids, and blood levels of glucose, insulin and glucagon were measured every 30 min for 120 min. Whereas glucagon secretion was suppressed and minimally affected by oral glucose intake and lipid intake, respectively, oral protein intake robustly increased glucagon secretion, as well as insulin secretion. Further studies are needed to elucidate the mechanism by which protein loading increases glucagon secretion.

Sweet taste preference is associated with greater hypothalamic response to glucose and longitudinal weight gain

The hypothalamus has an abundant expression of sweet taste receptors that play a role in glucose sensing and energy homeostasis. Evidence suggests that liking “sweets” can be associated with weight gain, but the relationship between sweet taste preference and hypothalamic regulation of appetite is unknown. This study tested the hypothesis that sweet taste preference is associated with increased hypothalamic activation in response to glucose (a purported neural marker for weight gain risk) and greater longitudinal increases in body mass index (BMI). Fifty-four adults aged 18–35 years with a mean (± SD) BMI of 27.99 ± 5.32 kg/m2 completed the study. Height and weight were measured at baseline and 6–12 months later in a subset of 36 participants. Sweet taste preference was assessed via the Monell 2-series, forced-choice tracking procedure. Arterial spin labeling magnetic resonance imaging was performed before and after oral glucose ingestion to determine hypothalamic blood flow response to glucose. Linear models were used to examine relationships between sweet taste preference and the hypothalamic response to glucose and longitudinal changes in BMI, adjusting for age, sex, and baseline BMI. Sweet taste preference was positively associated with glucose-linked hypothalamic blood flow (beta = 0.017, p = 0.043), adjusted for age, sex and BMI. We also observed a positive association between sweet taste preference and longitudinal change in BMI (beta = 0.088, p = 0.015), adjusted for age, sex and baseline BMI. These findings suggest that heightened sweet taste preference is associated with glucose-linked hypothalamic activation and may be linked to increased susceptibility for weight gain.

2-LB: Effect of Somatostatin Receptor 2 Antagonism (SSTR2a) on Oral Glucose Tolerance (OGT) in a Rat Model of Type 2 Diabetes (T2D)

Background: Hypoglycemia remains a concern for insulin-treated individuals living with diabetes. SSTR2a increases the endogenous glucagon counterregulatory response during hypoglycemia in rodent models of diabetes, but its impact on OGT is unclear. We examined the impact of SSTR2a on OGT in a rodent model of T2D maintained on basal insulin therapy. Methods: High fat fed (HFF), low dose streptozotocin (35 mg/kg) T2D rats received SSTR2a treatment (ZT-01 3 mg/kg) or vehicle (N=8-9/group) immediately before a fasted OGT test (OGTT, 2 g/kg). Glycemia, glucagon and c-peptide levels were measured pre- and post-dose and monitored for 120 minutes. Results: The OGTT resulted in comparable rises in blood glucose levels in both groups, consistent with an animal model of T2D. Glucagon levels rose within 15 minutes of SSTR2a and glucose administration (120 ± 70 vs 4.8 ± 3, p=0.006) and remained higher than controls for the duration of the OGTT. C-peptide levels also increased from baseline by 116 ± 77% in SSTR2a-treated animals compared to 28.9 ± 70% in controls. Conclusion: SSTR2a treatment increases glucagon and c-peptide levels following oral glucose ingestion in this rat model of T2D. These preliminary findings suggest that the use of the SSTR2a should not adversely impact glucose control around meals if used as a preventive therapy against insulin-induced hypoglycemia. Disclosure N. C. D'souza: None. M. C. Riddell: Advisory Panel; Zealand Pharma A/S, Zucara Therapeutics, Indigo Diabetes, Consultant; Lilly Diabetes, Eli Lilly and Company, Jaeb Center for Health Research, Speaker's Bureau; Dexcom, Inc., Novo Nordisk, Sanofi, Stock/Shareholder; Supersapiens, Zucara Therapeutics. N. Aleali: None. D. Shakeri: None. E. G. Hoffman: None. S. C. Atherley: None. S. Champsi: None. M. El-zahed: None. R. Liggins: Employee; Zucara Therapeutics, Stock/Shareholder; Zucara Therapeutics. O. Chan: None. Funding GlycoNet (CD-85)

34-OR: Postprandial Glucagon Action in the Human Brain

While elevated fasting glucagon is linked to hyperglycemia, the impact of postprandial changes in glucagon is less clear. Recent findings suggest potential metabolic benefits of rising glucagon after oral glucose intake. In addition to the prominent hepatic action of the hormone, animal data indicate that glucagon signaling in the brain contributes to its effects on whole-body metabolism. To elucidate the translational relevance of these findings, we studied postprandial effects of glucagon on the human brain. We performed oral glucose tolerance tests combined with fMRI to quantify brain activity and connectivity at fasting, 30- and 60-minutes post glucose load in 29 volunteers. In 14 out of 22 volunteers with physiologically suppressed glucagon during OGTT, a second OGTT with low-dose glucagon infusion was performed (0.5 pmol/kg/min). All participants had their first OGTT with intravenous saline infusion. This was compared to 7 participants with endogenous rising glucagon during OGTT. Low-dose glucagon infusion did not elevate plasma glucose levels during OGTT. Also, no changes in insulin sensitivity and insulin secretion were observed. However, experimentally elevating glucagon during the OGTT significantly increased postprandial brain responsivity in the hippocampal gyrus and in brain regions important for the regulation of food intake and systemic metabolism (i.e. hypothalamus, nucleus accumbens, midbrain). Postprandial brain responsivity during glucagon infusion was directionally consistent with the findings in persons with endogenously rising glucagon. Moreover, the postprandial brain response correlated with the rise in glucagon, regardless of exogenous or endogenous source of glucagon. Our findings demonstrate postprandial effects of glucagon in metabolically relevant human brain areas. This may underly the promising effects on body weight achieved with upcoming pharmacological multi-agonists that activate the glucagon receptor. Disclosure R.Wagner: Advisory Panel; Daiichi Sankyo, Speaker's Bureau; Novo Nordisk, Sanofi. A.Fritsche: Advisory Panel; Novo Nordisk, Lilly, Sanofi, Boehringer-Ingelheim, Speaker's Bureau; AstraZeneca, SYNLAB Holding Deutschland GmbH. A.Peter: None. M.Heni: Advisory Panel; Boehringer-Ingelheim, Sanofi, Research Support; Boehringer Ingelheim Inc., Speaker's Bureau; Lilly, Bayer Inc., Sanofi, Boehringer-Ingelheim, Novo Nordisk, Amryt Pharma Plc. S.Kullmann: None. J.Hummel: None. R.Veit: None. K.Prystupa: Other Relationship; Berlin-Chemie AG. E.Hosenfeld: None. A.L.Birkenfeld: None. H.Häring: None. H.Preissl: None.

3-LB: Effects of Sustained Somatostatin Receptor 2 Antagonism (SSTR2a) on Glycemia in Type 2 Diabetic (T2D) Male Rats—A Pilot Study

Introduction: Somatostatin may be elevated in diabetes, which can reduce glucagon secretion at mealtimes and during hypoglycemia. In this pilot study, we investigated the effect of a sustained low-dose delivery of a novel SSTR2a (ZT-01), using a mini-osmotic pump, on oral glucose tolerance (OGT) and response to an insulin-induced hypoglycemia challenge in a T2D rat model. Methods: Male Sprague Dawley rats (n=4/5 per group) were placed on a high-fat diet (3 weeks) then injected with low-dose streptozotocin (35 mg/kg), inducing T2D. Basal bolus insulin was administered for 7 days (2-3 units/day) to maintain fed-state glycemia targeting 12-25 mmol/L, after which the rats were treated with ZT-01 (0.18 mg/day) or vehicle using implanted mini-osmotic pumps (Alzet). An OGT test on day 3 was followed by a hypoglycemic challenge (12U regular insulin) on day 5. Results: Drug and vehicle groups displayed similar glycemic levels in the fasted state and post oral glucose ingestion. Glycemia was also similar prior to insulin challenge and there was no difference in basal glucagon between groups, but SSTR2a treatment attenuated the drop in blood glucose after bolus insulin. Conclusion: Sustained exposure to low-dose SSTR2a does not appear to affect basal glucose or glucagon levels, nor affect the response to OGT but may improve the glucose response to insulin-induced hypoglycemia in this T2D model. Disclosure N. Aleali: None. N. C. D'souza: None. D. Shakeri: None. E. Simonson: None. R. Liggins: Employee; Zucara Therapeutics, Stock/Shareholder; Zucara Therapeutics. O. Chan: None. M. C. Riddell: Advisory Panel; Zealand Pharma A/S, Zucara Therapeutics, Indigo Diabetes, Consultant; Lilly Diabetes, Eli Lilly and Company, Jaeb Center for Health Research, Speaker's Bureau; Dexcom, Inc., Novo Nordisk, Sanofi, Stock/Shareholder; Supersapiens, Zucara Therapeutics. Funding GlycoNet (CD-85); Zucara Therapeutics Inc.

The effect of forced oral glucose intake on alcohol craving and fMRI cue-reactivity in alcohol-dependence – role of appetite-regulating hormones

The effect of forced oral glucose intake on alcohol craving and fMRI cue-reactivity in alcohol-dependence – role of appetite-regulating hormones