Intravenous Glucose Infusion Research Articles

224-LB: A Study to Evaluate the Glucagon and Incretin Responses and Identify the Role of Extrapancreatic Glucagon in Patients with Fibrocalcific Pancreatic Diabetes

Aim: The aim of this study is to evaluate glucagon and incretin responses in patients with FCPD. Methods: Nine FCPD patients and six age- and body mass index-matched healthy controls were subjected to 75 g oral glucose tolerance test (OGTT) followed by isoglycemic intravenous glucose infusion (IIGI). Blood samples were analyzed for incretins and glucagon at nine pre-specified time-points over 3 h and the area under curve was calculated. Results: Glucagon was significantly higher during OGTT compared to IIGI in FCPD patients (98.8 ± 13 pg/ml vs. 63.4 ± 7 pg/ml, P = 0.03) and was also higher when compared to controls (98.8 ± 13 pg/ ml vs. 65.8 ± 18 pg/ml, P = ns). FCPD patients showed very low basal and stimulated c-peptide (0.43 ± 0.14 ng/ml and 1.09 ± 0.3 ng/ ml, respectively) and pancreatic polypeptide (12.3 ± 0.0pg/ml and 12.0 ± 0.6 pg/ml, respectively) levels. Glucagon-like peptide-1 (GLP-1) was significantly higher in cases on OGTT when compared to controls (44.5 ± 9.2 pM vs. 12.8 ± 7.5 pM, P = 0.02). Oxyntomodulin was also insignificantly higher in cases on OGTT when compared to controls (1252 ± 350 pg/ml vs. 859.8 ± 165 pg/ml, P = 0.43). GIP was lower in cases on IIGI when compared to controls (52.9 ± 23.9 pg/ml vs. 144.5 ± 36.1 pg/ml, P = 0.045) and there was blunted response on OGTT as well (106.8 ± 40.3 pg/ml vs. 557.8 ± 96.4 pg/ml, P = 0.003). Discussion: We found hyperglucagonemia in FCPD on OGTT, which was suppressed on IIGI. Increase in L-cell products: GLP-1 and oxyntomodulin and a good correlation between glucagon and GLP-1 during OGTT were suggestive of extrapancreatic glucagon production probably from L-cell. The blunted GIP could probably be due to: inadequate pancreatic enzyme supplements, a selective PC-2 enzyme up-regulation or a negative feedback regulation from extrapancreatic glucagon. Conclusion: Extrapancreatic glucagon does exist in FCPD and may contribute to postprandial hyperglycemia and lower GIP levels. Disclosure A. Shankar: None.

591-P: Glucose Dynamics during OGTT Identify Metabolic Subphenotypes in Individuals with Glucose Dysregulation

Type 2 diabetes (T2D) is a heterogeneous disorder, with a complex physiologic basis. Muscle insulin resistance, beta-cell dysfunction, and impaired incretin effect may be present to differing degrees. Identifying the underlying physiology of glucose dysregulation in a given individual would allow for tailored treatment. We hypothesized that glucose dynamics (i.e., glucotypes) during a frequently-sampled 3-hour OGTT could identify the underlying pathophysiology of glucose dysregulation. If true, glucotypes from OGTT and/or continuous glucose monitoring devices may extend current diagnostic approaches for T2D by defining the dominant metabolic subphenotype. A total of 33 participants underwent gold-standard metabolic tests including: OGTT with blood sampled every 5-10 min for 180 min with c-peptide deconvolution, isoglycemic intravenous glucose infusion (IIGI), and modified insulin suppression test (IST), to quantify beta-cell function, incretin effect, and insulin resistance. Glucotypes were constructed from a time series with glucose values from the OGTT. Missing timepoints were imputed using cubic smoothing splines. Each series was Z-normalized to focus on the shape of the curve rather than the amplitude. Singular value decomposition was performed and the first two principal components were used in cluster analysis, and related to gold-standard metabolic tests. Cluster analysis of glucose dynamics variables revealed 2 separable clusters identifying individuals classified as insulin resistant or sensitive based on IST. Beta-cell dysfunction was also distinguishable by cluster analysis. Although impaired incretin effect status was identified using the deconvolution of the c-peptide from the OGTT and IISI, it was not clearly separable through glucotypes. Glucotypes may be used to identify metabolic subphenotypes in glucose-dysregulated states, with the potential to personalize treatment approaches that address the dominant physiologic defect. Disclosure A. A. Metwally: None. D. Perelman: None. H. Park: None. A. Celli: None. T. Mclaughlin: Board Member; Self; January, Inc. M. Snyder: Research Support; Self; Fitbit, Inc., Stock/Shareholder; Self; January, Inc., Qbio. Funding National Institutes of Health (5R01DK110186-02); Precision Health and Integrated Diagnostics Center at Stanford

Meal Timing-Based Dietary Patterns Are Associated With Glucose Regulation, Insulin Resistance, and Incretin Effect in Individuals at Risk for Type 2 Diabetes

Abstract Objectives Food is an external cue to entrain the circadian rhythm, and when and how to eat may be a crucial factor for glucose homeostasis. This study sought to quantify the impact of meal timing-based dietary habits on glucose homeostasis in prediabetic and normal individuals by using digital monitoring technologies. Methods 35 study participants (56.6 y; prediabetes n = 19 and normoglycemia n = 16) tracked their food intake and timing by a food-logging mobile app for at least two weeks. Gold-standard glucose metabolic tests were performed such as OGTT, insulin suppression test, and isoglycemic intravenous glucose infusion to quantify insulin resistance, beta-cell function, and incretin effects. The energy contribution of six meal timings to the total daily energy intake was determined. Principal component analysis (PCA) was used to group participants in the cohort based on their meal timing patterns. Multivariate linear regression (MLR) models confirmed differences in each meal timing feature by glycemic control groups. Results A total of 2307 meals and 625 days of food logs were collected from study participants. From the PCA plot based on meal timing features, the cohort was clearly separated into two clusters by their HbA1c levels: normoglycemia (HbA1c < 5.7%) vs. prediabetes (5.7%< HbA1c < 6.5%). MLR models further showed that people with prediabetes had lower Meal_4 (2pm-5pm) energy contribution (P = 0.00,697) and higher Meal_5 (5pm-9pm) energy contribution (P = 0.0462) than normal group even after adjustment for age, sex, ethnicity, and BMI. Similarly, insulin resistant and sensitive groups were separated based on meal timing features, as did incretin function. However, beta-cell function groups were not distinguished by meal timing features. Conclusions The data suggest that meal timing-based dietary patterns can be used to predict different types of glucose metabolic dysregulation such as prolonged high blood glucose, insulin resistance, and incretin dysfunction. Funding Sources NIH 2T32HL09804911, NIH 5R01DK110186-02, Stanford PHIND Award.

A Rare Cause of Severe Hypoglycaemia

A 67-year old woman presented with an unwitnessed fall and decreased oral intake. She had a learning disability, hypertension, epilepsy, asthma, chronic iron deficiency anaemia, mild lymphopenia, osteoporosis and treated uterine cancer. After clinical review, she was treated for Hospital-acquired pneumonia (following a recent hospital admission) with possible aspiration. She was noted to have hyponatraemia secondary to dehydration. She was commenced on intravenous Levofloxacin and Metronidazole along with supportive care, based on antibiotic guidance due to her known allergy to penicillin.On day 3 of admission, she was found unresponsive with a capillary blood glucose of 0.6 mmol/L, which improved with 10% glucose infusion. The low blood glucose was attributed to poor oral intake. However, her serial blood sugar results demonstrated persistent hypoglycaemia for 72h needing further intravenous glucose infusions. A medication review was undertaken and Levofloxacin was discontinued. After 24hrs of discontinuation, the hypoglycaemic episode resolved. A short synacthen test showed a normal cortisol response. There were no further episodes of hypoglycaemia. Conclusion As her persistent hypoglycaemia resolved on discontinuation of Levofloxacin, a diagnosis of fluoroquinolone induced hypoglycaemia was reported to MHRA. Fluoroquinolones are thought to induce hypoglycaemia by increasing the insulin release via blockade of adenosine triphosphate-sensitive K+channels in the β cells of the pancreas. This effect may not be clinically evident in all patients because of physiologic mechanisms that regulate blood glucose levels. Health professionals should be aware of the potential risk of severe hypoglycaemia with the use of Fluoroquinolones which are a first or second-line treatment for common infective processes. Fluoroquinolones should be stopped immediately and switch to a non-Fluoroquinolones antibiotic if possible. In elderly patients with compromised oral intake or in those with other comorbidities, regular blood glucose monitoring should be carried out to avoid life-threatening hypoglycaemic episodes.

Successful Use of Intragastric Dextrose in a Unique Presentation of Congenital Hyperinsulinism

Introduction: Congenital hyperinsulinism (HI) is the most common cause of persistent hypoglycemia in infants and can pose challenges if unresponsive to diazoxide. HI can be caused by monogenic mutations or can be associated with genetic syndromes. Macrocephaly Capillary malformation (MCAP) is a rare overgrowth syndrome, caused by heterozygous variants in the PIK3CA gene. A small number of pathologic variants in this gene have been reported to cause HI. Clinical Case: A 4-month-old boy presented with a hypoglycemic seizure while fasting for an MRI. His history was notable for being born LGA and having macrocephaly, segmental infantile hemangioma, and ventriculomegaly requiring VP shunt. Critical labs were consistent with HI: plasma glucose (PG) of 23 mg/dL (54-117), inappropriately detectable insulin (2.7 mIU/mL) and c-peptide (1.6 ng/mL), low beta hydroxybutyrate (0.1 mmol/L) and low free fatty acids (0.16 mmol/L), and a positive glucagon stimulation test (increase in PG from 48 to 101 mg/dL in 30 minutes). Diazoxide was started at 5 mg/kg/day and titrated to 15 mg/kg/day, but he was unable to maintain PG >70 mg/dL. He was deemed unresponsive and the diazoxide was discontinued. His intravenous glucose infusion rate (GIR) was 14.4 mg/kg/min. An octreotide trial (8 mcg/kg/day) revealed a robust response: PG 64 mg/dL before initial dose, 105 mg/dL 3 hours later. However, he developed tachyphylaxis to the octreotide and it was discontinued. To further evaluate the etiology of his HI, he underwent an 18F-DOPA PET scan, which showed diffuse uptake. Genetic sequencing for the 9 known HI genes was negative. At 6-months-old, he was evaluated by genetics who based on his clinical features diagnosed him with MCAP.After failure of diazoxide and octreotide therapies, he was slowly transitioned from IV dextrose to continuous intragastric dextrose (IGD) using D20W. He was managed with a GIR of 10 mg/kg/min during the day (while receiving bolus feeds) and 5 mg/kg/min while on continuous feeds overnight. The continuous IGD allowed him to maintain euglycemia and develop his oral feeding skills. By 17-months-old, feeds by mouth improved and GIR had decreased to 6.5 mg/kg/min during the day and 2.5 mg/kg/min overnight. Genetic analysis eventually revealed a heterozygous p.Glu365Lys (c.1093 G>A) variant in the PIK3CA gene as the likely cause of the HI. Conclusion: Genetic syndromes should be considered in infants with persistent hyperinsulinism and multiple congenital anomalies. Clinical work-up may provide important clues to the diagnosis. Diazoxide unresponsive HI can be treated with continuous IGD to prevent hypoglycemia-induced brain damage. Continuous IGD likely leads to better oral skills and decreased oral aversion compared to using continuous formula feeds.

Intravenous infusion of glucose improved farrowing performance of hyperprolific crossbred sows.

The sow at parturition is challenged with respect to energy status due to increases in energetic expenses associated with 1) nest building 2) uterine contractions, and 3) colostrum production. A previous study indicated that sows were depleted of glucogenic energy around farrowing. The aim was to investigate whether intravenous infusion of glucose from observed nest-building behavior to 24 h postpartum affected the farrowing kinetics and colostrum production in sows. Ten multiparous sows (DanBred landrace × DanBred Yorkshire) were fitted with a jugular vein catheter on each side (one for infusion and the other one for blood sampling). Sows were infused with either 0.9% saline (CON; n = 5) or 10% glucose (GLU; n = 5) solution at a constant rate of 125 mL/h. From day 108 of gestation, sows were fed once daily with 3.33 kg of a standard lactation diet. During farrowing, sows were monitored to register the onset of farrowing, time of birth, birth status (live or dead), sex, stillbirth rate (SR), and weight of newborn piglets. Farrowing assistance (FA) was provided when the birth interval exceeded 60 min. In late gestation, 1 mL of blood was collected every third hour for blood gas analysis and every sixth hour for harvesting plasma. During farrowing, 1 mL (for blood gas) and 9 mL of blood were collected at 0, 3, 6, 9, 12, 15, 18, 21, and 24 h in milk (HIM). Colostrum and milk samples were collected at 0, 6, 12, 18, 24, and 36 HIM and also at 3, 10, 17, and 24 d in milk. Compared with CON sows, GLU infusion decreased the SR (16.1% vs. 7.4%; P = 0.03), FA (21% vs. 9.0%; P = 0.01), and surprisingly also blood glucose at the onset of farrowing (5.53 vs. 5.09 mmol/L; P = 0.03), respectively. A tendency to higher plasma lactate at the onset of farrowing (P = 0.05) but decreased piglet mortality from 0 to 24 h (P = 0.06) was also found for GLU sows. No effects of treatment on farrowing duration or mean birth intervals were found. Lactate in whole blood (P = 0.003) and plasma (P = 0.002) was increased for GLU sows as compared with CON sows during the colostrum period. No effect of GLU infusion was seen on colostrum and milk composition and yield. The increase in lactate was most likely due to a shift toward a greater proportion of glucose oxidation and insufficient O2 supply to fuel uterine contractions. In conclusion, infusion of glucose reduced the frequency of SR and FA, and improved energy status of the sow which seems to be crucial to enhance total piglet survival.

DRINKING AND HEDONIC BEHAVIOR OF ALCOHOLIZED RATS

Relevance. To relieve alcohol withdrawal syndrome, intravenous infusion of glucose and antidotes to neutralize ketone bodies is used. But after treatment, the craving for alcohol remains, and relapses of alcohol consumption are observed in 60-90% of patients. It remains unclear if there is a connection between hypoglycemia, ketosis, on the one hand, and the craving for alcohol consumption, on the other hand.
 Objective: to find out the effect of glycemic level normalization and prolonged maintenance of normal blood glucose concentration on ethanol consumption in alcoholized rats. At the same time, we have chosen two alternative ways to eliminate hypoglycemia: 1) by providing animals with unlimited access to a water trough filled with glucose solution; 2) by forced feeding of animals with a high-carbohydrate diet.
 Materials and methods. 70 rats were housed in the individual cages. First, two water troughs were placed in each cage for one week: the first one was filled with pure water and another one contained 5% glucose solution. Second, forced alcoholization of rats was performed by leaving one trough filled with 10% ethanol solution in each cage. Duration of alcoholization was different: 3 weeks for the 1st group of rats (n=20), 6 weeks for the 2nd group of animals (n=20), and 16 weeks for the 3rd group of rats (n=20). Animals of the control group (n=10) received pure water. Third, after forced alcoholization, animals of the experimental groups had free access to three different troughs for three weeks: the first trough was filled with pure water, the second one – with 5% glucose solution, and the third one contained 10% ethanol solution. Rats of the control group were able to choose between water and 5% glucose solution. At the third stage, animals of the experimental groups were divided into two subgroups with 10 rats in each one. Animals of one of the subgroups from each experimental group were kept on a high-carbohydrate diet: they were administered 1 ml of 40% starch kissel (2.0 g/kg, in terms of glucose) per os 3 times a day. The volumes of all consumed fluids were recorded daily throughout the experiment. The results were processed using the MedStat program. 
 Results. Healthy rats drank 2.5±0.6 ml of water and 1.6±0.6 ml of glucose solution per 100 g of body weight daily. In the first 7 days of forced alcoholization, the animals drank 3.1±0.7 ml of ethanol solution per 100 g of body weight. By the end of the third week, consumption of ethanol solution increased up to 4.9±0.8 ml per 100 g of body weight (p<0.001), which indicated development of adaptation. By the end of the sixth week, there was a prominent elevation of ethanol consumption up to 6.4±0.9 ml per 100 g of body weight, and the total volume of consumed alcohol solutions was 1.3 times higher than that of the third week (p<0.001). At the sixth week of observation, alcohol intake reached its climax, since further alcoholization up to 16 weeks did not lead to any changes in drinking behavior (p=0.712). We consider that the minimal duration of forced alcoholization is 6 weeks. During the process of alcoholization, the total daily consumption of fluids by animals was increasing, compared to healthy rats, and, by the end of the 16th week, it exceeded the indicator of healthy rats by 1.8 times. In alcoholized rats, glucose loses its hedonic properties. By the end of the 16th week of alcoholization, under the condition of free choice of drinks, glucose consumption was 8 times lower than that of in healthy animals. Rats consumed less ethanol if they were receiving an additional high-carbohydrate diet. The duration of metabolic correction with a starch solution is important: the longer it is, the less alcohol craving will be. 
 Conclusions. Alcohol-dependent rats reject the glucose solution offered as a drink. But prolonged and forced administration of glucose leads to a decrease in alcohol consumption.

Nutrient infusion in the dorsal vagal complex controls hepatic lipid and glucose metabolism in rats

SummaryHypothalamic regulation of lipid and glucose homeostasis is emerging, but whether the dorsal vagal complex (DVC) senses nutrients and regulates hepatic nutrient metabolism remains unclear. Here, we found in rats DVC oleic acid infusion suppressed hepatic secretion of triglyceride-rich very-low-density lipoprotein (VLDL-TG), which was disrupted by inhibiting DVC long-chain fatty acyl-CoA synthetase that in parallel disturbed lipid homeostasis during intravenous lipid infusion. DVC glucose infusion elevated local glucose levels similarly as intravenous glucose infusion and suppressed hepatic glucose production. This was independent of lactate metabolism as inhibiting lactate dehydrogenase failed to disrupt glucose sensing and neither could DVC lactate infusion recapitulate glucose effect. DVC oleic acid and glucose infusion failed to lower VLDL-TG secretion and glucose production in high-fat fed rats, while inhibiting DVC farnesoid X receptor enhanced oleic acid but not glucose sensing. Thus, an impairment of DVC nutrient sensing may lead to the disruption of lipid and glucose homeostasis in metabolic syndrome.

P0235 / #981: EXTRACORPOREAL MEMBRANE OXYGENATION AS A TREATMENT FOR REFRACTORY LACTIC ACIDOSIS DUE TO GLYCOGEN STORAGE DISEASE TYPE 1A: A CASE REPORT

Aims & Objectives: Glycogen storage disease (GSD) type Ia (Von Gierke’s Disease) is an infrequent metabolic disease characterized by the deficient activity of glucose-6-phosphate-a. This deficiency causes the accumulation of glycogen in the body leading to hypoglycemia, lactic acidosis, failure to thrive, hepatomegaly, hepatic adenomas, renal failure and inflammatory bowel disease. The aim of this study is to describe a case of GSD type Ia and to evaluate the utility of Extracorporeal Membrane Oxygenation (ECMO) to treat this condition. Methods: We present a 7-year-old male patient with a history of GSD type 1a. The patient arrived at the hospital due to diarrhea and emesis. Patient is treated with intravenous fluids and glucose infusion, however, clinical stabilization is not met after 24-hours. Patient develops hemodynamic instability secondary to lactic and metabolic acidosis and is transferred to the pediatric intensive care unit (PICU). At the fifth day of admission at the PICU hemodynamic and respiratory status worsens. Results: Mechanical ventilation and vasopressor therapy are initiated. Patient is placed into hemodialysis (PRISMA FLEX®) to treat refractory lactic acidosis, fluid overload, and acute kidney injury. 48-hours later the PICU team emergently cannulated for veno-arterial (VA) ECMO support. During the following days patient’s hemodynamic and metabolic status improves. Patient ECMO support was stopped 7 days after initiation. PRISMAFLEX® management continued for 9 days until renal function normalized. Patient was discharged 58 days after hospital admission with no neurological complications. Conclusions: This case emphasizes the efficacy of ECMO as a therapy to stabilize pediatric patients with metabolic diseases such as GSD Type 1a

Effects of energy source in milk replacer on glucose metabolism of neonatal dairy calves

Milk replacers (MR) formulated to contain more lactose than whole milk could potentially reduce insulin sensitivity in dairy calves. This study evaluated how partially replacing lactose in MR with fat on a weight/weight basis affects glucose-insulin kinetics in neonatal dairy calves fed high quantities of MR. Thirty-four Holstein bull calves were blocked by dam parity (1.6 ± 0.3) and randomly assigned to 1 of 2 treatments (n = 17): a high-lactose MR (HL; 46.1% lactose, 18.0% crude fat, and 23.9% crude protein on a dry matter basis) or a high fat MR (HF; 39.9% lactose, 24.6% crude fat, and 24.0% crude protein on a dry matter basis). Calves were individually housed and fed pooled colostrum at 1.5 h and 12 h postnatal at 18 and 9% of metabolic body weight (BW0.75), respectively. From 24 h postnatal until the end of the study (d 7), calves were transitioned to MR (prepared at 150 g/L) at 18% of BW0.75 twice daily at 0700 and 1900 h. On d 4, an insulin-modified intravenous glucose tolerance test was conducted 8 h after the morning meal by intravenous infusion of glucose (0.54 g/kg of BW0.75, min 0) and insulin (3.9 µg/kg of BW0.75, min 20). During postprandial sampling on d 6, abomasal emptying was assessed by dosing acetaminophen (0.13 g/kg of BW0.75) with MR and measuring its appearance within plasma. Sequential blood samples were collected and analyzed for plasma glucose, insulin, and acetaminophen concentrations. Calves were killed on d 7 and liver and pancreatic tissues were collected for histomorphological analysis. Partially replacing lactose in MR with fat increased body weight gain (679.6 vs. 462.0 ± 69.68 g/d) and gain:metabolizable energy intake (186.6 vs. 120.5 ± 20.21 g of body weight/Mcal) compared with feeding HL MR. Furthermore, abomasal emptying rate was reduced in calves fed HF MR. Calculated variables based on postprandial glucose and insulin concentrations, such as maximum concentration or area under the curve, were or tended to be lower in HF than in HL calves. Postprandial insulin sensitivity tended to be reduced in HL compared with HF, although insulin sensitivity estimated from the insulin-modified intravenous glucose tolerance test was not different. Calves fed HF MR showed enhanced glucose-stimulated insulin secretion. In conclusion, partially replacing lactose in MR with fat resulted in smaller fluctuations in postprandial glucose and insulin concentrations and tended to increase postprandial but not fasting insulin sensitivity in neonatal dairy calves.

Increasing preweaning milk replacer supply affects postweaning energy metabolism of Holstein male calves

Male Holstein calves commonly receive minimal quantities of milk replacer (MR) to speed up weaning and reduce costs. Studies with Holstein female calves show that early life feed restriction affects energy metabolism later in life. Aiming to test this hypothesis, 120 Holstein bull calves (48.4 ± 2.2 kg of BW and 20 ± 3.2 d of age) housed in 24 pens were blocked and randomized to two treatments: A low calf MR allowance (LP) (two daily doses of 2 l each, 582 g/d of DM), or a high MR allowance (HP) (two daily meals of 4 l each, 1164 g/d of DM). Calves were weaned at day 49 of the study and slaughtered at 32.8 ± 0.5 weeks of age. Throughout the study, animals had ad libitum access to a common compound feed, straw, and water. Twenty-four animals were randomly selected for an intravenous glucose tolerance test (IVGTT). The IVGTT was performed at week 6 and 12 of the study and consisted of an intravenous glucose infusion and sequential blood sampling up to 90 min after glucose infusions. Calves were heavier for HP until week 12, after which the difference disappeared. By design, the MR intake was higher in the HP group resulting in a higher energy intake and a higher average daily gain in the preweaning phase. Blood glucose curves were not different at week 6, but at week 12, 5 min after the infusion, glucose was higher in HP calves. Insulin curves were not different at week 6. Nevertheless, in week 12, a higher insulin concentration was observed for HP 5, 10, 15, 20, 30, 35, and 45 min’ postinfusion, indicating a higher requirement of insulin to control glycemia. Differences between HP and LP calves were also observed for the quantitative insulin sensitivity check index, maximum insulin concentration, and insulin delta at week 12. Blood glucose reached maximum concentration within 5–10 min of the IVGTT test, and the concentration was, on average, 8.58 and 10.80 mmol/l at weeks 6 and 12, respectively. Insulin reached maximum concentration within 10–15 min of the IVGTT, and concentrations were, on average, 33.32 and 32.61 μUI/ml at weeks 6 and 12, respectively. Doubling MR supply improved animal growth up to weaning, but these differences disappeared by the end of the feeding period. Despite similar responses to glucose infusions preweaning, higher milk supply seemed to decrease insulin sensitivity after weaning.

Lanreotide and diazoxide have comparable effects on glucose levels in an elderly Japanese insulinoma patient: a case report.

An insulinoma is a pancreatic neuroendocrine tumor that causes hypoglycemia. In the elderly, as surgery is not always possible, drugs are an important alternative. However, the effects of lanreotide on insulinomas have not yet been elucidated. We report the case of an 85-year-old Japanese woman who was admitted for loss of consciousness and hypoglycemia, which was resolved after intravenous glucose infusion. Insulin secretion was not inhibited during hypoglycemia. Enhanced computed tomography and OctreoScan scintigraphy revealed a pancreatic tumor (diameter, 13 mm) with radiotracer accumulation. Thus, clinical insulinoma was confirmed. However, the patient refused further examination and surgery. Diazoxide (150 mg/day) therapy resolved hypoglycemia but caused fluid retention. Consequently, we switched to lanreotide (120 mg/6 weeks). Continuous glucose monitoring revealed that both drugs had comparable effects on interstitial glucose normalization. Furthermore, 447 days after the initiation of lanreotide treatment, the patient had no hypoglycemic symptoms. Therefore, lanreotide may be a useful alternative treatment option for inoperable insulinomas in elderly individuals.

Ultrasound-guided Robotic Enucleation of Functioning Insulinoma

Purpose: Insulinoma is the most common functional pancreatic neuroendocrine tumor . Since the high prevalence of benign form, pancreatic parenchymal sparing surgery is suggested for well differentiated single lesion <2cm located at >3mm from the main duct. We present the case of a 57-year old caucasian man who presented with severe hypoglycemia episodes needing intravenous continuous infusion of glucose, despite medical treatment. Materials and Methods: CT scan, and RM were unable to detect the lesion, while a subsequent echoendoscopy showed an hypoechoic 1.5 cm lesion located at the head of the pancreas, far from the main duct but in contact with the duodenum and the anterior pancreaticoduodenal artery. Endoscopic biopsy showed a well differentiated insulinoma.During multidisciplinary discussion surgical therapy was indicated and consent for enucleation or pancreatoduodenectomy was shared.Robotic approach was considered feasible: after exposure of the anterior surface of the pancreas, ultrasound examination confirmed the location of the lesion. Nodule mobilization from the duodenum was achieved by bipolar section of few duodenal vessels, while dissection from the gastroduodenal and the anterior pancreatic artery was performed by sharp dissection with shears and by bipolar diathermy. Specimen was extracted with a small endobag and frozen section confirmed the nature of the lesion. After enucleation, glucose infusion was stopped and normal glicemia remained stable without any glucose support. Results: Postoperative course was uneventful and the patient was discharged at 4th postoperative days with normal insulin and glucose values. Conclusions: Enucleation is a well established indication for single insulinoma but the feasibility of the resection relies on dimension, site and the need of precise intraoperative image location and careful dissection. In our case robotic enucleation under ultrasound guidance was a safe and feasible technique avoiding a standard pancreatoduodenectomy procedure.

Acute hepatic porphyrias for the neurologist: current concepts and perspectives.

Acute hepatic porphyrias represent an expanding group of complex inherited metabolic disorders due to inborn errors of metabolism involving heme biosynthesis. We aimed to review the main clinical and therapeutic aspects associated with acute hepatic porphyrias. The authors provided a wide non-systematic review of current concepts and recently acquired knowledge about acute hepatic porphyrias. Acute neurovisceral attacks are the most common and life-threatening presentation of this group and are often considered the main clinical manifestation by clinicians during differential diagnosis and the start of proper diagnostic work-up for acute porphyrias. However, atypical presentations with central nervous system involvement, neuropsychiatric disturbances, and some subtypes with photosensitivity usually make the definite diagnosis difficult and late. Early therapeutic interventions are essential during emergency treatment and intercritical periods to avoid recurrent severe presentations. The availability of new disease-modifying therapeutic proposals based on small interfering RNA (siRNA)-based therapies, complementary to the classic intravenous glucose infusion and hemin-based treatments, emphasizes the importance of early diagnosis and genetic counseling of patients. This review article highlights the main biochemical, pathophysiological, clinical, and therapeutic aspects of acute hepatic porphyrias in clinical practice.

No detectable effect of a type 2 diabetes-associated TCF7L2 genotype on the incretin effect.

The T allele of TCF7L2 rs7903146 is a common genetic variant associated with type 2 diabetes (T2D), possibly by modulation of incretin action. In this study, we evaluated the effect of the TCF7L2 rs7903146 T allele on the incretin effect and other glucometabolic parameters in normal glucose tolerant individuals (NGT) and participants with T2D. The rs7903146 variant was genotyped in cohorts of 61 NGT individuals (23 were heterozygous (CT) or homozygous (TT) T allele carriers) and 43 participants with T2D (20 with CT/TT). Participants were previously examined by an oral glucose tolerance test (OGTT) and a subsequent isoglycemic intravenous glucose infusion (IIGI). The incretin effect was assessed by quantification of the difference in integrated beta cell secretory responses during the OGTT and IIGI. Glucose and hormonal levels were measured during experimental days, and from these, indices of beta cell function and insulin sensitivity were calculated. No genotype-specific differences in the incretin effect were observed in the NGT group (P = 0.70) or the T2D group (P = 0.68). NGT T allele carriers displayed diminished glucose-dependent insulinotropic polypeptide response during OGTT (P = 0.01) while T allele carriers with T2D were characterized by lower C-peptide AUC after OGTT (P = 0.04) and elevated glucose AUC after OGTT (P = 0.04). In conclusion, our findings do not exclude that this specific TCF7L2 variant increases the risk of developing T2D via diminished incretin effect, but genotype-related defects were not detectable in these cohorts.

Difficulties in Correction of Recurrent Hypoglycemia in a Patient With a Progressive Course of Malignant Metastatic Insulinoma

This article describes a clinical observation of a patient with a progressive course of malignant metastatic insulinoma, despite repeated embolization and chemoembolization (CE) of the right and left hepatic arteries with doxorubicin and gemcitabine, with metastatic liver lesion and subsequent increase in the size of secondary foci. The key clinical problem was severe recurrent hypoglycemia, which persisted against the background of massive intravenous (IV) glucose infusions, short-acting somatostatin therapy, and subcutaneous (SC) glucagon injections, which not only was an impediment to the pathogenic cytostatic therapy but also has led to the fatal outcome of the patient. J Endocrinol Metab. 2020;10(5):140-143 doi: https://doi.org/10.14740/jem666

Avoiding the incompatibility of peripheral parenteral nutrition solution and midazolam injection for intravenous sedation.

We have observed white turbidity when a midazolam injection is administered from a lateral tube during the administration of a peripheral parenteral nutrition (PPN) solution. The aim of the current study was to determine how to avoid compound changes when co-administering a midazolam injection and a PPN solution. Midazolam solutions were prepared by diluting a midazolam injection with a 5% glucose intravenous infusion. We examined the formulation of the midazolam injection and a PPN solution at the concentrations used in a clinical setting for changes in appearance, pH, and midazolam content in test tubes and during administration conditions. With a 1/4.8 dilution of midazolam in undiluted solution, clouding occurred. A strong correlation was revealed between the midazolam content as measured through high-performance liquid chromatography and the mixture's midazolam concentration (R2=0.9918). The capture rate of midazolam infused with PPN solution was 91.0% at a 1/6 dilution, whereas it decreased to <90% at a 1/4.8 dilution. Our results suggest that the administration of a midazolam injection solution diluted by ≥6-fold with glucose solution or saline from a side tube during the administration of a PPN solution did not cause changes in composition.

Circulating Levels of the Soluble Receptor for AGE (sRAGE) during Escalating Oral Glucose Dosages and Corresponding Isoglycaemic i.v. Glucose Infusions in Individuals with and without Type 2 Diabetes.

Postprandial glucose excursions are postulated to increase the risk for diabetes complications via the production of advanced glycation end products (AGEs). The soluble receptor of AGEs (sRAGE) likely acts as a decoy receptor, mopping up AGEs, diminishing their capacity for pro-inflammatory and pro-apoptotic signaling. Recent evidence suggests that AGEs and soluble receptor for AGEs (sRAGE) may be altered under postprandial and fasting conditions. Here, we investigated the effects of increasing oral glucose loads during oral glucose tolerance tests (OGTT) and matched isoglycaemic intravenous (i.v.) glucose infusions (IIGI) on circulating concentrations of sRAGE. Samples from eight individuals with type 2 diabetes and eight age-, gender-, and body mass index (BMI)-matched controls, all of whom underwent three differently dosed OGTTs (25 g, 75 g, and 125 g), and three matched IIGIs were utilised (NCT00529048). Serum concentrations of sRAGE were measured over 240 min during each test. For individuals with diabetes, sRAGE area under the curve (AUC0–240 min) declined with increasing i.v. glucose dosages (p < 0.0001 for trend) and was lower during IIGI compared to OGTT at the 125 g dosage (p = 0.004). In control subjects, sRAGE AUC0–240 min was only lower during IIGI compared to OGTT at the 25 g dose (p = 0.0015). sRAGE AUC0–240 min was negatively correlated to AUC0–240 min for the incretin hormone glucagon-like peptide −1 (GLP-1) during the 75 g OGTT and matched IIGI, but only in individuals with type 2 diabetes. These data suggest that gastrointestinal factors may play a role in regulating sRAGE concentrations during postprandial glucose excursions, thus warranting further investigation.

Abstract 5999: The Warburg Effect suggests a palliative care approach to cancer therapy

Abstract Introduction: Otto Warburg discovered in 1924 that cancer cells needed a lot more glucose than normal cells. Today, the “Warburg Effect” is not only recognized as a “hallmark of cancer” but also served as the scientific basis for cancer detection using fluorodeoxyglucose (FDG) Positron emission tomography (PET-scans). Warburg suggested in 1927 that treating cancer patients with insulin can deprive glucose to the cancer cells by lowering the blood glucose levels and may inhibit tumor growth. Although at least six peer-reviewed publications so far have provided support for the feasibility of this approach, no clinical trial has ever been done. We have previously presented an analysis of the data from hospitals in China suggesting that insulin can be safely administered for patients receiving a small dosage of standard chemotherapy drugs as palliative treatments for late-stage cancer patients. Here, we report additional data from more patients and medical facilities. Experimental procedures: Patients diagnosed with multiple types of late-stage solid tumors were treated with regular insulin (Humulin R) administered intravenously, and small doses of standard chemotherapy drugs (approximately 10% of the standard dosages). Blood glucose levels were monitored throughout the course of treatment. Hypoglycemia was reversed by ingestion of food and drink or injection of glucose solution. Depending on how well the patients tolerated the treatments, 5-30 units of insulin were used. No permanent side effects were observed or reported. Summary of data: Over 400 treatments have been performed on over 30 patients ranging from 30 to 76 years old, and diagnosed with 14 types of cancer. The average age of the patients was 56.2 years old. Symptoms of hypoglycemia were observed in all 30+ patients, and readily reversed by intravenous infusions of glucose or ingestion of food and drink. The insulin treatments were well tolerated and no longer -term side effects were observed. Conclusions: Our analysis supports the feasibility of using regular insulin as a reproducibly safe method to achieve glucose deprivation in patients with advanced stages of multiple types of cancer receiving palliative and hospice care. These and additional future studies could form the basis for eventually conducting a clinical trial testing whether regular insulin, which is inexpensive and available over the counter, can be an alternative therapeutic option for palliative and hospice care in some patients. Citation Format: Linda C. Meade-Tollin, Tom C. Tsang. The Warburg Effect suggests a palliative care approach to cancer therapy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5999.

A Reduced Incretin Effect Mediated by the rs7903146 Variant in the TCF7L2 Gene Is an Early Marker of β-Cell Dysfunction in Obese Youth.

The risk genotype for the common variant rs7903146 of the transcription factor 7-like-2 (TCF7L2) gene has been found to affect the incretin response in healthy and obese adults; however, whether a similar functional defect is also present in obese adolescents remains unexplored. Herein, we examined the functional effect of the rs7903146 variant in the TCF7L2 gene on the incretin effect and determined its translational metabolic manifestation by performing deep phenotyping of the incretin system, β-cell function relative to insulin sensitivity, the gastrointestinal-induced glucose disposal (GIGD) in obese youth with normal and impaired glucose tolerance. Thirty-nine obese adolescents without diabetes (median age 15 [25th, 75th percentile 14, 18] years; BMI 37 [33, 43] kg/m2) were genotyped for the rs7903146 variant of TCF7L2 and underwent a 3-h oral glucose tolerance test (OGTT) followed by an isoglycemic intravenous glucose infusion (iso-intravenous glucose tolerance test [IVGTT]) to match the plasma glucose concentrations during the OGTT and a hyperglycemic clamp with arginine stimulation. The incretin effect was measured as 100 * (AUC-SROGTT - AUC-SRiso-IVGTT) / AUC-SROGTT, where AUC-SR = area under the curve of C-peptide secretion rate. Participants were grouped into tertiles according to the percentage incretin effect (high, moderate, and low) to describe their metabolic phenotype. The presence of T risk allele for TCF7L2 was associated with a markedly reduced incretin effect compared with the wild-type genotype (0.3% [-7.2, 14] vs. 37.8% [12.5, 52.4], P < 0.002). When the cohort was stratified by incretin effect, the high, moderate, and low incretin effect groups did not differ with respect to anthropometric features, while the low incretin effect group exhibited higher 1-h glucose (P = 0.015) and a reduced disposition index, insulin sensitivity, and insulin clearance compared with the high incretin effect group. GIGD was reduced in the low incretin effect group (P = 0.001). The three groups did not differ with respect to intravenous glucose-induced insulin secretion and arginine response during the hyperglycemic clamp. A reduced incretin effect and its association with the TCF7L2 variant rs7903146 identify an early metabolic phenotype in obese youth without diabetes, featuring a higher plasma glucose peak at 1 h; lower insulin secretion, sensitivity, and clearance; and GIGD.