Mild Hyperglycemia Research Articles

8197 A Captivating Case Report of Teprotumumab Induced Hyperglycemic Hyperosmolar State

Abstract Disclosure: K.M. Tuna: None. J.P. Perdomo Rodriguez: None. Introduction: Teprotumumab, a monoclonal antibody targeting the IGF-1 receptor, is increasingly utilized for moderate to severe thyroid eye disease. Initial trials noted mild hyperglycemia in patients with diabetes, while recent trials revealed a significant elevation in Hemoglobin A1c (HbA1c) among those with diabetes or pre-diabetes post-infusion. Here, we discuss a case of a patient with diet-controlled diabetes who developed hyperglycemic hyperosmolar state (HHS) two months after Teprotumumab infusion. Case Presentation: A 43-year-old male, with class III obesity, obstructive sleep apnea, dyslipidemia, coronary artery disease, and diet-controlled diabetes (HbA1c 6.5%) presented with worsening proptosis, decreased color vision, severe visual field depression. Laboratory evaluation revealed elevated TSH (6.3 mIU/ml), normal free T4 (0.67 ng/dl, ref: 0.60-1.2 ng/dl), and undetectable Thyroid Stimulating Immunoglobulin (<0.1 IU/L). Blood cell count, renal and liver function tests were normal. Due to high clinical suspicion of thyroid eye disease, he was treated with timolol, dorzolamide, brimonidine, and methylprednisolone 1g daily for 3 days. Glycemic control was achieved with 30 units of daily insulin while on pulse steroids. On outpatient ophthalmology follow-up, Teprotumumab was initiated and he received 2 doses. Eight weeks later, the patient was hospitalized with altered mental status caused by HHS (glucose 617 mg/dl, serum osmolality 316 osm). HbA1c was found to be significantly increased to 12% and the patient required 150 units total daily insulin and metformin upon discharge. Of note, the patient did not have significant weight changes during this time. GAD, IA2, and Zinc Transporter-8 antibodies were obtained prior to discharge and results are pending. Discussion: The IGF-1 receptor, a partial homologue of the insulin receptor, plays a pivotal role in glucose homeostasis. Inhibiting this receptor can lead to hyperglycemia. Initial randomized controlled trials (RCTs) reported a 10% incidence of mild hyperglycemia. A recent RCT from a cohort of 42 patients demonstrated a 50% incidence of hyperglycemia, in which two-thirds of the patients remained in a dysglycemic state with one patient with pre-existing prediabetes developing diabetic ketoacidosis (DKA). Our patient mirrored this scenario with no identifiable confounding factors. Conclusion: Teprotumumab-induced hyperglycemia, though rare, can lead to life-threatening complications. Baseline glycemic assessment, identification of high-risk patients, and comprehensive discussions on risks and benefits are crucial before initiating therapy. Close monitoring, especially in those with prediabetes, is recommended. Patient education plays a pivotal role in early symptom recognition, averting delayed diagnoses, and subsequent hospitalization. Presentation: 6/3/2024

7491 Post operative Euglycemic Diabetic Ketoacidosis in Type 2 Diabetic patient - A diagnostic challenge

Abstract Disclosure: S. Azmat: None. O. Lodhi: None. H. Ashok: None. M.F. Siddiqui: None. Euglycemic Diabetic Ketoacidosis (EDKA) is a rare but potentially fatal condition that is often difficult to diagnose as underlying ketoacidosis is masked by euglycemia. The diagnosis and management of this condition requires a swift and comprehensive approach to avoid delay. We report a case of 66-year-old female with Insulin-dependent Type 2 DM who developed postoperative euglycemic diabetic ketoacidosis, highlighting the significance of maintaining a high degree of suspicion for EDKA in postoperative patients, whose surgical course may obscure the underlying diabetic ketoacidosis symptoms. Clinical Case: A 66-year-old female with past medical history of Insulin dependent Type 2 DM presented to the emergency department with severe epigastric pain. CT Abdomen revealed perforated gastric ulcer with pneumoperitoneum requiring urgent laparoscopic graham patch repair. Patient’s outpatient medications include Lantus and metformin. She had mild hyperglycemia on admission with blood glucose of 176 mg/dL (140-160mg/dL) without metabolic abnormality. Insulin administration was omitted due to pre and post operative normoglycemia. The patient was NPO followed by initiation of nasogastric tube feeds. Postoperative course was complicated by hypotension, generalized abdominal discomfort and anion gap metabolic acidosis. Graham patch failure, abdominal infection, and post-surgical complications were systematically ruled out. Patient continued to decline with worsening anion gap metabolic acidosis; pH of 7.18 (7.35-7.45), HCO3 < 10 mEq/L (21 mEq/L - 31 mEq/L), anion gap15 mmol/L (8 to 12 mmol/L), blood sugar (147-208 mg/dl). There was no lactic acidosis or renal impairment. Beta hydroxybutyrate levels were elevated at > 4.5 mmol/L. Thus diagnosis of euglycemic DKA was established and treated with insulin drip per DKA protocol and dextrose fluids. EDKA resolved within five days with clinical improvement. She was transitioned to subcutaneous basal bolus insulin. She remained euglycemic and and had good surgical outcomes.Discussion: Euglycemic DKA is rare with only 2.6% to 3.2% of DKA, presenting as euglycemic. It presents as unique diagnostic challenge due to atypical DKA presentation with blood glucose less than 250 mg/dL. The primary driver for EDKA is either a reduction in hepatic glucose production at times of fasting or the overabundance of counter-regulatory hormones resulting in excess glucosuria. Literature has reported the effects short-term fasting on developing EDKA and starvation induced ketosis secondary to extreme ketogenic diets or bariatric surgery primarily among Type 1 diabetics. Clinically patients may exhibit symptoms similar to classic DKA, however, this classic picture may be confounded in a critically ill post-surgical patient, thus delaying recognition. This emphasizes the importance of including EDKA in differentials while evaluating such patients. Presentation: 6/1/2024

6985 Intravenous Immunoglobulin induced Type 1 diabetes remission

Abstract Disclosure: N. Shahid: None. D. Newbern: None. Introduction: Intravenous immunoglobulin [IVIG] is an immunomodulatory agent used for treatment of autoimmune and inflammatory conditions. However, it is not indicated in patients with type 1 diabetes [T1D] as its efficacy has not been established. Clinical Case: A 9-year-old previously healthy boy presented to the Emergency Department with several days of unexplained bruising and mucosal bleeding with no prior history of trauma, bleeding disorders or other systemic symptoms. Physical examination showed generalized petechiae, ecchymosis and purpura. Vitals were normal including weight and BMI. Initial labs confirmed Immune thrombocytopenic purpura [ITP] as his platelets were less than 1K/µL with otherwise normal peripheral blood cell counts and smear. Concomitantly, labs showed significant hyperglycemia [260mg/dL] with glycosuria and trace ketonuria. Glycated hemoglobin [Hba1c] was elevated at 10.5% and ultimately Pancreatic autoantibodies [GAD65, Zinc transporter-8 and islet cell antibody] came back positive confirming T1D. Other autoimmune disorders such as adrenal insufficiency, thyroiditis, and celiac disease were ruled out. For the treatment of ITP, he the patient received 1 dose of IVIG 1g/kg and responded well with a rise in platelets to 6K/µL. The morning following the infusion, due to fasting hyperglycemia, the patient was started on basal-bolus insulin regimen. By 2nd day post IVIG, he had hypoglycemia, so insulin was discontinued with normalization of blood sugars. He is now 7 months post IVIG with no recurrent episodes of thrombocytopenia. He also remains off insulin with Hba1c in the 5.9-6.5% range. He eats a regular diet with avoidance of simple carbohydrates. He wears onwears a a continuous glucose monitor, which shows that blood sugars are in range 93% of the time He remains euglycemic overnight with transient self-resolving mild post-prandial hyperglycemia. Pancreatic autoantibodies have been reassessed and remain positive Conclusions: This case demonstrates that IVIG used for the treatment of ITP has induced a state of remission in our patient with newly diagnosed with T1D. IVIG is not a standard of treatment for T1D, however, when given for other autoantibody- or T-cell-mediated autoimmune conditions, it may reduce the insulin need in patients with known diabetes or induce remission in patients with newly diagnosed diabetes.

8616 A Novel Mutation of Maturity Onset Diabetes of the Young

Abstract Disclosure: K.H. Weerasinghe: None. N. Branis: None. Background: Maturity onset diabetes of the young (MODY) is an autosomal dominant condition characterized by various subsets (Nkonge et al., 2020). A mutation in the glucokinase gene (GCK), otherwise known as MODY type 2, is often characterized by mild hyperglycemia managed with lifestyle modifications (Nkonge et al., 2020). Novel mutations in this gene may differ in their clinical course and need close clinical monitoring. Clinical Case: A 19 year old male presented for evaluation of his diabetes mellitus. In 2020, the patient was hyperglycemic on routine blood work, with asymptomatic features. His condition was managed with lifestyle modifications. The HbA1c was 6.8 and 7; while fructosamine was 338 mmol/L (normal 205-285 mmol/L). Subsequent workup revealed GAD 65 to be less than 5 U/ml(normal range being 0-5 U/ml) with negative islet antibodies. C-peptide was similarly measured and found to be 1.5 ng/ml, within the limits of 1.1-4.4 ng/ml, demonstrating a good pancreatic reserve. A MODY genetic profile was then conducted which revealed a novel mutation in the GCK gene, variant c.1064T>C (p.L355P). As this is a novel mutation, the probability of MODY was calculated, and found to be 75% using the Exeter maturity-onset diabetes of the young (MODY) probability calculator (EMPC).The patient’s clinical course thus far has been managed conservatively as his hyperglycemia has been mild. However, recently the patient’s post prandial sugars were found to be persistently elevated. Pharmacotherapy such as sulfonylureas was discussed however, as per the patient’s wishes, stricter dietary modifications will be applied prior to the initiation of medication. Conclusion: Patients with novel mutations should be closely monitored as the general expected clinical course may vary. These changes are demonstrated in this case report as the patient started developing elevation in postprandial sugar levels uncharacteristically. Close monitoring of the patient’s future clinical status will be essential in learning more about the differences in prognosis and long term management.

Postoperative Hydration in Children Using Intermittent Boluses of Balanced Salt Solution: Results of a Randomized Control Trial

BackgroundPostoperative maintenance fluids are traditionally provided via hypotonic dextrose containing fluids administered intravenously by continuous infusion. We hypothesized that scheduled weight-based boluses of balanced salt solution would be more physiologic, reduce fluid volumes, and improve patient comfort. MethodsAs part of an IRB-approved randomized controlled trial (Boluses of Ringer's in Surgical Kids, BRiSK), we randomized patients aged 1–21 years undergoing elective abdominal or thoracic surgery to post-operatively receive weight-based D50.45NS+20mEq/L KCl at a continuous rate or intermittent boluses of Lactated Ringer's solution until oral liquid toleration. Patients with nephropathy, diabetes, or receiving parenteral nutrition were excluded. We analyzed electrolytes, urine output, fluid volume, and adverse events. ResultsWe enrolled and randomized 60 patients: 29 to continuous fluids and 31 to bolus fluids. One patient from the bolus group dropped out. No patients crossed over due to difficulties with application of the bolus protocol. There were no baseline differences between groups with a mean age of 12.6 ± 1.4yr and weight of 50.9 ± 7.2 kg. There were no serious adverse events or electrolyte disturbances in either group. Patients in the bolus group received significantly less total fluid than those in the continuous group (0.43 mL/kg/h vs 1.1 mL/kg/h, p < 0.001) with no difference in urine output [1.4 ± 0.2 mL/kg/h vs 1.6 ± 0.3 mL/kg/h, p = 0.211]. There were two episodes of mild hypoglycemia in the bolus group compared to seven episodes of mild hyperglycemia in the continuous group. ConclusionsAdministration of post-operative intravenous fluids as boluses of balanced salt solution is feasible, safe, and results in significantly less fluid administered compared to a traditional continuous protocol. Level of EvidenceII.

Impact of Mild Gestational Diabetes Mellitus on Maternal and Fetal Liver Histopathological Alterations

Background: Gestational diabetes mellitus (GDM) is one of the most common pregnancy complications that can affect the organ systems of the body in both the mother and fetus. This study aimed to determine the impact of mild GDM on maternal and fetal liver histopathological alterations. Materials and Methods: In this experimental study, 20 pregnant Wistar rats were randomly allocated in control and diabetic groups. Mild hyperglycemia was induced by intraperitoneal injection of streptozotocin (40 mg/kg body weight) on the 5th day of gestation. The control group received an equal volume of citrate buffer. The diabetic state was confirmed by a blood glucose level of 120–300 mg/dL. Maternal and fetal liver samples were obtained on day 19 of gestation and stained with hematoxylin and eosin for histopathological investigation. Results: Liver sections of diabetic dams exhibited edematous hepatocytes and scattered pyknotic and necrotic cells with dilated sinusoids and congested central veins. The portal tracts showed the proliferation of bile ducts with mild chronic inflammatory cells infiltrating together with fibrosis beyond the limited plate which extends to the central vein (porto-central fibrosis). Liver sections of their fetuses revealed edematous hepatocytes with increased necrotic cells, with pyknotic nuclei, dilatation of the hepatic sinusoids, and their central veins. There was also a relative increase in megakaryocytes, which promoted fibrosis and distorted vascular beds of the hepatic tissue. The portal tracts also showed bile duct proliferation. Conclusion: This study highlighted the adverse effects of uncontrolled mild GDM on liver structure in rat dams and their fetuses.

Association between hyperglycemia at ICU admission and postoperative acute kidney injury in patients undergoing cardiac surgery: Analysis of the MIMIC-IV database

BackgroundThis study aimed to explore the correlation between hyperglycemia at intensive care unit (ICU) admission and the incidence of acute kidney injury (AKI) in patients after cardiac surgery. MethodsWe conducted a retrospective cohort study, in which clinical data were extracted from the Medical Information Mart for Intensive Care (MIMIC)-IV database. Adults (≥18 years) in the database who were admitted to the cardiovascular intensive care unit after cardiac surgery were enrolled. The primary outcome was the incidence of AKI within 7 days following ICU admission. Secondary outcomes included ICU mortality, hospital mortality, ICU length of stay, and the 28-day and 90-day mortality. Multivariable Cox regression analysis was used to assess the association between ICU-admission hyperglycemia and AKI incidence within 7 days of ICU admission. Different adjustment strategies were used to adjust for potential confounders. Patients were divided into three groups according to their highest blood glucose levels recorded within 24 h of ICU admission: no hyperglycemia (<140 mg/dL), mild hyperglycemia (140–200 mg/dL), and severe hyperglycemia (≥200 mg/dL). ResultsOf the 6905 included patients, 2201 (31.9%) were female, and the median (IQR) age was 68.2 (60.1–75.9) years. In all, 1836 (26.6%) patients had severe hyperglycemia. The incidence of AKI within 7 days of ICU admission, ICU mortality, and hospital mortality was significantly higher in patients with severe admission hyperglycemia than those with mild hyperglycemia or no hyperglycemia (80.3% vs. 73.6% and 61.2%, respectively; 2.8% vs. 0.9% and 1.9%, respectively; and 3.4% vs. 1.2% and 2.5%, respectively; all P <0.001). Severe hyperglycemia was a risk factor for 7-day AKI (Model 1: hazard ratio [HR]=1.4809, 95% confidence interval [CI]: 1.3126 to 1.6707; Model 2: HR=1.1639, 95% CI: 1.0176 to 1.3313; Model 3: HR=1.2014, 95% CI: 1.0490 to 1.3760; all P <0.050). Patients with normal glucose levels (glucose levels <140 mg/dL) had a higher 28-day mortality rate than those with severe hyperglycemia (glucose levels ≥200 mg/dL) (4.0% vs. 3.8%, P <0.001). ConclusionsIn post-cardiac surgery patients, severe hyperglycemia within 24 h of ICU admission increases the risk of 7-day AKI, ICU mortality, and hospital mortality. Clinicians should be extra cautious regarding AKI among patients with hyperglycemia at ICU admission after cardiac surgery.

Fetal abdominal obesity in women with one value abnormality on diagnostic test for gestational diabetes mellitus.

Previous studies have shown that fetal abdominal obesity (FAO) was already observed at the time of gestational diabetes mellitus (GDM) diagnosis and persisted until delivery despite management in older and/or obese women. In this study, we investigated whether fetuses of women with milder hyperglycemia than GDM have accelerated abdominal growth, leading to adverse pregnancy outcomes. We retrospectively reviewed the medical records of 7,569 singleton pregnant women who were universally screened using a 50-g glucose challenge test (GCT) and underwent a 3-h 100-g oral glucose tolerance test (OGTT) if GCT result was ≥140mg/dL. GDM, one value abnormality (OVA), and normal glucose tolerance (NGT, NGT1: GCT negative, NGT2: GCT positive & OGTT negative) were diagnosed using Carpenter-Coustan criteria. With fetal biometry data measured simultaneously with 50-g GCT, relative fetal abdominal overgrowth was investigated by assessing the fetal abdominal overgrowth ratios (FAORs) of the ultrasonographically estimated gestational age (GA) of abdominal circumference(AC) per actual GA by the last menstruation period(LMP), biparietal diameter(BPD) or femur length(FL), respectively. FAO was defined as FAOR ≥90th percentile The FAORs of GA-AC/GA-LMP and GA-AC/GA-BPD were significantly higher in OVA subjects compared to NGT subjects but not in NGT2 subjects. Although the frequency of FAO in OVA (12.1%) was between that of NGT (9.6%) and GDM (18.3%) without statistically significant difference, the prevalence of large for gestational age at birth and primary cesarean delivery rates were significantly higher in OVA (9.8% and 29.7%) than in NGT (5.1% and 21.5%, p<0.05). Particularly, among OVA subjects with FAO, the prevalence (33.3% and 66.7%) was significantly higher than in those without FAO (9.7% and 24.2%, p<0.05). The degree of fetal abdominal growth acceleration in OVA subjects was intermediate between that of NGT and GDM subjects. OVA subjects with FAO at the time of GDM diagnosis were strongly associated with adverse pregnancy outcomes.

Case Report: Chest Pain as an Uncommon Presentation for Euglycemic Diabetic Ketoacidosis in a Female Patient Using SGLT2 inhibitor

Sodium-glucose co-transporter-2 (SGLT2) inhibitors are well-recognised antidiabetic medications among clinicians due to its highly protective effects on cardiovascular and renal systems on diabetic patients. However, one of its uncommonly reported side effects is the development of euglycemic diabetic ketoacidosis (EuDKA) which is characterized by mild hyperglycemia, ketosis and acidosis. Chest pain as a clinical presentation of EuDKA has been rarely reported in the literature. We present a case of a 46-year-old female with a past medical history of type 2 diabetes mellitus (T2DM), hypertension, and hypertriglyceridemia presented to the hospital with central chest pain that radiates to the back and is associated with mild shortness of breath and one bout of vomiting. She had been taking dapagliflozin, an SGLT2 inhibitor, for four years. She was found to have a blood glucose level of 7 mmol\L, high anion gap metabolic acidosis and ketonuria. Toxicology screening was unremarkable. She was diagnosed as a case of SGLT2-induced EuDKA and was treated with fluid, insulin and potassium chloride (KCL). Her hospital course went smoothly. Dapagloflzi was discontinued, and she was discharged home on oral metformin and subcutaneous insulin. This study highlights the rare occurance of chest pain as a presentation of EuDKA, an uncommon side effect of the widely used SGLT2 inhibitors. Chest pain in patients using SGLT2 Inhibitors should raise the clinician’s suspicion for possible EuDKA.

Efficacy and safety of advanced hybrid closed loop systems in children with type 1 diabetes younger than 6 years.

Tight glycemic control is essential for the normal growth and development of preschool children. The aim of our study was to evaluate the impact of advanced hybrid closed loop (AHCL) systems in a real-life setting in children younger than 6 years. We conducted a two-center prospective study. We enrolled 19 patients with a median age at disease onset of 2.6 years [interquartile range (IQR) 1.6; 4.4] and a median disease duration of 1.4 years (IQR 0.9; 2.8) who were switched to AHCL from multiple daily injections or open-loop insulin therapy and with a 6-month follow-up. Clinical data, sensor glycemic metrics, and pump settings were collected and analyzed. After 6 months of follow-up, there was a significant reduction in median HbA1c (p = 0.0007) and glucose management indicator (p = 0.03). A reduction in both mild (>180 mg/dL) (p = 0.04) and severe (>250 mg/dL) (p = 0.01) hyperglycemia was observed after 1 month of auto mode, and in mild hyperglycemia, it persisted up to 6 months (p = 0.02). A small increase in time below range (<70 mg/dL) was observed (p = 0.04) without a significant difference in time <54 mg/dL (p = 0.73). Time in range increased significantly, reaching a 10% increment (p = 0.03) compared with baseline. A significant reduction in the average sensor glucose was observed (p = 0.01) while coefficient of glucose variability (CV%) remained stable (p = 0.12). No episodes of ketoacidosis or severe hypoglycemia have been recorded. AHCL systems are effective and safe for children younger than 6 years and should be considered as a valid therapeutic option from diabetes onset.

Clinical characteristics and prognosis of five children with maturity onset of diabetes of the young 12 subtype

Objective: To analyze the genetic and clinical characteristics, treatment and prognosis of patients diagnosed with maturity onset of diabetes of the young (MODY) 12 subtype. Methods: This retrospective study collected and analyzed data from 5 children with MODY12 subtype caused by ABCC8 gene variants who underwent inpatient and outpatient genetic testing at Beijing Children's Hospital from January 2016 to December 2023. Their clinical and genetic features, treatment, and follow-up results were analyzed. Results: Among the 5 patients with MODY12 subtype, 4 were male and 1 was female, with an age of 13.4 (5.5, 14.6) years. Four of the patients were born large for gestational age, while one was born small for gestational age. Two patients were overweight or obese. Three patients exhibited typical symptoms of diabetes, while 2 were incidentally found to have elevated blood glucose level. One patient was found to have diabetic ketoacidosis at onset, who was diagnosed with congenital hyperinsulinism during the neonatal period and received diazoxide treatment, and experienced intellectual developmental delay. All 5 patients had autosomal dominant inherited diabetes within 3 generations. The fasting blood glucose at onset was 7.5 (6.5, 10.0) mmol/L, the haemoglobin, A1c (HbA1c) was 11.8% (7.5%, 13.5%), and the fasting C-peptide was 1.2 (1.1, 2.2)μg/L. The duration of follow-up was 15 (9, 32) months. One patient underwent lifestyle intervention, two received metformin orally, one received insulin therapy, and the other received subcutaneous injection of insulin combined with sulfonylurea orally. At the last follow-up, the median fasting blood glucose was 6.1 (5.1, 7.0) mmol/L, the HbA1c was 5.9% (5.7%, 7.1%), and the fasting C-peptide was 1.7 (0.9, 2.9)μg/L. One patient developed diabetic retinopathy. There were 4 missense variations in ABCC8 gene and one in-frame deletion, all of which were maternally inherited heterozygotes. Conclusions: MODY12 subtype is a heterogeneous disorder with the age of onset from infancy to adolescence. It can present as mild hyperglycemia or diabetic ketoacidosis, and has a high incidence of obesity. Definitive diagnosis can be achieved through genetic test, and individualized treatment is recommended based on glucose levels.

237 Disrupted insulin signaling due to an acute immune response in swine

Abstract Insulin is an anabolic hormone involved in glucose uptake and synthesis of fats, proteins, and glycogen. Altered insulin signaling can occur due to metabolic state, pathogen exposure, and autoimmune disorders. Lipopolysaccharide (LPS), an endotoxin secreted produced by gram-negative bacteria, can induce a severe, systemic immune response. In pigs, chronic LPS exposure has induced insulin resistance. However, the effects of acute exposure to LPS on insulin signaling and resistance have not been elucidated. Crossbred nursery pigs [n = 58, initial body weight (BW) = 12.1 kg ± 0.23 kg] were randomly assigned into two experimental subsets, where 10 animals were designated for repeated blood sampling and 48 animals underwent timed euthanasia for tissue collection. For repeated blood sampling, jugular catheters were placed under anesthesia and the animals were given 48 h to recover before being randomly assigned to treatments. These treatments were an intraperitoneal injection of either 15µg/kg BW LPS or an equal volume of 0.9% Saline (n = 5 pigs/treatment). Blood was collected for 48 h followed by euthanasia. The other 48 pigs were randomly assigned to the same treatments, and then randomly assigned to euthanasia timepoints of 0, 3, 6, 12, 24 or 48 h post injection for tissue collection. Among the catheterized pigs, 2-h post LPS challenge there was a decrease in serum insulin concentration (P &amp;lt; 0.05) and mild hyperglycemia (P &amp;lt; 0.05) post challenge. At 12- and 24-h post LPS challenge there was a decrease in insulin (P &amp;lt; 0.05) and a trend hyperglycemia was also apparent at 24 h (P = 0.063). In liver tissue, insulin related genes exhibited alterations post LPS injection. Phosphoinositide 3-kinase (pi3k) and insulin receptor substrate 1 (irs1) expression were decreased at 3 and 6 h (p&amp;lt; 0.05) and protein kinase b (akt) expression were decreased at 3 h (P &amp;lt; 0.05) post challenge. The expression of insulin inhibitor growth factor receptor bound protein 10 (grb10) was decreased at 6-, 12-, and 24-h after challenge (P &amp;lt; 0.05). Fructose-1-6-bisphosphatase (f16bp) expression was reduced at 3-, 6-, and 12-h (P &amp;lt; 0.05) in the liver while phosphoenolpyruvate carboxykinase (pepck) expression was decreased at 3- and 6-h (P &amp;lt; 0.01) post challenge. Other metabolic genes were decreased at 3-, 6-, and 12-h post LPS challenge, including fatty acid synthase (fas; P &amp;lt; 0.05), carbohydrate response element binding protein (chrebp; P &amp;lt; 0.05), and acetyl CoA carboxylase (acc; P &amp;lt; 0.05). Protein abundance of Akt 3 h after LPS injection was decreased in the liver (P &amp;lt; 0.05). In skeletal muscle 6 h post LPS injection, insulin receptor (insr), insulin-like growth factor receptor (igfr) and fas were all increased (P &amp;lt; 0.05) These results indicate disrupted insulin signaling at various levels after an acute immune response.

Disrupted Insulin Signaling Due to an Acute Immune Response in Swine

Insulin is an anabolic hormone involved in glucose uptake and synthesis of fats, proteins, and glycogen. Altered insulin signaling can occur due to metabolic state, pathogen exposure, and autoimmune disorders. Lipopolysaccharide (LPS), an endotoxin secreted produced by gram-negative bacteria, can induce a severe, systemic immune response. In pigs, chronic LPS exposure has induced insulin resistance. However, the effects of acute exposure to LPS on insulin signaling and resistance has not been elucidated. Crossbred nursery pigs (58, 12.1 kg ± 0.23kg BW) were randomly assigned into two experimental subsets, where 10 animals were designated for repeated blood sampling and 48 animals underwent timed euthanasia for tissue collection. For repeated blood sampling, jugular catheters were placed under anesthesia and the animals were given 48 hours to recover before being randomly assigned to treatments. These treatments were an intraperitoneal injection of either 15μg/kg BW LPS or an equal volume of 0.9% Saline (n=5 pigs/treatment). Blood was collected for 48 hours followed by euthanasia. The other 48 pigs were randomly assigned to the same treatments, and then randomly assigned to euthanasia timepoints of 0, 3, 6, 12, 24 or 48 hours post injection for tissue collection. Among the catheterized pigs, two hours post LPS challenge there was a decrease in serum insulin concentration (p&lt;0.05) and mild hyperglycemia (p&lt;0.05) post challenge. At 12 and 24 hours post LPS challenge there was a decrease in insulin (p&lt;0.05) and a trend hyperglycemia was also apparent at 24 hours (p=0.063). In liver tissue, insulin related genes exhibited alterations post LPS injection. Phosphoinositide 3-kinase ( pi3k) and insulin receptor substrate 1 ( irs1) expression were decreased at 3 and 6 hours (p&lt;0.05) and protein kinase b ( akt) expression were decreased at 3 hours (p&lt;0.05) post challenge. The expression of insulin inhibitor growth factor receptor bound protein 10 ( grb10) was decreased at 6, 12, and 24 hours after challenge (p&lt;0.05). Fructose-1-6-bisphosphatase ( f16bp) expression was reduced at 3, 6, and 12 hours (p&lt;0.05) in the liver while phosphoenolpyruvate carboxykinase ( pepck) expression was decreased at 3 and 6 hours (p&lt;0.01) post challenge. Other metabolic genes were decreased at 3, 6, and 12 hours post LPS challenge, including fatty acid synthase ( fas) (p&lt;0.05), carbohydrate response element binding protein ( chrebp) (p&lt;0.05), and acetyl CoA carboxylase ( acc)(p&lt;0.05). Protein abundance of Akt 3 hours after LPS injection was decreased in the liver (p&lt;0.05). In skeletal muscle 6 hours post LPS injection, insulin receptor ( insr), insulin-like growth factor receptor ( igfr) and fas were all increased (p&lt;0.05) These results indicate disrupted insulin signaling at various levels after an acute immune response. Research reported in this abstract was supported by Eunice Kennedy Shriver National Institute of Child Health &amp; Human Development (NICHD) of the National Institutes of Health under award number R01HD092304A. 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.

Нарушения углеводного обмена у пациентов с боевыми травмами

Aim. To investigate the prevalence and some aspects of the carbohydrate metabolism pathology in patients with combat limb injuries. Materials and methods. 210 patients who suffered from combat injuries of the lower and/or upper extremities from 4 to 58 days (mean 15.9±8.7 days) before admission to the hospital were enrolled in the study. All study participants were men. The mean age of the patients was 36.0±8.4 years (19–59 years). Fasting venous blood glucose concentrations were determined in all patients. Patients with hyperglycemia underwent a study of the glycemic profile and HbA1c. Stress-induced hyperglycemia, estimated mean glucose level over the past 3 months (ADAG), and glycemic gap were calculated. Insulin in fasting blood plasma was determined and the HOMA-IR insulin resistance index was calculated. Results. The incidence of hyperglycemia was 23.3%. In the general group of patients, the mean glucose concentration was 5.5±1.0 mmol/l (3.1–9.73 mmol/l). In the group of patients with hyperglycemia, the mean blood glucose level reached 6.7±0.9 mmol/l, in patients with normal glucose concentration – 5.1±0.5 mmol/l (p&lt;0.000001). The mean fasting blood glucose concentration in patients aged 40 years and older reached 5.7±1.1 mmol/l, those under 40 years old – 5.2±0.8 mmol/l (p=0.005). A significant direct correlation was registered between the fasting glucose level upon admission to the hospital and the age of the patients (r=0.26; p=0.00003). The relative risk of hyperglycemia in patients aged 40 years and older was 1.84 (confidence interval 1.005–3.37; p=0.01). The mean time elapsed since injury in patients with hyperglycemia reached 13.2±5.7 days, with normal glucose concentration – 16.7±9.2 days (p=0.02). Patients with hyperglycemia had lower levels of total protein (58.3±10.2 and 62.1±6.9 g/l, respectively; p=0.004), albumin (31.2±4.6 and 33.2±4.9 g/l; p=0.04), hemoglobin (97.7±18.9 and 105.9±16.9 g/l; p=0.004), but higher levels of C-reactive protein (61.0±55.4 and 32.9±38.1 mg/l; p=0.0001), leukocytes (10.6±4.4 and 9.3±3.4×109/l; p=0.02), count of neutrophils (7.8±4.3 and 6.4±2.9×109/l; p=0.01), proportion of neutrophils (71.6±9.6% and 67.7±7.7%; p=0.004), as well as fibrinogen concentration (5.7±1.4 and 4.8±1.2 g/l; p=0.0002) than patients with normal blood glucose levels. In patients with hyperglycemia, the mean HbA1c level was 5.3±0.6%, stress-induced hyperglycemia – 1.4±0.2 mmol/l. The median glycemic gap reached 1.51 mmol/l (Q1–Q3: 0.88–2.1 mmol/l). The median insulin concentration was 12.9 µIU/ml (Q1–Q3: 9.2–27.0 µIU/ml), the insulin resistance index was 3.3 (Q1–Q3: 2.1–8.8). The mean fasting blood glucose concentration at the last determination in patients with initial hyperglycemia reached 5.8±1.3 mmol/l. During observation, in 64.6% of the patients with hyperglycemia upon admission, glucose levels returned to normal, while in 35.4% mild hyperglycemia remained. The median time to normalization of fasting blood glucose concentration or to the last determination of this indicator was 17.5 days (Q1–Q3: 8–30 days). Conclusions. The study results indicate a frequent detection of hyperglycemia in patients with combat limb injuries. In most cases the increase in fasting glucose levels is small and in most patients this indicator returns to normal within a relatively short time. It is necessary to continue research of stress-induced hyperglycemia in the patients with combat injuries and to elucidate the pathogenetic basis of this pathology.

Neonatal outcomes according to different glucose threshold values in gestational diabetes: a register-based study

BackgroundMild hyperglycaemia is associated with increased birth weight but association with other neonatal outcomes is controversial. We aimed to study neonatal outcomes in untreated mild hyperglycaemia using different oral glucose tolerance test (OGTT) thresholds.MethodsThis register-based study included all (n = 4,939) singleton pregnant women participating a 75 g 2-h OGTT in six delivery hospitals in Finland in 2009. Finnish diagnostic cut-offs for GDM were fasting ≥ 5.3, 1 h ≥ 10.0 or 2-h glucose ≥ 8.6 mmol/L. Women who did not meet these criteria but met the International Association of the Diabetes and Pregnancy Study Groups (IADPSG) criteria (fasting 5.1–5.2 mmol/L and/or 2-h glucose 8.5 mmol/L, n = 509) or the National Institute for Health and Clinical Excellence (NICE) criteria (2-h glucose 7.8–8.5 mmol/L, n = 166) were considered as mild untreated hyperglycaemia. Women who met both the Finnish criteria and the IADPSG or the NICE criteria were considered as treated GDM groups (n = 1292 and n = 612, respectively). Controls were normoglycaemic according to all criteria (fasting glucose < 5.1 mmol/L, 1-h glucose < 10.0 mmol/L and 2-h glucose < 8.5 mmol/L, n = 3031). Untreated mild hyperglycemia groups were compared to controls and treated GDM groups. The primary outcome – a composite of adverse neonatal outcomes, including neonatal hypoglycaemia, hyperbilirubinaemia, birth trauma or perinatal mortality – was analysed using multivariate logistic regression.ResultsThe risk for the adverse neonatal outcome in untreated mild hyperglycemia was not increased compared to controls (adjusted odds ratio [aOR]: 1.01, 95% confidence interval [CI]: 0.71–1.44, using the IADPSG criteria; aOR: 1.05, 95% CI: 0.60–1.85, using the NICE criteria). The risk was lower compared to the treated IADPSG (aOR 0.38, 95% CI 0.27–0.53) or the treated NICE group (aOR 0.32, 95% CI 0.18–0.57).DiscussionThe risk of adverse neonatal outcomes was not increased in mild untreated hyperglycaemia compared to normoglycaemic controls and was lower than in the treated GDM groups. The OGTT cut-offs of 5.3 mmol/L at fasting and 8.6 mmol/L at 2 h seem to sufficiently identify clinically relevant GDM, without excluding neonates with a risk of adverse outcomes.

Alterations of whole body glucose metabolism in a feline SARS-CoV-2 infection model.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been especially devastating to patients with comorbidities, including metabolic and cardiovascular diseases. Elevated blood glucose during SARS-CoV-2 infection increased mortality of patients with COVID-19, although the mechanisms are not well understood. It has been previously demonstrated that glucose transport and utilization is a crucial pathway for other highly infectious RNA viruses. Thus, we hypothesized that SARS-CoV-2 infection could lead to alterations in cellular and whole body glucose metabolism. Specific pathogen-free domestic cats were intratracheally inoculated with USA-WA1/2020 (wild-type) SARS-CoV-2 or vehicle-inoculated, then euthanized at 4- and 8-days postinoculation (dpi). Blood glucose and cortisol concentrations were elevated at 4 and 8 dpi. Blood ketones, insulin, and angiotensin II concentrations remained unchanged throughout the experimental timeline. SARS-CoV-2 RNA was detected in the lung and heart, without changes in angiotensin-converting enzyme 2 (ACE2) RNA expression. In the lung, SARS-CoV-2 infection increased glucose transporter 1 (GLUT1) protein levels at 4 and 8 dpi, whereas GLUT4 level was only upregulated at 8 dpi. In the heart, GLUT-1 and -4 protein levels remained unchanged. Furthermore, GLUT1 level was upregulated in the skeletal muscle at 8 dpi, and AMPK was activated in the hearts of infected cats. SARS-CoV-2 infection increased blood glucose concentration and pulmonary GLUT protein levels. These findings suggest that SARS-CoV-2 infection induces metabolic reprogramming primarily in the lung to support viral replication. Furthermore, this translational feline model mimicked human COVID-19 and could be used to explore novel therapeutic targets to treat metabolic disease during SARS-CoV-2 infection.NEW & NOTEWORTHY Our study on a feline model of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, mirroring human COVID-19, revealed alterations in whole body and cellular glucose metabolism. Infected cats developed mild hyperglycemia, increased protein levels of glucose transporters in the lung, and AMPK activation in the heart. These findings suggest that SARS-CoV-2 infection induces metabolic reprogramming in the cardiorespiratory system to support viral replication. Understanding these mechanisms could lead to novel antiviral therapeutic strategies.

Association of persistent postoperative hyperglycemia with mortality after elective craniotomy.

The influence of persistent postoperative hyperglycemia after craniotomy has not yet been explored. This study aimed to investigate the hypothesis that persistent postoperative hyperglycemia is associated with mortality in patients undergoing an elective craniotomy. This study included adult patients (age ≥ 18 years) undergoing an elective craniotomy between January 2011 and March 2021 at the West China Hospital, Sichuan University. Peak daily blood glucose values measured within the first 7 days after craniotomy were collected. Persistent hyperglycemia was defined by two or more consecutive serum glucose levels of mild, moderate, or severe hyperglycemia. Normoglycemia, mild hyperglycemia, moderate hyperglycemia, and severe hyperglycemia were defined as glucose values of ≤ 6.1 mmol/L, > 6.1 and ≤ 7.8 mmol/L, > 7.8 and ≤ 10.0 mmol/L, and > 10.0 mmol/L, respectively. This study included 14,907 patients undergoing an elective craniotomy. In the multivariable analysis, both moderate (adjusted OR 3.76, 95% CI 2.68-5.27) and severe (adjusted OR 3.82, 95% CI 2.54-5.76) persistent hyperglycemia in patients were associated with higher 30-day mortality compared with normoglycemia. However, this association was not observed in patients with mild hyperglycemia (adjusted OR 1.32, 95% CI 0.93-1.88). Interestingly, this association was observed regardless of whether patients had preoperative hyperglycemia. There was no interaction between moderate or severe hyperglycemia and preexisting diabetes (p for interaction = 0.65). When postoperative peak blood glucose values within the first 7 days after craniotomy were evaluated as a continuous variable, for each 1-mmol/L increase in blood glucose, the adjusted OR of 30-day mortality was 1.17 (95% CI 1.14-1.21). Postoperative blood glucose (area under the curve [AUC] = 0.78) was superior to preoperative blood glucose (AUC = 0.65; p < 0.001) for predicting mortality. Moderate and severe persistent hyperglycemia in patients were associated with an increased risk of deep venous thrombosis (adjusted OR 3.20, 95% CI 2.31-4.42), pneumonia (adjusted OR 2.77, 95% CI 2.40-3.21), myocardial infarction (adjusted OR 4.38, 95% CI 3.41-5.61), and prolonged hospital stays (adjusted OR 1.43, 95% CI 1.29-1.59). In patients undergoing an elective craniotomy, moderate and severe persistent postoperative hyperglycemia were associated with an increased risk of mortality compared with normoglycemia, regardless of preoperative hyperglycemia.

A loss-of-function mutation in KCNJ11 causing sulfonylurea-sensitive diabetes in early adult life

Aims/hypothesisThe ATP-sensitive potassium (KATP) channel couples beta cell electrical activity to glucose-stimulated insulin secretion. Loss-of-function mutations in either the pore-forming (inwardly rectifying potassium channel 6.2 [Kir6.2], encoded by KCNJ11) or regulatory (sulfonylurea receptor 1, encoded by ABCC8) subunits result in congenital hyperinsulinism, whereas gain-of-function mutations cause neonatal diabetes. Here, we report a novel loss-of-function mutation (Ser118Leu) in the pore helix of Kir6.2 paradoxically associated with sulfonylurea-sensitive diabetes that presents in early adult life.MethodsA 31-year-old woman was diagnosed with mild hyperglycaemia during an employee screen. After three pregnancies, during which she was diagnosed with gestational diabetes, the patient continued to show elevated blood glucose and was treated with glibenclamide (known as glyburide in the USA and Canada) and metformin. Genetic testing identified a heterozygous mutation (S118L) in the KCNJ11 gene. Neither parent was known to have diabetes. We investigated the functional properties and membrane trafficking of mutant and wild-type KATP channels in Xenopus oocytes and in HEK-293T cells, using patch-clamp, two-electrode voltage-clamp and surface expression assays.ResultsFunctional analysis showed no changes in the ATP sensitivity or metabolic regulation of the mutant channel. However, the Kir6.2-S118L mutation impaired surface expression of the KATP channel by 40%, categorising this as a loss-of-function mutation.Conclusions/interpretationOur data support the increasing evidence that individuals with mild loss-of-function KATP channel mutations may develop insulin deficiency in early adulthood and even frank diabetes in middle age. In this case, the patient may have had hyperinsulinism that escaped detection in early life. Our results support the importance of functional analysis of KATP channel mutations in cases of atypical diabetes.Graphical

Pancreatic enzyme replacement therapy in subjects with exocrine pancreatic insufficiency and diabetes mellitus: a real-life, case–control study

BackgroundExocrine pancreatic insufficiency (EPI) can be associated with all types of diabetes. Pancreatic enzyme replacement therapy (PERT) has short and long-term benefits in subjects with EPI, but its effects on diabetes control are uncertain. We aimed to study the effects of PERT initiation on glycemic control in subjects with diabetes and EPI from any cause.MethodsIn this retrospective study, we compared subjects with EPI and diabetes who were prescribed PERT with subjects with diabetes who had a fecal elastase-1 concentration dosage, but did not receive PERT. The primary outcome was the effect of PERT on hypoglycemia frequency and severity. The secondary outcomes were the effects of PERT on gastro-intestinal disorders, HbA1c and body mass index (BMI).Results48 subjects were included in each group. Overall, PERT did not have any significant effect on hypoglycemia frequency or severity, but hypoglycemia frequency tended to decrease in subjects with chronic pancreatitis. While 19% of subjects experienced mild hyperglycemia after PERT initiation, we did not report any keto-acidosis or any other severe adverse event. Gastro-intestinal disorders improved in 80% of subjects treated with PERT, versus in 20% of control subjects (p = 0.02). Gastro-intestinal disorders improved in 87% of subjects with recommended dosage of PERT, versus in 50% of subjects with underdosage (NS). HbA1c and BMI evolution did not differ between the groups.ConclusionsPERT initiation is safe in subjects with diabetes and EPI. It does not globally decrease hypoglycemia severity of frequency, but is associated with a decrease in gastro-intestinal disorders.Trial registration Retrospectively registered. The database was registered with the Commission Nationale Informatique et Libertés (CNIL), registration number: 2203351v0. The study was approved by the local ethics committee CLEP, registration number: AAA-2023-09047

Effects of maternal mild hyperglycemia associated with snack intake on offspring metabolism and behavior across the lifespan

The increasing prevalence of diabetes is of particular concern in women of childbearing age because of the short and long-term consequences of maternal diabetes for the health of the offspring, such as a greater risk of developing metabolic impairments and cognitive deficits. In addition, maternal diet during pregnancy and lactation might contribute to preventing or ameliorating adverse offspring outcomes. Recently, we described that access to snacks exacerbates glucose intolerance in mildly hyperglycemic pregnant dams. Therefore, we hypothesized that these offspring would show greater impairment in metabolic and behavioral outcomes across the lifespan. Neonatal STZ treatment was employed to induce maternal mild hyperglycemia in females. After mating, normo- and hyperglycemic dams were given access either to standard chow or standard show plus snacks. Male and female offspring were evaluated on postnatal days (PND) 30, 90, and 360. Offspring behavior was assessed in the marble burying task, the open-field test, the elevated-plus maze, and sucrose preference. Glucose tolerance and morphometric analyses were also carried out. Maternal hyperglycemia increased body weight and fat deposition only on PND 30, while retroperitoneal fat deposition was reduced in the offspring of snack-fed dams. However, maternal snack intake reduced offspring body weight and length on PND 90. Fasting glucose was increased in females born to hyperglycemic, snack-fed dams on PND 90. Glucose clearance was altered by both maternal conditions in male offspring on PND 30, however, this sex difference was reversed on PND 90, with maternal hyperglycemia impairing glucose clearance only in females. In addition, maternal hyperglycemia reduced anxiety-like behavior in female offspring on PND 30, especially in the offspring of snack-fed dams, while maternal snack intake reduced sucrose preference in both males and females in adulthood. These results suggest that the effects of maternal hyperglycemia during pregnancy and lactation on offspring outcomes were not exacerbated by snack intake. Although additive effects of the two maternal conditions were hypothesized, the absence of such effects could be related to the mild maternal hyperglycemia induced by STZ treatment even when combined with snack intake. While maternal hyperglycemia alone impaired some offspring outcomes, its association with snack intake did not aggravate those impairments but rather resulted in outcomes more similar to those of offspring born to normoglycemic dams. Finally, females were found to be more susceptible to both the effects of maternal hyperglycemia and snack intake on metabolism and behavior.