Glucose Infusion Rate Research Articles

1648-P: Triagonism Targeting GCGR/GLP-1/GIP-1 Receptors Improves Insulin Sensitivity in Obese Mice

Glucagon is best known as the primary counter-regulatory hormone against insulin action. Glucagon secretion is likewise elevated in Diabetes and thus it is often implicated as a diabetogenic hormone. However, emerging data from our group and others have uncovered that Glucagon receptor (GCGR) agonism improves insulin sensitivity in both lean and obese mice. Mechanistically, this improvement is associated with enhanced AKT phosphorylation and mTOR signaling in the liver. Novel, single-molecule, triagonists targeting GCG/GLP-1/GIP receptors (GGG) have recently been described to exert stronger anti-obesity effects than dual or single agonism in obese mice. Thus, we evaluated the effect of these agonists on insulin sensitivity using hyperinsulinemic euglycemic clamp. Diet-induced obese (DIO) mice were randomly assigned to 4d treatment (10 nmole/kg subcutaneous injection) of vehicle, GGG, GCGR agonism (IUB288), GLP-1R agonism (Semaglutide), or a long-acting GIP-1R agonist (GIP-FA 085). On the fourth day, mice were fasted for 5 hours, continuously infused with 1.2mU/kg/min insulin, and blood glucose levels clamped around 80-100 mg/dL. Under these conditions Semaglutide and GGG treatments stimulated the greatest glucose infusion rate (p<0.0001) and significantly improved insulin-mediated suppression of Endo Ra (p<0.01). Smaller, but significant, enhancement was also observed in the IUB288-treated mice. Moreover, [14C]-2GDp uptake into brown adipose tissue was improved in GGG, Semaglutide, and IUB288 treated mice compared to Vehicle treated mice. Importantly, these improvements in insulin sensitivity and glucose dynamics were body-weight independent. Therefore, GCGR and GLP-1R signaling combine in GGG triagonism to improve insulin sensitivity mainly via suppression of hepatic glucose production. Disclosure T.Kim: None. S.Nason: None. J.Antipenko: None. K.M.Habegger: Consultant; Glyscend Inc., Research Support; Eli Lilly and Company, Novo Nordisk, Glyscend Inc., Stock/Shareholder; Glyscend Inc. Funding Eli Lilly and Company

1660-P: Lactate Inhibits Lipolysis in Healthy Males—A Randomized Crossover Trial

Background: The intermediary metabolite lactate has signaling capacities through the lactate specific receptor GPR81/HCA1. Ex-vivo, lactate inhibits lipolysis through GPR81, but in-vivo human data are scarce. Lactate-mediated inhibition of lipolysis could improve insulin sensitivity. The aim of the study was to investigate if hyperlactatemia at physiological concentrations inhibits palmitate lipolysis and affects glucose metabolism in healthy males. Methods: In a randomized cross-over design, eight healthy men were studied after an overnight fast on two occasions 1) during a sodium-lactate infusion (LAC) and 2) during a NaCl infusion (CTL). Both study days comprised a 3-hour basal period followed by a 3-hour hyperinsulinemic euglycemic clamp (HEC) period. Lipolysis rate and endogenous glucose production (EGP) were evaluated using [9,10-3H]-palmitate and [3H]-glucose tracers. Average glucose infusion rate (mg/kg/min) during the last 30 min of the HEC (M-value) was used as a measure of insulin sensitivity. Data are mean±SD Results: Plasma lactate increased to 2.6 ±0.6 mmol/L during LAC vs. 0.8 ±0.3 mmol/L during CTL (p<0.001). At the end of the basal period, palmitate flux was 30% lower during LAC compared with CTL (84 ±32 μmol/min vs. 120 ±35 μmol/min, p=0.003). At the end of the HEC, palmitate flux was similarly suppressed during both interventions (p=0.7). Plasma FFA were lower during LAC compared with CTL (0.2 ±0.1 mmol/L vs. 0.3 ±0.1 mmol/L, p=0.03) at the end of the basal period and equally suppressed during both interventions at the end of the HEC (p=0.7). EGP was unaffected by LAC compared with CTL at the end of the basal period (p=1.0) and suppressed at the end of the HEC during both interventions (p=1.0). M-value was unaffected by LAC compared with CTL (p=0.8). Conclusion: Lactate inhibits palmitate lipolysis by 30 %, an effect which per se may improve insulin sensitivity. Hyperlactatemia did not affect EGP or insulin sensitivity, possibly because lactate intrinsically may induce insulin resistance. Disclosure M.G.B.Pedersen: None. N.Rittig: Research Support; ARLA. E.Søndergaard: None. L.C.Gormsen: None. N.Møller: Other Relationship; Aarhus University/Ketlace.

1514-P: Insulin Sensitivity Initially Worsens but Later Improves with Aging in C57BL/6N Mice

Objective: Aging is believed to induce insulin resistance in humans. However, when and how insulin sensitivity changes with aging remain unclear in both humans and mice. Methods: Groups of C57BL/6N mice at 9-15 weeks (young), 34-67 weeks (one-year-old) and 107-121 weeks (two-year-old) of age underwent hyperinsulinemic-euglycemic clamp studies with somatostatin infusion under awake and non-restrained conditions. Results: The glucose infusion rates for maintaining euglycemia were 17.11±2.94, 5.58±1.28 and 25.30±4.42 mg/kg/min in young, one-year-old and two-year-old mice, respectively. Thus, compared with young mice, one-year-old mice exhibited the expected insulin resistance. In contrast, the insulin sensitivity of two-year-old mice showed significant improvement. These age-related changes were mainly observed in glucose uptake into adipose tissue and skeletal muscle. Epididymal fat weight and hepatic triglyceride levels were highest in one-year-old mice, while being similar in young and two-year-old mice. Conclusions: Our observations indicate that, in mice, insulin resistance appears at one year of age but subsequently improves markedly. These alterations in insulin sensitivity are attributable to changes in visceral fat accumulations and age-related factors. Disclosure H.Kondo: None. H.Ono: None. K.Yokote: None. Funding Japan Society for the Promotion of Science (15K09398, 18K08502, 20H00524); Japan Agency for Medical Research and Development (17GM5010002H0001, 18GM5010002H0002, 19GM5010002H0003, 20GM5010002H0004)

1559-P: Glucagon Receptor–Mediated Improvements in Glycemia Are Dependent on Agonist Pharmacodynamics

Glucagon is considered the main glucose counter-regulatory hormone to insulin. Although, chronic glucagon receptor (GCGR) agonism induces hyperglycemia and glucose intolerance, it also improves insulin secretion and action. Surprisingly, we found chronic treatment with the selective, long-acting GCGR agonist, IUB288, improves ad libitum glycemia and glucose tolerance 4h after treatment. These glycemic improvements were associated with enhanced AKT phosphorylation, despite control-like insulin levels. We next tested if these results could be replicated with a short acting GCGR agonist. IUB94 displays improved aqueous solubility but maintains the short half-life and potency of native glucagon. 4h glucose excursion was monitored in lean mice after injection of IUB288, IUB94, or vehicle. We observed a transient rise in blood glucose (BG) 15min after either IUB288 or IUB94 compared to vehicle. Intriguingly, IUB288-treated mice exhibited improved BG from 120-240min, while BG in IUB94-treated mice was similar to vehicle controls. These data suggest that acute BG regulation is agonist-dependent yet, it remains unclear if pharmacodynamics or some inherent difference in potency is influencing the 4h BG. We next treated lean mice for 4d with vehicle or IUB288, measuring ad libitum glycemia over the final 24h period. IUB288-treated mice displayed improved glycemia 4h after the last injection and hyperglycemia after 12h, compared to vehicle-treated controls, suggesting chronic GCGR agonism is not exclusively hyperglycemic. Surprisingly, 4d IUB288 treatment in diet-induced obese (DIO) mice reduced ad libitum glycemia for a longer duration than observed in chow IUB288-treated mice. IUB288 treatment also increased glucose infusion rate, suppression of endogenous glucose production, and AKT phosphorylation during hyperinsulinemic-euglycemic clamps. These data provide insight into the potential therapeutic use of sustained-acting GCGR agonists against diabetes and obesity. Disclosure S.Nason: None. T.Kim: None. J.Antipenko: None. B.Yang: None. R.Dimarchi: None. K.M.Habegger: Consultant; Glyscend Inc., Research Support; Eli Lilly and Company, Novo Nordisk, Glyscend Inc., Stock/Shareholder; Glyscend Inc. Funding National Institutes of Health

Cerebral Glucose Concentration in Neonatal Hypoxic–Ischemic Encephalopathy during Therapeutic Hypothermia

To determine cerebral glucose concentration and its relationship with glucose infusion rate (GIR) and blood glucose concentration in neonatal encephalopathy during therapeutic hypothermia (TH). This was an observational study in which cerebral glucose during TH was quantified by magnetic resonance (MR) spectroscopy and compared with mean blood glucose at the time of scan. Clinical data (gestational age, birth weight, GIR, sedative use) that could affect glucose use were collected. The severity and pattern of brain injury on MR imaging were scored by a neuroradiologist. Student t test, Pearson correlation, repeated measures ANOVA, and multiple regression analysis were performed. Three-hundred-sixty blood glucose values and 402MR spectra from 54 infants (30 female infants; mean gestational age 38.6± 1.9weeks) were analyzed. In total, 41 infants had normal-mild and 13 had moderate-severe injury. Median GIR and blood glucose during TH were 6.0mg/kg/min (IQR 5-7) and 90mg/dL (IQR 80-102), respectively. GIR did not correlate with blood or cerebral glucose. Cerebral glucose was significantly greater during than after TH (65.9± 22.9 vs 60.0± 25.2mg/dL, P<.01), and there was a significant correlation between blood glucose and cerebral glucose during TH (basal ganglia: r=0.42, thalamus: r=0.42, cortical gray matter: r=0.39, white matter: r=0.39, all P<.01). There was no significant difference in cerebral glucose concentration in relation to injury severity or pattern. During TH, cerebral glucose concentration is partly dependent on blood glucose concentration. Further studies to understand brain glucose use and optimal glucose concentrations during hypothermic neuroprotection are needed.

Insulin sensitivity initially worsens but later improves with aging in male C57BL/6N mice.

Aging is believed to induce insulin resistance in humans. However, when and how insulin sensitivity changes with aging remain unclear in both humans and mice. In this study, groups of male C57BL/6N mice at 9-19 weeks (young), 34-67 weeks (mature adult), 84-85 weeks (presenile) and 107-121 weeks (aged) of age underwent hyperinsulinemic-euglycemic clamp studies with somatostatin infusion under awake and non-restrained conditions. The glucose infusion rates for maintaining euglycemia were 18.4±2.9, 5.9±1.3, 20.3±7.2 and 25.3±4.4mg/kg/min in young, mature adult, presenile and aged mice, respectively. Thus, compared with young mice, mature adult mice exhibited the expected insulin resistance. In contrast, presenile and aged mice showed significantly higher insulin sensitivity than the mature adult mice. These age-related changes were mainly observed in glucose uptake into adipose tissue and skeletal muscle (rates of glucose disappearance were 24.3±2.0, 17.1±1.0, 25.5±5.2 and 31.8±2.9mg/kg/min in young, mature adult, presenile and aged mice, respectively). Epididymal fat weight and hepatic triglyceride levels were higher in mature adult mice than those in young and aged mice. Our observations indicate that, in male C57BL/6N mice, insulin resistance appears at the mature adult stage of life but subsequently improves markedly. These alterations in insulin sensitivity are attributable to changes in visceral fat accumulations and age-related factors.

Continuous subcutaneous insulin infusion via an insulin pump in extremely premature neonates—a case series

Extremely preterm infants are prone to hyperglycemia which is associated with increased mortality and morbidity. Insulin sensitivity is variable in extreme prematurity, and its monitoring, prevention, and treatment are a significant challenge in the NICU. Frequent changes in fluid composition and volumes, as well as large growth and adaptational nutrient requirements are limited by difficult vascular access and blood sampling and risk of drug incompatibilities. Insulin treatment requires specific access and significantly increases fluid intake and sampling. Clinicians, therefore, often compromise by reducing glucose intake and accepting higher glycemia. We report a case series of 11 extremely low birth weight (ELBW) preterms, born between 23 5/7 and 27 6/7 weeks of gestation, treated for transient hyperglycemia during the first 2 weeks of life by continuous subcutaneous insulin infusion (CSII). Insulin concentration was 10 IU/ml, administered via 13 mm Accu-Chek® Tenderlink catheters and a commercial insulin pump (Accu-Chek® Combo, Roche Diabetes Care). Insulin treatment was initiated when glycemia was > 252 mg/dL (14 mmol/l) in two consecutive blood glucose determinations, except for one case when glycemia was 234 mg/dL (13 mmol/l), despite a previous decrease in glucose infusion rate. The starting dose for the CSII was between 0.01 and 0.08 IU/kg/h. The average duration of the CSII was 5 days (1–16 days). CSII in extreme preterm neonates with hyperglycemia was clinically feasible and practical by sparing IV lines and volume and appeared as more rapidly effective than continuous IV administration. No adverse events like hypoglycemia or skin infection were recorded.

Bioequivalence and immunogenicity of insulin LisPro biosimilar compared to reference drug

Introduction. Insulin therapy is the only treatment for type 1 DM and one of the options for intensifying the treatment for type 2 DM. The production of own insulin biosimilars will increase patients access to the providing drugs and can potentially reduce medical costs on healthcare for government. Aim. Compare the equivalence of pharmacokinetics (PK) and pharmacodynamics (PD), safety, efficacy, and immunogenicity between insulin biosimilar RinLis®, 100 IU/ml (LLC GEROPHARM, Russia) to original Humalog®, 100 IU/ml (Lilly France, France). Materials and methods. The clinical trial was conducted in two phases. Phase I – randomized double-blind, two-arm crossover study of PK and PD using hyperinsulinemic euglycemic clamp (HEC) method in 28 healthy volunteers (NCT03604575). During HEC regular blood sampling was performed to assess glucose and insulin concentrations. The glucose infusion rate (GIR) was adjusted based on glycemia measurement. These data were used to calculate the PD parameters: the total area under the GIR-time curve (AUCGIR) and the maximum GIR over the observation period (GIRmax); PK parameters: the total area under the concentration – time curve (AUCins.) and the maximum insulin concentration over the HEC (Сins. max). Phase II – randomized multicenter open-label comparative study in parallel groups with an assessment the frequency of an immune response after 26 weeks of therapy (NCT04023344). The comparability of the studied drugs was considered proven if 90% confidence intervals (CI) for the ratio of geometric means of FC and PD were in the range of 80–125%. Results. In the course of the study, it was revealed that RinLiz® and Humalog® insulin had comparable PK and PD profiles. The ratio of the geometric mean values of the AUCGIR and GIRmax were in the range of 80–125% and amounted to 106 [95–118] % and 108 [97–121] %, respectively. The equivalence also was confirmed by the ratio of the geometric mean values of the AUCins. and Сins. max, which amounted to 91 [86–97] % and 94 [91–97] %. In the second phase of the study after 26 weeks of therapy the frequency of immune response between two groups did not differ. Conclusion. The obtained data have demonstrated the bioequivalence and immunogenicity of RinLiz® insulin to the original Humalog® in terms of PK, PD and safety parameters.

Role for insulin sensitivity in the cerebrovascular response to hyperinsulinemia in young adults

Objective: Cerebral blood flow is highly regulated and cerebrovascular responsiveness to vasodilatory stimuli is predictive of brain health. In preclinical animal models, insulin elicits cerebrovascular dilation and subsequent increases in cerebral blood flow. Contrary to this, preliminary data from our group in a large cohort of healthy humans indicate surrogate measures of cerebral blood flow remain at baseline levels during hyperinsulinemia – although responses were highly variable. In the peripheral circulation, insulin-stimulated vasodilation is closely associated with markers of insulin sensitivity (e.g., elevated fasting glucose, insulin, HOMA-IR); whether these associations translate to the cerebral circulation remains unclear. With this information in mind, we hypothesized the degree of insulin-mediated increases in cerebral blood flow would correlate with indices of peripheral insulin sensitivity.Methods: Middle cerebral artery blood velocity (MCAv) was measured with transcranial Doppler ultrasound in 17 adults (11M/6F, 28±2 yrs, 24±1 kg/m 2 ) at baseline and following a 60-min hyperinsulinemic (40 mU/m 2 body surface area/min), euglycemic infusion. Correlations between MCAv and indices of peripheral insulin sensitivity [i.e., fasting glucose, insulin, HOMA-IR, glucose infusion rate, weight, body mass index (BMI), age, physical activity] were determined. Results: Intravenous insulin infusion increased plasma insulin concentrations (6±1 to 49±3 μIU/mL, p&lt;0.001) with blood glucose maintained (73±4 to 82±6 mg/dL, p=0.196). There was no net change in MCAv during hyperinsulinemia (60±4 to 60±4 cm/s, p=0.930). We observed negative associations between the change in MCAv during hyperinsulinemia (Δ=Insulin–Baseline) and both body weight (R=-0.49, p=0.047) and BMI (R=-0.50, p=0.040). No correlations between ΔMCAv and fasting glucose (p=0.435), insulin (p=0.733), HOMA-IR (p=0.960), age (p=0.132), physical activity (p=0.179), or glucose infusion rate (p=0.599) were observed. Conclusions: As previously shown in these participants, hyperinsulinemia in young adults elicits no net change in MCAv. Any increases in MCAv during hyperinsulinemia occur primarily in individuals with lower body weight and lower BMI. Future studies are needed to translate results to disease states (e.g., diabetes). Margaret W. Mangel Faculty Research Catalyst Fund (JP, JKL), NIH HL137769 (JP), NIH HL130339 (JKL) This is the full abstract presented at the American Physiology Summit 2023 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.

Factors influencing bioequivalence evaluation of insulin biosimilars based on a structural equation model.

Objective: This study aimed to explore the factors affecting the bioequivalence of test and reference insulin preparations so as to provide a scientific basis for the consistency evaluation of the quality and efficacy of insulin biosimilars. Methods: A randomized, open, two-sequence, single-dose, crossover design was used in this study. Subjects were randomly divided into TR or RT groups in equal proportion. The glucose infusion rate and blood glucose were measured by a 24-h glucose clamp test to evaluate the pharmacodynamic parameters of the preparation. The plasma insulin concentration was determined by liquid chromatography-mass spectrometry (LC-MS/MS) to evaluate pharmacokinetic parameters. WinNonlin 8.1 and SPSS 23.0 were applied for PK/PD parameter calculation and statistical analysis. The structural equation model (SEM) was constructed to analyze the influencing factors of bioequivalence by using Amos 24.0. Results: A total of 177 healthy male subjects aged 18-45years were analyzed. Subjects were assigned to the equivalent group (N = 55) and the non-equivalent group (N = 122) by bioequivalence results, according to the EMA guideline. Univariate analysis showed statistical differences in albumin, creatinine, Tmax, bioactive substance content, and adverse events between the two groups. In the structural equation model, adverse events (β = 0.342; p < 0.001) and bioactive substance content (β = -0.189; p = 0.007) had significant impacts on the bioequivalence of two preparations, and the bioactive substance content significantly affected adverse events (β = 0.200; p = 0.007). Conclusion: A multivariate statistical model was used to explore the influencing factors for the bioequivalence of two preparations. According to the result of the structural equation model, we proposed that adverse events and bioactive substance content should be optimized for consistency evaluation of the quality and efficacy of insulin biosimilars. Furthermore, bioequivalence trials of insulin biosimilars should strictly obey inclusion and exclusion criteria to ensure the consistency of subjects and avoid confounding factors affecting the equivalence evaluation.

Probing the mechanism of reduced in vivo potency of insulin detemir

ABSTRACT Background Insulin detemir (IDet) is an insulin analog used to treat diabetes. IDet shows full efficacy but reduced potency compared to human insulin (HI) in both man and rat. In contrast, in pigs and dogs, IDet appears to have full in vivo potency. Non-receptor mediated degradation (NRMD) has previously been suggested as an explanation for the low potency of IDet, but this hypothesis has not been investigated further until now. Bacitracin is a nonspecific protease inhibitor which we hypothesized could inhibit NRMD of IDet in rats. Research design and methods Healthy male rats instrumented with permanent catheters underwent euglycemic clamp during constant infusion of either HI or IDet at effect-matched doses with co-infusion of vehicle or bacitracin. Results Plasma concentrations of IDet increased significantly (p < 0.005) during bacitracin compared to vehicle co-infusion and the concomitant increase in glucose infusion rate (GIR, p < 0.001) required to maintain euglycemic clamp indicates that the IDet rescued from NRMD indeed was active. No significant differences were detected with co-infusions of HI with either bacitracin or vehicle. Conclusions A large proportion of NRMD of IDet which can be inhibited by bacitracin may partly explain the reduced potency of IDet observed in rats and likely also in man.

A retrospective review of the 5-year nutritional and clinical outcomes in pediatric patients undergoing intestinal rehabilitation

The mainstay of modern medical therapy for intestinal failure (IF) is parenteral nutrition (PN). The Intestinal Rehabilitation Program (IRP) goal is enhancing nutritional outcomes for patients receiving total parenteral nutrition (TPN), optimizing/transitioning patients from TPN to enteral nutrition (EN), achieving enteral autonomy, monitoring growth and development. The objective of this study is to describe nutritional and clinical outcomes for children undergoing intestinal rehabilitation during 5 years of the program. Retrospective chart review for children from birth to <18 years old with IF who were on TPN from July 2015 to Dec 2020 or to the endpoint of the study when they either weaned from TPN during the 5 year period or continued TPN by Dec 2020 and participated at our IRP. The mean age of the cohort was 2.4 years (±4.22), 53% male. The 3 most common diagnosis were necrotizing enterocolitis (28%), gastroschisis (14%) and intestinal atresia (14%). Nutritional data including days/hours per week on TPN, glucose infusion rate, amino acids, total EN calories, % of total nutrition received from TPN and EN per day all showed statistically significant differences. Our program showed 0% intestinal failure associated liver disease (IFALD), 0% mortality, 100% survival, 41% patients were weaned from TPN (13/32) with mean of 39 months (±32). Early referral to a center that can offer IRP, such as ours can lead to tremendous positive clinical outcomes and help patients with intestinal failure avoid transplant as shown in our study.

Insulin-induced vasoconstriction is prevalent in muscle microvasculature of otherwise healthy persons with type 1 diabetes.

Insulin's microvascular actions and their relationship to insulin's metabolic actions have not been well studied in adults with type 1 diabetes mellitus (T1DM). We compared the metabolic and selected micro- and macrovascular responses to insulin by healthy adult control (n = 16) and subjects with T1DM (n = 15) without clinical microvascular disease. We measured insulin's effect on 1) skeletal muscle microvascular perfusion using contrast-enhanced ultrasound (CEU), 2) arterial stiffness using carotid-femoral pulse-wave velocity (cfPWV) and radial artery pulse wave analysis (PWA), and 3) metabolic insulin sensitivity by the glucose infusion rate (GIR) during a 2-h, 1 mU/min/kg euglycemic-insulin clamp. Subjects with T1DM were metabolically insulin resistant (GIR = 5.2 ± 0.7 vs. 6.6 ± 0.6 mg/min/kg, P < 0.001). Insulin increased muscle microvascular blood volume and flow in control (P < 0.001, for each) but not in subjects with T1DM. Metabolic insulin sensitivity correlated with increases of muscle microvascular perfused volume (P < 0.05). Baseline measures of vascular stiffness did not differ between groups. However, during hyperinsulinemia, cfPWV was greater (P < 0.02) in the T1DM group and the backward pulse wave pressure declined with insulin only in controls (P < 0.03), both indices indicating that insulin-induced vascular relaxation in controls only. Subjects with T1DM have muscle microvascular insulin resistance that may precede clinical microvascular disease.NEW & NOTEWORTHY Using contrast ultrasound and measures of vascular stiffness, we compared vascular and metabolic responses to insulin in patients with type 1 diabetes with age-matched controls. The patients with type 1 diabetes demonstrated both vascular and metabolic insulin resistance with more than half of the patients with diabetes having a paradoxical vasoconstrictive vascular response to insulin.

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

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

Enhanced Parenteral Nutrition Is Feasible and Safe in Very Low Birth Weight Preterm Infants: A Randomized Trial

Objective: The objective of this study was to determine the feasibility and safety of enhanced early (PN) (early initiation of intralipids and faster advancement of glucose infusion rate) during the first week of life for very low birth weight (VLBW) preterm infants. Methods: 90 VLBW preterm infants (<32 weeks gestational age at birth) admitted to the University of Minnesota Masonic Children’s Hospital between August 2017 and June 2019 were included. Enrolled infants were stratified by gestational age-groups and randomized to either the enhanced nutrition protocol (intervention group) or the standard PN protocol (standard group). Welch’s two-sample t tests were used to investigate differences in calorie and protein intake, insulin use, days of hyperglycemia, hyperbilirubinemia, and hypertriglyceridemia, and proportion of bronchopulmonary dysplasia, necrotizing enterocolitis, and death between groups. Results: Intervention and standard groups were similar in baseline characteristics. The intervention group received higher weekly mean caloric intake (102.6 [SD 24.9] kcal/kg/day versus 89.7 [SD 30.2] kcal/kg/day; p = 0.001) and higher mean caloric intake on days of life 2–4 (p < 0.05 for all). Both groups received the recommended protein intake (≥4 g/kg/day). There were no significant differences in safety or feasibility outcomes between groups (all p values >0.12). Conclusion: Utilization of an enhanced nutrition protocol during the first week of life resulted in increased caloric intake and was feasible with no evidence of harm. Follow-up of this cohort is needed to determine if enhanced PN will result in improved growth and neurodevelopment.

Differences in protein expression, at the basal state and at 2h of insulin infusion, in muscle biopsies from healthy Arab men with high or low insulin sensitivity measured by hyperinsulinemic euglycemic clamp.

Skeletal muscle is the main site for insulin-dependent glucose disposal. The hyperinsulinemic euglycemic clamp (HIEC) is the gold standard for the assessment of insulin sensitivity (IS). We have previously shown that insulin sensitivity, measured by HIEC, varied widely among a group of 60 young healthy men with normoglycemia. The aim of this study was to correlate the proteomic profile of skeletal muscles to insulin sensitivity. Muscle biopsies from 16 subjects having the highest (M ≥ 13; n = 8, HIS) and lowest (M ¾ 6, n = 8, LIS) IS were obtained at baseline and during insulin infusion after stabilization of the blood glucose level and glucose infusion rate at the end of the HIEC. The samples were processed using a quantitative proteomic analysis approach. At baseline, 924 proteins were identified in the HIS and LIS groups. Among the 924 proteins detected in both groups, three were suppressed and three were increased significantly in the LIS subjects compared with the HIS subjects. Following insulin infusion, 835 proteins were detected in both groups. Among the 835 proteins, two showed differential responsiveness to insulin; ATP5F1 protein was decreased, and MYLK2 was higher in the LIS group compared with that in the HIS group. Our data suggest that alteration in mitochondrial proteins and an increased number of proteins involved in fast-twitch fiber correlate to insulin sensitivity in healthy young Arab men. These results suggest a change in a small number of differentially expressed proteins. A possible reason for this small change could be our study cohorts representing a homogeneous and healthy population. Additionally, we show differences in protein levels from skeletal muscle in low and high insulin sensitivity groups. Therefore, these differences may represent early events for the development of insulin resistance, pre-diabetes, and type 2 diabetes.

Skeletal muscle and intermuscular adipose tissue gene expression profiling identifies new biomarkers with prognostic significance for insulin resistance progression and intervention response

Aims/hypothesisAlthough insulin resistance often leads to type 2 diabetes mellitus, its early stages are often unrecognised, thus reducing the probability of successful prevention and intervention. Moreover, treatment efficacy is affected by the genetics of the individual. We used gene expression profiles from a cross-sectional study to identify potential candidate genes for the prediction of diabetes risk and intervention response.MethodsUsing a multivariate regression model, we linked gene expression profiles of human skeletal muscle and intermuscular adipose tissue (IMAT) to fasting glucose levels and glucose infusion rate. Based on the expression patterns of the top predictive genes, we characterised and compared individual gene expression with clinical classifications using k-nearest neighbour clustering. The predictive potential of the candidate genes identified was validated using muscle gene expression data from a longitudinal intervention study.ResultsWe found that genes with a strong association with clinical measures clustered into three distinct expression patterns. Their predictive values for insulin resistance varied substantially between skeletal muscle and IMAT. Moreover, we discovered that individual gene expression-based classifications may differ from classifications based predominantly on clinical variables, indicating that participant stratification may be imprecise if only clinical variables are used for classification. Of the 15 top candidate genes, ST3GAL2, AASS, ARF1 and the transcription factor SIN3A are novel candidates for predicting a refined diabetes risk and intervention response.Conclusion/interpretationOur results confirm that disease progression and successful intervention depend on individual gene expression states. We anticipate that our findings may lead to a better understanding and prediction of individual diabetes risk and may help to develop individualised intervention strategies.Graphical abstract

Altered glucose-dependent secretion of glucagon and ACTH is associated with insulin resistance, assessed by population analysis.

This study aimed to characterize how the dysregulation of counter-regulatory hormones can contribute to insulin resistance and potentially to diabetes. Therefore, we investigated the association between insulin sensitivity and the glucose- and insulin-dependent secretion of glucagon, adrenocorticotropic hormone (ACTH), and cortisol in non-diabetic individuals using a population model analysis. Data, from hyperinsulinemic-hypoglycemic clamps, were pooled for analysis, including 52 individuals with a wide range of insulin resistance (reflected by glucose infusion rate 20-60 min; GIR20-60min). Glucagon secretion was suppressed by glucose and, to a lesser extent, insulin. The GIR20-60min and BMI were identified as predictors of the insulin effect on glucagon. At normoglycemia (5 mmol/L), a 90% suppression of glucagon was achieved at insulin concentrations of 16.3 and 43.4 µU/mL in individuals belonging to the highest and lowest quantiles of insulin sensitivity, respectively. Insulin resistance of glucagon secretion explained the elevated fasting glucagon for individuals with a low GIR20-60min. ACTH secretion was suppressed by glucose and not affected by insulin. The GIR20-60min was superior to other measures as a predictor of glucose-dependent ACTH secretion, with 90% suppression of ACTH secretion by glucose at 3.1 and 3.5 mmol/L for insulin-sensitive and insulin-resistant individuals, respectively. This difference may appear small but shifts the suppression range into normoglycemia for individuals with insulin resistance, thus, leading to earlier and greater ACTH/cortisol response when the glucose falls. Based on modeling of pooled glucose-clamp data, insulin resistance was associated with generally elevated glucagon and a potentiated cortisol-axis response to hypoglycemia, and over time both hormonal pathways may therefore contribute to dysglycemia and possibly type 2 diabetes.

The Effect of BMI on Pharmacokinetic and Pharmacodynamic Parameters of Insulin Degludec: Results from an Euglycemic Glucose Clamp Study.

This study evaluated the effect of body mass index (BMI) on pharmacokinetic (PK) and pharmacodynamic (PD) parameters of insulin degludec in healthy Chinese males, depending on an euglycemic glucose clamp study. Sixty-five healthy male subjects were divided into four groups according to quartile of BMI value. Group A: BMI ≤ 20.7 kg/m2; group B: 20.7 < BMI ≤ 22.5 kg/m2; group C: 22.5 < BMI ≤ 23.6 kg/m2; group D: BMI > 23.6 kg/m2. Each volunteer received a single subcutaneous dose (0.4 U/kg) of insulin degludec and accepted a 24-h euglycemic glucose clamp study. The primary PK parameters were maximum observed drug concentration (Cmax) and the area under the curve (AUCINS) for the specified time intervals. The primary PD parameters were the time to the start of glucose infusion (Tonset), maximal glucose infusion rate (GIRmax) and area under the curve (AUCGIR) for the specified time intervals. The differences of these PK/PD parameters were compared among groups. Cmax and the AUC of insulin (0-6 h, 6-12 h and 0-24 h) were more than onefold higher in group A than those in groups B, C, D, and the concentration-time curve of group A was significantly shifted to the left compared with the other three groups. The GIRmax, total AUCGIR, and AUCGIR for each time interval were significantly higher in group A than those in other three groups. The proportion of AUCGIR in group A was the lowest proportion among four groups seen in the late stage. Multiple linear regression analysis showed that BMI was negatively correlated with AUCGIR,0-24 h. Insulin degludec in healthy Chinese male subjects with BMI ≤ 20.7 kg/m2 had a faster absorption, clearance, and a stronger glucose-lowering effect, but a steeper decrease of insulin action in the late stage after dosing.

Pharmacokinetics and Pharmacodynamics of a Novel U500 Insulin Aspart Formulation: A Randomized, Double-Blind, Crossover Study in People With Type 1 Diabetes.

To evaluate the pharmacokinetics, pharmacodynamics, and safety of a novel U500 insulin aspart formulation (AT278 U500) compared with insulin aspart (IAsp U100). This single-center, randomized, double-blind study was conducted in 38 men with type 1 diabetes (body weight ≤100 kg and total insulin dose <1.2 units/kg/day). Participants received a single dose of either AT278 U500 or IAsp U100 (0.3 units/kg s.c.) in a crossover design, followed by an 8-h euglycemic clamp in the absence of basal insulin. With AT278 U500, onset of appearance in serum was 6 min earlier (P < 0.0001) and reached 50% of maximum concentration 23 min faster (P < 0.0001). Insulin exposure with AT278 U500 was 4.0-fold higher within the first 30 min (95% CI 3.29, 4.90), 1.5-fold higher within the first 60 min (95% CI 1.35, 1.76), and statistically superior up to 90 min postdose (P < 0.05). With AT278 U500, onset of action was 10 min earlier (P < 0.0001) and reached 50% of maximum glucose infusion rate 20 min faster (P < 0.0001). The glucose-lowering effect with AT278 U500 was 8.9-fold higher within the first 30 min (95% CI 5.96, 17.46), 2.4-fold higher within the first 60 min (95% CI 1.92, 3.22), and statistically superior up to 2 h postdose (P < 0.0001). Overall insulin exposure and glucose-lowering effect were comparable. No significant safety findings were observed. AT278 U500 offers rapid-acting characteristics in a reduced dose volume, with accelerated absorption and onset of action compared with IAsp U100 in the studied population.