Intravenous Glucose Research Articles

Long-term health after Severe Acute Malnutrition in children and adults- the role of the Pancreas (SAMPA): Protocol

Background: Prenatal growth retardation may increase the risk of later chronic non-communicable diseases (NCDs), including diabetes; however, long-term effects of wasting malnutrition in childhood or adulthood are less studied. Pancreatic exocrine and endocrine functions, both critical for nutrition and NCD aetiology, may not fully recover following malnutrition. However, the evidence and mechanistic information is piecemeal. We hypothesise that wasting malnutrition at any age has long-term detrimental effects on endocrine and exocrine pancreatic structure and function. Methods: The SAMPA international research programme will assess pancreatic structure and function in 3700 participants from ongoing observational nutrition cohorts, two adolescent and four adult, in Zambia, Tanzania, Philippines, and India. Pancreas size, structure, and calcification will be assessed by ultrasound and computed tomography (CT) scan; exocrine function by faecal elastase and serum lipase; and endocrine function by haemoglobin A1c (HbA1c) and blood glucose, insulin and C-peptide concentrations during an oral glucose tolerance test (OGTT). In-depth hormonal analyses of incretins, glucagon, proinsulin and trypsinogen during OGTT and intravenous glucose tolerance tests will be done in subsets of adult participants. Pancreatic size and function outcomes will be compared between people with and without prior wasting malnutrition. Analyses will investigate effect modification by sex, current age, time since malnutrition, current body mass index and dietary patterns. Mathematical modelling of OGTT data will be used to estimate the relative contribution to glucose dysregulation of decreased insulin production, changes in insulin clearance and increased insulin resistance. Proinsulin/insulin ratio will be analysed in archived samples from the Tanzanian cohort using a nested case-control design to investigate whether abnormal values precede diabetes. Conclusions: SAMPA, a large-scale multi-centre research programme using data from people with or without prior wasting malnutrition to assess several aspects of pancreatic phenotype, will provide coherent evidence for future policies and programmes for malnutrition and diabetes.

Berberine supplementation modulates the somatotropic axis and ameliorates glucose tolerance in dairy goats during late gestation and early lactation

BackgroundPregnancy, parturition, and the onset of lactation represent an enormous physiological and hormonal challenge to the homeostasis of dairy animals, being a risk for their health and reproduction. Thus, as a part of the homothetic changes in preparturition period, goats undergo a period of IR as well as uncoupled GH/IGF-1 axis. The objective for this study was to determine the effect of berberine (BBR) during the peripartal period on hormonal alteration and somatotropic axis in dairy goats as well as glucose and insulin kinetics during an intravenous glucose tolerance test (IVGTT). At 21 days before the expected kidding date, 24 primiparous Saanen goats were assigned randomly to 4 dietary treatments. Goats were fed a basal diet from wk. 3 antepartum (AP) until wk. 3 postpartum (PP) supplemented with 0 (CTRL), 1 (BBR1), 2 (BBR2), and 4 (BBR4) g/d BBR. Blood samples were collected on days − 21, − 14, − 7, 0, 7, 14, and 21 relative to the expected kidding date. An IVGTT was also performed on day 22 PP.ResultsCompared with CTRL, supplementation with either BBR2 or BBR4 increased DMI at kidding day and PP, as well as body conditional score (BCS) and milk production (p ≤ 0.05). On d 7 and 14 PP plasma glucose was higher in BBR2- and BBR4-treated than in CTRL. The glucagon concentration was not affected by BBR during the experimental period. However, supplemental BBR indicated a tendency to decrease in cortisol concentration on days 7 (p = 0.093) and 14 (p = 0.100) PP. Lower plasma GH was observed in BBR than in non-BBR goats (p ≤ 0.05). Plasma IGF-1 concentration was enhanced in both BBR2 and BBR4 at kidding and day 7 PP (p ≤ 0.05). During the IVGTT, glucose area under the curve (AUC), clearance rate (CR), T1/2, and Tbasal was lower (p ≤ 0.05) in both BBR2 and BBR4 goats as compared with CTRL. Likewise, the insulin CR was higher (p ≤ 0.05) in goats receiving either BBR2 or BBR4 which was accompanied by a lower insulin T1/2 and AUC.ConclusionsAltogether, our results indicated an improved glucose and insulin status along with the modulation of the somatotropic axis and glucose and insulin response to IVGTT in dairy goats supplemented with 2 and 4 g/d BBR.

204 Awardee Talk: Poor Maternal Nutrition Impacts Metabolic Factors and Glucose Tolerance in Sheep Offspring

Abstract To evaluate the hypothesis that offspring born to restricted- and over-fed ewes would exhibit decreased glucose tolerance, total cholesterol (TC), and triglyceride (TG), and increased leptin, multiparous Dorset ewes (n = 46) pregnant with twins were fed 100%, 60% or 140% of National Research Council (NRC) requirements from d30±0.02 of gestation until parturition. Offspring are referred to as CON (n=10 ewes; 12 rams), RES (n=13 ewes; 21 rams), and OVER (n =16 ewes; 15 rams), respectively. Blood samples were collected from offspring at d0, 7, 14, 58, 210, and 252 of age and plasma TC, plasma TG, and serum leptin were analyzed with commercial kits. Concentrations of TG were greater in rams than ewes (P=0.029). Leptin was greater (P< 0.0001) in ewes than rams at d30 and 36, and greater in CON than RES and OVER at d252 (P=0.058). At d133±0.25 an intravenous glucose tolerance test was performed, and blood samples collected at -30, -15, 0, 2, 5, 10, 15, 30, 60, and 120 min relative to glucose infusion (0.25 g/kg body weight of a 50% dextrose solution). Glucose and insulin concentrations were determined using commercial kits. Glucose concentrations were greater at 5 and 15 min in ewes than rams (P≤0.04) and at 2 min, OVER were greater than CON and RES (P=0.03). Insulin concentrations were greater in rams than ewes between 5 and 15 min (P=0.0251). Insulin in RES rams tended to be greater than OVER and RES ewes between 5 and 10 min (P=0.06) and continued to be greater than RES ewes at 15 min (P=0.05). First-phase response of insulin tended to be greater in RES compared with CON and OVER (P=0.092). There were no differences detected in insulin:glucose (P=0.312). In conclusion, poor maternal nutrition negatively impacts key metabolic hormones in offspring thereby contributing to altered growth and metabolism.

PSII-B-12 Association of Glucose Metabolism with Feed Intake, Growth, and Efficiency of Beef Steers

Abstract The objective of this experiment was to determine the association of glucose metabolism and insulin sensitivity with dry matter intake (DMI), average daily gain (ADG), and feed efficiency (G:F) of steers fed a finishing diet. Steers (n = 55; initial body weight 518 ± 26.7 kg) were subjected to an intravenous glucose tolerance test (IVGTT) where glucose was dosed through a jugular catheter and serial blood samples were collected. Three days after the final IVGTT, steers began a 63-d DMI and ADG test. Body weight was measured on d 0, 1, 21, 42, 62, and 63, and DMI was measured using an Insentec Roughage Intake Control system (Insentec, Markenesse, The Netherlands). Peak insulin concentration in response to the IVGTT tended to be correlated with ADG (r = 0.25; P = 0.07) and DMI (r = 0.23; P = 0.09), indicating cattle with greater ADG and DMI tend to require a greater insulin release in response to glucose. Glucose nadir concentrations were correlated with ADG (r = 0.27; P = 0.044) and G:F (r = 0.37; P = 0.005). Additionally, when steers within 0.5 standard deviations of the mean for DMI are classed as displaying high- or low-ADG, glucose nadir was greater in high-ADG steers (P = 0.042). The association of greater glucose nadir with high-ADG could indicate that high-ADG steers do not clear glucose as efficiently as low-ADG steers, potentially indicating reduced insulin sensitivity. Carcass marbling score was negatively correlated with area under the glucose curve (r = -0.38; P = 0.006), glucose clearance rate (r = -0.33; P = 0.016), and glucose nadir concentration (r = -0.40; P = 0.004). These results indicate that glucose metabolism and insulin signaling are associated with growth, efficiency, and carcass quality, but the molecular mechanisms that drive these effects need to be elucidated.

162 Differential Late Gestation Metabolizable Energy Intake Alters Adipose-Specific Insulin Responsiveness in Antepartum Beef Cattle

Abstract We evaluated how metabolizable energy (ME) intake influences antepartum insulin sensitivity in beef cattle. Angus-Simmental cattle (primiparous: n = 17; multiparous: n = 21) were randomly assigned to treatments supplying 80 (LowME, n = 19) or 120% (HighME, n = 19) of predicted ME requirements for 53 d prepartum. At 7 d antepartum, intravenous glucose tolerance tests (IVGTT) were imposed by infusing 1.36 g glucose/kg BW0.75 and sampling from -3 to 90 min to measure plasma glucose and insulin and serum non-esterified fatty acids (NEFA) concentrations. Data were analyzed using PROC GLIMMIX with the fixed effects of treatment, parity, time (repeated), and treatment×time and considering cow(treatment) as random. Baseline glucose concentration increased (P = 0.03) and baseline insulin concentration tended to increase (P = 0.06) for HighME relative to LowME cattle irrespective (P ≥ 0.33) of parity, whereas baseline NEFA concentration was elevated (P < 0.01) for LowME vs. HighME. Plasma glucose-insulin concentrations during the IVGTT did not differ (P ≥ 0.25) by treatment, treatment×time, or parity. However, serum NEFA was elevated (P < 0.01) throughout the IVGTT for LowME vs. HighME cattle and tended to be affected (P = 0.09) by the treatment×time interaction as NEFA concentrations became similar at 90 min due to HighME cattle having a shallower (treatment×time: P < 0.01) decremental NEFA response than LowME cattle. Low ME cattle cleared NEFA more quickly (75% increase; P < 0.01) than HighME. The glucose positive incremental area-under-the-curve throughout the IVGTT tended to be lesser (P = 0.06) for heifers than cows but heifers had a blunted (P ≤ 0.05) glucose-stimulated reduction in NEFA and NEFA clearance rate compared to cows. These data demonstrate that ME provision may alter adipose insulin responsiveness in antepartum beef cattle and that heifers respond to excess glucose and NEFA differently than cows.

Childhood growth hormone treatment and metabolic and cardiovascular risk in adults born small for gestational age after growth hormone cessation in the Netherlands: a 12-year follow-up study

Childhood growth hormone treatment has been associated with increased cardiovascular mortality and morbidity in adults born small for gestational age (SGA) compared with the general population, but these risks have not been compared with untreated control groups. We aimed to investigate longitundinal metabolic and cardiovascular health in adults born SGA after cessation of growth hormone treatment. We longitudinally investigated the metabolic and cardiovascular health profile of 167 adults born SGA and previously treated with growth hormone during the 12 years after growth hormone cessation. Metabolic and cardiovascular parameters were assessed with the frequently sampled intravenous glucose tolerance test, serum lipids and blood pressure were measured, body composition was determined by dual-energy x-ray absorptiometry, and visceral fat was measured by MRI. At approximately age 30 years, we compared the metabolic and cardiovascular health profile of adults born SGA and previously treated with growth hormone (SGA-GH) with 219 untreated adults: 127 born SGA with either persistent short stature (SGA-S) or spontaneous catch-up to typical adult stature (SGA-CU), and 92 born appropriate for gestational age. During 12 years of follow-up, SGA-GH adults maintained normal β-cell function (p=0·157 for the difference from growth hormone cessation to 12-year follow-up) and showed an increase in insulin sensitivity (p=0·002), fat mass (p<0·001), total cholesterol (p<0·001), and blood pressure (p<0·001). By around age 30 years, these parameters reached similar levels to those in SGA-S adults (insulin sensitivity p=0·242; fat mass p=0·449; total cholesterol p=0·616; systolic blood pressure p=0·523; diastolic blood pressure p=0·538). By around age 30 years, SGA-GH adults also had similar metabolic and cardiovascular health parameters to adults born appropriate for gestational age, with the exception of lower lean body mass (estimated marginal mean 44·67 kg [95% CI 43·54-45·80] in SGA-GH adults vs 47·65 kg [46·39-48·92] in adults born appropriate for gestational age) and higher concentrations of adverse serum lipids, such as cholesterol (4·75 mmol/L [4·55-4·95] vs 4·33 mmol/L [4·13-4·5]), which were present in all groups born SGA. Abdominal adiposity (visceral adipose tissue p=0·107; subcutaneous adipose tissue: p=0·244), liver fat fraction (p=0·104), and blood pressure (systolic blood pressure 0·927; diastolic blood pressure: 0·737) were similar between SGA-GH adults and all control groups. At approximately age 30 years, SGA-GH adults had a similar metabolic and cardiovascular health profile to untreated adults born SGA or appropriate for gestational age, indicating long-term metabolic and cardiovascular safety of growth hormone treatment for children born SGA with short stature. Novo Nordisk.

Long-term remission of type 2 diabetes after very-low-calorie restriction and related predictors.

PurposeVery low-calorie restriction (VLCR) can induce remission of type 2 diabetes mellitus (T2DM), but its long-term remission and related predictors have not been clarified. The aim of present study is to investigate the effect of VLCR in inducing long-term T2DM remission, and the underlying predictors.MethodsA total of 61 participants with T2DM who received 9 days of VLCR from Dec 2012 to Oct 2020 were followed up in Nov 2021, and divided into responders and non-responders groups. Responders were defined as HbA1c < 6.5% over at least 3 months in the absence of pharmacotherapy. Clinical characteristics were compared between responders and non-responders. Potential predictors were examined by logistic regression analyses based on clinical data before and after VLCR.ResultsForty-four participants were successfully followed up, including 19 males and 25 females. Long-term remission was observed in 17 participants (38.64%) after VLCR, with a median 7.83 years. Compared with non-responders, responders had a shorter disease duration, a lower fasting blood glucose (FBG) level, a higher fasting insulin level, and better HOMA-β after VLCR. Besides, acute insulin response (AIR), insulin area under curve in intravenous and oral glucose tolerance test (IVGTT-IAUC and OGTT-IAUC) in responders were higher than those in non-responders after VLCR. Multivariable logistic analysis showed that higher post-VLCR IVGTT-IAUC predicted a longer T2DM remission.ConclusionsAfter VLCR, more than one third of the participants presented remission over up to 8 years. The improvement of β-cell function, especially the restoration of first-phase insulin-secreting capacity, could prolongate the remission.

Gluclas: A software for computer-aided modulation of glucose infusion in glucose clamp experiments

Background and ObjectiveThe glucose clamp (GC) is an experimental technique for assessing several aspects of glucose metabolism. In these experiments, investigators face the non-trivial challenge of accurately adjusting the rate of intravenous glucose infusion to drive subjects’ blood glucose (BG) concentration towards a desired plateau level. In this work we present Gluclas, an open-source software to support researchers in the modulation of glucose infusion rate (GIR) during GC experiments. MethodsGluclas uses a proportional-integrative-derivative controller to provide GIR suggestions based on BG measurements. The controller embeds an anti-wind-up scheme to account for actuator physical limits and suitable corrections of control action to accommodate for possible sampling jitter due to manual measurement and actuation. The software also provides a graphic user interface to increase its usability. A preliminary validation of the controller is performed for different clamp scenarios (hyperglycemic, euglycemic, hypoglycemic) on a simulator of glucose metabolism in healthy subjects, which also includes models of measurement error and sampling delay for increased realism. In silico trials are performed on 50 virtual subjects. We also report the results of the first in-vivo application of the software in three subjects undergoing a hypoglycemic clamp. ResultsIn silico, during the plateau period, the coefficient of variation (CV) is in median below 5% for every protocol, with 5% being considered the threshold for sufficient quality. In terms of median [5th percentile, 95th percentile], average BG level during the plateau period is 12.18 [11.58 - 12.53] mmol/l in the hyperglycemic clamp (target: 12.4 mmol/), 4.92 [4.51 – 5.14] mmol/l in the euglycemic clamp (target: 5.5 mmol/) and 2.38 [2.33 – 2.64] in the hypoglycemic clamp (target: 2.5 mmol/). Results in vivo are consistent with those obtained in silico during the plateau period: average BG levels are between 2.56 and 2.68 mmol/l (target: 2.5 mmol/l); CV is below 5% for all three experiments. ConclusionsGluclas offered satisfactory control for tested GC protocols. Although its safety and efficacy need to be further validated in vivo, this preliminary validation suggest that Gluclas offers a reliable and non-expensive solution for reducing investigator bias and improving the quality of GC experiments.

Diagnostic Significance of Combined Calcitoninogen, Platelet, and D-Dimer Assay in Severe Heatstroke: with Clinical Data Analysis of 70 Patients with Severe Heatstroke.

The significance of calcitoninogen detection among inpatients was discussed by analyzing the clinical characteristics of severe heatstroke (HS). HS patients who were admitted to the Second Hospital of Nantong University, Jiangsu Province, China, between July 1, 2015, and October 30, 2020, were reviewed. Patients' clinical characteristics and laboratory data were recorded, and they were divided into three groups, that is, a control group (heat cramps and heat exhaustion), an exertional HS (EHS) group, and a classical HS (CHS) group to compare the differences among them. Receiver operating characteristic (ROC) curves were plotted to evaluate patients' clinical utility. (1) The body temperatures in the EHS and CHS groups were significantly higher than in the control group (all p < 0.05). (2) The D-dimer (DD), procalcitonin (PCT), and Acute Physiology and Chronic Health Evaluation (APACHE) II score of the EHS group were significantly higher compared with the control and CHS groups (all p < 0.05); the platelets (PLT), C-reactive protein (CRP), blood sodium (Na), and intravenous glucose (GLU) of the EHS group were lower than in the control and CHS groups (all p < 0.05). (3) The ROC curve analysis showed the performance results for DD (area under the curve [AUC] 0.670, 95% confidence interval [CI] 0.547-0.777), PCT (AUC 0.705, 95% CI 0.584-0.808), and PLT (AUC 0.791, 95% CI 0.677-0.879). The sensitivity was 40.48%, 100%, and 73.81%, and the specificity was 96.43%, 32.14%, and 78.57%, respectively. Using three combined analyses, an elevated AUC of 0.838, 95% CI 0.731-0.916, with a sensitivity of 71.43% and a specificity of 85.71%, respectively, was revealed. Patients in the EHS group had higher DD, PCT, and APACHE II values, whereas PLT, CRP, Na, and GLU were reduced. The apparent decrease in the PLT, as well as the increase in PCT and DD values, could be considered as early sensitivity indicators of severe HS. A combined test of these three indicators presented significant diagnostic value for detecting severe cases of HS.

Dietary Chromium Picolinate Supplementation Improves Glucose Utilization in Transition Calf by Ameliorating Insulin Response.

The decrease in insulin sensitivity during the transition of preruminant calves into ruminant animals is the common denominator. Meanwhile, this adaptation predisposes dairy calves towards various health issues and metabolic disorders that occur in later life. Chromium (Cr) has been shown to potentiate insulin functioning and is thereby helpful in reducing the risk of these metabolic disorders. The aim of this study was to assess the effect of Cr supplementation on the insulin sensitivity and health status in Hariana calves during their transition period. A total of 24 preruminant Hariana calves were randomly allocated into four groups (6 calves per group) for a period of 90days. Calves either received a basal diet devoid of supplemental Cr (control; Cr0.0 group) or were supplemented with 0.05mg (Cr0.05 group), 0.10mg (Cr0.10 group), and 0.15mg (Cr0.15 group) of Cr per kg BW0.75 as Cr-picolinate (Cr-Pic). To determine the effect of Cr supplementation on the insulin response, glucose-insulin-non-esterified fatty acids (NEFAs) kinetics was studied during the intravenous glucose tolerance test (IVGTT) and oral glucose tolerance test (OGTT). A rapid glucose disappearance (p < 0.05) with unaltered insulin kinetics during IVGTT and OLTT indicates greater insulin sensitivity in calves supplemented with 0.10 and 0.15mg of Cr per kg BW0.75. Improved insulin sensitivity in the Cr0.10 and Cr0.15 groups was further confirmed by higher (p < 0.05) values of the insulin sensitivity check index (QUICKI), revised quantitative insulin sensitivity check index (RQUICKI), and lower (p < 0.05) values of the homeostasis model assessment-insulin resistance (HOMA-IR) during IVGTT. Mean serum non-esterified fatty acids (NEFAm), and insulin receptor substrate-1 (IRS-1) levels were the highest (p < 0.05) and cortisol concentrations were the lowest (p < 0.05) in the Cr0.15 groups. Unlike IVGTT, there was no effect of treatment, period, and treatment × period interaction on mean serum glucose and insulin levels during OGTT. However, Cr-supplemented calves had a higher (p < 0.05) glucose clearance rate (gCR). Serum IRS-1 concentrations during OGTT were also higher (p < 0.05) in the Cr0.10 and Cr0.15 groups than in the other groups. Serum Cr levels increased dose dependently and were the highest (p < 0.05) in calves fed a diet supplemented with 0.15mg Cr per kg BW0.75. There was no effect of treatment on average daily gain (ADG) and body condition score (BCS) while frequency and duration of diarrhea were lower and fecal score was better in Cr-supplemented calves. The current findings show that Cr supplementation improved glucose utilization and health status in calves during their transition period by improving insulin sensitivity.

A glucose-insulin-glucagon coupled model of the isoglycemic intravenous glucose infusion experiment.

Type 2 diabetes (T2D) is a pathophysiology that is characterized by insulin resistance, beta- and alpha-cell dysfunction. Mathematical models of various glucose challenge experiments have been developed to quantify the contribution of insulin and beta-cell dysfunction to the pathophysiology of T2D. There is a need for effective extended models that also capture the impact of alpha-cell dysregulation on T2D. In this paper a delay differential equation-based model is developed to describe the coupled glucose-insulin-glucagon dynamics in the isoglycemic intravenous glucose infusion (IIGI) experiment. As the glucose profile in IIGI is tailored to match that of a corresponding oral glucose tolerance test (OGTT), it provides a perfect method for studying hormone responses that are in the normal physiological domain and without the confounding effect of incretins and other gut mediated factors. The model was fit to IIGI data from individuals with and without T2D. Parameters related to glucagon action, suppression, and secretion as well as measures of insulin sensitivity, and glucose stimulated response were determined simultaneously. Significant impairment in glucose dependent glucagon suppression was observed in patients with T2D (duration of T2D: 8 (6–36) months) relative to weight matched control subjects (CS) without diabetes (k1 (mM)−1: 0.16 ± 0.015 (T2D, n = 7); 0.26 ± 0.047 (CS, n = 7)). Insulin action was significantly lower in patients with T2D (a1 (10 pM min)−1: 0.000084 ± 0.0000075 (T2D); 0.00052 ± 0.00015 (CS)) and the Hill coefficient in the equation for glucose dependent insulin response was found to be significantly different in T2D patients relative to CS (h: 1.4 ± 0.15; 1.9 ± 0.14). Trends in parameters with respect to fasting plasma glucose, HbA1c and 2-h glucose values are also presented. Significantly, a negative linear relationship is observed between the glucagon suppression parameter, k1, and the three markers for diabetes and is thus indicative of the role of glucagon in exacerbating the pathophysiology of diabetes (Spearman Rank Correlation: (n = 12; (−0.79, 0.002), (−0.73,.007), (−0.86,.0003)) respectively).

The Use of Ceramides to Predict Metabolic Response to Metformin in Women With PCOS.

ContextPolycystic ovarian syndrome (PCOS) is a complex disorder in which metabolic abnormalities are associated with reproductive dysfunction. Women with PCOS have increased ceramide concentrations. Previous studies demonstrated that treating metabolic abnormalities of PCOS with metformin improved glucose effectiveness after 12 weeks.ObjectiveWe evaluated whether, in women with PCOS, lower baseline ceramide, diacylglycerol (DAG), and triacylglycerol (TAG) concentrations were associated with improved metabolic response to metformin.MethodsWomen (n = 29), aged 29 ± 5 years and diagnosed with PCOS by the NIH criteria underwent an intravenous glucose tolerance test (IVGTT) before and after 12-week treatment with metformin (1500 mg per day). Metabolic responders were defined by improved glucose effectiveness, specifically, the ability of glucose to stimulate uptake and suppress production, after metformin treatment.ResultsTwelve weeks of metformin resulted in weight loss (−1.7 ± 2.6 kg, P < 0.01) and a reduction in BMI (−0.6 ± 0.9 kg/m2, P < 0.01) with no change in HbA1c. The concentrations of Cer(d18:1/22:0), Cer(d18:1/24:0), total ceramides, total Cer(d16:0), total Cer(d18:2), DAG, dihydrosphingomyelin (DHSM), and TAG decreased after metformin treatment (P < 0.05). Baseline total Cer(d16:0) concentration <204.1 pmol/mL was 82% sensitive (AUC 0.72, P = 0.03) and total DHSM concentration <32237 pmol/mL was 100% specific (AUC 0.73, P = 0.03) in predicting improved metabolic response to metformin, as measured by IVGTT.ConclusionLower total Cer(16:0) and DHSM concentrations are associated with a beneficial metabolic response to metformin in women with PCOS. Based on the known association between higher ceramide levels and type 2 diabetes, the data suggest that metformin improves metabolic parameters in women with mild metabolic derangements.

Significance of pancreatic duodenal homeobox-1 (PDX-1) genetic polymorphism in insulin secretion in Japanese patients with type 2 diabetes

IntroductionPancreatic and duodenal homeobox factor-1 (PDX-1) is an imperative gene for insulin secretion in maturity-onset diabetes of the young 4. PDX-1 gene polymorphism was associated with lower first-phase insulin secretion...

Comprehensive validation of fasting-based and oral glucose tolerance test–based indices of insulin secretion against gold standard measures

IntroductionWith pre-diabetes and diabetes increasingly recognized as heterogeneous conditions, assessment of beta-cell function is gaining clinical importance to identify disease subphenotypes. Our study aims to comprehensively validate all types of...

Positive input observer‐based controller design for blood glucose regulation for type 1 diabetic patients: A backstepping approach

In practice, there are many physical systems that can have only positive inputs, such as physiological systems. Most conventional control methods cannot ensure that the main system input is positive. A positive input observer‐based controller is designed for an intravenous glucose tolerance test model of type 1 diabetes mellitus (T1DM). The backstepping (BS) approach is employed to design the feedback controller for artificial pancreas (AP) systems, based on the Extended Bergman's Minimal Model (EBMM). The EBMM represents the T1DM in terms of the blood glucose concentration (BGC), insulin concentration, and plasma level and the disturbance of insulin during medication due to either meal intake or burning sugar by doing some physical exercise. The insulin concentration and plasma level are estimated using observers, and these estimations are applied as feedback to the controller. The asymptotic stability of the observer‐based controller is proved using the Lyapunov theorem. Moreover, it is proved that the system is bounded input‐bounded output (BIBO) stable in the presence of uncertainties generated by uncertain parameters and external disturbance. For realistic situations, we consider only the BGC to be available for measurement and additionally inter‐and intra‐patient variability of system parameters is considered.

STABILITY ANALYSIS AND NUMERICAL SIMULATIONS OF IVGTT GLUCOSE-INSULIN INTERACTION MODELS WITH TWO TIME DELAYS

This paper presents a systematic study of a mathematical model of glucose and insulin interaction with two time delays, with a focus on analytical studies, bifurcation analysis, and very well numerical simulations. This model based on the Intra-Venous Glucose Tolerance Test (IVGTT) and is presented with two time delays. One delay is the insulin response time to an increase in glucose concentration, and the hepatic glucose production time delay is the other. Then, we establish results on positivity, boundedness, and persistence. We also provide sufficient stability analysis conditions for both local and global asymptotic stability of the proposed models. For the latter, two different strategies are used: stability bifurcation analysis and Lyapunov-Krasovskii functionals. We investigate different regions of parameter space using two approaches, that yield different sets of sufficient conditions for global stability. The bifurcation graphs generated from our extensive and carefully designed simulations complement and confirm these analytical results. The insulin concentration level peaks after the glucose concentration level, according to the numerical simulations.

Not only for caregivers: intranasal glucagon for severe hypoglycaemia in a simulation study.

To evaluate: (i) the propensity of paediatrics and emergency medicine residents to select different therapeutic options and (ii) the speed and administration success in a high-fidelity simulation of severe hypoglycaemia in a child with type 1 diabetes (T1DM). In this single-centre high-fidelity simulation study, 51 paediatrics or emergency medicine residents were exposed to a scenario of severe hypoglycaemia in a T1DM child attending an ambulatory setting, before and after a training on the preparation and administration of both injectable and IN glucagon. Time for drug delivery and its effectiveness were collected. Before training, 45.1% of participants chose to administer injectable glucagon, 43.1% intravenous glucose solution, 5.9% intranasal (IN) glucagon, and 5.9% took no action. Administration was successful in 74% of injectable glucagon, 33.3% intravenous glucose solution, and 22.7% IN glucagon. After training, 58.8% of participants chose IN and 41.2% injectable glucagon, with 100% of successful administrations for IN glucagon and 90.5% for injectable glucagon. Time to successful administration was shorter for IN than injectable glucagon (23 ± 10 vs. 38 ± 7s, p < 0.0001). IN glucagon is an easy and effective option for severe hypoglycaemia treatment, with an almost zero possibility of failure provided that adequate training is imparted.

Measuring and estimating insulin resistance in clinical and research settings

The article discusses how to measure insulin resistance in muscle, liver, and adipose tissue in human participants. The most frequently used methodologies to evaluate insulin resistance are described in detail starting from the gold standard, that is, the euglycemic hyperinsulinemic clamp, to the intravenous glucose tolerance test, surrogate indices based on fasting measurements, or dynamic tests (such as oral glucose or mixed meal tolerance tests). The accuracy, precision, and reproducibility of the tests as well as cutoff values are reported.

Circulating levels of five proglucagon-derived peptides in response to intravenous or oral glucose or lipids and to a mixed-meal in subjects with normal weight, overweight, and obesity

Proglucagon-derived peptides (PGDPs) secreted by the gut and pancreas play a major role in metabolism. We measured concentrations of five PGDPs in response to per os (PO) or intravenous (IV) glucose or lipid intake and a mixed meal test (MMT) consumed by subjects with normal weight, overweight or obesity. GLP-1, oxyntomodulin and glicentin (gut-secreted PGDPs) and glucagon and MPGF (pancreas-secreted PGDPs) were assessed in: (a) 32 subjects receiving PO or IV glucose, lipids or water over 6h, (b) 33 subjects with normal weight, overweight or obesity who consumed a MMT. (a) GLP-1, oxyntomodulin, glicentin and glucagon levels increase more profoundly and persistently after lipids PO (2.5g/kg) than glucose PO (2.5g/kg) or IV lipids (Intralipid/Liposyn II 20% at 0.35ml/kg/hand Intralipid/Liposyn II 20% at 0.83ml/kg/h for 6h) or IV glucose (10% glucose at 3.6ml/kg/hfor 6h). Oxyntomodulin and glicentin increased more than GLP-1 in response to lipids PO. MPGF levels decrease in response to glucose PO or IV indicating a shift towards preferential production of gut-secreted peptides. (b) Fasting and postprandial areas under the curve (AUCs) after MMT of GLP-1, MPGF and glucagon levels correlated positively with BMI. The fasting levels of glucagon and MPGF were elevated in obesity and remained elevated after the MMT. Circulating levels of PGDPs are differentially regulated by body weight, the type of macronutrients administered and the respective route of administration. Mechanistic studies are needed to define the exact mechanisms underlying this regulation. Study 1 has the NCT01520454 and the NCT04888325 number in ClinicalTrials.gov. Study 2 has the number NCT01495754 in ClinicalTrials.gov.

Long-term health after Severe Acute Malnutrition in children and adults- the role of the Pancreas (SAMPA): Protocol.

Background: Prenatal growth retardation may increase the risk of later chronic non-communicable diseases (NCDs), including diabetes; however, long-term effects of wasting malnutrition in childhood or adulthood are less studied. Pancreatic exocrine and endocrine functions, both critical for nutrition and NCD aetiology, may not fully recover following malnutrition. However, the evidence and mechanistic information is piecemeal. We hypothesise that wasting malnutrition at any age has long-term detrimental effects on endocrine and exocrine pancreatic structure and function. Methods: The SAMPA international research programme will assess pancreatic structure and function in 3700 participants from ongoing observational nutrition cohorts, two adolescent and four adult, in Zambia, Tanzania, Philippines, and India. Pancreas size, structure, and calcification will be assessed by ultrasound and computed tomography (CT) scan; exocrine function by faecal elastase and serum lipase; and endocrine function by haemoglobin A1c (HbA1c) and blood glucose, insulin and C-peptide concentrations during an oral glucose tolerance test (OGTT). In-depth hormonal analyses of incretins, glucagon, proinsulin and trypsinogen during OGTT and intravenous glucose tolerance tests will be done in subsets of adult participants. Pancreatic size and function outcomes will be compared between people with and without prior wasting malnutrition. Analyses will investigate effect modification by sex, current age, time since malnutrition, current body mass index and dietary patterns. Mathematical modelling of OGTT data will be used to estimate the relative contribution to glucose dysregulation of decreased insulin production, changes in insulin clearance and increased insulin resistance. Proinsulin/insulin ratio will be analysed in archived samples from the Tanzanian cohort using a nested case-control design to investigate whether abnormal values precede diabetes. Conclusions: SAMPA, a large-scale multi-centre research programme using data from people with or without prior wasting malnutrition to assess several aspects of pancreatic phenotype, will provide coherent evidence for future policies and programmes for malnutrition and diabetes.