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Residual beta cells are present in most patients with longstanding type 1 diabetes but it is unknown whether these beta cells react normally to different stimuli. Moreover a defect in proinsulin conversion and abnormal alpha cell response are also part of the islet dysfunction. A three-phase [euglycemia, hyperglycemia, and hyperglycemia + glucagon-like peptide 1 (GLP-1)] clamp was performed in patients with longstanding type 1 diabetes. Intravenous arginine boluses were administered at the end of each phase. On another day, a mixed meal stimulation test with a subsequent intravenous arginine bolus was performed. C-peptide was detectable in a subgroup of subjects at baseline (2/15) or only after stimulation (3/15). When detectable, C-peptide increased 2.9-fold [95% CI: 1.2-7.1] during the hyperglycemia phase and 14.1-fold [95% CI: 3.1-65.2] during the hyperglycemia + GLP-1 phase, and 22.3-fold [95% CI: 5.6-89.1] during hyperglycemia + GLP-1 + arginine phase when compared with baseline. The same subset of patients with a C-peptide response were identified during the mixed meal stimulation test as during the clamp. There was an inhibition of glucagon secretion (0.72-fold, [95% CI: 0.63-0.84]) during the glucose clamp irrespective of the presence of detectable beta cell function. Proinsulin was only present in a subset of subjects with detectable C-peptide (3/15) and proinsulin mimicked the C-peptide response to the different stimuli when detectable. Residual beta cells in longstanding type 1 diabetes respond adequately to different stimuli and could be of clinical benefit. NEW & NOTEWORTHY If beta cell function is detectable, the beta cells react relatively normal to the different stimuli except for the first phase response to intravenous glucose. An oral mixed meal followed by an intravenous arginine bolus can identify residual beta cell function/mass as well as the more commonly used glucose potentiated arginine-induced insulin secretion during a hyperglycemic clamp.

Background and Objective: The 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., Methods: Gluclas 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., Results: In 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., Conclusions: Gluclas 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., Competing Interests: Declaration of Competing Interest The authors of this paper declare no conflict of interest., (Copyright © 2022. Published by Elsevier B.V.)

Summary Background & aims In elective surgery, postoperative hyperglycaemia and insulin resistance are independent risk factors for complications. Since the simpler HOMA method has been used as an alternative to the hyperinsulinemic normoglycemic clamp in studies of surgery induced insulin resistance, we compared the two methods in patients undergoing elective surgery. Methods Data from 113 non-diabetic patients undergoing elective surgery were used. Insulin sensitivity, both before and after surgery, was quantified by the clamp and HOMA. Pre- and postoperatively, the results of the clamp were compared to HOMA using regression- and correlation analysis. Degree of agreement between the methods was studied using weighted linear kappa and the Bland–Altman test. Results Both the clamp and HOMA recorded a mean relative reduction in insulin sensitivity of 39 ± 24% and 39 ± 61% respectively after surgery; with significant correlations ( p < 0.01) for pre- and post-operative measures as well as for relative changes. However r 2 values were low: 0.04, 0.07 and 0.03 respectively. The degree of agreement for the relative change in insulin sensitivity using the Bland–Altman test gave a mean of difference 0% but “limits of agreement” (±2SD) was ±125%. This poor inter-method agreement was consolidated by a weighted linear kappa value of 0.18. Conclusion While the hyperinsulinemic euglycemic clamp measures the postoperative changes in insulin sensitivity, HOMA measures something different. Data using the HOMA method must therefore be interpreted cautiously and is not interchangeable with data obtained from the clamp. [ABSTRACT FROM AUTHOR]

Background & Aims: Insulin sensitivity often decreases after surgery in spite of normal insulin secretion, and may worsen the outcome. This post-operative insulin resistance increases according to the magnitude of surgical invasion. However, supplementation of carbohydrates before surgery attenuates the post-operative insulin resistance. This study aimed to investigate the effect of intra-operative administration of low-dose glucose on the post-operative insulin resistance. Methods: Patients undergoing maxillofacial surgery were randomly assigned to two groups throughout the surgical procedure: The glucose group receiving acetated Ringer solution with 1.5% glucose and the control group receiving acetated Ringer solution without glucose. Insulin resistance quantified by the mean glucose infusion rate (the glucose infusion rate) was evaluated by glucose clamp using the STG-22TM instrument on the previous day and on the next day of surgery. Blood glucose level was monitored continuously during surgery. In addition, serum insulin, ketone bodies and 3-methylhistidine were measured during perioperative period. Results: Patients in the glucose group (n=11) received 0.15±0.06 g/kg/h of glucose during surgery, while patients in the control group (n=11) received no glucose. In both groups, however, the mean blood glucose levels were maintained stable at less than 150 mg/dL during and after surgery. The serum ketone bodies significantly increased after surgery in the control group (p=0.0035), while it decreased significantly in the glucose group (p=0.043). The reduction rate in the glucose infusion rate was significantly lower in the glucose group, 43.3 ± 20.7%, than that in the control group, 57.7 ± 9.3% (p=0.041). Conclusions: Intra-operative small-dose of glucose administration may suppress ketogenesis and attenuate the post-operative insulin resistance without causing hyperglycemia. [ABSTRACT FROM AUTHOR]

Carbohydrate stores within muscle are considered essential as a fuel for prolonged endurance exercise, and regimes for enhancing such stores have proved successful in aiding performance. This study explored the effects of a hyperglycaemic-hyperinsulinemic clamp performed 18 h previously on subsequent prolonged endurance performance in cycling. Seven male subjects, accustomed to prolonged endurance cycling, performed 90 min of cycling at ~65% VO(2max) followed by a 16-km time trial 18 h after a 2-h hyperglycemic-hyperinsulinemic clamp (HCC). Hyperglycemia (10 mM) with insulin infused at 300 mU/m(2)/min over a 2-h period resulted in a total glucose uptake of 275 g (assessed by the area under the curve) of which glucose storage accounted for about 73% (i.e. 198 g). Patterns of substrate oxidation during 90-min exercise at 65% VO(2max) were not altered by HCC. Blood glucose and plasma insulin concentrations were higher during exercise after HCC compared with control (p < 0.05) while plasma NEFA was similar. Exercise performance was improved by 49 s and power output was 10-11% higher during the time trial (p < 0.05) after HCC. These data suggest that carbohydrate loading 18 h previously by means of a 2-h HCC improves cycling performance by 3.3% without any change in pattern of substrate oxidation. [ABSTRACT FROM AUTHOR]

We studied the effect of sodium selenate on insulin resistance of Goto-Kakizaki (GK) rats. Rats were kept on standard laboratory chow with and without i.p. injections of sodium selenate (0.173 mg/kg body weight) for 14 days, and then subjected to the glucose clamp. The glucose clamp studies confirmed an improvement in insulin-stimulated glucose disposal in GK rats treated with sodium selenate, with respect to both insulin sensitivity and responsiveness. This amelioration of insulin resistance may be partly due to a direct effect of the sodium selenate on peripheral tissues. 2-Deoxyglucose uptake in sodium selenate-treated adipocytes was increased and the insulin findings suggest that sodium selenate increases not only insulin sensitivity but also insulin responsiveness. Sodium selenate also accelerated glucose incorporation into adipocytes of rats, suggesting that the action of sodium selenate is peripheral. Interestingly, sodium selenate at a high concentration (about 1 mmol/L) was more effective than insulin in enhancing glucose uptake. The present study suggested that sodium selenate treatment led to substantial improvement in peripheral insulin resistance. [ABSTRACT FROM AUTHOR]

Aim: Low diurnal fluctuation and high day-to-day reproducibility in exposure and effect characterize beneficial basal insulin products. Two insulin glargine (LANTUS) formulations [without (R) or with polysorbate-20 (T)], added to minimize unfolding of proteins and subsequent formation of fibril structures, were assessed for equivalence in exposure and effect, and aspects of fluctuation and reproducibility in time–concentration and time–action profiles. Methods: A dose of 0.4 U/kg was subcutaneously administered to 24 healthy subjects in a two-sequence (R-T-R-T or T-R-T-R), randomized, four-way crossover trial utilizing 30-h Biostator-based euglycaemic glucose clamps. Results: Identical serum insulin glargine concentration and time–action profiles established average, individual and population equivalence in insulin exposure and effect. Point estimates for 24-h area under the curve for insulin (INS–AUC0–24 h) and glucose infusion rates (GIR–AUC0–24 h) were 97% [90% confidence interval (CI): 91–103%] and 100% (88–114%), respectively. Within-subject variability (coefficient of variation) for INS–AUC0–24 h and GIR–AUC0–24 h were 19% (95% CI: 14–25%) and 34% (24–43%), respectively. The diurnal relative fluctuation of the serum insulin glargine concentration was 20% (95% CI: 19–21%). Conclusion: Insulin glargine in either formulation presents with a high day-to-day reproducibility of a uniform release after injection enabling an effective basal insulin supplementation. [ABSTRACT FROM AUTHOR]

Insulin resistance contributes to the pathophysiology of diabetes and is a hallmark of obesity, metabolic syndrome, and many cardiovascular diseases. Therefore, quantifying insulin sensitivity/resistance in humans and animal models is of great importance for epidemiological studies, clinical and basic science investigations, and eventual use in clinical practice. Direct and indirect methods of varying complexity are currently employed for these purposes. Some methods rely on steady-state analysis of glucose and insulin, whereas others rely on dynamic testing. Each of these methods has distinct advantages and limitations. Thus, optimal choice and employment of a specific method depends on the nature of the studies being performed. Established direct methods for measuring insulin sensitivity in vivo are relatively complex. The hyperinsulinemic euglycemic glucose clamp and the insulin suppression test directly assess insulin-mediated glucose utilization under steady-state conditions that are both labor and time intensive. A slightly less complex indirect method relies on minimal model analysis of a frequently sampled intravenous glucose tolerance test. Finally, simple surrogate indexes for insulin sensitivity/resistance are available (e.g., QUICKI, HOMA, 1/insulin, Matusda index) that are derived from blood insulin and glucose concentrations under fasting conditions (steady state) or after an oral glucose load (dynamic). In particular, the quantitative insulin sensitivity check index (QUICKI) has been validated extensively against the reference standard glucose clamp method. QUICKI is a simple, robust, accurate, reproducible method that appropriately predicts changes in insulin sensitivity after therapeutic interventions as well as the onset of diabetes. In this Frontiers article, we highlight merits, limitations, and appropriate use of current in vivo measures of insulin sensitivity/resistance. [ABSTRACT FROM AUTHOR]

Insulin resistance is a component of several health disorders, most notably impaired glucose tolerance and type 2 diabetes mellitus. Insulin-resistant individuals have an impaired biological response to the usual action of insulin; that is, they have reduced insulin sensitivity. Various methods are used to assess insulin sensitivity both in individuals and in study populations. Validity, reproducibility, cost, and degree of subject burden are important factors .for both clinicians and researchers" to consider when weighing the merits of a particular method. This article describes several in vivo methods used to assess insulin sensitivity and presents the advantages and disadvantages of each. [ABSTRACT FROM AUTHOR]

Exercise superimposed on insulin stimulation is shown to increase muscle glucose metabolism and these two stimuli have synergistic effects. The objective of this study was to investigate glucose infusion rates (GIR) in groups with a wide variation in terms of insulin sensitivity during insulin stimulation alone and with superimposed exercise. Patients with type 2 diabetes, subjects with impaired glucose tolerance (IGT), healthy controls, and endurance-trained subjects were studied. The groups were matched for age and lean body mass (LBM), and differed in peak oxygen uptake (VO2 peak), body fat percentage, body mass index (BMI), fasting plasma glucose concentration, and oral glucose-tolerance test (OGTT). Each subject underwent a two-step sequential hyperinsulinemic, euglycemic clamp. During the last 30 min of the 2nd clamp step, subjects exercised on a bicycle at 43% ±2% of VO2 peak. In agreement with the OGTT data, the presence of different GIR during insulin stimulation alone demonstrated varying levels of insulin sensitivity between groups. However, the impairment of GIR in IGT observed during insulin stimulation alone was abolished compared to controls when exercise was superimposed on insulin stimulation. Humans with IGT are resistant to insulin-stimulated but not to exercise-induced glucose uptake. [ABSTRACT FROM AUTHOR]

Insulin sensitivity is a crucial parameter of glucose metabolism. The standard measures of insulin sensitivity obtained by an euglycaemic hyperinsulinaemic clamp, SI(clamp), or by the minimal model (MM), SI, do not account for the dynamics of insulin action, i.e., how fast or slow insulin action reaches its plateau value. This is an important physiological information. In this paper we formally define a new insulin sensitivity index which also incorporates information on the dynamics of insulin action, SID, show its properties, and exemplify how it can be measured both with the clamp and the MM method. Then, by resorting to real and synthetic data, we show both in IVGTT MM and clamp studies why this new index SID offers, in comparison with SI, a more comprehensive picture of the control of insulin on glucose. [ABSTRACT FROM AUTHOR]

The article compares the ability of HIV protease inhibitors (PIs) to alter peripheral glucose disposal acutely in a genetically identical model system at therapeutically relevant drug levels. The clinical use of HIV PI is associated with the development of peripheral insulin resistance. The incidence and degree of impaired glucose tolerance observed in treated patients vary considerably between drugs. Preclinical testing of model candidate PIs in a rodent model system may be useful in identifying the future risk of altering glucose homeostasis.

Aims/hypothesis: We compared five surrogate insulin sensitivity (IS) methods against the euglycaemic- hyperinsulinaemic clamp. These methods were the homeo stasis model assessment (HOMA) and four methods based on the OGTT (OGIS, MCRest, ISlcomp, SIORAL). Methods: We compared these IS methods against the clamp (0.28 nmobmin1 m2 insulin infusion) M value in 147 women (58-61 years; BMI 19-38 kg/m2 116 NGT, 25 IFG/IGT, six type 2 diabetic), by evaluating the cor- relation coefficient with M. We also tested the ability to reproduce the relationships between IS and typical IS correlates (BMI, fasting insulin, insulin to glucose OGTT area ratio and fasting, 2 h and mean glucose) by means of the "discrepancy index" D, in which (1) D=0 if the corre- lation between IS and the variable of interest is as with the clamp, (2) D is smaller than 0 if the correlation is over- estimated, and (3) D is greater than 0 if underestimated. Results: All IS methods correlated with M (r0.57-0.83, p

Aims African-Americans have a higher prevalence of Type 2 diabetes than Caucasians, but a lower prevalence than Pima Indians. Studies suggest that both African-Americans and Pima Indians are more insulin resistant and have higher acute insulin secretory responses to glucose than Caucasians; however, a direct comparison between these three populations is lacking. Methods We measured insulin secretory responses to intravenous glucose (acute insulin response, AIR, 25 g ivGTT); insulin action at physiological (M-low) and supra-physiological (M-high) levels of hyperinsulinaemia (2-step hyperinsulinaemic clamp); basal and insulin-suppressed endogenous glucose production in 30 African-Americans, 30 Pima Indians and 30 Caucasians with normal glucose tolerance who were carefully matched for age, sex, and body fat (hydrodensitometry or DEXA). A subgroup of 24 subjects from each group additionally underwent a standardized mixed meal test. Results M-low was lower in Pima Indians (0.50 ± 0.03) compared to Caucasians (0.59 ± 0.02, P = 0.02) and African-Americans [0.58 ± 0.03 mg/kgEMBS/ min, log 10 (means ± SE), P = 0.03] but was not different between African- Americans and Caucasians. Basal endogenous glucose production was lower in Pima Indians (2.43 ± 0.06) compared to African-Americans (2.70 ± 0.06, P = 0.02) and was not different between Pima Indians and Caucasians (2.59 ± 0.09 mg/kgEMBS/min) or African-Americans and Caucasians (all P >8). Insulin-suppressed endogenous glucose production during the clamp was not different among the groups (all P >0). AIR was higher in both African-Americans (13.51 ± 0.26) and Pima Indians (13.72 ± 0.27) compared to Caucasians (12.33 ± 0.25 p M, log 10 , both P <1). The areas under the curve for glucose in response to the oral glucose tolerance test and mixed meal test were higher in Pima Indians compared to African- Americans (P = 0.03 and P = 0.03, respectively) and Caucasians (P = 0.01, mixed meal test), but not different between African-Americans and Caucasians. Conclusions Exaggerated glucose-stimulated insulin secretion, manifested initially as an increased response to an intravenous glucose challenge, appears to be a characteristic in people with normal glucose tolerance at higher risk for diabetes. Lower whole-body insulin sensitivity in Pima Indians compared to African-Americans, however, may contribute to the higher risk for Type 2 diabetes in Pima Indians compared to African-Americans. [ABSTRACT FROM AUTHOR]

Aim: Protein tyrosine phosphatase-1B (PTP-1B) is an intracellular PTP known to dephosphorylate and inactivate upstream tyrosine phosphoproteins in the insulin signalling cascade. We and others reported increased abundance of catalytically impaired PTP-1B in tissue lysates from obese human subjects with and without type 2 diabetes, while genetic knockout of PTP-1B improves insulin sensitivity and prevents nutritionally mediated insulin resistance and obesity. The aim of the present work was to further elucidate the role of PTP-1B in glucose metabolism in vivo. Methods: We used adenoviral constructs incorporating cDNAs for either wild-type (W/T) or a catalytically inactive C215S (C/S) mutant PTP-1B to achieve liver-selective PTP-1B overexpression in young Sprague–Dawley rats using tail vein injection, based on the high degree of hepatotropism of adenovirus 5 (Ad5). An Ad5-lacZ construct encoding β-galactosidase was used as a control for viral effects alone. A hyperinsulinaemic euglycaemic clamp was used to study whole body glucose disposal and endogenous glucose production rates. Results: Control studies in HIRcB cells confirmed catalytic activity and inactivity of W/T and C/S respectively. Mean PTP-1B abundance was 2.24 ± 0.02- and 2.33 ± 0.04-fold of saline-treated control in liver lysates of W/T and C/S rats respectively. Liver selective overexpression was confirmed by analysis of tissue lysates from liver, fat and muscle tissues. Ad5 treatment did not result in a statistically or clinically significant liver injury, as determined by serum alanine aminotransferase and histological examination. Seven days post injection, no significant difference in rate of weight gain, fasting blood glucose or insulin levels were seen in any group. Similarly, under steady-state glucose clamp conditions, glucose disposal rate (Rd), endogenous glucose production rate (EGP) and serum insulin levels were similar in all groups. Conclusion: We conclude that moderate medium-term overabundance, to a degree resembling that seen in insulin-resistant states, of PTP-1B in liver tissue does not alter insulin action on glucose metabolism and that the major site of action of PTP-1B is presumably at insulin-responsive target tissue or tissues other than the liver. [ABSTRACT FROM AUTHOR]

The glucose clamp technique is widely used in clinical research studies to maintain a constant blood glucose (BG) level during metabolic perturbation. An algorithm is used to set the rate of an intravenous glucose infusion according to measured BG concentrations. Currently used clamp algorithms are unnecessarily complex. This paper describes the development and use of a new algorithm which is simpler to implement. The algorithm employs proportional and differential feedback control. Discrete BG sampling with a sampling period of 5 min is used. Computer simulation with a two-compartment model of glucose dynamics was used to refine the algorithm. A Monte Carlo approach was adopted to examine the effects of random variations in measured BG concentrations and the elapsed time between blood sampling and adjustment of the glucose infusion rate. A coefficient of variation in BG concentration of less than 4 per cent was predicted for a euglycemic clamp. This was confirmed when the algorithm was applied in clinical research studies. This degree of BG control compares well with other published algorithms. [ABSTRACT FROM AUTHOR]

The steady-state basal plasma glucose and insulin concentrations are determined by their interaction in a feedback loop. A computer-solved model has been used to predict the homeostatic concentrations which arise from varying degrees of β-cell deficiency and insulin resistance. Comparison of a patient's fasting values with the model's predictions allows a quantitative assessment of the contributions of insulin resistance and deficient β-cell function to the fasting hyperglycaemia (homeostasis model assessment, HOMA). The accuracy and precision of the estimate have been determined by comparison with independent measures of insulin resistance and β-cell function using hyperglycaemic and euglycaemic clamps and an intravenous glucose tolerance test. The estimate of insulin resistance obtained by homeostasis model assessment correlated with estimates obtained by use of the euglycaemic clamp (R = 0.88, p < 0.0001), the fasting insulin concentration (R = 0.81, p < 0.0001), and the hyperglycaemic clamp, (R = 0.69, p < 0.01). There was no correlation with any aspect of insulin-receptor binding. The estimate of deficient β-cell function obtained by homeostasis model assessment correlated with that derived using the hyperglycaemic clamp (R = 0.61, p < 0.01) and with the estimate from the intravenous glucose tolerance test (R = 0.64, p < 0.05). The low precision of the estimates from the model (coefficients of variation: 31% for insulin resistance and 32% for β-cell deficit) limits its use, but the correlation of the model's estimates with patient data accords with the hypothesis that basal glucose and insulin interactions are largely determined by a simple feed back loop. [ABSTRACT FROM AUTHOR]