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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. [ABSTRACT FROM AUTHOR]

Objective To investigate the the clinical application of triglyceride-glucose (TyG) index and its correlation with atherosclerosis in patients with type 2 diabetes mellitus (T2DM). Methods From January 2020 to December 2022，499 patients with T2DM were screened from the inpatients and physical examination populations of Nanjing Jiangbei Hospital. Based on the presence or absence of atherosclerotic plaques， the subjects were divided into T2DM with plaques group (n=249) and T2DM without plaques group (n=250). The subjects underwent medical history collection，physical examination，and serum biochemical testing. The TyG index was calculated，and the correlation between TyG and common risk factors for T2DM atherosclerosis was statistically analyzed. Results The age，systolic blood pressure (SBP)，triglyceride (TG)，total cholesterol (TC)，fasting blood glucose (FBG)，glycosylated hemoglobin (HbA1c)，and apolipoprotein A of the T2DM without plaques group were lower than those in the T2DM with plaques group, the diastolic blood pressure (DBP) was higher than that in the T2DM with plaques group (P＜0.05). The TyG index in the T2DM with plaques group was higher than that in the T2DM without plaques group (11.52±0.37 vs 9.34±0.48, t=56.803, P＜0.01). TyG index was positively correlated with age, SBP, TG, TC, low-density lipoprotein cholesterol (LDL-C), uric acid (UA), and HbA1c (P＜0.05)，and negatively correlated with high-density lipoprotein cholesterol (HDL-C) and fasting C-peptide (P＜0.05). The area under ROC curve of TyG index for predicting T2DM atherosclerosis was 0.611 ，with a best cut-off value of 10.21，sensitivity of 84.8%, and specificity of 62.2%. Conclusion TyG index is closely related to multiple risk factors for atherosclerosis in patients with T2DM. TyG index combined with risk factors for atherosclerosis can comprehensively assess the risk of T2DM atherosclerosis development.

Dual amylin and calcitonin receptor agonists (DACRAs) are known to induce significant weight loss as well as improve glucose tolerance, glucose control, and insulin action in rats. However, to what extent DACRAs affect insulin sensitivity beyond that induced by weight loss and if DACRAs affect glucose turnover including tissue-specific glucose uptake is still unknown. Hyperinsulinemic glucose clamp studies were carried out in pre-diabetic ZDSD and diabetic ZDF rats treated with either the DACRA KBP or the long-acting DACRA KBP-A for 12 days. The glucose rate of disappearance was assessed using 3-3H glucose and tissue-specific glucose uptake was evaluated using 14C-2-deoxy-D-glucose (14C-2DG). In diabetic ZDF rats, KBP treatment significantly reduced fasting blood glucose and improved insulin sensitivity independent of weight loss. Furthermore, KBP increased the rate of glucose clearance, likely by increasing glucose storage, but without altering the endogenous glucose production. This was confirmed in pre-diabetic ZDSD rats. Direct assessment of tissue-specific glucose uptake showed, that both KBP and KBP-A significantly increased glucose uptake in muscles. In summary, KBP treatment significantly improved insulin sensitivity in diabetic rats and markedly increased glucose uptake in muscles. Importantly, in addition to their well-established weight loss potential, the KBPs have an insulin-sensitizing effect independent of weight loss, highlighting DACRAs as promising agents for the treatment of type 2 diabetes and obesity.

ObjectiveDiabetes is characterized by pancreatic β-cell dedifferentiation. Dedifferentiating β cells inappropriately metabolize lipids over carbohydrates and exhibit impaired mitochondrial oxidative phosphorylation. However, the mechanism linking the β-cell's response to an adverse metabolic environment with impaired mitochondrial function remains unclear.MethodsHere we report that the oxidoreductase cytochrome b5 reductase 3 (Cyb5r3) links FoxO1 signaling to β-cell stimulus/secretion coupling by regulating mitochondrial function, reactive oxygen species generation, and nicotinamide actin dysfunction (NAD)/reduced nicotinamide actin dysfunction (NADH) ratios.ResultsThe expression of Cyb5r3 is decreased in FoxO1-deficient β cells. Mice with β-cell-specific deletion of Cyb5r3 have impaired insulin secretion, resulting in glucose intolerance and diet-induced hyperglycemia. Cyb5r3-deficient β cells have a blunted respiratory response to glucose and display extensive mitochondrial and secretory granule abnormalities, consistent with altered differentiation. Moreover, FoxO1 is unable to maintain expression of key differentiation markers in Cyb5r3-deficient β cells, suggesting that Cyb5r3 is required for FoxO1-dependent lineage stability.ConclusionsThe findings highlight a pathway linking FoxO1 to mitochondrial dysfunction that can mediate β-cell failure.

Abstract Background Dipeptidyl peptidase 4 inhibitor (DPP4i) is an effective medicine for type 2 diabetes mellitus (T2DM). Some articles reported DPP4i improves insulin secretion and insulin resistance. However, these effects are not well established by glucose clamp test and test meal in Japanese. We investigated the effect of DPP4i on insulin resistance and insulin secretion by using the glucose clamp test and meal tolerance test (MTT). Methods We performed a MTT, and the hyperinsulinemic-euglycemic clamp in 8 Japanese patients with T2DM. This study was a single-arm study. We measured fasting and postprandial glucose, insulin, incretins, and glucagon levels. We also measured serum adiponectin levels. Results HbA1c was significantly decreased after 3 months. The fasting and postprandial glucose levels were significantly decreased. Fasting and postprandial insulin levels were not changed. The insulin resistance derived from the glucose clamp test was significantly improved. HOMA-IR was not significantly changed. GLP-1 and GIP were significantly increased but glucagon did not change. Adiponectin was not significantly changed. Conclusions Although the number of patients was very small, these results suggested that DPP4i treatment might improve insulin resistance without changing insulin secretion.

Abstract Aims Whereas homeostasis model assessment of insulin resistance (HOMA‐IR), an easily measured but limited index of insulin resistance, has been shown to correlate with impairment of cardiac function in individuals without diabetes, the pathological relevance of insulin resistance to the development of cardiac dysfunction in individuals with type 2 diabetes has remained unclear. Here we investigated the relation between left ventricular (LV) function as assessed by echocardiography and insulin resistance as evaluated by hyperinsulinemic‐euglycemic clamp analysis, the gold standard for measurement of this parameter, in individuals with type 2 diabetes. Methods This retrospective study included 34 individuals with type 2 diabetes who underwent both hyperinsulinemic‐euglycemic clamp analysis and echocardiography. Both the insulin sensitivity index (ISI) as determined by glucose clamp analysis as well as HOMA‐IR were determined as measures of insulin resistance. The ratio of the peak early‐ to late‐diastolic mitral inflow velocities (E/A) and the LV ejection fraction (LVEF) were determined as measures of diastolic and systolic function, respectively. Results The ISI was significantly correlated with both the E/A ratio and LVEF (correlation coefficients of 0.480 and 0.360, respectively), whereas HOMA‐IR was not correlated with either cardiac parameter. Multivariate analysis revealed that ISI was an independent predictor for both a high log [E/A] (P = 0.031) and a high LVEF (P = 0.045). Conclusions Insulin resistance as evaluated by hyperinsulinemic‐euglycemic clamp analysis may be causally related to LV diastolic and systolic dysfunction in individuals with type 2 diabetes.

Background: Dipeptidyl peptidase 4 inhibitor (DPP4i) is an effective medicine for type 2 diabetes mellitus (T2DM). Some articles reported DPP4i improves insulin secretion and insulin resistance. However, these effects are not well established by glucose clamp test and test meal in Japanese. We investigated the effect of DPP4i on insulin resistance and insulin secretion by using the glucose clamp test and meal tolerance test (MTT). Methods: We performed a MTT, and the hyperinsulinemic-euglycemic clamp in 8 Japanese patients with T2DM. This study was a single-arm study. We measured fasting and postprandial glucose, insulin, incretins, and glucagon levels. We also measured serum adiponectin levels. Results: HbA1c was significantly decreased after 3 months. The fasting and postprandial glucose levels were significantly decreased. Fasting and postprandial insulin levels were not changed. The insulin resistance derived from the glucose clamp test was significantly improved. HOMA-IR was not significantly changed. GLP-1 and GIP were significantly increased but glucagon did not change. Adiponectin was not significantly changed. Conclusions: Although the number of patients was very small, these results suggested that DPP4i treatment might improve insulin resistance without changing insulin secretion. [ABSTRACT FROM AUTHOR]

Aims: Whereas homeostasis model assessment of insulin resistance (HOMA‐IR), an easily measured but limited index of insulin resistance, has been shown to correlate with impairment of cardiac function in individuals without diabetes, the pathological relevance of insulin resistance to the development of cardiac dysfunction in individuals with type 2 diabetes has remained unclear. Here we investigated the relation between left ventricular (LV) function as assessed by echocardiography and insulin resistance as evaluated by hyperinsulinemic‐euglycemic clamp analysis, the gold standard for measurement of this parameter, in individuals with type 2 diabetes. Methods: This retrospective study included 34 individuals with type 2 diabetes who underwent both hyperinsulinemic‐euglycemic clamp analysis and echocardiography. Both the insulin sensitivity index (ISI) as determined by glucose clamp analysis as well as HOMA‐IR were determined as measures of insulin resistance. The ratio of the peak early‐ to late‐diastolic mitral inflow velocities (E/A) and the LV ejection fraction (LVEF) were determined as measures of diastolic and systolic function, respectively. Results: The ISI was significantly correlated with both the E/A ratio and LVEF (correlation coefficients of 0.480 and 0.360, respectively), whereas HOMA‐IR was not correlated with either cardiac parameter. Multivariate analysis revealed that ISI was an independent predictor for both a high log [E/A] (P = 0.031) and a high LVEF (P = 0.045). Conclusions: Insulin resistance as evaluated by hyperinsulinemic‐euglycemic clamp analysis may be causally related to LV diastolic and systolic dysfunction in individuals with type 2 diabetes. [ABSTRACT FROM AUTHOR]

Application of glucose clamp methodologies in multicenter studies brings challenges for standardization. The Restoring Insulin Secretion (RISE) Consortium implemented a hyperglycemic clamp protocol across seven centers using a combination of technical and management approaches to achieve standardization. Two-stage hyperglycemic clamps with glucose targets of 200 mg/dL and >450 mg/dL were performed utilizing a centralized spreadsheet-based algorithm that guided dextrose infusion rates using bedside plasma glucose measurements. Clamp operators received initial and repeated training with ongoing feedback based on surveillance of clamp performance. The precision and accuracy of the achieved stage-specific glucose targets were evaluated, including differences by study center. We also evaluated robustness of the method to baseline physiologic differences and on-study treatment effects. The RISE approach produced high overall precision (3%–9% variance in achieved plasma glucose from target at various times across the procedure) and accuracy (SD < 10% overall). Statistically significant but numerically small differences in achieved target glucose concentrations were observed across study centers, within the magnitude of the observed technical variability. Variation of the achieved target glucose over time in placebo-treated individuals was low (<3% variation), and the method was robust to differences in baseline physiology (youth vs. adult, IGT vs. diabetes status) and differences in physiology induced by study treatments. The RISE approach to standardization of the hyperglycemic clamp methodology across multiple study centers produced technically excellent standardization of achieved glucose concentrations. This approach provides a reliable method for implementing glucose clamp methodology across multiple study centers. NEW & NOTEWORTHY The Restoring Insulin Secretion (RISE) study centers undertook hyperglycemic clamps using a simplified methodology and a decision guidance algorithm implemented in an easy-to-use spreadsheet. This approach, combined with active management including ongoing central data surveillance and routine feedback to study centers, produced technically excellent standardization of achieved glucose concentrations on repeat studies within and across study centers. [ABSTRACT FROM AUTHOR]

Insulin-induced hypoglycemia is a major limiting factor in maintaining optimal blood glucose in patients with type 1 diabetes and advanced type 2 diabetes. Luckily, a counterregulatory response (1) system exists to help minimize and reverse hypoglycemia, although more studies are needed to better characterize its components. Recently, we showed that the hormone ghrelin is permissive for the normal CRR to insulin-induced hypoglycemia when assessed in mice without diabetes. Here, we tested the hypothesis that ghrelin also is protective against insulin-induced hypoglycemia in the streptozotocin (2) mouse model of type 1 diabetes. STZ-treated ghrelin-knockout (KO) (3) mice as well as STZ-treated wild-type (WT) littermates were subjected to a low-dose hyperinsulinemic-hypoglycemic clamp procedure. The STZ-treated ghrelin-KO mice required a much higher glucose infusion rate than the STZ-treated WT mice. Also, the STZ-treated ghrelin-KO mice exhibited attenuated plasma epinephrine and norepinephrine responses to the insulin-induced hypoglycemia. Taken together, our data suggest that without ghrelin, STZ-treated mice modeling type 1 diabetes are unable to mount the usual CRR to insulin-induced hypoglycemia.

Glucose clamp studies form an integral part of the early development of insulin therapies. Data generated in these studies are used to establish pharmacokinetic (PK) and pharmacodynamic (PD) profiles of the agents, but methodological differences confound comparison of results from different glucose clamp studies. The first part of this series on glucose clamp studies discussed practical tips for the interpretation of glucose clamp studies. The second part of the series compares the PK/PD profiles of longer-acting basal analogue insulins, insulin degludec (IDeg) and insulin glargine U300 (Gla-300). The patient populations for glucose clamp studies with these analogue insulins differ, and therefore direct comparison of the data is not always possible. The maximum duration of action of IDeg is reported as 42 h and that of Gla-300 as 36 h, translating to 24 h coverage. The plasma insulin concentration of IDeg is 56 times that of Gla-300. Results from phase III clinical trials for these analogue insulins confirm the predictability and low within-subject variability observed in glucose clamp studies. Insight into the PK/PD profiles of longer-acting basal analogue insulins allows the treating physician to utilise these characteristics to optimise the treatment of their patients with diabetes.

Glucose clamp studies are used to determine pharmacokinetics (PK) and pharmacodynamics (PD) of analogue insulins. With the development of longer-acting basal analogue insulins, including glargine 300 (Gla-300) and insulin degludec (IDeg), results from numerous glucose clamp studies are readily available. However, interpreting PK/PD profiles in a scientifically sound manner can be a challenging feat. This is the first in a series of publications that will suggest practical tips for interpreting and comparing results from glucose clamp studies. Variations in the glucose clamp methodology, duration of clamp studies and glucose clamp targets influence the study design and results significantly. Selection of study populations, including healthy patients or patients with Type 1 or 2 diabetes mellitus, has important implications. The dose of study insulin should reflect that of the general treatment population, and ideally steady-state conditions should be used. During the study the plasma insulin concentration and glucose infusion rate describe the pharmacokinetics and pharmacodynamics of the study insulin. With these practical tips in mind, results of glucose clamp studies can be interpreted in a scientifically correct manner. The next article in this series will discuss the interpretation of PK/PD profiles using two newly developed longer-acting basal analogue insulins: Gla-300 and IDeg.

Insulin-induced hypoglycemia is a major limiting factor in maintaining optimal blood glucose in patients with type 1 diabetes and advanced type 2 diabetes. Luckily, a counterregulatory response (1) system exists to help minimize and reverse hypoglycemia, although more studies are needed to better characterize its components. Recently, we showed that the hormone ghrelin is permissive for the normal CRR to insulin-induced hypoglycemia when assessed in mice without diabetes. Here, we tested the hypothesis that ghrelin also is protective against insulin-induced hypoglycemia in the streptozotocin (2) mouse model of type 1 diabetes. STZ-treated ghrelin-knockout (KO) (3) mice as well as STZ-treated wild-type (WT) littermates were subjected to a low-dose hyperinsulinemic-hypoglycemic clamp procedure. The STZ-treated ghrelin-KO mice required a much higher glucose infusion rate than the STZ-treated WT mice. Also, the STZ-treated ghrelin-KO mice exhibited attenuated plasma epinephrine and norepinephrine responses to the insulin-induced hypoglycemia. Taken together, our data suggest that without ghrelin, STZ-treated mice modeling type 1 diabetes are unable to mount the usual CRR to insulin-induced hypoglycemia. [ABSTRACT FROM AUTHOR]

Introduction: Administration of a preoperative containing complex carbohydrate (CHO) preserves insulin sensitivity after traditional colorectal surgery compared with water or fasting; however, its benefits compared with simple CHO drinks have not been investigated. This randomized controlled trial estimated the extent to which a preoperative simple CHO drink preserves insulin sensitivity, compared with a complex CHO drink. Methods: This randomized trial involved 30 nondiabetic adult patients undergoing laparoscopic colon resection. Perioperative care followed an established Enhanced Recovery Pathway (ERP). Patients were randomized 1:1 to receive either a simple CHO drink (400mL containing 50 gr of fructose) or a complex CHO drink (400mL containing 40 gr of maltodextrin and 10 gr of fructose) 2 hours before surgery. The primary outcome was intraoperative insulin sensitivity assessed by peripheral glucose uptake (M value) during hyperinsulinemic euglycemic clamp. Secondary outcomes included postoperative hepatic insulin resistance assessed by Homeostatic model assessment (HOMA2-IR), fasting blood glucose (FBG), and C-reactive protein (CRP) at baseline and postoperative day (POD 1-3), 30-day complications, and hospital length of stay (LOS). Results: Intraoperative insulin sensitivity was maintained in both groups with no difference after ingestion of the simple or complex CHO drink [mean (SD) M value 8.3 (3.3) vs 8.8 (3.8) mg/kg/min, P = 0.7). Postoperative insulin sensitivity was maintained, with no differences in hepatic insulin resistance (HOMA2-IR) or fasting blood glucose on POD 1 to 3. There were no differences in complications or LOS. Conclusions: After laparoscopic colectomy in an ERP, perioperative insulin sensitivity was maintained and not further impacted by the preoperative ingestion of a complex or simple CHO drink. [ABSTRACT FROM AUTHOR]

G‐protein coupled receptor 119 (GPR119) expression in pancreatic β‐cells and intestinal L cells is a potential therapeutic target for treating type 2 diabetes. A natural GPR119 agonist oleoylethanolamide is well known to enhance a glucose‐stimulated insulin secretion (GSIS) and glucagon‐like peptide‐1 (GLP‐1) secretion by elevating intracellular cAMP levels. In the present study, a glucose lowering effect of the GPR119 agonist, JTP‐109192 leading to improvement of insulin sensitivity was examined in Zucker Fatty (ZF) rats. We investigated the in vitro effects of JTP‐109192 on GSIS in the rat pancreatic β‐cell line (INS1E) cells and on GLP‐1 secretion in the murine enteroendocrine cell line (GLUTag) cells. We also investigated the effect of JTP‐109192 on GSIS in Sprague‐Dawley (SD) rats with single administration and its effect on glucose metabolism in ZF rats with repeated administration once daily for about 6 weeks. After repeated administration, the hyperinsulinaemic euglycaemic glucose clamp test was performed to evaluate insulin sensitivity. JTP‐109192 increased intracellular cAMP levels (EC50 value: 3.6 nmol/L) and enhanced GSIS in the INS1E cells and GLP‐1 secretion in GLUTag cells. In SD rats, a single administration of JTP‐109192 enhanced GSIS at high blood glucose levels. The repeated administrations in ZF rats improved glucose metabolism without lack of drug efficacy (tachyphylaxis) and increased glucose infusion rates due to improvement of insulin sensitivity. [ABSTRACT FROM AUTHOR]

Hepatic lipid accumulation has been implicated in the development of insulin resistance, but translational evidence in humans is limited. We investigated the relationship between liver fat and tissue-specific insulin sensitivity in 133 obese subjects. Although the presence of hepatic steatosis in obese subjects was associated with hepatic, adipose tissue, and peripheral insulin resistance, we found that intrahepatic triglycerides were not strictly sufficient or essential for hepatic insulin resistance. Thus, to examine the molecular mechanisms that link hepatic steatosis to hepatic insulin resistance, we comprehensively analyzed liver biopsies from a subset of 29 subjects. Here, hepatic cytosolic diacylglycerol content, but not hepatic ceramide content, was increased in subjects with hepatic insulin resistance. Moreover, cytosolic diacylglycerols were strongly associated with hepatic PKCε activation, as reflected by PKCε translocation to the plasma membrane. These results demonstrate the relevance of hepatic diacylglycerol-induced PKCε activation in the pathogenesis of NAFLD-associated hepatic insulin resistance in humans.

Hyperpolarized [1-13C]pyruvate magnetic resonance (MR) spectroscopy has the unique ability to detect real-time metabolic changes in vivo owing to its high sensitivity compared with thermal MR and high specificity compared with othe r metabolic imaging methods. The aim of this study was to explore the potential of hyperpolarized MR spectroscopy for quantification of liver pyruvate metabolism dur ing a hyperinsulinemic- isoglycemic clamp in mice. Hyperpolarized [1-13C]pyruvate was used for in vivo MR spectroscopy of liver pyruvate metabolism in mice. Mice were divided into two groups: (i) non-stimulated 5-h fasted mice and (ii) hyperinsulinemic-isoglycemic clamped mice. During clamp conditions, insulin and donor blood were administered at a constant rate, whereas glucose was infused to maintain isoglycemia. When steady state was reached, insulin-stimulated mice were rapidly infused with hyperpolarized [1-13C]pyruvate for real-time tracking of the dynamic distribution of metabolic derivatives from pyruvate, such as [1-13C]lactate, [1-13C]alanine and [13C]bicarbonate. Isotopomer analysis of plasma glucose confirmed 13C-incorporation from [1-13C]pyruvate into glucose was increased in fasted mice compared with insulin-stimulated mice, demonstrating an increased gluconeogenesis in fasted mice. The AUC ratios for [1-13C]alanine/ [1-13C]pyruvate (38.2%), [1-13C]lactate/[1-13C]pyruvate (41.8%) and [13C]bicarbonate/ [1-13C]pyruvate (169%) all increased significantly during insulin sti mulation. Hyperpolarized [1-13C]pyruvate can be used for in vivo MR spectroscopy of liver pyruvate metabolism during hyperinsulinemic-isoglycemic clamp conditions. Under these conditions, insulin decreased gluconeogenesis and increased [1-13C]alanine, [1-13C]lactate and [13C]bicarbonate after a [1-13C]pyruvate bolus. This application of in vivo spectroscopy has the potential to identify impairments in spec ific metabolic pathways in the liver associated with obesity, insulin resistance and nonalcoholic fatty liver disease. [ABSTRACT FROM AUTHOR]

Highlights • Canagliflozin, an SGLT2 inhibitor, decreased both blood glucose and body fat. • Improvement of insulin resistance was demonstrated using euglycemic hyperinsulinemic clamp study. • Reduction of visceral fat and ectopic fat is considered to be important. • SGLT2 inhibitors are useful therapeutic agent for Japanese T2DM patients. Abstract Aims Information on the clinical efficacy of SGLT2 inhibitors in the Japanese population is limited. The aim of this single-arm, single-center, open-label study was to confirm the body weight- and fat mass-lowering effects of canagliflozin (CANA) and the accompanying improvement in insulin resistance in Japanese patients with Type 2 diabetes mellitus (T2DM). Methods Thirty-eight patients were enrolled and administered 100 mg CANA once daily for 24 weeks. Blood and anthropometric parameters were examined before and after treatment. In a subset of patients, insulin sensitivity was assessed based on the glucose infusion rate (GIR) during a hyperinsulinemic euglycemic clamp test. Results CANA treatment significantly decreased hemoglobin A1c, fasting plasma glucose, and plasma liver enzyme levels, and increased plasma adiponectin levels. In addition, a significant reduction in body weight, visceral and subcutaneous fat area, fat and lean mass, and liver steatosis was also observed. The change in plasma adiponectin levels significantly correlated with the changes in both body fat mass and visceral fat area. GIR increased from 3.25 ± 1.53 to 4.11 ± 1.30 mg/kg/min (P < 0.05). Conclusions CANA improved insulin resistance and decreased visceral fat mass in Japanese patients with T2DM. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of the present study was to investigate the age-related carbohydrate oxidation and glucose utilisation rate response during exercise at the same relative intensity under hyperglycaemia in aged and young males.Methods: 16 endurance-trained aged (n = 8; 69.1 ± 5.2 year) and young (n = 8; 22.4 ± 2.9 year) males were studied during 40 min of cycling exercise (60% [Formula: see text]) under both hyperglycaemic and euglycaemic (control) conditions. Venous blood samples were collected at baseline, post-infusion, mid- and post-exercise. Carbohydrate and fat oxidation rates were determined at both 15 and 35 min during exercise, and glucose utilisation rates were calculated.Results: The aged group displayed significantly lower rates of carbohydrate oxidation during exercise during maintained hyperglycemia (15 min = 2.3 ± 0.4 vs. 1.6 ± 0.5 g min-1; 35 min = 2.3 ± 0.5 vs. 1.5 ± 0.5 g min-1) and control (15 min = 2.2 ± 0.4 vs. 1.6 ± 0.7 g min-1; 35 min = 1.9 ± 0.7 vs. 1.3 ± 0.7 g min-1) conditions (P = 0.01). The rate of glucose utilisation during exercise was also significantly reduced (85.76 ± 23.95 vs. 56.67 ± 15.09 μM kg-1 min-1). There were no differences between age groups for anthropometric measures, fat oxidation, insulin, glucose, NEFA, glycerol and lactate (P > 0.05) although hyperglycemia resulted in elevated glucose and insulin, and attenuated fat metabolite levels.Conclusion: Our findings highlight that ageing results in a reduction in carbohydrate oxidation and utilisation rates during exercise at the same relative exercise intensity. [ABSTRACT FROM AUTHOR]

We investigated the short‐term effects of dapagliflozin as adjunct to insulin on insulin sensitivity, postprandial glucose excursions and ketone body production in type 1 diabetes mellitus (T1DM). A total of seven male patients completed the randomized, double‐blind, placebo‐controlled cross‐over trial, receiving 10 mg of dapagliflozin daily for 3 days, followed by placebo, or the reverse. At Day 3, hyperinsulinaemic, euglycaemic clamps and oral glucose tolerance test clamps with repeated blood sampling were performed. Required glucose infusion and blood glucose excursions did not differ significantly between dapagliflozin treatment and placebo (P = 0.491; P = 0.342). Prior to oral glucose, total ketone bodies showed a higher trend following dapagliflozin treatment (P = 0.051). Following oral glucose, total ketone bodies decreased while concentrations of total GLP‐1 were higher following dapagliflozin (P = 0.009). Non‐esterified free fatty acids did not differ between dapagliflozin treatment and placebo and ketonuria was absent under both conditions. In T1DM, short‐term addition of dapagliflozin to insulin influenced neither postprandial glucose excursions nor insulin sensitivity. Following oral glucose, total ketone bodies decreased in parallel with an increase in GLP‐1 concentrations, which were higher under dapagliflozin treatment as compared with placebo. [ABSTRACT FROM AUTHOR]

A stroke can lead to reduced mobility affecting skeletal muscle mass and fatty infiltration which could lead to systemic insulin resistance, but this has not been examined and the mechanisms are currently unknown. The objective was to compare the effects of in vivo insulin on skeletal muscle glycogen synthase (GS) activity in paretic (P) and nonparetic (NP) skeletal muscle in chronic stroke, and to compare to nonstroke controls. Participants were mild to moderately disabled adults with chronic stroke (n = 30, 60 ± 8 years) and sedentary controls (n = 35, 62 ± 8 years). Insulin sensitivity (M) and bilateral GS activity were determined after an overnight fast and during a hyperinsulinemic-euglycemic clamp. Stroke subjects had lower aerobic capacity than controls, but M was not significantly different. Insulin-stimulated activities of GS (independent, total, fractional), as well as absolute differences (insulin minus basal) and the percent change (insulin minus basal, relative to basal) in GS activities, were all significantly lower in P versus NP muscle. Basal GS fractional activity was 3-fold higher, and the increase in GS fractional activity during the clamp was 2-fold higher in control versus P and NP muscle. Visceral fat and intermuscular fat were associated with lower M. The effect of in vivo insulin to increase GS fractional activity was associated with M in control and P muscle. A reduction in insulin action on GS in paretic muscle likely contributes to skeletal muscle-specific insulin resistance in chronic stroke.

Dual amylin and calcitonin receptor agonists (DACRAs) are known to induce significant weight loss as well as improve glucose tolerance, glucose control, and insulin action in rats. However, to what extent DACRAs affect insulin sensitivity beyond that induced by weight loss and if DACRAs affect glucose turnover including tissue-specific glucose uptake is still unknown. Hyperinsulinemic glucose clamp studies were carried out in pre-diabetic ZDSD and diabetic ZDF rats treated with either the DACRA KBP or the long-acting DACRA KBP-A for 12 days. The glucose rate of disappearance was assessed using 3-3H glucose and tissue-specific glucose uptake was evaluated using 14C-2-deoxy- D -glucose (14C-2DG). In diabetic ZDF rats, KBP treatment significantly reduced fasting blood glucose and improved insulin sensitivity independent of weight loss. Furthermore, KBP increased the rate of glucose clearance, likely by increasing glucose storage, but without altering the endogenous glucose production. This was confirmed in pre-diabetic ZDSD rats. Direct assessment of tissue-specific glucose uptake showed, that both KBP and KBP-A significantly increased glucose uptake in muscles. In summary, KBP treatment significantly improved insulin sensitivity in diabetic rats and markedly increased glucose uptake in muscles. Importantly, in addition to their well-established weight loss potential, the KBPs have an insulin-sensitizing effect independent of weight loss, highlighting DACRAs as promising agents for the treatment of type 2 diabetes and obesity. [Display omitted] • KBP is a dual amylin and calcitonin receptor agonist. • KBP improves glucose control and insulin sensitivity in diabetic rats. • KBP increases glucose uptake in muscles. • KBP has insulin-sensitizing effects independent of weight loss. • KBP is a promising agent for treating type 2 diabetes and obesity. [ABSTRACT FROM AUTHOR]

Background: Insulin resistance heightens the risk for type 2 diabetes mellitus and cardiovascular disease. Amelioration of insulin resistance may reduce this risk. The thiazolidinedone class of insulin sensitizers improves insulin action in individuals with insulin-resistant diabetes and nondiabetic individuals. However, there are few reports on the time of onset of such effects independent of reversal of glucotoxicity. Objective: The goal of our study was to test whether the thiazolidinedione pioglitazone has prominent early metabolic effects that can be detected in an obese, nondiabetic, insulin-resistant population. Methods: We conducted a randomized, double-blind, placebo-controlled, parallel-group trial in men with nondiabetic insulin resistance using a hyperinsulinemic euglycemic clamp technique (at low and high doses of insulin at 10 and 40 mU/m2/min, respectively). The patients were given 30 mg daily oral pioglitazone or placebo for 28 days. Patients underwent a baseline clamp before initiation of treatment, and again at 14 and 28 days of treatment. Results: Compared with placebo, under high-dose hyperinsulinemia, pioglitazone led to significant increases in glucose disposal rates (GDR) of 1.29 mg/kg/min (90% CI, 0.43–2.15; 39%; P=0.008) that were detectable at 2 weeks of treatment and persisted at 4 weeks of treatment. Under low-dose hyperinsulinemia, significant increases in GDR of 0.40 mg/kg/min (90% CI, 0.17–0.62; 95%; P=0.003) were observed at 4 weeks of treatment. These responses were accompanied by robust suppression of free fatty acids under hyperinsulinemic conditions, and by significant increases in circulating basal total adiponectin at 2 and 4 weeks of treatment. Conclusions: Significant changes in insulin action across multiple insulin-sensitive tissues can be detected within 2 weeks of initiation of insulin-sensitizing therapy with pioglitazone in obese patients with nondiabetic insulin resistance. ClinicalTrials.gov identifier: NCT01115712.

Background: Previous studies have indicated an association between interleukin-18 and glucose. Interleukin-18 becomes active when cleaved by caspase-1, activated by the NLR family pyrin domain containing-3 inflammasome. Aim: To investigate associations between glucometabolic variables and serum levels of interleukin-18 and genetic expression of interleukin-18, caspase-1 and NLR family pyrin domain containing-3 in adipose tissue and circulating leukocytes, and whether these mediators are related to the amount of abdominal adipose tissue . Materials and Methods: Fasting blood samples and subcutaneous adipose tissue were collected in a cohort of 103 middle-aged men. Serum levels of interleukin-18 were determined by enzyme-linked immunosorbent assay, gene expression by real-time polymerase chain reaction and insulin sensitivity by glucose clamp. The distribution of abdominal adipose tissue, separated into superficial- and deep subcutaneous, and visceral adipose tissue, was assessed by computed tomography scan. Results: Glucometabolic variables correlated significantly to serum levels of interleukin-18, and to the expression of interleukin-18 and NLR family pyrin domain containing-3 in subcutaneous adipose tissue (p < 0.05). Significant correlations were further observed between the amount of fat in the different compartments of abdominal adipose tissue and both serum levels of interleukin-18 and genetic expression of interleukin-18 and NLR family pyrin domain containing-3 in adipose tissue. Conclusion: The results implicate that the glucometabolic state is of importance for the inflammasome-related inflammation expressed both circulatory and genetically in subcutaneous adipose tissue, the latter highly reflected in the amount of abdominal adipose tissue. [ABSTRACT FROM AUTHOR]

Glucose clamp studies form an integral part of the early development of insulin therapies. Data generated in these studies are used to establish pharmacokinetic (PK) and pharmacodynamic (PD) profiles of the agents, but methodological differences confound comparison of results from different glucose clamp studies. The first part of this series on glucose clamp studies discussed practical tips for the interpretation of glucose clamp studies. The second part of the series compares the PK/PD profiles of longer-acting basal analogue insulins, insulin degludec (IDeg) and insulin glargine U300 (Gla-300). The patient populations for glucose clamp studies with these analogue insulins differ, and therefore direct comparison of the data is not always possible. The maximum duration of action of IDeg is reported as 42 h and that of Gla-300 as 36 h, translating to 24 h coverage. The plasma insulin concentration of IDeg is 56 times that of Gla-300. Results from phase III clinical trials for these analogue insulins confirm the predictability and low within-subject variability observed in glucose clamp studies. Insight into the PK/PD profiles of longer-acting basal analogue insulins allows the treating physician to utilise these characteristics to optimise the treatment of their patients with diabetes. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: The euglycaemic-hyperinsulinaemic clamp is the gold-standard method for measuring insulin sensitivity, but is less suitable for large clinical trials. Thus, several indices have been developed for evaluating insulin sensitivity from the oral glucose tolerance test (OGTT). However, most of them yield values different from those obtained by the clamp method. The aim of this study was to develop a new index to predict clamp-derived insulin sensitivity (M value) from the OGTT-derived oral glucose insulin sensitivity index (OGIS).Methods: We analysed datasets of people that underwent both a clamp and an OGTT or meal test, thereby allowing calculation of both the M value and OGIS. The population was divided into a training and a validation cohort (n = 359 and n = 154, respectively). After a stepwise selection approach, the best model for M value prediction was applied to the validation cohort. This cohort was also divided into subgroups according to glucose tolerance, obesity category and age.Results: The new index, called PREDIcted M (PREDIM), was based on OGIS, BMI, 2 h glucose during OGTT and fasting insulin. Bland-Altman analysis revealed a good relationship between the M value and PREDIM in the validation dataset (only 9 of 154 observations outside limits of agreement). Also, no significant differences were found between the M value and PREDIM (equivalence test: p < 0.0063). Subgroup stratification showed that measured M value and PREDIM have a similar ability to detect intergroup differences (p < 0.02, both M value and PREDIM).Conclusions/interpretation: The new index PREDIM provides excellent prediction of M values from OGTT or meal data, thereby allowing comparison of insulin sensitivity between studies using different tests. [ABSTRACT FROM AUTHOR]

Glucose clamp studies are used to determine pharmacokinetics (PK) and pharmacodynamics (PD) of analogue insulins. With the development of longer-acting basal analogue insulins, including glargine 300 (Gla-300) and insulin degludec (IDeg), results from numerous glucose clamp studies are readily available. However, interpreting PK/PD profiles in a scientifically sound manner can be a challenging feat. This is the first in a series of publications that will suggest practical tips for interpreting and comparing results from glucose clamp studies. Variations in the glucose clamp methodology, duration of clamp studies and glucose clamp targets influence the study design and results significantly. Selection of study populations, including healthy patients or patients with Type 1 or 2 diabetes mellitus, has important implications. The dose of study insulin should reflect that of the general treatment population, and ideally steady-state conditions should be used. During the study the plasma insulin concentration and glucose infusion rate describe the pharmacokinetics and pharmacodynamics of the study insulin. With these practical tips in mind, results of glucose clamp studies can be interpreted in a scientifically correct manner. The next article in this series will discuss the interpretation of PK/PD profiles using two newly developed longer-acting basal analogue insulins: Gla-300 and IDeg. [ABSTRACT FROM AUTHOR]

Although intense endurance and resistance exercise training and whey protein supplementation have both been shown to independently improve glycemic control, no known studies have examined the effect of high-intensity mixed-mode interval training (MMIT) and whey supplementation in adults with Type 2 diabetes (T2D). Purpose This study aimed to determine if peritraining whey protein supplementation combined with MMIT can improve glycemic control. Methods In a double-blind, randomized, placebo-controlled trial, 24 men (55.7 ± 5.6 yr) with T2D performed MMIT with whey (20 g) or placebo control for 10 wk. Glycemic control was assessed via glucose disposal rate during a euglycemic insulin clamp, fasting blood glucose concentration, and homeostatic model assessment of insulin resistance. Changes in peak oxygen consumption, 1-repetition maximum strength, vastus lateralis muscle, and subcutaneous adipose thicknesses, and waist circumference were also assessed. Results Ten weeks of MMIT substantially improved glucose disposal rate by 27.5% (90% confidence interval, 1.2%-60.7%) and 24.8% (-5.4% to 64.8%) in the whey and control groups, respectively. There were likely and possible reductions in fasting blood glucose by -17.4% (-30.6% to -1.6%) and homeostatic model assessment of insulin resistance by -14.1% (-25.3% to 1.08%) in the whey group; however, whey effects were not clearly beneficial to glycemic outcomes relative to the control. MMIT also clearly substantially improved 1-repetition maximum by 20.6% (16.3%-24.9%) and 22.7% (18.4%-27.2%), peak oxygen consumption by 22.6% (12.0%-26.2%) and 18.5% (10.5%-27.4%), and vastus lateralis muscle thickness by 18.9% (12.0%-26.2%) and 18.6% (10.5%-27.4%) and possibly reduced waist circumference by -2.1% (-3.1% to -1.0%) and -1.9% (-3.7% to -0.1%) in the control and whey groups, respectively, but the whey-control outcome was trivial or unclear. Conclusions A clinically meaningful enhancement in glycemic control after 10 wk of MMIT was not clearly advanced with peritraining whey protein supplementation in middle-age men with T2D. [ABSTRACT FROM AUTHOR]

Introduction: Physical endurance can be limited by muscle glycogen stores, in that glycogen depletion markedly reduces external work. During carbohydrate restriction, the liver synthesizes the ketone bodies, D-β-hydroxybutyrate, and acetoacetate from fatty acids. In animals and in the presence of glucose, D-β-hydroxybutyrate promotes insulin secretion and increases glycogen synthesis. Here we determined whether a dietary ketone ester, combined with plentiful glucose, can increase postexercise glycogen synthesis in human skeletal muscle. Methods: After an interval-based glycogen depletion exercise protocol, 12 well-trained male athletes completed a randomized, three-arm, blinded crossover recovery study that consisted of consumption of either a taste-matched, zero-calorie control or a ketone monoester drink, followed by a 10-mM glucose clamp or saline infusion for 2 h. The three postexercise conditions were control drink then saline infusion, control drink then hyperglycemic clamp, or ketone ester drink then hyperglycemic clamp. Skeletal muscle glycogen content was determined in muscle biopsies of vastus lateralis taken before and after the 2-h clamps. Results: The ketone ester drink increased blood D-β-hydroxybutyrate concentrations to a maximum of 5.3 versus 0.7 mM for the control drink (P < 0.0001). During the 2-h glucose clamps, insulin levels were twofold higher (31 vs 16 mU•L-1, P < 0.01) and glucose uptake 32% faster (1.66 vs 1.26 g•kg-1, P < 0.001). The ketone drink increased by 61 g, the total glucose infused for 2 h, from 197 to 258 g, and muscle glycogen was 50% higher (246 vs 164 mmol glycosyl units per kilogram dry weight, P < 0.05) than after the control drink. Conclusion: In the presence of constant high glucose concentrations, a ketone ester drink increased endogenous insulin levels, glucose uptake, and muscle glycogen synthesis. [ABSTRACT FROM AUTHOR]

Summary Hepatic lipid accumulation has been implicated in the development of insulin resistance, but translational evidence in humans is limited. We investigated the relationship between liver fat and tissue-specific insulin sensitivity in 133 obese subjects. Although the presence of hepatic steatosis in obese subjects was associated with hepatic, adipose tissue, and peripheral insulin resistance, we found that intrahepatic triglycerides were not strictly sufficient or essential for hepatic insulin resistance. Thus, to examine the molecular mechanisms that link hepatic steatosis to hepatic insulin resistance, we comprehensively analyzed liver biopsies from a subset of 29 subjects. Here, hepatic cytosolic diacylglycerol content, but not hepatic ceramide content, was increased in subjects with hepatic insulin resistance. Moreover, cytosolic diacylglycerols were strongly associated with hepatic PKCε activation, as reflected by PKCε translocation to the plasma membrane. These results demonstrate the relevance of hepatic diacylglycerol-induced PKCε activation in the pathogenesis of NAFLD-associated hepatic insulin resistance in humans. [ABSTRACT FROM AUTHOR]

Background: In glucose clamp experiments, blood glucose concentrations (BGs) are kept as close as possible to a predefined target level using variable glucose infusion rates (GIRs). In automated clamps, GIRs are calculated by algorithms implemented in the device (e.g., the Biostator). Low BG- and GIR-variability is needed for high clamp quality. We therefore tried to reduce oscillations in both BG and GIR with an improved algorithm implemented in ClampArt, a modern clamp device.Subjects and Methods: The Biostator algorithm was first improved by numerical simulations of glucose clamps (in silico). With the results of the simulations, we started in vitro experiments using the ClampArt device and a container with water and glucose as "test subject." After a small pilot in vivo study, a larger clinical study was performed to compare the original with the optimized algorithm.Results: With the improved algorithm, in silico, in vitro, and in vivo experiments showed reduced oscillations in both BG and GIR. In the clinical study, the coefficient of variation (CV) of BG values was lowered from 6.0% (4.6%-7.8%) [median (interquartile range)] to 4.2% (3.6%-5.0%), P < 0.0001 and the CV of GIR from 60.7% (49.6%-82.0%) to 43.5% (32.8%-57.2%), P < 0.0001. Other clamp quality parameters did not change substantially, median deviation from target slightly increased from 0.6% (0.2%-1.0%) to 1.1% (0.7%-1.5%), P = 0.0005, whereas utility did not change [97.0% (93.4%-100.0%) vs. 97.0% (94.0%-98.8%), P = 0.57].Conclusions: With the improved algorithm, all experiments confirmed a reduction in BG- and GIR-oscillations without a major impact on other glucose clamp parameters. The optimized algorithm has been implemented in ClampArt for all future glucose clamp studies. [ABSTRACT FROM AUTHOR]

Background: High fructose consumption has been suggested to contribute to several features of metabolic syndrome including insulin resistance, but to our knowledge, no previous meta-analyses have investigated the effect of fructose on insulin sensitivity in nondiabetic subjects. Objective: We performed a systematic review and meta-analysis of controlled diet-intervention studies in nondiabetic subjects to determine the effect of fructose on insulin sensitivity. Design: We searched MEDLINE, EMBASE, and the Cochrane Library for relevant trials on the basis of predetermined eligibility criteria. Two investigators independently performed the study selection, quality assessment, and data extraction. Results were pooled with the use of the generic inverse-variance method with random effects weighting and were expressed as mean differences (MDs) or standardized mean differences (SMDs) with 95% CIs. Results: Twenty-nine articles that described 46 comparisons in 1005 normal-weight and overweight or obese participants met the eligibility criteria. An energy-matched (isocaloric) exchange of dietary carbohydrates by fructose promoted hepatic insulin resistance (SMD: 0.47; 95% CI: 0.03, 0.91; P = 0.04) but had no effect on fasting plasma insulin concentrations (MD: -0.79 pmol/L; 95% CI: -6.41, 4.84 pmol/L; P = 0.78), the homeostasis model assessment of insulin resistance (HOMA-IR) (MD: 0.13; 95% CI: -0.07, 0.34; P = 0.21), or glucose disposal rates under euglycemic hyperinsulinemic clamp conditions (SMD: 0.00; 95% CI: 20.41, 0.41; P = 1.00). Hypercaloric fructose (~25% excess of energy compared with that of the weight-maintenance control diet) raised fasting plasma insulin concentrations (MD: 3.38 pmol/L; 95% CI: 0.03, 6.73 pmol/L; P < 0.05) and induced hepatic insulin resistance (SMD: 0.77; 95% CI: 0.28, 1.26; P < 0.01) without affecting the HOMA-IR (MD: 0.18; 95% CI: -0.02, 0.39; P = 0.08) or glucose disposal rates (SMD: 0.10; 95% CI: -0.21, 0.40; P = 0.54). Results may have been limited by the low quality, small sample size, and short duration (mostly <60 d) of included trials. Conclusions: Short-term fructose consumption, in isocaloric exchange or in hypercaloric supplementation, promotes the development of hepatic insulin resistance in nondiabetic adults without affecting peripheral or muscle insulin sensitivity. Larger and longer-term studies are needed to assess whether real-world fructose consumption has adverse effects on insulin sensitivity and long-term outcomes. [ABSTRACT FROM AUTHOR]

The hyperinsulinaemic-euglycaemic glucose clamp has always been regarded as the 'gold standard' for the assessment of pharmacodynamic ( PD) properties of insulin preparations; however, there has been controversy over a variety of methodogical details, such as study population, dosing time and the initial stabilization of blood glucose ( BG) concentrations at the clamp target level, among clamp groups. As the impact of these details on PD results is unclear, the present review provides an overview of different methodological approaches for both the manual and the automated hyperinsulinaemic-euglycaemic glucose clamp. The advantages and limitations of several methodological details are discussed as well as the relevance of clamp results for the prediction of clinical outcomes. Overall, the best method strongly depends on the exact objective of the trial. If, for instance, duration of action is the primary objective, studies should be carried out in patients with type 1 diabetes to avoid any interference of endogenous insulin. This is less important for variables such as onset of action or early metabolic activity. The hyperinsulinaemic-euglycaemic glucose clamp has a high sensitivity to detect even minor differences between different insulin preparations. The practical relevance of potential differences, however, needs to be investigated in clinical studies. A major prerequisite for obtaining reliable glucose clamp results is the attainment of high clamp quality (i.e. keeping BG concentrations close to the clamp target throughout the experiments). Unfortunately, measures of clamp quality are often under-reported, as is the variability in PD profiles, although these might explain some unconfirmed extreme results obtained in a few clamp studies. [ABSTRACT FROM AUTHOR]

• Glucose clamps are experimental techniques used for studying glucose metabolism. • Subjects' blood glucose is maintained to target via glucose infusion. • Modulating glucose infusion rate is a challenging task for investigators. • Gluclas is a PID-based decision support system suggesting glucose infusion. • Gluclas algorithm is validated in silico and in vivo for different clamp protocols. 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. 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. 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. 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. [ABSTRACT FROM AUTHOR]

Purpose/Aim: Negative feedback controls in endocrine regulatory systems are well recognized. The incretins and their role in glucose regulation have been of major interest recently. Whether the same negative control system applies to the regulation of incretin secretion is not clear. We sought to examine the hypothesis that exogenous administration of glucagon like peptide-1, GLP-1(7–36) amide or its metabolite GLP-1(9–36) amide, reduces the endogenous basal release of this incretin.Materials and Methods: We evaluated the endogenous basal release of GLP-1 using two separate study designs. In protocol A we examined the GLP-1(7–36) amide levels during the infusion of GLP-1(9–36) amide. In protocol B, we used PYY and GLP-2 as biomarkers for the endogenous basal release of GLP-1(7–36) amide and assessed the endogenous basal release of these two hormones during the GLP-1(7–36) infusion. Twelve lean and 12 obese subjects were enrolled in protocol A and 10 obese volunteers in protocol B.Results: The plasma levels of GLP-1(7–36) amide in protocol A and PYY and GLP-2 in protocol B remained unchanged during the exogenous infusion of GLP-1(9–36) and GLP-1(7–36) amide, respectively.Conclusions: The negative feedback control system as described by inhibition of the release of endogenous hormone while infusing it exogenously was not observed for the basal secretion of GLP-1(7–36) amide. [ABSTRACT FROM PUBLISHER]

Background Insulin resistance heightens the risk for type 2 diabetes mellitus and cardiovascular disease. Amelioration of insulin resistance may reduce this risk. The thiazolidinedone class of insulin sensitizers improves insulin action in individuals with insulin-resistant diabetes and nondiabetic individuals. However, there are few reports on the time of onset of such effects independent of reversal of glucotoxicity. Objective The goal of our study was to test whether the thiazolidinedione pioglitazone has prominent early metabolic effects that can be detected in an obese, nondiabetic, insulin-resistant population. Methods We conducted a randomized, double-blind, placebo-controlled, parallel-group trial in men with nondiabetic insulin resistance using a hyperinsulinemic euglycemic clamp technique (at low and high doses of insulin at 10 and 40 mU/m 2 /min, respectively). The patients were given 30 mg daily oral pioglitazone or placebo for 28 days. Patients underwent a baseline clamp before initiation of treatment, and again at 14 and 28 days of treatment. Results Compared with placebo, under high-dose hyperinsulinemia, pioglitazone led to significant increases in glucose disposal rates (GDR) of 1.29 mg/kg/min (90% CI, 0.43–2.15; 39%; P =0.008) that were detectable at 2 weeks of treatment and persisted at 4 weeks of treatment. Under low-dose hyperinsulinemia, significant increases in GDR of 0.40 mg/kg/min (90% CI, 0.17–0.62; 95%; P =0.003) were observed at 4 weeks of treatment. These responses were accompanied by robust suppression of free fatty acids under hyperinsulinemic conditions, and by significant increases in circulating basal total adiponectin at 2 and 4 weeks of treatment. Conclusions Significant changes in insulin action across multiple insulin-sensitive tissues can be detected within 2 weeks of initiation of insulin-sensitizing therapy with pioglitazone in obese patients with nondiabetic insulin resistance. ClinicalTrials.gov identifier: NCT01115712. [ABSTRACT FROM AUTHOR]

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]

Purpose: An insulin-resistant rat model, induced by dexamethasone, was used to evaluate a Michaelis-Menten-based kinetic model using 6-deoxy-6-[(18)F]fluoro-D-glucose (6-[(18)F]FDG) to quantify glucose transport with PET.Procedures: Seventeen, male, Sprague-Dawley rats were studied in three groups: control (Ctrl), control + insulin (Ctrl + I), and dexamethasone + insulin (Dex + I). PET scans were acquired for 2 h under euglycemic conditions in the Ctrl group and under hyperinsulinemic-euglycemic conditions in the Ctrl + I and Dex + I groups.Results: Glucose transport, assessed according to the 6-[(18)F]FDG concentration, was highest in skeletal muscle in the Ctrl + I, intermediate in the Dex + I, and lowest in the Ctrl group, while that in the brain was similar among the groups. Modeling analysis applied to the skeletal muscle uptake curves yielded values of parameters related to glucose transport that were greatest in the Ctrl + I group and increased to a lesser degree in the Dex + I group, compared to the Ctrl group.Conclusion: 6-[(18)F]FDG and the Michaelis-Menten-based model can be used to measure insulin-stimulated glucose transport under basal and an insulin resistant state in vivo. [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]