المؤلفون: Voigt, Jens Hohwü, Lauritsen, Katrine M., Pedersen, Steen Bønløkke, Hansen, Troels K., Møller, Niels, Jessen, Niels, Laurenti, Marcello C., Man, Chiara Dalla, Vella, Adrian, Gormsen, Lars C., Søndergaard, Esben

المصدر: Basic & Clinical Pharmacology & Toxicology; May2024, Vol. 134 Issue 5, p643-656, 14p

مصطلحات موضوعية: PANCREATIC beta cells, TYPE 2 diabetes, BETA functions, CELL physiology, GLUCOSE, POSITRON emission tomography, FREE fatty acids, METFORMIN

مستخلص: Aims: Sodium glucose co-transporter-2 (SGLT2) inhibition lowers glucose levels independently of insulin, leading to reduced insulin secretion and increased lipolysis, resulting in elevated circulating free fatty acids (FFAs). While SGLT2 inhibition improves tissue insulin sensitivity, the increase in circulating FFAs could reduce insulin sensitivity in skeletal muscle and the liver. We aimed to investigate the effects of SGLT2 inhibition on substrate utilization in skeletal muscle and the liver and to measure beta-cell function and glucose tolerance. Methods: Thirteen metformin-treated individuals with type 2 diabetes were randomized to once-daily empagliflozin 25 mg or placebo for 4 weeks in a crossover design. Skeletal muscle glucose and FFA uptake together with hepatic tissue FFA uptake were measured using [18F]FDG positron emission tomography/computed tomography (PET/CT) and [11C]palmitate PET/CT. Insulin secretion and action were estimated using the oral minimal model. Results: Empagliflozin did not affect glucose (0.73 ± 0.30 vs. 1.16 ± 0.64, µmol/g/min p = 0.11) or FFA (0.60 ± 0.30 vs. 0.56 ± 0.3, µmol/g/min p = 0.54) uptake in skeletal muscle. FFA uptake in the liver (21.2 ± 10.1 vs. 19 ± 8.8, µmol/100 ml/min p = 0.32) was unaffected. Empagliflozin increased total beta-cell responsivity (20 ± 8 vs. 14±9, 10^-9 min^-1, p < 0.01) and glucose effectiveness (2.6 x 10^-2 ± 0.3 x 10^-2 vs. 2.4 x 10^-2 ± 0.3 x 10^-2, dL/kg/min, p = 0.02). Conclusions: Despite improved beta-cell function and glucose tolerance, empagliflozin does not appear to affect skeletal muscle FFA or glucose uptake. [ABSTRACT FROM AUTHOR]

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المؤلفون: Karakaplan, Nesrin Damla, Song, Yilin, Laurenti, Marcello C, Vella, Adrian, Jensen, Michael D

المصدر: Journal of Clinical Endocrinology & Metabolism; Feb2024, Vol. 109 Issue 2, pe596-e601, 6p

مصطلحات موضوعية: INSULIN resistance, HYPERINSULINISM, C-peptide

مستخلص: Context The impact of insulin, particularly exogenous hyperinsulinemia, on insulin secretion in humans is debated. Objective We assessed the effects of exogenous hyperinsulinemia on insulin secretion and whether the response is altered in insulin resistance associated with obesity. Methods Insulin secretion rates (ISRs) during euglycemic hyperinsulinemic clamp studies (52 volunteers) were calculated using a model that employs plasma C-peptide concentrations. One study involved a 2-step insulin clamp and the other study was a single step insulin clamp. For both studies the goal was to achieve plasma glucose concentrations of 95 mg/dL during the clamp irrespective of fasting glucose concentrations. The percent change in ISR from fasting to the end of the insulin clamp interval was the main outcome. Linear regression and analysis of covariance were used to test for the effects of insulin on ISR and to test for group differences. Results ISR was greater in obese volunteers (P <.001) under fasting and hyperinsulinemic clamp conditions. The change in plasma glucose from baseline to the end of the insulin clamp interval was highly correlated with the change in ISR (r = 0.61, P <.001). From baseline to the end of the clamp we observed a 27% (SD 20) suppression of ISR. The participants who underwent a 2-step insulin clamp had greater suppression of ISR during the second step than the first step (P <.001). The proportional suppression of ISR during euglycemic hyperinsulinemia was not different between nonobese and obese groups (P =.19). Conclusion Hyperinsulinemia suppresses endogenous insulin secretion and the relative change in insulin secretion produced by exogenous insulin did not differ between nonobese and obese people. [ABSTRACT FROM AUTHOR]

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المؤلفون: Wismayer, Daniel Schembri, Laurenti, Marcello C., Yilin Song, Egan, Aoife M., Welch, Andrew A., Bailey, Kent R., Cobelli, Claudio, Man, Chiara Dalla, Jensen, Michael D., Vella, Adrian

المصدر: American Journal of Physiology: Endocrinology & Metabolism; Aug2023, Vol. 325 Issue 2, pE119-E131, 13p

مصطلحات موضوعية: GLUCOSE metabolism, GLUCOSE, FREE fatty acids, METABOLISM

مستخلص: Elevated fasting free fatty acids (FFAs) and fasting glucose are additively associated with impaired glucose tolerance (IGT) and decreased β-cell function [quantified as disposition index (DI)]. We sought to examine how changes in fasting FFA and glucose alter islet function. We studied 10 subjects with normal fasting glucose (NFG) and normal glucose tolerance (NGT) on two occasions. On one occasion, Intralipid and glucose were infused overnight to mimic conditions present in IFG/IGT. In addition, we studied seven subjects with IFG/IGT on two occasions. On one occasion, insulin was infused to lower overnight FFA and glucose concentrations to those observed in people with NFG/NGT. The following morning, a labeled mixed meal was used to measure postprandial glucose metabolism and β-cell function. Elevation of overnight fasting FFA and glucose in NFG/NGT did not alter peak or integrated glucose concentrations (2.0 ± 0.1 vs. 2.0 ± 0.1 Mol per 5 h, Saline vs. Intralipid/glucose, P = 0.55). Although overall β-cell function quantified by the Disposition Index was unchanged, the dynamic component of β-cell responsivity (/d) was decreased by Intralipid and glucose infusion (9 ± 1 vs. 16 ± 3 109, P = 0.02). In people with IFG/IGT, insulin did not alter postprandial glucose concentrations or indices of β-cell function. Endogenous glucose production and glucose disappearance were also unchanged in both groups. We conclude that acute, overnight changes in FFA, and glucose concentrations do not alter islet function or glucose metabolism in prediabetes. [ABSTRACT FROM AUTHOR]

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المؤلفون: Farahani, Rahele A., Egan, Aoife M., Welch, Andrew A., Laurenti, Marcello C., Cobelli, Claudio, Dalla Man, Chiara, Vella, Adrian

المصدر: Diabetes; Apr2023, Vol. 72 Issue 4, p449-454, 6p

مصطلحات موضوعية: GLUCAGON-like peptide 1, PEPTIDE receptors, SECRETION, INSULIN, GLUCAGON-like peptide-1 agonists, GASTRIC inhibitory polypeptide, GLUCAGON

مستخلص: Data from transgenic rodent models suggest that glucagon acts as an insulin secretagogue by signaling through the glucagon-like peptide 1 receptor (GLP-1R) present on β-cells. However, its net contribution to physiologic insulin secretion in humans is unknown. To address this question, we studied individuals without diabetes in two separate experiments. Each subject was studied on two occasions in random order. In the first experiment, during a hyperglycemic clamp, glucagon was infused at 0.4 ng/kg/min, increasing by 0.2 ng/kg/min every hour for 5 h. On one day, exendin-9,39 (300 pmol/kg/min) was infused to block GLP-1R, while on the other, saline was infused. The insulin secretion rate (ISR) was calculated by nonparametric deconvolution from plasma concentrations of C-peptide. Endogenous glucose production and glucose disappearance were measured using the tracer-dilution technique. Glucagon concentrations, by design, did not differ between study days. Integrated ISR was lower during exendin-9,39 infusion (213 ± 26 vs. 191 ± 22 nmol/5 h, saline vs. exendin-9,39, respectively; P = 0.02). In the separate experiment, exendin-9,39 infusion, compared with saline infusion, also decreased the β-cell secretory response to a 1-mg glucagon bolus. These data show that, in humans without diabetes, glucagon partially stimulates the β-cell through GLP-1R. [ABSTRACT FROM AUTHOR]

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المؤلفون: Kohlenberg, Jacob D., Laurenti, Marcello C., Egan, Aoife M., Wismayer, Daniel Schembri, Bailey, Kent R., Cobelli, Claudio, Man, Chiara Dalla, Vella, Adrian

المصدر: Diabetologia; Jan2023, Vol. 66 Issue 1, p201-212, 12p

مستخلص: Aims/hypothesis: People with isolated impaired fasting glucose (IFG) have normal beta cell function. We hypothesised that an increased glucose threshold for beta cell secretion explains IFG. Methods: We used graded glucose infusion to examine the relationship of insulin secretion rate (ISR) and glucagon secretion rate (GSR) with rising glucose. We studied 39 non-diabetic individuals (53 ± 2 years, BMI 30 ± 1 kg/m²), categorised by fasting glucose and glucose tolerance status. After an overnight fast, a variable insulin infusion was used to maintain glucose at ~4.44 mmol/l (07:00 to 08:30 hours). At 09:00 hours, graded glucose infusion commenced at 1 mg kg⁻¹ min⁻¹ and doubled every 60 min until 13:00 hours. GSR and ISR were calculated by nonparametric deconvolution from concentrations of glucagon and C-peptide, respectively. Results: The relationship of ISR with glucose was linear and the threshold for insulin secretion in isolated IFG did not differ from that in people with normal fasting glucose and normal glucose tolerance. GSR exhibited a single-exponential relationship with glucose that could be characterised by G50, the change in glucose necessary to suppress GSR by 50%. G50 was increased in IFG compared with normal fasting glucose regardless of the presence of impaired or normal glucose tolerance. Conclusions/interpretation: These data show that, in non-diabetic humans, alpha cell dysfunction contributes to the pathogenesis of IFG independently of defects in insulin secretion. We also describe a new index that quantifies the suppression of glucagon secretion by glucose. [ABSTRACT FROM AUTHOR]

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المؤلفون: Adams, Jon D., Egan, Aoife M., Laurenti, Marcello C., Schembri Wismayer, Daniel, Bailey, Kent R., Cobelli, Claudio, Dalla Man, Chiara, Vella, Adrian

المصدر: Metabolic Syndrome & Related Disorders; Aug2022, Vol. 20 Issue 6, p329-335, 7p

مستخلص: Background: The rs7903146 variant in the TCF7L2 gene is associated with defects in postprandial insulin and glucagon secretion and increased risk of type 2 diabetes. However, it is unclear if this variant has effects on glucose metabolism that are independent of islet function. Methods: We studied 54 nondiabetic subjects on two occasions where endogenous hormone secretion was inhibited by somatostatin. Twenty-nine subjects were homozygous for the diabetes-associated allele (TT) and 25 for the diabetes-protective allele (CC) at rs7903146, but otherwise matched for anthropometric characteristics. On 1 day, glucagon infused at a rate of 0.65 ng/kg/min, and at 0 min prevented a fall in glucagon (nonsuppressed day). On the contrary, infusion commenced at 120 min to create a transient fall in glucagon (suppressed day). Subjects received glucose (labeled with [3-³H]-glucose) infused to mimic the systemic appearance of oral glucose. Insulin was infused to mimic a prandial insulin response. Endogenous glucose production (EGP) was measured using the tracer dilution technique. Results: Lack of glucagon suppression increased postchallenge glucose concentrations and impaired EGP suppression. However, in the presence of matched insulin and glucagon concentrations, genetic variation in TCF7L2 did not alter glucose metabolism. Conclusion: These data suggest that genetic variation in TCF7L2 alters glucose metabolism through changes in islet hormone secretion. [ABSTRACT FROM AUTHOR]

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المؤلفون: Laurenti, Marcello C., Arora, Praveer, Dalla Man, Chiara, Andrews, James C., Rizza, Robert A., Matveyenko, Aleksey, Bailey, Kent R., Cobelli, Claudio, Vella, Adrian

المصدر: Physiological Reports; Jul2022, Vol. 10 Issue 13, p1-8, 8p

مصطلحات موضوعية: GLUCAGON, INSULIN, TYPE 2 diabetes, HEPATIC veins, CELL physiology

مستخلص: Abnormal postprandial suppression of glucagon in Type 2 diabetes (T2DM) has been attributed to impaired insulin secretion. Prior work suggests that insulin and glucagon show an inverse coordinated relationship. However, dysregulation of α‐cell function in prediabetes occurs early and independently of changes in β‐cells, which suggests insulin having a less significant role on glucagon control. We therefore, sought to examine whether hepatic vein hormone concentrations provide evidence to further support the modulation of glucagon secretion by insulin. As part of a series of experiments to measure the effect of diabetes‐associated genetic variation in TCF7L2 on islet cell function, hepatic vein insulin and glucagon concentrations were measured at 2‐minute intervals during fasting and a hyperglycemic clamp. The experiment was performed on 29 nondiabetic subjects (age = 46 ± 2 years, BMI 28 ± 1 Kg/m2) and enabled post‐hoc analysis, using Cross‐Correlation and Cross‐Approximate Entropy (Cross‐ApEn) to evaluate the interaction of insulin and glucose. Mean insulin concentrations rose from fasting (33 ± 4 vs. 146 ± 12 pmol/L, p < 0.01) while glucagon was suppressed (96 ± 8 vs. 62 ± 5 ng/L, p < 0.01) during the clamp. Cross‐ApEn was used to measure pattern reproducibility in the two hormones using glucagon as control mechanism (0.78 ± 0.03 vs. 0.76 ± 0.03, fasting vs. hyperglycemia) and using insulin as a control mechanism (0.78 ± 0.02 vs. 0.76 ± 0.03, fasting vs. hyperglycemia). Values did not differ between the two scenarios. Cross‐correlation analysis demonstrated a small in‐phase coordination between insulin and glucagon concentrations during fasting, which inverted during hyperglycemia. This data suggests that the interaction between the two hormones is not driven by either. On a minute‐to‐minute basis, direct control and secretion of glucagon is not mediated (or restrained) by insulin. [ABSTRACT FROM AUTHOR]

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المؤلفون: Simha, Vinaya, Lanza, Ian R., Dasari, Surendra, Klaus, Katherine A., Le Brasseur, Nathan, Vuckovic, Ivan, Laurenti, Marcello C., Cobelli, Claudio, Port, John D., Nair, K. Sreekumaran

المصدر: Journal of Clinical Endocrinology & Metabolism; Feb2022, Vol. 107 Issue 2, p346-362, 17p

مصطلحات موضوعية: LIPODYSTROPHY, INSULIN resistance, MUSCLE proteins

مستخلص: Context: Familial partial lipodystrophy (FPL), Dunnigan variety is characterized by skeletal muscle hypertrophy and insulin resistance besides fat loss from the extremities. The cause for the muscle hypertrophy and its functional consequences is not known. Objective: To compare muscle strength and endurance, besides muscle protein synthesis rate between subjects with FPL and matched controls (n = 6 in each group). In addition, we studied skeletal muscle mitochondrial function and gene expression pattern to help understand the mechanisms for the observed differences. Methods: Body composition by dual-energy X-ray absorptiometry, insulin sensitivity by minimal modelling, assessment of peak muscle strength and fatigue, skeletal muscle biopsy and calculation of muscle protein synthesis rate, mitochondrial respirometry, skeletal muscle transcriptome, proteome, and gene set enrichment analysis. Results: Despite increased muscularity, FPL subjects did not demonstrate increased muscle strength but had earlier fatigue on chest press exercise. Decreased mitochondrial state 3 respiration in the presence of fatty acid substrate was noted, concurrent to elevated muscle lactate and decreased long-chain acylcarnitine. Based on gene transcriptome, there was significant downregulation of many critical metabolic pathways involved in mitochondrial biogenesis and function. Moreover, the overall pattern of gene expression was indicative of accelerated aging in FPL subjects. A lower muscle protein synthesis and downregulation of gene transcripts involved in muscle protein catabolism was observed. Conclusion: Increased muscularity in FPL is not due to increased muscle protein synthesis and is likely due to reduced muscle protein degradation. Impaired mitochondrial function and altered gene expression likely explain the metabolic abnormalities and skeletal muscle dysfunction in FPL subjects. [ABSTRACT FROM AUTHOR]

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المؤلفون: Adams, Jon D., Egan, Aoife M., Laurenti, Marcello C., Wismayer, Daniel Schembri, Bailey, Kent R., Cobelli, Claudio, Man, Chiara Dalla, Vella, Adrian

المصدر: American Journal of Physiology: Endocrinology & Metabolism; Nov2021, Vol. 321 Issue 5, pE728-E736, 9p

مصطلحات موضوعية: GLUCAGON, INSULIN, SECRETION, GLUCOSE, INSULIN therapy

مستخلص: Type 2 diabetes is a disease characterized by impaired insulin secretion and defective glucagon suppression in the postprandial period. We examined the effect of impaired glucagon suppression on glucose concentrations and endogenous glucose production (EGP) at different degrees of insulin secretory impairment. The contribution of anthropometric characteristics, peripheral, and hepatic insulin action to this variability was also examined. To do so, we studied 54 nondiabetic subjects on two occasions in which endogenous hormone secretion was inhibited by somatostatin, with glucagon infused at a rate of 0.65 ng/kg/min, at 0 min to prevent a fall in glucagon (nonsuppressed day) or at 120 min to create a transient fall in glucagon (suppressed day). Subjects received glucose (labeled with [3-³H]-glucose) infused to mimic the systemic appearance of 50-g oral glucose. Insulin was infused to mimic a prandial insulin response in 18 subjects, another 18 received 80% of the dose, and the remaining 18 received 60%. EGP was measured using the tracer-dilution technique. Decreased prandial insulin resulted in greater % increase in peak glucose but not in integrated glucose concentrations attributable to nonsuppressed glucagon. The % change in integrated EGP was unaffected by insulin dose. Multivariate regression analysis, adjusted for age, sex, weight, and insulin dose, did not show a relationship between the EGP response to impaired suppression of glucagon and insulin action as measured at the time of screening by oral glucose tolerance. A similar analysis for hepatic insulin action also did not show a relationship with the EGP response. These data indicate that the effect of impaired glucagon suppression on EGP is independent of anthropometric characteristics and insulin action. [ABSTRACT FROM AUTHOR]

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المؤلفون: Egan, Aoife M., Laurenti, Marcello C., Hurtado Andrade, Maria Daniela, Dalla Man, Chiara, Cobelli, Claudio, Bailey, Kent R., Vella, Adrian

المصدر: European Journal of Clinical Investigation; Jun2021, Vol. 51 Issue 6, p1-9, 9p

مصطلحات موضوعية: PROINSULIN, INSULIN, FREE fatty acids, GLUCOSE, TYPE 2 diabetes

مستخلص: Background: The fasting proinsulin to insulin ratio is elevated in people with type 2 diabetes and has been suggested as a marker of β‐cell health. However, its utility in discriminating between individuals with varying degrees of β‐cell dysfunction is unclear. Proinsulin has a very different half‐life to insulin and unlike insulin does not undergo hepatic extraction prior to reaching the systemic circulation. Given these limitations, we sought to examine the relationship between fasting and postprandial concentrations of β‐cell polypeptides (proinsulin, insulin and C‐peptide) in people with normal and impaired glucose tolerance in differing metabolic environments. Design: Subjects were studied on two occasions in random order while undergoing an oral challenge. During one study day, free fatty acids were elevated (to induce insulin resistance) by infusion of Intralipid with heparin. Proinsulin to insulin and proinsulin to C‐peptide ratios were calculated for the 0‐, 30‐, 60‐ and 240‐minute time points. Insulin action (Si) and β‐cell responsivity (Φ) indices were calculated using the oral minimal model. Results: The fasting proinsulin to c‐peptide or fasting proinsulin to insulin ratios did not differ between groups and did not predict subsequent β‐cell responsivity to glucose during the glycerol or Intralipid study days in either group. Conclusions: Among nondiabetic individuals, the fasting proinsulin to insulin ratio is not a useful marker of β‐cell function. [ABSTRACT FROM AUTHOR]

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