Improvement of skeletal muscle insulin sensitivity by 1 week of SGLT2 inhibitor use

Background and Aims: It is currently unclear whether sodium–glucose co-transporter 2 (SGLT2) inhibitor administration can improve the insulin sensitivity as well as rapidly reduce plasma glucose concentrations in humans during the early phase of treatment initiation. This study aimed to investigate the effect of SGLT2 inhibitor on insulin sensitivity in the early phase of treatment initiation. Methods and Results This single-center, open label, and single-arm prospective study recruited 20 patients (14 men) with type 2 diabetes mellitus (T2DM). We examined the patients’ metabolic parameters before and 1 week after SGLT2 inhibitor (10 mg/day of empagliflozin) administration. The glucose infusion rate (GIR) was evaluated using the euglycemic hyperinsulinemic glucose clamp technique. Changes in laboratory and anthropometric parameters before and after SGLT2 inhibitor administration were analyzed according to the change in the GIR. The BMI, body fat amount, skeletal muscle amount, systolic blood pressure, and triglyceride level significantly decreased along with the treatment, while urinary glucose level and log GIR value significantly increased. Notably, changes in the GIR after SGLT2 inhibitor administration, which indicated improvement in peripheral insulin sensitivity, were negatively correlated with T2DM duration and positively with reduction in fluctuation of daily plasma glucose profiles before and after treatment. Conclusion SGLT2 inhibitor improved insulin sensitivity in the skeletal muscle independent of anthropometric changes. Patients with short duration of T2DM and insulin resistance can be good candidates for short-term SGLT2 inhibitor administration to improve insulin sensitivity in the skeletal muscle.

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Muscle Oxidative Capacity Is a Better Predictor of Insulin Sensitivity than Lipid Status

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2003-030791 ◽

2003 ◽

Vol 88 (11) ◽

pp. 5444-5451 ◽

Cited By ~ 159

Author(s):

Clinton R. Bruce ◽

Mitchell J. Anderson ◽

Andrew L. Carey ◽

David G. Newman ◽

Arend Bonen ◽

...

Keyword(s):

Skeletal Muscle ◽

Insulin Sensitivity ◽

Citrate Synthase ◽

Oxidative Capacity ◽

Fatty Acyl ◽

Whole Body ◽

Before And After ◽

Hydroxyacyl Coa Dehydrogenase ◽

Long Chain

Abstract We determined whole-body insulin sensitivity, long-chain fatty acyl coenzyme A (LCACoA) content, skeletal muscle triglyceride (TGm) concentration, fatty acid transporter protein content, and oxidative enzyme activity in eight patients with type 2 diabetes (TYPE 2); six healthy control subjects matched for age (OLD), body mass index, percentage of body fat, and maximum pulmonary O2 uptake; nine well-trained athletes (TRAINED); and four age-matched controls (YOUNG). Muscle biopsies from the vastus lateralis were taken before and after a 2-h euglycemic-hyperinsulinemic clamp. Oxidative enzyme activities, fatty acid transporters (FAT/CD36 and FABPpm), and TGm were measured from basal muscle samples, and total LCACoA content was determined before and after insulin stimulation. Whole-body insulin-stimulated glucose uptake was lower in TYPE 2 (P < 0.05) than in OLD, YOUNG, and TRAINED. TGm was elevated in TYPE 2 compared with all other groups (P < 0.05). However, both basal and insulin-stimulated skeletal muscle LCACoA content were similar. Basal citrate synthase activity was higher in TRAINED (P < 0.01), whereas β-hydroxyacyl CoA dehydrogenase activity was higher in TRAINED compared with TYPE 2 and OLD. There was a significant relationship between the oxidative capacity of skeletal muscle and insulin sensitivity (citrate synthase, r = 0.71, P < 0.001; β-hydroxyacyl CoA dehydrogenase, r = 0.61, P = 0.001). No differences were found in FAT/CD36 protein content between groups. In contrast, FABPpm protein was lower in OLD compared with TYPE 2 and YOUNG (P < 0.05). In conclusion, despite markedly elevated skeletal muscle TGm in type 2 diabetic patients and strikingly different levels of whole-body glucose disposal, both basal and insulin-stimulated LCACoA content were similar across groups. Furthermore, skeletal muscle oxidative capacity was a better predictor of insulin sensitivity than either TGm concentration or long-chain fatty acyl CoA content.

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Effects of the SGLT2 Inhibitor Dapagliflozin on Energy Metabolism in Patients With Type 2 Diabetes: A Randomized, Double-Blind Crossover Trial

10.2337/figshare.14058038.v1 ◽

2021 ◽

Author(s):

Yvo J.M. Op den Kamp ◽

Marlies de Ligt ◽

Bas Dautzenberg ◽

Esther Kornips ◽

Russell Esterline ◽

...

Keyword(s):

Type 2 Diabetes ◽

Insulin Sensitivity ◽

Energy Metabolism ◽

Caloric Restriction ◽

Sglt2 Inhibitor ◽

Metabolic Effects ◽

Night Time ◽

Double Blind ◽

Urinary Glucose

Background: SGTL2 inhibitors increase urinary glucose excretion and have beneficial effects on cardiovascular and renal outcomes; the underlying mechanism may involve caloric restriction-like metabolic effects due to urinary glucose loss. We investigated the effects of dapagliflozin on 24h energy metabolism and insulin sensitivity in patients with type 2 diabetes mellitus. Methods: Twenty-six type 2 diabetes patients were randomized to a 5-week double-blind, cross-over study with 6-8-week wash-out. 24h energy metabolism and respiratory exchange ratio (RER) were measured by indirect calorimetry, both by whole-room calorimetry and by ventilated hood during a two-step euglycemic hyperinsulinemic clamp. Results are presented as the differences in least squares mean (LSM) (95% CI) between treatments. Results: Evaluable patients (n=24) had a mean (SD) age of 64.2(4.6) years, BMI of 28.1(2.4) kg/m2, and HbA1c of 6.9 (0.7)% (51.7 (6.8) mmol/mol). Rate of glucose disappearance was unaffected by dapagliflozin, while fasting endogenous glucose production (EGP) increased by dapagliflozin (+2.27 (1.39, 3.14) μmol/kg/min, p<0.0001). Insulin-induced suppression of EGP (-1.71 (-2.75, -0.63) μmol/kg/min, p=0.0036) and plasma free fatty acids (-21.93 (-39.31, -4.54) %, p=0.016) was greater with dapagliflozin. 24h energy expenditure (-0.11 (-0.24, 0.03) MJ/day) remained unaffected by dapagliflozin, but dapagliflozin reduced RER during day- and night-time resulting in an increased day to night-time difference in RER (-0.010 (-0.017, -0.002), p=0.016). Dapagliflozin treatment resulted in a negative 24h energy and fat balance (-20.51 (-27.90, -13.12) g/day). Interpretation: Dapagliflozin treatment for 5 weeks resulted in major adjustments of metabolism mimicking caloric restriction; increased fat oxidation, improved hepatic and adipose insulin sensitivity and improved 24h energy metabolism.

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Effect of short-term exercise training on insulin-stimulated PI 3-kinase activity in human skeletal muscle

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1999.277.6.e1055 ◽

1999 ◽

Vol 277 (6) ◽

pp. E1055-E1060 ◽

Cited By ~ 30

Author(s):

Joseph A. Houmard ◽

Christopher D. Shaw ◽

Matthew S. Hickey ◽

Charles J. Tanner

Keyword(s):

Skeletal Muscle ◽

Insulin Sensitivity ◽

Exercise Training ◽

Kinase Activity ◽

Vastus Lateralis ◽

Maximal Oxygen Consumption ◽

Exercise Bout ◽

Phosphatidylinositol 3 Kinase ◽

Insulin Signal Transduction ◽

Before And After

The purpose of this study was to determine if the improvement in insulin sensitivity with exercise training is associated with enhanced phosphatidylinositol 3-kinase (PI 3-kinase) activity. Nine sedentary men were studied before and after 7 days of exercise training (1 h/day, ≈75% maximal oxygen consumption). Insulin sensitivity was determined with a euglycemic-hyperinsulinemic glucose clamp in the sedentary state and 15–17 h after the final exercise bout. PI 3-kinase activity was determined from samples (vastus lateralis) obtained in the fasted condition and after 60 min of submaximal insulin stimulation during the clamp. After exercise, glucose infusion rate increased ( P < 0.05) significantly (means ± SE, 7.8 ± 0.5 vs. 9.8 ± 0.8 mg ⋅ kg−1 ⋅ min−1), indicating improved insulin sensitivity. Insulin-stimulated (insulin stimulated/fasting) phosphotyrosine immunoprecipitable PI 3-kinase activity also increased significantly ( P < 0.05) with exercise (3.1 ± 0.8-fold) compared with the sedentary condition (1.3 ± 0.1-fold). There was no change in fasting PI 3-kinase activity. These data suggest that an enhancement of insulin signal transduction in skeletal muscle may contribute to the improvement in insulin action with exercise.

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Insulin sensitivity is independent of lipid binding protein trafficking at the plasma membrane in human skeletal muscle: effect of a 3-day, high-fat diet

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00124.2014 ◽

2014 ◽

Vol 307 (9) ◽

pp. R1136-R1145 ◽

Cited By ~ 6

Author(s):

Andreas B. Jordy ◽

Annette K. Serup ◽

Kristian Karstoft ◽

Henriette Pilegaard ◽

Bente Kiens ◽

...

Keyword(s):

Skeletal Muscle ◽

Insulin Sensitivity ◽

Protein Trafficking ◽

High Fat Diet ◽

Human Skeletal Muscle ◽

Lipid Binding ◽

High Fat ◽

Before And After ◽

The Impact ◽

Sarcolemmal Vesicles

The aim of the present study was to investigate lipid-induced regulation of lipid binding proteins in human skeletal muscle and the impact hereof on insulin sensitivity. Eleven healthy male subjects underwent a 3-day hypercaloric and high-fat diet regime. Muscle biopsies were taken before and after the diet intervention, and giant sarcolemmal vesicles were prepared. The high-fat diet induced decreased insulin sensitivity, but this was not associated with a relocation of FAT/CD36 or FABPpm protein to the sarcolemma. However, FAT/CD36 and FABPpm mRNA, but not the proteins, were upregulated by increased fatty acid availability. This suggests a time dependency in the upregulation of FAT/CD36 and FABPpm protein during high availability of plasma fatty acids. Furthermore, we did not detect FATP1 and FATP4 protein in giant sarcolemmal vesicles obtained from human skeletal muscle. In conclusion, this study shows that a short-term lipid-load increases mRNA content of key lipid handling proteins in human muscle. However, decreased insulin sensitivity after a high-fat diet is not accompanied with relocation of FAT/CD36 or FABPpm protein to the sarcolemma. Finally, FATP1 and FATP4 protein was located intracellularly but not at the sarcolemma in humans.

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Training Does Not Alter Muscle Ceramide and Diacylglycerol in Offsprings of Type 2 Diabetic Patients Despite Improved Insulin Sensitivity

Journal of Diabetes Research ◽

10.1155/2016/2372741 ◽

2016 ◽

Vol 2016 ◽

pp. 1-12 ◽

Cited By ~ 12

Author(s):

Ditte Søgaard ◽

Torben Østergård ◽

Agnieszka U. Blachnio-Zabielska ◽

Marcin Baranowski ◽

Andreas Hansen Vigelsø ◽

...

Keyword(s):

Insulin Resistance ◽

Insulin Sensitivity ◽

Endurance Training ◽

Early Phase ◽

Bicycle Ergometer ◽

Diabetic Patients ◽

Type 2 Diabetic Patients ◽

Before And After ◽

Muscle Biopsies

Ceramide and diacylglycerol (DAG) may be involved in the early phase of insulin resistance but data are inconsistent in man. We evaluated if an increase in insulin sensitivity after endurance training was accompanied by changes in these lipids in skeletal muscle. Nineteen first-degree type 2 diabetes Offsprings (Offsprings) (age:33.1±1.4 yrs; BMI:26.4±0.4 kg/m2) and sixteen matched Controls (age:31.3±1.5 yrs; BMI:25.3±0.7 kg/m2) performed 10 weeks of endurance training three times a week at 70% of VO2max on a bicycle ergometer. Before and after the intervention a hyperinsulinemic-euglycemic clamp and VO2max test were performed and muscle biopsies obtained. Insulin sensitivity was significantly lower in Offsprings compared to control subjects (p<0.01) but improved in both groups after 10 weeks of endurance training (Off:17±6%; Con:12±9%,p<0.01). The content of muscle ceramide, DAG, and their subspecies were similar between groups and did not change in response to the endurance training except for an overall reduction in C22:0-Cer (p<0.05). Finally, the intervention induced an increase in AKT protein expression (Off:27±11%; Con:20±24%,p<0.05). This study showed no relation between insulin sensitivity and ceramide or DAG content suggesting that ceramide and DAG are not major players in the early phase of insulin resistance in human muscle.

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Enhanced insulin sensitivity of gene-targeted mice lacking functional KCNQ1

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.90839.2008 ◽

2009 ◽

Vol 296 (6) ◽

pp. R1695-R1701 ◽

Cited By ~ 36

Author(s):

Krishna M. Boini ◽

Dirk Graf ◽

Anita M. Hennige ◽

Saisudha Koka ◽

Daniela S. Kempe ◽

...

Keyword(s):

Skeletal Muscle ◽

Insulin Sensitivity ◽

Glucose Metabolism ◽

Plasma Glucose ◽

Glucose Concentration ◽

Peak Plasma ◽

Plasma Glucose Concentration ◽

Α Subunit ◽

Glucose Injection ◽

Regulation Of Metabolism

The pore-forming K+-channel α-subunit KCNQ1 is expressed in a wide variety of tissues including heart, skeletal muscle, liver, and epithelia. Most recent evidence revealed an association of the KCNQ1 gene with the susceptibility to type 2 diabetes. KCNQ1 participates in the regulation of cell volume, which is, in turn, critically important for the regulation of metabolism by insulin. The present study explored the influence of KCNQ1 on insulin-induced cellular K+ uptake and glucose metabolism. Insulin (100 nM)-induced K+ uptake was determined in isolated perfused livers from KCNQ1-deficient mice ( kcnq1−/−) and their wild-type littermates ( kcnq1+/+). Moreover, plasma glucose and insulin levels, intraperitoneal glucose (3 g/kg) tolerance, insulin (0.15 U/kg)-induced hypoglycemia, and peripheral uptake of radiolabeled 3H-deoxy-glucose were determined in both genotypes. Insulin-stimulated hepatocellular K+ uptake was significantly more sustained in isolated perfused livers from kcnq1−/− mice than from kcnq1+/+mice. The decline of plasma glucose concentration following an intraperitoneal injection of insulin was again significantly more sustained in kcnq1−/− than in kcnq1+/+ mice. Both fasted and nonfasted plasma glucose and insulin concentrations were significantly lower in kcnq1−/− than in kcnq1+/+mice. Following an intraperitoneal glucose injection, the peak plasma glucose concentration was significantly lower in kcnq1−/− than in kcnq1+/+mice. Uptake of 3H-deoxy-glucose into skeletal muscle, liver, kidney and lung tissue was significantly higher in kcnq1−/− than in kcnq1+/+mice. In conclusion, KCNQ1 counteracts the stimulation of cellular K+ uptake by insulin and thereby influences K+-dependent insulin signaling on glucose metabolism. The observations indicate that KCNQ1 is a novel molecule affecting insulin sensitivity of glucose metabolism.

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Effects of the SGLT2 Inhibitor Dapagliflozin on Energy Metabolism in Patients With Type 2 Diabetes: A Randomized, Double-Blind Crossover Trial

10.2337/figshare.14058038 ◽

2021 ◽

Author(s):

Yvo J.M. Op den Kamp ◽

Marlies de Ligt ◽

Bas Dautzenberg ◽

Esther Kornips ◽

Russell Esterline ◽

...

Keyword(s):

Type 2 Diabetes ◽

Insulin Sensitivity ◽

Energy Metabolism ◽

Caloric Restriction ◽

Sglt2 Inhibitor ◽

Metabolic Effects ◽

Night Time ◽

Double Blind ◽

Urinary Glucose

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Plasma Sulphur-Containing Amino Acids, Physical Exercise and Insulin Sensitivity in Overweight Dysglycemic and Normal Weight Normoglycemic Men

Nutrients ◽

10.3390/nu11010010 ◽

2018 ◽

Vol 11 (1) ◽

pp. 10 ◽

Cited By ~ 11

Author(s):

Sindre Lee ◽

Thomas Olsen ◽

Kathrine Vinknes ◽

Helga Refsum ◽

Hanne Gulseth ◽

...

Keyword(s):

Skeletal Muscle ◽

Amino Acids ◽

Adipose Tissue ◽

Insulin Sensitivity ◽

Exercise Intervention ◽

Plasma Concentrations ◽

Normal Weight ◽

Plasma Metabolites ◽

Glutathione Biosynthesis ◽

Before And After

Plasma sulphur-containing amino acids and related metabolites are associated with insulin sensitivity, although the mechanisms are unclear. We examined the effect of exercise on this relationship. Dysglycemic (n = 13) and normoglycemic (n = 13) men underwent 45 min cycling before and after 12 weeks exercise intervention. We performed hyperinsulinemic euglycemic clamp, mRNA-sequencing of skeletal muscle and adipose tissue biopsies, and targeted profiling of plasma metabolites by LC-MS/MS. Insulin sensitivity increased similarly in dysglycemic and normoglycemic men after 12 weeks of exercise, in parallel to similar increases in concentration of plasma glutamine, and decreased concentrations of plasma glutamate, cysteine, taurine, and glutathione. Change in plasma concentrations of cysteine and glutathione exhibited the strongest correlations to exercise-improved insulin sensitivity, and expression of a cluster of genes essential for oxidative phosphorylation and fatty acid metabolism in both skeletal muscle and adipose tissue, as well as mitochondria-related genes such as mitofilin. Forty-five min of cycling decreased plasma concentrations of glutamine and methionine, and increased plasma concentrations of glutamate, homocysteine, cystathionine, cysteine, glutathione, and taurine. Similar acute responses were seen in both groups before and after the 12 weeks training period. Both acute and long-term exercise may influence transsulphuration and glutathione biosynthesis, linking exercise-improved insulin sensitivity to oxidative stress and mitochondrial function.

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Effects of Weight Loss on Adipose and Muscular Neuropilin 1 mRNA Expression in Obesity: Potential Implication in SARS-CoV-2 Infections?

Obesity Facts ◽

10.1159/000520419 ◽

2021 ◽

pp. 1-9

Author(s):

Dominik Soll ◽

Finja Beer ◽

Leonard Spranger ◽

Linna Li ◽

Joachim Spranger ◽

...

Keyword(s):

Skeletal Muscle ◽

Weight Loss ◽

Adipose Tissue ◽

Insulin Sensitivity ◽

Mrna Expression ◽

Neuropilin 1 ◽

Before And After ◽

Short And Long Term

Introduction: Neuropilin 1 (NRP-1) is a novel co-receptor promoting SARS-CoV-2 infectivity. Animal data indicate a role in trans-endothelial lipid transport and storage. As human data are sparse, we aimed to assess the role of NRP-1 in 2 metabolic active tissues in human obesity and in the context of weight loss-induced short- and long-term metabolic changes. Methods: After a standardized 12-week weight reduction program, 143 subjects (age >18; body mass index ≥27 kg/m2, 78% female) were randomized to a 12-month lifestyle intervention or a control group using a stratified randomization scheme. This was followed by 6-month follow-up without any intervention. Phenotyping was performed before and after weight loss, after 12-month intervention and after subsequent 6 months of follow-up. Tissue-specific insulin sensitivity was estimated by HOMA-IR (whole body and mostly driven by liver), insulin sensitivity index (ISI)Clamp (predominantly skeletal muscle), and free fatty acid (FFA) suppression during hyperinsulinemic-euglycemic clamp (FFASupp) (predominantly adipose tissue). NRP-1 mRNA expression was measured in subcutaneous adipose tissue (NRP-1AT) and skeletal muscle (NRP-1SM) before and after weight loss. Results: NRP-1 was highly expressed in adipose tissue (7,893 [7,303–8,536] counts), but neither NRP-1AT nor NRP-1SM were related to estimates of obesity. Higher NRP-1AT was associated with stronger FFASupp (r = −0.343, p = 0.003) and a tendency to higher ISIClamp (r = 0.202, p = 0.085). Weight loss induced a decline of NRP-1AT but not NRP-1SM. This was more pronounced in subjects with stronger reduction of adipose ACE-2 mRNA expression (r = 0.250; p = 0.032) but was not associated with short- and long-term improvement of FFASupp and ISIClamp. Conclusion: NRP-1AT is related to adipose insulin sensitivity in obesity. Weight loss-induced decline of NRP-1AT seems not to be involved in metabolic short- and long-term improvements after weight loss. However, weight loss-induced reduction of both NRP-1AT and ACE-2AT indicates a lower susceptibility of adipose tissue for SARS-CoV-2 after body weight reduction.

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Lipidomic Changes in Skeletal Muscle in Patients after Biliopancreatic Diversion

Hormone and Metabolic Research ◽

10.1055/s-0043-120065 ◽

2017 ◽

Vol 49 (11) ◽

pp. 880-885

Author(s):

Carola Mehnert ◽

Juergen Graessler ◽

Virginia Kamvissi-Lorenz ◽

Lidia Castagneto Gissey ◽

James Casella Mariolo ◽

...

Keyword(s):

Skeletal Muscle ◽

Insulin Sensitivity ◽

Biliopancreatic Diversion ◽

Muscle Cells ◽

Phospholipid Metabolism ◽

Cellular Level ◽

Skeletal Muscle Cells ◽

Euglycemic Hyperinsulinemic Clamp ◽

Before And After ◽

The Individual

AbstractThe mechanisms behind the fast improvements of insulin sensitivity and release of the diabetic metabolic state after bariatric surgery are still not completely understood. To further elucidate the effects on the individual cellular level, we applied mass spectrometry to investigate the changes in the lipidomic profile of skeletal muscle cells before and after biliopancreatic diversion in six patients. We found a decrease in lipid storage species, mainly triacylglycerides (e. g., TAG 52:2 from 19.84 to 13.26 mol%; p=0.028), and an increase in structural and signaling lipids, including phosphatidylcholines [PC 36:2 (18:1/18:1) from 0.12 to 0.65 mol%; p=0.046], phosphatidylinositols (PI 36:2 from 0.008 to 0.039 mol%; p=0.046), and cardiolipins (CL 72:8 from 0.16 to 1.22 mol%; p=0.043). The proportional increase in structural lipids was directly and the decrease in TAGs was inversely correlated to improved post-operative insulin sensitivity, measured by euglycemic hyperinsulinemic clamp. Thus, short-term recovery of insulin sensitivity after biliopancreatic diversion may, beside gut hormonal adaptation, mechanical factors, shifts in the gut microbiome, and changes in bile acid and phospholipid metabolism, additionally be attributed to a metabolic recovery of skeletal muscle cells, reflected by normalization of the cellular lipidomic profile. Further studies are needed to investigate whether improved insulin sensitivity of skeletal muscle might be directly associated with the degradation of ectopic triglycerides, thereby reducing the reservoir of lipotoxic intermediates, which might interfere with insulin signaling and hamper mitochondrial metabolism.

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