scholarly journals Resting Whole Body Energy Metabolism in Class 3 Obesity; from Preserved Insulin Sensitivity to Overt Type 2 Diabetes

2020 ◽  
Vol Volume 13 ◽  
pp. 489-497 ◽  
Author(s):  
Giuseppina Manzoni ◽  
Alice Oltolini ◽  
Silvia Perra ◽  
Emanuele Muraca ◽  
Stefano Ciardullo ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Sensitivity ◽  
Energy Metabolism ◽  
Whole Body ◽  
Body Energy

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

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

<b>Background:</b> 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. <p><b>Methods</b>: 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.</p> <p><b>Results</b>: Evaluable patients (n=24) had a mean (SD) age of 64<b>.</b>2(4<b>.</b>6) years, BMI of 28<b>.</b>1(2<b>.</b>4) kg/m2, and HbA1c of 6.9 (0.7)% (51<b>.</b>7 (6<b>.</b>8) mmol/mol). Rate of glucose disappearance was unaffected by dapagliflozin, while fasting endogenous glucose production (EGP) increased by dapagliflozin (+2<b>.</b>27 (1<b>.</b>39, 3<b>.</b>14) μmol/kg/min, p<0<b>.</b>0001). Insulin-induced suppression of EGP (-1<b>.</b>71 (-2<b>.</b>75, -0<b>.</b>63) μmol/kg/min, p=0<b>.</b>0036) and plasma free fatty acids (-21<b>.</b>93 (-39<b>.</b>31, -4<b>.</b>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). </p> <p><b>Interpretation</b>: 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.</p>

Examining the benefits of cold exposure as a therapeutic strategy for obesity and type 2 diabetes.

2021 ◽  
Author(s):  
Yoanna M. Ivanova ◽  
Denis P. Blondin
Keyword(s):  
Type 2 Diabetes ◽  
Fatty Acid ◽  
Insulin Sensitivity ◽  
Energy Expenditure ◽  
Cold Exposure ◽  
Skeletal Muscles ◽  
Cardiovascular Responses ◽  
Whole Body ◽  
Healthy Individuals

The pathogenesis of metabolic diseases such as obesity and type 2 diabetes are characterized by a progressive dysregulation in energy partitioning, often leading to end-organ complications. One emerging approach proposed to target this metabolic dysregulation is the application of mild cold exposure. In healthy individuals, cold exposure can increase energy expenditure and whole-body glucose and fatty acid utilization. Repeated exposures can lower fasting glucose and insulin levels and improve dietary fatty acid handling, even in healthy individuals. Despite its apparent therapeutic potential, little is known regarding the effects of cold exposure in populations for which this stimulation could benefit the most. The few studies available, have shown that both acute and repeated exposures to the cold improve insulin sensitivity and reduce fasting glycemia in individuals with type 2 diabetes. However, critical gaps remain in understanding the prolonged effects of repeated cold exposures on glucose regulation and whole-body insulin sensitivity in individuals with metabolic syndrome. Much of the metabolic benefits appear to be attributable to the recruitment of shivering skeletal muscles. However, further work is required to determine whether the broader recruitment of skeletal muscles observed during cold exposure can confer metabolic benefits that surpass what has been historically observed from endurance exercise. In addition, while cold exposure offers unique cardiovascular responses for a physiological stimulus that increases energy expenditure, further work is required to determine how acute and repeated cold exposure can impact cardiovascular responses and myocardial function across a broader scope of individuals.

Effect of 10 days of bedrest on metabolic and vascular insulin action: a study in individuals at risk for type 2 diabetes

2010 ◽  
Vol 108 (4) ◽  
pp. 830-837 ◽  
Author(s):  
Mette P. Sonne ◽  
Amra C. Alibegovic ◽  
Lise Højbjerre ◽  
Allan Vaag ◽  
Bente Stallknecht ◽  
...  
Keyword(s):  
Physical Activity ◽  
Type 2 Diabetes ◽  
Insulin Sensitivity ◽  
High Sensitivity ◽  
Whole Body ◽  
Diabetic Patients ◽  
Activity Levels ◽  
Type 2 Diabetic Patients ◽  
Increased Risk

Physical inactivity is a known risk factor for type 2 diabetes. We studied whole body and forearm insulin sensitivity in subjects at increased risk for type 2 diabetes [persons with low birth weight (LBW group; n = 20) and first-degree relatives to type 2 diabetic patients (FDR group; n = 13)] as well as a control (CON) group ( n = 20) matched for body mass index, age, and physical activity levels before and after 10 days of bedrest. Subjects were studied by hyperinsulinemic isoglycemic clamp combined with arterial and deep venous catheterization of the forearm. Forearm blood flow (FBF) was measured by venous occlusion plethysmography. All groups responded with a decrease in whole body insulin sensitivity in response to bedrest [CON group: 6.8 ± 0.5 to 4.3 ± 0.3 mg·min−1·kg−1( P < 0.0001), LBW group: 6.2 ± 0.5 to 4.3 ± 0.3 mg·min−1·kg−1( P < 0.0001), and FDR group: 4.3 ± 0.7 to 3.1 ± 0.3 mg·min−1·kg−1( P = 0.068)]. The percent decrease was significantly greater in the CON group compared with the FDR group (CON group: 34 ± 4%, LBW group: 27 ± 4%, and FDR group: 10 ± 13%). Forearm insulin-stimulated glucose clearance decreased significantly in the CON and LBW groups in response to bedrest; in the FDR group, clearance was very low before bedrest and no change was observed. Before bedrest, the CON and LBW groups demonstrated a significant increase in FBF during hyperinsulinemia; after bedrest, an increase in FBF was observed only in the CON group. In conclusion, bedrest induced a pronounced reduction in whole body, skeletal muscle, and vascular insulin sensitivity in the CON and LBW groups. The changes were most pronounced in the CON group. In the FDR group, insulin resistance was already present before bedrest, but even this group displayed a high sensitivity to changes in daily physical activity.

Effect of IL-6 on the insulin sensitivity in patients with type 2 diabetes

2014 ◽  
Vol 306 (7) ◽  
pp. E769-E778 ◽  
Author(s):  
N. M. Harder-Lauridsen ◽  
R. Krogh-Madsen ◽  
J. J. Holst ◽  
P. Plomgaard ◽  
L. Leick ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Glucose Metabolism ◽  
Glucose Uptake ◽  
Whole Body ◽  
Cytokine Signaling ◽  
Contributing Factors ◽  
Stat3 Phosphorylation ◽  
Socs3 Expression ◽  
Body Energy

Elevated interleukin-6 (IL-6) levels are associated with type 2 diabetes, but its role in glucose metabolism is controversial. We investigated the effect of IL-6 on insulin-stimulated glucose metabolism in type 2 diabetes patients and hypothesized that an acute, moderate IL-6 elevation would increase the insulin-mediated glucose uptake. Men with type 2 diabetes not treated with insulin [ n = 9, age 54.9 ± 9.7 (mean ± SD) yr, body mass index 34.8 ± 6.1 kg/m2, HbA1c7.0 ± 1.0%] received continuous intravenous infusion with either recombinant human IL-6 (rhIL-6) or placebo. After 1 h with placebo or rhIL-6, a 3-h hyperinsulinemic-isoglycemic clamp was initiated. Whole body glucose metabolism was measured using stable isotope-labeled tracers. Signal transducer and activator of transcription 3 (STAT3) phosphorylation and suppressor of cytokine signaling 3 (SOCS3) expression were measured in muscle biopsies. Whole body energy expenditure was measured using indirect calorimetry. In response to the infusion of rhIL-6, circulating levels of IL-6 ( P < 0.001), neutrophils ( P < 0.001), and cortisol ( P < 0.001) increased while lymphocytes decreased ( P < 0.01). However, IL-6 infusion did not change glucose infusion rate, rate of appearance, or rate of disappearance during the clamp. While IL-6 enhanced phosphorylation of STAT3 in skeletal muscle ( P = 0.041), the expression of SOCS3 remained unchanged. Whole body oxygen uptake ( P < 0.01) and expired carbon dioxide ( P < 0.01) increased during rhIL-6 infusion. In summary, although IL-6 induced local and systemic responses, the insulin-stimulated glucose uptake was not affected. While different contributing factors may be involved, our results are in contrast to our hypothesis and previous findings in young, healthy men.

scholarly journals Astrocyte Clocks and Glucose Homeostasis

2021 ◽  
Vol 12 ◽  
Author(s):  
Olga Barca-Mayo ◽  
Miguel López
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Sensitivity ◽  
Glucose Metabolism ◽  
Circadian Clock ◽  
Glucose Homeostasis ◽  
Metabolic Diseases ◽  
Current Knowledge ◽  
Genetic Alterations ◽  
Whole Body

The endogenous timekeeping system evolved to anticipate the time of the day through the 24 hours cycle of the Earth’s rotation. In mammals, the circadian clock governs rhythmic physiological and behavioral processes, including the daily oscillation in glucose metabolism, food intake, energy expenditure, and whole-body insulin sensitivity. The results from a series of studies have demonstrated that environmental or genetic alterations of the circadian cycle in humans and rodents are strongly associated with metabolic diseases such as obesity and type 2 diabetes. Emerging evidence suggests that astrocyte clocks have a crucial role in regulating molecular, physiological, and behavioral circadian rhythms such as glucose metabolism and insulin sensitivity. Given the concurrent high prevalence of type 2 diabetes and circadian disruption, understanding the mechanisms underlying glucose homeostasis regulation by the circadian clock and its dysregulation may improve glycemic control. In this review, we summarize the current knowledge on the tight interconnection between the timekeeping system, glucose homeostasis, and insulin sensitivity. We focus specifically on the involvement of astrocyte clocks, at the organism, cellular, and molecular levels, in the regulation of glucose metabolism.

scholarly journals Mitophagy-mediated adipose inflammation contributes to type 2 diabetes with hepatic insulin resistance

2020 ◽  
Vol 218 (3) ◽  
Author(s):  
Feng He ◽  
Yanrui Huang ◽  
Zhi Song ◽  
Huanjiao Jenny Zhou ◽  
Haifeng Zhang ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Energy Homeostasis ◽  
Hepatic Insulin Resistance ◽  
Whole Body ◽  
Ros Generation ◽  
Polyubiquitin Chains ◽  
Adipose Inflammation ◽  
Body Energy

White adipose tissues (WAT) play crucial roles in maintaining whole-body energy homeostasis, and their dysfunction can contribute to hepatic insulin resistance and type 2 diabetes mellitus (T2DM). However, the mechanisms underlying these alterations remain unknown. By analyzing the transcriptome landscape in human adipocytes based on available RNA-seq datasets from lean, obese, and T2DM patients, we reveal elevated mitochondrial reactive oxygen species (ROS) pathway and NF-κB signaling with altered fatty acid metabolism in T2DM adipocytes. Mice with adipose-specific deletion of mitochondrial redox Trx2 develop hyperglycemia, hepatic insulin resistance, and hepatic steatosis. Trx2-deficient WAT exhibited excessive mitophagy, increased inflammation, and lipolysis. Mechanistically, mitophagy was induced through increasing ROS generation and NF-κB–dependent accumulation of autophagy receptor p62/SQSTM1, which recruits damaged mitochondria with polyubiquitin chains. Importantly, administration of ROS scavenger or NF-κB inhibitor ameliorates glucose and lipid metabolic disorders and T2DM progression in mice. Taken together, this study reveals a previously unrecognized mechanism linking mitophagy-mediated adipose inflammation to T2DM with hepatic insulin resistance.

scholarly journals Metabolic Characteristics of Recently Diagnosed Adult-Onset Autoimmune Diabetes Mellitus

2017 ◽  
Vol 103 (2) ◽  
pp. 429-437 ◽  
Author(s):  
Oana P Zaharia ◽  
Pavel Bobrov ◽  
Klaus Strassburger ◽  
Kálmán Bódis ◽  
Yanislava Karusheva ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Sensitivity ◽  
Cell Function ◽  
Autoimmune Diabetes ◽  
Whole Body ◽  
Β Cell ◽  
Intravenous Glucose ◽  
Chronic Hyperglycemia ◽  
Β Cell Function

Abstract Context and Objective Among patients diagnosed with type 2 diabetes, autoimmune diabetes often remains undetected. Metabolic features of these patients are insufficiently characterized at present. Design, Setting, and Patients This study compared age- and sex-matched adult (aged 41 to 62 years) humans with recent-onset diabetes: patients positive for antibodies against glutamic acid decarboxylase (GAD) and/or cytoplasmic islet-cell antigen with an insulin-free period of &gt;6 months [antibody positive/insulin negative (ab+/ins−); previously termed latent autoimmune diabetes of adults], type 1 diabetes [antibody positive/insulin positive (ab+/ins+)], and type 2 diabetes [antibody negative/insulin negative (ab−/ins−)], as well as glucose-tolerant humans (controls) of the German Diabetes Study (n = 41/group). β-Cell function was assessed from glucagon tests and intravenous glucose tolerance tests (IVGTTs), and insulin sensitivity was determined from hyperinsulinemic-euglycemic clamps. Results Of the ab+/ins− patients, 33 (81%) were initially diagnosed as having type 2 diabetes. In ab+/ins−, body mass index (BMI) was higher than in ab+/ins+ (27.8 ± 5.3 kg/m2 vs 25.0 ± 3.5 kg/m2, P &lt; 0.05), lower than in ab−/ins− (31.9 ± 5.8 kg/m2, P &lt; 0.05), and similar to controls (29.4 ± 6.6 kg/m2). In ab+/ins−, GAD antibody titers correlated negatively with BMI (r = −0.40, P &lt; 0.05) and with C-peptide secretion in glucagon stimulation tests (r = −0.33, P &lt; 0.05). β-Cell function from IVGTT was 228% higher in ab+/ins− than in ab+/ins+ but 35% lower than in ab−/ins− and 61% lower than in controls (all P &lt; 0.05). Insulin sensitivity in ab+/ins− was comparable to ab+/ins+ and controls but 41% higher than in ab−/ins− (P &lt; 0.05) after adjustment for BMI and fasting blood glucose or hemoglobin A1c. Conclusion Even shortly after diagnosis, ab+/ins− patients feature partly preserved β-cell function and chronic hyperglycemia, which possibly contributes to the observed impairment of whole-body insulin sensitivity.

The effects of 3 weeks of oral glutathione supplementation on whole body insulin sensitivity in obese males with and without type 2 diabetes: A randomized trial

2021 ◽  
Author(s):  
Stine D. Søndergård ◽  
Ida Cintin ◽  
Anja Birk Kuhlman ◽  
Thomas Morville ◽  
Marie Louise Bergmann ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Type 2 Diabetes ◽  
Skeletal Muscle ◽  
Insulin Sensitivity ◽  
Oxidation Product ◽  
Emission Rate ◽  
Whole Body ◽  
Markers Of Oxidative Stress ◽  
Obese Subjects

The effect of oral glutathione (GSH) supplementation was studied in obese subjects with and without type 2 diabetes (T2DM) on measures of glucose homeostasis and markers of oxidative stress. Twenty subjects (10 patients with T2DM and 10 obese subjects) were recruited for the study, and randomized in a double-blinded placebo-controlled manner to consume either 1000mg GSH per day or placebo for three weeks. Before and after the 3 weeks insulin sensitivity was measured with the hyperinsulinemic-euglycemic clamp and a muscle biopsy was obtained to measure GSH and skeletal muscle mitochondrial hydrogen peroxide (H2O2) emission rate. Whole body insulin sensitivity increased significantly in the GSH group. Skeletal muscle GSH was numerically increased (app. 19%) in the GSH group, no change was seen in GSH to glutathione disulfide (GSSG) ratio. Skeletal muscle mitochondrial H2O2 emission rate did not change in response to the intervention and neither did the urinary excretion of the RNA oxidation product 8-oxo-7,8-dihydroguanosine (8-oxoGuo) or the DNA oxidation product 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodG ), although 8-oxodG decreased as a main effect of time. Oral GSH supplementation improves insulin sensitivity in obese subjects with and without T2DM, although it does not alter markers of oxidative stress. The study has been registered in clinicaltrials.gov (NCT02948673). Novelty bullets: • Reduced glutathione supplementation increases insulin sensitivity in obese subjects with and without type 2 diabetes • H2O2 emission rate from skeletal muscle mitochondria was not affected by glutathione supplementation

scholarly journals Efficacy of increased resistant starch consumption in human type 2 diabetes

2014 ◽  
Vol 3 (2) ◽  
pp. 75-84 ◽  
Author(s):  
C L Bodinham ◽  
L Smith ◽  
E L Thomas ◽  
J D Bell ◽  
J R Swann ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Sensitivity ◽  
Resistant Starch ◽  
Random Order ◽  
Postprandial Glucose ◽  
Whole Body ◽  
Whole Body Imaging ◽  
Euglycemic Hyperinsulinemic Clamp ◽  
Human Type

Resistant starch (RS) has been shown to beneficially affect insulin sensitivity in healthy individuals and those with metabolic syndrome, but its effects on human type 2 diabetes (T2DM) are unknown. This study aimed to determine the effects of increased RS consumption on insulin sensitivity and glucose control and changes in postprandial metabolites and body fat in T2DM. Seventeen individuals with well-controlled T2DM (HbA1c 46.6±2 mmol/mol) consumed, in a random order, either 40 g of type 2 RS (HAM-RS2) or a placebo, daily for 12 weeks with a 12-week washout period in between. At the end of each intervention period, participants attended for three metabolic investigations: a two-step euglycemic–hyperinsulinemic clamp combined with an infusion of [6,6-2H2] glucose, a meal tolerance test (MTT) with arterio-venous sampling across the forearm, and whole-body imaging. HAM-RS2 resulted in significantly lower postprandial glucose concentrations (P=0.045) and a trend for greater glucose uptake across the forearm muscle (P=0.077); however, there was no effect of HAM-RS2 on hepatic or peripheral insulin sensitivity, or on HbA1c. Fasting non-esterified fatty acid (NEFA) concentrations were significantly lower (P=0.004) and NEFA suppression was greater during the clamp with HAM-RS2 (P=0.001). Fasting triglyceride (TG) concentrations and soleus intramuscular TG concentrations were significantly higher following the consumption of HAM-RS2 (P=0.039 and P=0.027 respectively). Although fasting GLP1 concentrations were significantly lower following HAM-RS2 consumption (P=0.049), postprandial GLP1 excursions during the MTT were significantly greater (P=0.009). HAM-RS2 did not improve tissue insulin sensitivity in well-controlled T2DM, but demonstrated beneficial effects on meal handling, possibly due to higher postprandial GLP1.

Effects of insulin therapy on liver fat content and hepatic insulin sensitivity in patients with type 2 diabetes

2007 ◽  
Vol 292 (3) ◽  
pp. E829-E835 ◽  
Author(s):  
Leena Juurinen ◽  
Mirja Tiikkainen ◽  
Anna-Maija Häkkinen ◽  
Antti Hakkarainen ◽  
Hannele Yki-Järvinen
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Sensitivity ◽  
Insulin Therapy ◽  
Fat Content ◽  
Fat Free Mass ◽  
Liver Fat ◽  
Whole Body ◽  
Liver Fat Content ◽  
Hepatic Insulin Sensitivity

We determined whether insulin therapy changes liver fat content (LFAT) or hepatic insulin sensitivity in type 2 diabetes. Fourteen patients with type 2 diabetes (age 51 ± 2 yr, body mass index 33.1 ± 1.4 kg/m2) treated with metformin alone received additional basal insulin for 7 mo. Liver fat (proton magnetic resonance spectroscopy), fat distribution (MRI), fat-free and fat mass, and whole body and hepatic insulin sensitivity (6-h euglycemic hyperinsulinemic clamp combined with infusion of [3-3H]glucose) were measured. The insulin dose averaged 75 ± 10 IU/day (0.69 ± 0.08 IU/kg, range 24–132 IU/day). Glycosylated hemoglobin A1c (Hb A1c) decreased from 8.9 ± 0.3 to 7.4 ± 0.2% ( P < 0.001). Whole body insulin sensitivity increased from 2.21 ± 0.38 to 3.08 ± 0.40 mg/kg fat-free mass (FFM)·min ( P < 0.05). This improvement could be attributed to enhanced suppression of hepatic glucose production (HGP) by insulin (HGP 1.04 ± 0.28 vs. 0.21 ± 0.19 mg/kg FFM·min, P < 0.01). The percent suppression of HGP by insulin increased from 72 ± 8 to 105 ± 11% ( P < 0.01). LFAT decreased from 17 ± 3 to 14 ± 3% ( P < 0.05). The change in LFAT was significantly correlated with that in hepatic insulin sensitivity ( r = 0.56, P < 0.05). Body weight increased by 3.0 ± 1.1 kg ( P < 0.05). Of this, 83% was due to an increase in fat-free mass ( P < 0.01). Fat distribution and serum adiponectin concentrations remained unchanged while serum free fatty acids decreased significantly. Conclusions: insulin therapy improves hepatic insulin sensitivity and slightly but significantly reduces liver fat content, independent of serum adiponectin.

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