Diurnal variation in skeletal muscle and liver glycogen in humans with normal health and Type 2 diabetes

2015 ◽  
Vol 128 (10) ◽  
pp. 707-713 ◽  
Author(s):  
Mavin Macauley ◽  
Fiona E Smith ◽  
Peter E Thelwall ◽  
Kieren G Hollingsworth ◽  
Roy Taylor
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Skeletal Muscle ◽  
Muscle Glycogen ◽  
Liver Glycogen ◽  
Glycogen Storage ◽  
Resonance Spectroscopy ◽  
Model Assessment ◽  
Glycogen Concentration

In health, food carbohydrate is stored as glycogen in muscle and liver, preventing a deleterious rise in osmotically active plasma glucose after eating. Glycogen concentrations increase sequentially after each meal to peak in the evening, and fall to fasting levels thereafter. Skeletal muscle accounts for the larger part of this diurnal buffering capacity with liver also contributing. The effectiveness of this diurnal mechanism has not been previously studied in Type 2 diabetes. We have quantified the changes in muscle and liver glycogen concentration with 13C magnetic resonance spectroscopy at 3.0 T before and after three meals consumed at 4 h intervals. We studied 40 (25 males; 15 females) well-controlled Type 2 diabetes subjects on metformin only (HbA1c (glycated haemoglobin) 6.4±0.07% or 47±0.8 mmol/mol) and 14 (8 males; 6 females) glucose-tolerant controls matched for age, weight and body mass index (BMI). Muscle glycogen concentration increased by 17% after day-long eating in the control group (68.1±4.8 to 79.7±4.2 mmol/l; P=0.006), and this change inversely correlated with homoeostatic model assessment of insulin resistance [HOMA-IR] (r=−0.56; P=0.02). There was no change in muscle glycogen in the Type 2 diabetes group after day-long eating (68.3±2.6 to 67.1±2.0 mmol/mol; P=0.62). Liver glycogen rose similarly in normal control (325.9±25.0 to 388.1±30.3 mmol/l; P=0.005) and Type 2 diabetes groups (296.1±16.0 to 350.5±6.7 mmol/l; P<0.0001). In early Type 2 diabetes, the major physiological mechanism for skeletal muscle postprandial glycogen storage is completely inactive. This is directly related to insulin resistance, although liver glycogen storage is normal.

Direct assessment of muscle glycogen storage after mixed meals in normal and type 2 diabetic subjects

2003 ◽  
Vol 284 (4) ◽  
pp. E688-E694 ◽  
Author(s):  
P. E. Carey ◽  
J. Halliday ◽  
J. E. M. Snaar ◽  
P. G. Morris ◽  
R. Taylor
Keyword(s):  
Type 2 Diabetes ◽  
G Protein ◽  
Muscle Glycogen ◽  
Serum Insulin ◽  
Glycogen Storage ◽  
Diabetic Group ◽  
Control Group ◽  
Glycogen Concentration ◽  
Muscle Glycogen Concentration

To understand the day-to-day pathophysiology of impaired muscle glycogen storage in type 2 diabetes, glycogen concentrations were measured before and after the consumption of sequential mixed meals (breakfast: 190.5 g carbohydrate, 41.0 g fat, 28.8 g protein, 1,253 kcal; lunch: 203.3 g carbohydrate, 48.1 g fat, 44.0 g protein, 1,497.5 kcal) by use of natural abundance 13C magnetic resonance spectroscopy. Subjects with diet-controlled type 2 diabetes ( n = 9) and age- and body mass index-matched nondiabetic controls ( n = 9) were studied. Mean fasting gastrocnemius glycogen concentration was significantly lower in the diabetic group (57.1 ± 3.6 vs. 68.9 ± 4.1 mmol/l; P < 0.05). After the first meal, mean glycogen concentration in the control group rose significantly from basal (97.1 ± 7.0 mmol/l at 240 min; P = 0.005). After the second meal, the high level of muscle glycogen concentration in the control group was maintained, with a further rise to 108.0 ± 11.6 mmol/l by 480 min. In the diabetic group, the postprandial rise was markedly lower than that of the control group (65.9 ± 5.2 mmol/l at 240 min, P < 0.005, and 70.8 ± 6.7 mmol/l at 480 min, P = 0.01) despite considerably greater serum insulin levels (752.0 ± 109.0 vs. 372.3 ± 78.2 pmol/l at 300 min, P = 0.013). This was associated with a significantly greater postprandial hyperglycemia (10.8 ± 1.3 vs. 5.3 ± 0.2 mmol/l at 240 min, P < 0.005). Basal muscle glycogen concentration correlated inversely with fasting blood glucose ( r = −0.55, P < 0.02) and fasting serum insulin ( r = −0.57, P < 0.02). The increment in muscle glycogen correlated with initial increment in serum insulin only in the control group ( r = 0.87, P< 0.002). This study quantitates for the first time the subnormal basal muscle glycogen concentration and the inadequate glycogen storage after meals in type 2 diabetes.

Real-time assessment of postprandial fat storage in liver and skeletal muscle in health and type 2 diabetes

2005 ◽  
Vol 288 (4) ◽  
pp. E789-E797 ◽  
Author(s):  
B. Ravikumar ◽  
P. E. Carey ◽  
J. E. M. Snaar ◽  
D. K. Deelchand ◽  
D. B. Cook ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Skeletal Muscle ◽  
Fatty Acids ◽  
Control Group ◽  
Resonance Spectroscopy ◽  
Fat Storage ◽  
The Mean ◽  
Muscle Triglyceride

Liver and skeletal muscle triglyceride stores are elevated in type 2 diabetes and correlate with insulin resistance. As postprandial handling of dietary fat may be a critical determinant of tissue triglyceride levels, we quantified postprandial fat storage in normal and type 2 diabetes subjects. Healthy volunteers ( n = 8) and diet-controlled type 2 diabetes subjects ( n = 12) were studied using a novel 13C magnetic resonance spectroscopy protocol to measure the postprandial increment in liver and skeletal muscle triglyceride following ingestion of 13C-labeled fatty acids given with a standard mixed meal. The postprandial increment in hepatic triglyceride was rapid in both groups (peak increment controls: +7.3 ± 1.5 mmol/l at 6 h, P = 0.002; peak increment diabetics: +10.8 ± 3.4 mmol/l at 4 h, P = 0.009). The mean postprandial incremental AUC of hepatic 13C enrichment between the first and second meals (0 and 4 h) was significantly higher in the diabetes group (6.1 ± 1.4 vs. 1.7 ± 0.6 mmol·l−1·h−1, P = 0.019). Postprandial increment in skeletal muscle triglyceride in the control group was small compared with the diabetic group, the mean 24-h postprandial incremental AUC being 0.2 ± 0.3 vs. 1.7 ± 0.4 mmol·l−1·h−1 ( P = 0.009). We conclude that the postprandial uptake of fatty acids by liver and skeletal muscle is increased in type 2 diabetes and may underlie the elevated tissue triglyceride stores and consequent insulin resistance.

scholarly journals Early or advanced stage type 2 diabetes is not accompanied by in vivo skeletal muscle mitochondrial dysfunction

2008 ◽  
Vol 158 (5) ◽  
pp. 643-653 ◽  
Author(s):  
H M De Feyter ◽  
N M A van den Broek ◽  
S F E Praet ◽  
K Nicolay ◽  
L J C van Loon ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Skeletal Muscle ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Function ◽  
Resonance Spectroscopy ◽  
Diabetes Patients

ObjectiveSeveral lines of evidence support a potential role of skeletal muscle mitochondrial dysfunction in the pathogenesis of insulin resistance and/or type 2 diabetes. However, it remains to be established whether mitochondrial dysfunction represents either cause or consequence of the disease. We examined in vivo skeletal muscle mitochondrial function in early and advanced stages of type 2 diabetes, with the aim to gain insight in the proposed role of mitochondrial dysfunction in the aetiology of insulin resistance and/or type 2 diabetes.MethodsTen long-standing, insulin-treated type 2 diabetes patients, 11 subjects with impaired fasting glucose, impaired glucose tolerance and/or recently diagnosed type 2 diabetes, and 12 healthy, normoglycaemic controls, matched for age and body composition and with low habitual physical activity levels were studied. In vivo mitochondrial function of the vastus lateralis muscle was evaluated from post-exercise phosphocreatine (PCr) recovery kinetics using 31P magnetic resonance spectroscopy (MRS). Intramyocellular lipid (IMCL) content was assessed in the same muscle using single-voxel 1H MRS.ResultsIMCL content tended to be higher in the type 2 diabetes patients when compared with normoglycaemic controls (P=0.06). The31P MRS parameters for mitochondrial function, i.e. PCr and ADP recovery time constants and maximum aerobic capacity, did not differ between groups.ConclusionsThe finding that in vivo skeletal muscle oxidative capacity does not differ between long-standing, insulin-treated type 2 diabetes patients, subjects with early stage type 2 diabetes and sedentary, normoglycaemic controls suggests that mitochondrial dysfunction does not necessarily represent either cause or consequence of insulin resistance and/or type 2 diabetes.

scholarly journals Modelling ethnic differences in the distribution of insulin resistance via Bayesian nonparametric processes: an application to the SABRE cohort study

2020 ◽  
Vol 0 (0) ◽  
Author(s):  
Marco Molinari ◽  
Maria de Iorio ◽  
Nishi Chaturvedi ◽  
Alun Hughes ◽  
Therese Tillin
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Mcmc Methods ◽  
Model Assessment ◽  
Bayesian Nonparametric ◽  
Nonparametric Prior ◽  
Posterior Inference ◽  
Regression Framework ◽  
Analyse Data

AbstractWe analyse data from the Southall And Brent REvisited (SABRE) tri-ethnic study, where measurements of metabolic and anthropometric variables have been recorded. In particular, we focus on modelling the distribution of insulin resistance which is strongly associated with the development of type 2 diabetes. We propose the use of a Bayesian nonparametric prior to model the distribution of Homeostasis Model Assessment insulin resistance, as it allows for data-driven clustering of the observations. Anthropometric variables and metabolites concentrations are included as covariates in a regression framework. This strategy highlights the presence of sub-populations in the data, characterised by different levels of risk of developing type 2 diabetes across ethnicities. Posterior inference is performed through Markov Chains Monte Carlo (MCMC) methods.

scholarly journals Analysis of gene expression profiles in insulin-sensitive tissues from pre-diabetic and diabetic Zucker diabetic fatty rats

2005 ◽  
Vol 34 (2) ◽  
pp. 299-315 ◽  
Author(s):  
Young Ho Suh ◽  
Younyoung Kim ◽  
Jeong Hyun Bang ◽  
Kyoung Suk Choi ◽  
June Woo Lee ◽  
...  
Keyword(s):  
Gene Expression ◽  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Skeletal Muscle ◽  
Adipose Tissue ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Zucker Diabetic Fatty Rats ◽  
Zdf Rats

Insulin resistance occurs early in the disease process, preceding the development of type 2 diabetes. Therefore, the identification of molecules that contribute to insulin resistance and leading up to type 2 diabetes is important to elucidate the molecular pathogenesis of the disease. To this end, we characterized gene expression profiles from insulin-sensitive tissues, including adipose tissue, skeletal muscle, and liver tissue of Zucker diabetic fatty (ZDF) rats, a well characterized type 2 diabetes animal model. Gene expression profiles from ZDF rats at 6 weeks (pre-diabetes), 12 weeks (diabetes), and 20 weeks (late-stage diabetes) were compared with age- and sex-matched Zucker lean control (ZLC) rats using 5000 cDNA chips. Differentially regulated genes demonstrating > 1.3-fold change at age were identified and categorized through hierarchical clustering analysis. Our results showed that while expression of lipolytic genes was elevated in adipose tissue of diabetic ZDF rats at 12 weeks of age, expression of lipogenic genes was decreased in liver but increased in skeletal muscle of 12 week old diabetic ZDF rats. These results suggest that impairment of hepatic lipogenesis accompanied with the reduced lipogenesis of adipose tissue may contribute to development of diabetes in ZDF rats by increasing lipogenesis in skeletal muscle. Moreover, expression of antioxidant defense genes was decreased in the liver of 12-week old diabetic ZDF rats as well as in the adipose tissue of ZDF rats both at 6 and 12 weeks of age. Cytochrome P450 (CYP) genes were also significantly reduced in 12 week old diabetic liver of ZDF rats. Genes involved in glucose utilization were downregulated in skeletal muscle of diabetic ZDF rats, and the hepatic gluconeogenic gene was upregulated in diabetic ZDF rats. Genes commonly expressed in all three tissue types were also observed. These profilings might provide better fundamental understanding of insulin resistance and development of type 2 diabetes.

scholarly journals Docking protein 1 and free fatty acids are associated with insulin resistance in patients with type 2 diabetes mellitus

2021 ◽  
Vol 49 (11) ◽  
pp. 030006052110482
Author(s):  
Xiaoqin Ha ◽  
Xiaoling Cai ◽  
Huizhe Cao ◽  
Jie Li ◽  
Bo Yang ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Effective Means ◽  
Model Assessment ◽  
High Concentration ◽  
Obesity And Diabetes ◽  
Docking Protein

Objective Insulin resistance (IR) is a key defect in type 2 diabetes mellitus (T2DM); therefore, effective means of ameliorating IR are sought. Methods We performed a retrospective cohort study of 154 patients with T2DM and 39 with pre-diabetes (pre-DM). The effects of IR and a high concentration of FFA on gene expression were determined using microarray analysis and quantitative reverse transcription polymerase chain reaction (RT-qPCR) in patients with T2DM or pre-DM. Results Serum FFA concentration and homeostasis model assessment of IR (HOMA-IR) were significantly higher in patients with T2DM but no obesity and in those with pre-DM than in controls. HOMA-IR was significantly associated with T2DM. RT-qPCR showed that the expression of FBJ murine osteosarcoma viral oncogene homolog ( FOS) and AE binding protein 1 ( AEBP1) was much lower in the circulation of participants with obesity and diabetes. RT-qPCR showed that the expression of docking protein 1 ( DOK1) was significantly lower in the blood of participants with diabetes but no obesity and in those with pre-DM than in controls. Conclusions FFA and DOK1 are associated with IR in patients with T2DM but no obesity or pre-DM. The downregulation of DOK1 might inhibit lipid synthesis and induce lipolysis, inducing or worsening IR.

scholarly journals Serum and urinary concentrations of calprotectin as markers of insulin resistance and type 2 diabetes

2012 ◽  
Vol 167 (4) ◽  
pp. 569-578 ◽  
Author(s):  
Francisco J Ortega ◽  
Mónica Sabater ◽  
José M Moreno-Navarrete ◽  
Neus Pueyo ◽  
Patricia Botas ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Weight Loss ◽  
Lipid Metabolism ◽  
Inflammatory Markers ◽  
Low Grade ◽  
Model Assessment ◽  
Glucose And Lipid Metabolism ◽  
Obese Subjects

ObjectiveIncreased circulating calprotectin has been reported in obese subjects but not in association with measures of insulin resistance and type 2 diabetes (T2D). The main aim of this study was to determine whether calprotectins in plasma and urine are associated with insulin resistance.DesignWe performed both cross-sectional and longitudinal (diet-induced weight loss) studies.MethodsCirculating calprotectin concentrations (ELISA), other inflammatory markers, homeostasis model assessment of insulin resistance (HOMA-IR), and parameters of glucose and lipid metabolism were evaluated in 298 subjects (185 with normal (NGT) and 62 with impaired (IGT) glucose tolerance and 51 T2D subjects). Calprotectin was also evaluated in urine samples from 71 participants (50 NGT and 21 subjects with IGT). Insulin sensitivity (SI, Minimal Model) was determined in a subset of 156 subjects, and the effects of weight loss were investigated in an independent cohort of obese subjects (n=19).ResultsCirculating calprotectin was significantly increased in IGT–T2D (independently of BMI) and positively associated with HOMA-IR, obesity measures, inflammatory markers, and parameters of glucose and lipid metabolism. Similar findings were reported for calprotectin concentrations in urine. In the subset of subjects, the association of calprotectin withSIwas independent of BMI and age. In fact,SItogether with C-reactive protein contributed to 27.4% of calprotectin variance after controlling for age and blood neutrophils count. Otherwise, weight loss led to decreased circulating calprotectin in parallel to fasting glucose and HOMA-IR.ConclusionThese findings suggest that circulating and urinary concentrations of calprotectin are linked to chronic low-grade inflammation and insulin resistance beyond obesity.

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