A Comprehensive Model of Glucose-Insulin Regulation Including Acute and Prolonged Effects of Physical Activity in Type 1 Diabetes

Objective: For type 1 diabetic patients, accurate adjustment of insulin treatment to physical activity (PA) is a challenging open problem. Glucose uptake by the exercising muscles increases acutely, causing increased hepatic glucose production to maintain glucose homeostasis. Meanwhile, insulin sensitivity is elevated for a prolonged period to drive glycogen repletion during recovery. These processes strongly depend on PA duration and intensity, making their combined effects difficult to predict accurately. In this work, we develop a model of glucose-insulin regulation that captures PA from low to high intensity including acute and prolonged effects on glucose metabolism. Methods: We extended an existing minimal model of glucose-insulin regulation to capture PA-driven changes in glucose metabolism. We incorporated the insulin-independent increase in glucose uptake and production, including the effects of glycogen depletion and of high-intensity PA on production. The model also captures the prolonged increase in insulin sensitivity. Results: The model accurately predicts glucose dynamics of published data during short and prolonged PA of moderate to high intensity and during subsequent recovery. In-silico full-day studies elucidate the effects of timing, duration and intensity of PA and of insulin bolus reduction on glucose levels during and after the activity. Conclusion: The proposed model captures the blood glucose dynamics during all main PA regimes. Significance: Mathematical models of glucose-insulin regulation are critical components of closed-loop insulin delivery and clinical decision support systems for achieving good glycemic control. The presented model shows potential for the development and assessment of algorithms targeting treatment adjustment to PA.

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Relationship between oral glucose tolerance and insulin sensitivity in healthy man and type 1 diabetic patients

Acta Endocrinologica ◽

10.1530/acta.0.1120355 ◽

1986 ◽

Vol 112 (3) ◽

pp. 355-360 ◽

Cited By ~ 6

Author(s):

Hannele Yki-Järvinen ◽

Eero Helve ◽

Veikko A. Koivisto

Keyword(s):

Insulin Sensitivity ◽

Glucose Metabolism ◽

Glucose Tolerance ◽

Normal Subjects ◽

Oral Glucose ◽

Diabetic Patients ◽

Oral Glucose Tolerance ◽

Healthy Man ◽

Type 1 Diabetic Patients

Abstract. The relationship between insulin sensitivity and oral glucose tolerance was studied in 8 conventionally treated type 1 diabetic patients (age 34 ± 4 years, relative body weight (RBW) 113 ± 5%) and in 11 healthy subjects (age 35 ± 3 years, RBW 114 ± 2%). In each subject and patient, oral glucose tolerance (75 g glucose) and in vivo sensitivity to insulin (euglycaemic clamp technique, 1 mU/kg/min insulin infusion) were measured. The response to oral glucose in the diabetic patients was measured during maintenance of similar peripheral plasma free insulin levels as in the normal subjects during the oral glucose tolerance test (OGTT). During the OGTT, the post-glucose plasma glucose values in the diabetic patients were markedly higher (P < 0.001) than in the normal subjects. During the clamp study, the rate of glucose metabolism in the diabetic patients (4.53 ± 0.58 mg/kg/min) was 37% lower than in the normal subjects (7.19 ± 0.67 mg/kg/min, P < 0.02). The area under the glucose curve was inversely related to the rate of glucose metabolism in both the diabetic (r = −0.72, P < 0.02) and the normal (r = −0.69, P < 0.02) subjects. The slope of the curve was substantially steeper in the diabetic than the control subjects. Thus, peripheral insulin sensitivity contributes to oral glucose tolerance both in healthy man, and even to a greater extent, in type 1 diabetic patients.

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Low-Dose Acrolein, an Endogenous and Exogenous Toxic Molecule, Inhibits Glucose Transport via an Inhibition of Akt-Regulated GLUT4 Signaling in Skeletal Muscle Cells

International Journal of Molecular Sciences ◽

10.3390/ijms22137228 ◽

2021 ◽

Vol 22 (13) ◽

pp. 7228

Author(s):

Ching-Chia Wang ◽

Huang-Jen Chen ◽

Ding-Cheng Chan ◽

Chen-Yuan Chiu ◽

Shing-Hwa Liu ◽

...

Keyword(s):

Skeletal Muscle ◽

Glucose Metabolism ◽

Glucose Tolerance ◽

Protein Expression ◽

Glucose Uptake ◽

Glucose Transport ◽

Diabetic Patients ◽

Type 2 Diabetic Patients ◽

Type 2 Diabetic

Urinary acrolein adduct levels have been reported to be increased in both habitual smokers and type-2 diabetic patients. The impairment of glucose transport in skeletal muscles is a major factor responsible for glucose uptake reduction in type-2 diabetic patients. The effect of acrolein on glucose metabolism in skeletal muscle remains unclear. Here, we investigated whether acrolein affects muscular glucose metabolism in vitro and glucose tolerance in vivo. Exposure of mice to acrolein (2.5 and 5 mg/kg/day) for 4 weeks substantially increased fasting blood glucose and impaired glucose tolerance. The glucose transporter-4 (GLUT4) protein expression was significantly decreased in soleus muscles of acrolein-treated mice. The glucose uptake was significantly decreased in differentiated C2C12 myotubes treated with a non-cytotoxic dose of acrolein (1 μM) for 24 and 72 h. Acrolein (0.5–2 μM) also significantly decreased the GLUT4 expression in myotubes. Acrolein suppressed the phosphorylation of glucose metabolic signals IRS1, Akt, mTOR, p70S6K, and GSK3α/β. Over-expression of constitutive activation of Akt reversed the inhibitory effects of acrolein on GLUT4 protein expression and glucose uptake in myotubes. These results suggest that acrolein at doses relevant to human exposure dysregulates glucose metabolism in skeletal muscle cells and impairs glucose tolerance in mice.

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Insulin resistance is localized to skeletal but not heart muscle in type 1 diabetes

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1993.264.5.e756 ◽

1993 ◽

Vol 264 (5) ◽

pp. E756-E762 ◽

Cited By ~ 7

Author(s):

P. Nuutila ◽

J. Knuuti ◽

U. Ruotsalainen ◽

V. A. Koivisto ◽

E. Eronen ◽

...

Keyword(s):

Insulin Resistance ◽

Glucose Uptake ◽

Compartment Model ◽

Normal Subjects ◽

Whole Body ◽

Diabetic Patients ◽

Uptake Rates ◽

Arm Muscles ◽

Type 1 Diabetic Patients

To determine the tissue localization of insulin resistance in type 1 diabetic patients, whole body and regional glucose uptake rates were determined under euglycemic hyperinsulinemic conditions. Leg, arm, and heart glucose uptake rates were measured using positron emission tomography-derived 2-deoxy-2-[18F]-fluoro-D-glucose kinetics and the three-compartment model described by Sokoloff et al. (L. Sokoloff, M. Reivich, C. Kennedy, M.C. DesRosiers, C.S. Patlak, K.D. Pettigrew, O. Sakurada, and M. Shinohara. J. Neurochem. 28: 897–916, 1977) in eight type 1 diabetic patients and eight matched normal subjects. Whole body glucose uptake was quantitated by the euglycemic insulin clamp technique. Whole body glucose uptake was approximately 31% lower in the diabetic patients (P < 0.01) than in the normal subjects, thus confirming the presence of whole body insulin resistance. The rate of glucose uptake was approximately 45% lower in leg muscle when measured in the femoral region (55 +/- 7 vs. 102 +/- 13 mumol.kg muscle-1.min-1, diabetic patients vs. normal subjects, P < 0.05) and approximately 27% lower in the arm muscles (66 +/- 4 vs. 90 +/- 13 mumol.kg muscle-1.min-1, respectively, P < 0.05), whereas no difference was observed in heart glucose uptake [789 +/- 80 vs. 763 +/- 58 mumol.kg muscle-1.min-1 not significant (NS)]. Whole body glucose uptake correlated with glucose uptake in femoral (r = 0.93, P < 0.005) and arm muscles (r = 0.66, P < 0.05) but not with glucose uptake in the heart (r = 0.04, NS). We conclude that insulin resistance in type 1 diabetic patients is localized to skeletal muscle, whereas heart glucose uptake is unaffected.(ABSTRACT TRUNCATED AT 250 WORDS)

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Effects of physical activity on the progression of diabetic nephropathy: a meta-analysis

Bioscience Reports ◽

10.1042/bsr20203624 ◽

2021 ◽

Vol 41 (1) ◽

Author(s):

Zixin Cai ◽

Yan Yang ◽

Jingjing Zhang

Keyword(s):

Physical Activity ◽

Diabetic Nephropathy ◽

Healthy Lifestyle ◽

Meta Analysis ◽

Kidney Injury ◽

Cochrane Library ◽

Diabetic Patients ◽

Mean Differences

Abstract Background: Diabetic nephropathy (DN) is an important microvascular complication of diabetes. Physical activity (PA) is part of a healthy lifestyle for diabetic patients; however, the role of PA in DN has not been clarified. Our aim was to conduct a meta-analysis to explore the association between PA and DN risk. Methods: PubMed, Embase, Cochrane Library and Web of Science were systematically searched for articles examining PA in diabetic patients and its effect on renal function. Standardized mean differences (SMDs) and odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. The study protocol is registered with PROSPERO (CRD42020191379). Results: A total of 38991 participants were identified from 18 studies. The results indicated that PA was associated with increases in the glomerular filtration rate (SMD = 0.01, 95% CI = [0.02–0.17]) and decreases in the urinary albumin creatinine ratio (SMD = −0.53, 95% CI: −0.72 to −0.34), rate of microalbuminuria (OR = 0.61, 95% CI = [0.46–0.81]), rate of acute kidney injury (OR = 0.02, 95% CI = [0.01–0.04]), rate of renal failure (OR = 0.71, 95% CI = [0.52–0.97]) and risk of DN in patients with Type 1 diabetes (OR = 0.67, 95% CI = [0.51–0.89]). Conclusions: This meta-analysis indicated that PA is effective for improving DN and slowing its progression; however, more high-quality randomized controlled trials are required on this topic.

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Effect of needle biopsy from the vastus lateralis muscle on insulin-stimulated glucose metabolism in humans

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1994.267.4.e544 ◽

1994 ◽

Vol 267 (4) ◽

pp. E544-E548 ◽

Cited By ~ 3

Author(s):

P. Holck ◽

N. Porksen ◽

M. F. Nielsen ◽

B. Nyholm ◽

J. F. Bak ◽

...

Keyword(s):

Insulin Sensitivity ◽

Glucose Metabolism ◽

Glucose Uptake ◽

Muscle Biopsy ◽

Needle Biopsy ◽

Vastus Lateralis ◽

Whole Body ◽

Vastus Lateralis Muscle ◽

Lateralis Muscle ◽

Glucose Output

To examine the cellular mechanisms behind conditions characterized by insulin resistance, the clamp technique is often combined with muscle biopsies. To test whether the trauma of a needle biopsy from the vastus lateralis muscle per se may influence insulin-stimulated glucose uptake, eight healthy subjects underwent two randomly sequenced hyperinsulinemic (insulin infusion rate: 0.6 mU.kg-1.min-1 for 150 min) euglycemic clamps with an interval of 4-6 wk. In one study (study B) a muscle biopsy (approximately 250 mg, i.e., larger than normal standard) was taken in the basal state just before the clamp procedure, whereas the other was a control study (study C). Insulin-stimulated glucose uptake was significantly reduced in study B (5.36 +/- 0.96 mg.kg-1.min-1) compared with study C (6.06 +/- 0.68 mg.kg-1.min-1; P < 0.05). Nonoxidative glucose disposal (indirect calorimetry) was decreased (2.81 +/- 1.08 vs. 3.64 +/- 1.34 mg.kg-1.min-1; P < 0.05), whereas glucose oxidation was unaltered. Likewise, endogenous glucose output ([3-3H]glucose) was identically suppressed during hyperinsulinemia. Circulating levels of epinephrine, glucagon, and growth hormone did not differ significantly in studies B and C. In contrast, plasma norepinephrine, serum cortisol, and free fatty acid rose after biopsy (P < 0.05). In conclusion, performance of a muscle biopsy may diminish insulin sensitivity by affecting nonoxidative glucose metabolism. This should be considered when assessing whole body insulin sensitivity after a percutaneous needle muscle biopsy.

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Glucose metabolism in epitrochlearis muscle of acutely exercised and trained rats

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1986.250.2.e137 ◽

1986 ◽

Vol 250 (2) ◽

pp. E137-E143 ◽

Cited By ~ 2

Author(s):

T. A. Davis ◽

S. Klahr ◽

E. D. Tegtmeyer ◽

D. F. Osborne ◽

T. L. Howard ◽

...

Keyword(s):

Insulin Sensitivity ◽

Glucose Metabolism ◽

Glucose Uptake ◽

Acute Exercise ◽

Glycogen Synthesis ◽

Prior Training ◽

Glycogen Stores

Effects of insulin on glycogen synthesis (GS), glycolytic utilization (GU), and glucose uptake (GT) were studied in isolated epitrochlearis muscles from exercise-trained or sedentary rats during recovery from acute exercise or at rest. During the 1st h after acute exercise, the enhanced basal and insulin-stimulated GT was directed mainly toward replenishment of glycogen but basal GU was also increased. During the second through third hours after exercise, basal GS decreased but remained greater than rest and basal GU and GT returned to normal. Insulin sensitivity of these parameters was enhanced. Training alone reduced basal GS but enhanced insulin sensitivity of GT and GU. Training reduced the acute exercise-stimulated increase in basal and insulin sensitivity of GS during recovery from acute exercise, probably due to elevated glycogen stores. Thus recovery from acute exercise or training, either alone or in combination, enhances insulin stimulated GT in muscle; however, the increased glucose is primarily channeled toward GS after acute exercise, which is reduced by prior training and is directed to GU in trained animals either at rest or after acute exercise.

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Assessment of Serum Concentrations of Adropin, Afamin, and Neudesin in Children with Type 1 Diabetes

BioMed Research International ◽

10.1155/2019/6128410 ◽

2019 ◽

Vol 2019 ◽

pp. 1-6 ◽

Cited By ~ 1

Author(s):

Agnieszka Polkowska ◽

Izabela Elżbieta Pasierowska ◽

Marta Pasławska ◽

Elżbieta Pawluczuk ◽

Artur Bossowski

Keyword(s):

Type 1 Diabetes ◽

Glucose Metabolism ◽

Statistical Significance ◽

Serum Levels ◽

Control Group ◽

Diabetic Patients ◽

Serum Concentrations ◽

Novel Biomarkers ◽

Varied Duration

Introduction. The increasing knowledge of adropin, afamin, and neudesin and the regulation of glucose metabolism and insulin resistance allows for the assessment of the differences in their concentrations between the groups with varied duration of diabetes mellitus (DM). Aim of the Study. Assessment of serum levels of adropin, afamin, and neudesin in children with type 1 diabetes, with respect to the disease duration. Materials and Methods. The study consisted of 138 patients aged 5–18 years (M 40.58%). Children with type 1 diabetes (n = 68) were compared to the control group (n = 70). The diabetic group was divided into 4 subgroups: (I) newly diagnosed patients, after an episode of ketoacidosis (n = 14), (II) duration no longer than 5 years (n = 18), (III) 5 to 10 years (n = 27), and (IV) longer than 10 years (n = 9). Serum concentrations of adropin, afamin, and neudesin were assessed and compared between the groups of patients. The criterion for statistical significance was p<0.05. Results. The concentrations of adropin and afamin across all subgroups were lower than that in the control group, while neudesin levels were higher in diabetic patients compared to the control group. The differences were statistically significant. Conclusions. Adropin, afamin, and neudesin may play a major role in the regulation of glucose metabolism and have a significant potential as novel biomarkers to predict future metabolic disorders. However, further multicentre studies on a larger cohort of patients are necessary to specify the role of these substances in the course and treatment of type 1 diabetes.

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Higher intramuscular triacylglycerol in women does not impair insulin sensitivity and proximal insulin signaling

Journal of Applied Physiology ◽

10.1152/japplphysiol.91382.2008 ◽

2009 ◽

Vol 107 (3) ◽

pp. 824-831 ◽

Cited By ~ 41

Author(s):

Louise Høeg ◽

Carsten Roepstorff ◽

Maja Thiele ◽

Erik A. Richter ◽

Jørgen F. P. Wojtaszewski ◽

...

Keyword(s):

Insulin Sensitivity ◽

Glucose Uptake ◽

Muscle Fiber ◽

Insulin Signaling ◽

Capillary Density ◽

Follicular Phase ◽

Activity Level ◽

Whole Body ◽

Vastus Lateralis Muscle

Women have been shown to have higher muscle triacylglycerol (IMTG) levels than men and could therefore be expected to have lower insulin sensitivity than men, since previous studies have linked high IMTG to decreased insulin sensitivity. Therefore, insulin sensitivity of whole body and leg glucose uptake was studied in 9 women in the follicular phase and 8 men on a controlled diet and matched for maximal oxygen uptake per kilogram of lean body mass and habitual activity level. A 47% higher ( P < 0.05) IMTG level was found in women than in men, and, at the same time, women also displayed 22% higher whole body insulin sensitivity ( P < 0.05) and 29% higher insulin-stimulated leg glucose uptake ( P = 0.05) during an euglycemic-hyperinsulinemic (≈70 μU/ml) clamp compared with matched male subjects. The higher insulin sensitivity in women could not be explained by higher expression of muscle glucose transporter GLUT4, insulin receptor, or Akt expression or by the ability of insulin to stimulate Akt Thr308 or Akt Ser473 phosphorylation. However, a 30% higher ( P < 0.05) capillary density and 31% more type 1 muscle fiber expressed per area in the vastus lateralis muscle were noted in women than in matched men. It is concluded that despite 47% higher IMTG levels in women in the follicular phase, whole body as well as leg insulin sensitivity are higher than in matched men. This was not explained by sex differences in proximal insulin signaling in women. In women, it seems that a high capillary density and type 1 muscle fiber expression may be important for insulin action.

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