scholarly journals Plasma cathepsin D activity is negatively associated with hepatic insulin sensitivity in overweight and obese humans

Diabetologia ◽  
2019 ◽  
Vol 63 (2) ◽  
pp. 374-384 ◽  
Author(s):  
Lingling Ding ◽  
Gijs H. Goossens ◽  
Yvonne Oligschlaeger ◽  
Tom Houben ◽  
Ellen E. Blaak ◽  
...  
Keyword(s):  
Insulin Sensitivity ◽  
Cathepsin D ◽  
Insulin Infusion ◽  
Hepatic Insulin Sensitivity ◽  
Euglycaemic Clamp ◽  
Negatively Associated ◽  
Peripheral Insulin Sensitivity ◽  
Hyperinsulinaemic Euglycaemic Clamp ◽  
Tnf Α ◽  
Glucose Output

Abstract Aims/hypothesis Insulin resistance in skeletal muscle and liver plays a major role in the pathophysiology of type 2 diabetes. The hyperinsulinaemic–euglycaemic clamp is considered the gold standard for assessing peripheral and hepatic insulin sensitivity, yet it is a costly and labour-intensive procedure. Therefore, easy-to-measure, cost-effective approaches to determine insulin sensitivity are needed to enable organ-specific interventions. Recently, evidence emerged that plasma cathepsin D (CTSD) is associated with insulin sensitivity and hepatic inflammation. Here, we aimed to investigate whether plasma CTSD is associated with hepatic and/or peripheral insulin sensitivity in humans. Methods As part of two large clinical trials (one designed to investigate the effects of antibiotics, and the other to investigate polyphenol supplementation, on insulin sensitivity), 94 overweight and obese adults (BMI 25–35 kg/m2) previously underwent a two-step hyperinsulinaemic–euglycaemic clamp (using [6,6-2H2]glucose) to assess hepatic and peripheral insulin sensitivity (per cent suppression of endogenous glucose output during the low-insulin-infusion step, and the rate of glucose disappearance during high-insulin infusion [40 mU/(m2 × min)], respectively). In this secondary analysis, plasma CTSD levels, CTSD activity and plasma inflammatory cytokines were measured. Results Plasma CTSD levels were positively associated with the proinflammatory cytokines IL-8 and TNF-α (IL-8: standardised β = 0.495, p < 0.001; TNF-α: standardised β = 0.264, p = 0.012). Plasma CTSD activity was negatively associated with hepatic insulin sensitivity (standardised β = −0.206, p = 0.043), independent of age, sex, BMI and waist circumference, but it was not associated with peripheral insulin sensitivity. However, plasma IL-8 and TNF-α were not significantly correlated with hepatic insulin sensitivity. Conclusions/interpretation We demonstrate that plasma CTSD activity, but not systemic inflammation, is inversely related to hepatic insulin sensitivity, suggesting that plasma CTSD activity may be used as a non-invasive marker for hepatic insulin sensitivity in humans.

Salt intake and insulin sensitivity in healthy human volunteers

2007 ◽  
Vol 113 (3) ◽  
pp. 141-148 ◽  
Author(s):  
Raymond R. Townsend ◽  
Shiv Kapoor ◽  
Christopher B. McFadden
Keyword(s):  
Insulin Sensitivity ◽  
Insulin Infusion ◽  
Salt Intake ◽  
Sodium Intake ◽  
High Salt ◽  
High Salt Diet ◽  
Salt Diet ◽  
Euglycaemic Clamp ◽  
Noradrenaline Concentration ◽  
Low Salt

The literature on salt intake and insulin sensitivity presents a mixed picture, as some studies have shown an increase, whereas others have shown a decrease, in insulin action as sodium intake is enhanced. In some cases, this may relate to the study of salt intake in patients with co-morbidities such as hypertension or diabetes. In the present study, we selected healthy normotensive lean volunteers who underwent a euglycaemic clamp following 6 days of a low-salt diet (20 mmol sodium daily) and, subsequently, 6 days of a high-salt diet (200 mmol sodium daily). Our results show an increase in insulin-mediated glucose disposal during euglycaemic clamp conditions that was significantly higher following the high-salt diet compared with the low-salt diet (7.41±0.41 compared with 6.11±0.40 mg·kg−1 of body weight·min−1 respectively; P=0.03). We measured calf blood flow before and during insulin infusion (no significant change after the two dietary salt interventions was detected) and plasma non-esterified fatty acids (also no significant differences were detected). We observed the expected increases in renin concentration and aldosterone activity in subjects on the low-salt diet, and also observed a significantly less increase in plasma noradrenaline concentration during euglycaemic insulin infusion following the high-salt compared with the low-salt diet. We propose that the 4–5-fold increase in serum aldosterone and the greater increase in plasma noradrenaline concentration following the low-salt intervention compared with the high-salt period may have contributed to the differences in insulin sensitivity following the adjustment in dietary sodium intake.

scholarly journals Insulin sensitivity and metabolic flexibility following exercise training among different obese insulin-resistant phenotypes

2013 ◽  
Vol 305 (10) ◽  
pp. E1292-E1298 ◽  
Author(s):  
Steven K. Malin ◽  
Jacob M. Haus ◽  
Thomas P. J. Solomon ◽  
Alecia Blaszczak ◽  
Sangeeta R. Kashyap ◽  
...  
Keyword(s):  
Insulin Sensitivity ◽  
Exercise Training ◽  
Glucose Tolerance ◽  
Glucose Disposal ◽  
Oral Glucose ◽  
Metabolic Flexibility ◽  
Euglycemic Hyperinsulinemic Clamp ◽  
Hepatic Insulin Sensitivity ◽  
Peripheral Insulin Sensitivity ◽  
Chronic Hyperglycemia

Impaired fasting glucose (IFG) blunts the reversal of impaired glucose tolerance (IGT) after exercise training. Metabolic inflexibility has been implicated in the etiology of insulin resistance; however, the efficacy of exercise on peripheral and hepatic insulin sensitivity or substrate utilization in adults with IFG, IGT, or IFG + IGT is unknown. Twenty-four older (66.7 ± 0.8 yr) obese (34.2 ± 0.9 kg/m2) adults were categorized as IFG ( n = 8), IGT ( n = 8), or IFG + IGT ( n = 8) according to a 75-g oral glucose tolerance test (OGTT). Subjects underwent 12-wk of exercise (60 min/day for 5 days/wk at ∼85% HRmax) and were instructed to maintain a eucaloric diet. A euglycemic hyperinsulinemic clamp (40 mU·m2·min−1) with [6,6-2H]glucose was used to determine peripheral and hepatic insulin sensitivity. Nonoxidative glucose disposal and metabolic flexibility [insulin-stimulated respiratory quotient (RQ) minus fasting RQ] were also assessed. Glucose incremental area under the curve (iAUCOGTT) was calculated from the OGTT. Exercise increased clamp-derived peripheral and hepatic insulin sensitivity more in adults with IFG or IGT alone than with IFG + IGT ( P < 0.05). Exercise reduced glucose iAUCOGTT in IGT only ( P < 0.05), and the decrease in glucose iAUCOGTT was inversely correlated with the increase in peripheral but not hepatic insulin sensitivity ( P < 0.01). Increased clamp-derived peripheral insulin sensitivity was also correlated with enhanced metabolic flexibility, reduced fasting RQ, and higher nonoxidative glucose disposal ( P < 0.05). Adults with IFG + IGT had smaller gains in clamp-derived peripheral insulin sensitivity and metabolic flexibility, which was related to blunted improvements in postprandial glucose. Additional work is required to assess the molecular mechanism(s) by which chronic hyperglycemia modifies insulin sensitivity following exercise training.

scholarly journals The effects of underfeeding for 7 d on the thermogenic and physiological response to glucose and insulin infusion (hyperinsulinaemic euglycaemic clamp)

1990 ◽  
Vol 64 (2) ◽  
pp. 427-437 ◽  
Author(s):  
I. W. Gallen ◽  
I. A. Macdonald
Keyword(s):  
Blood Pressure ◽  
Metabolic Rate ◽  
Glucose Uptake ◽  
Glucose Oxidation ◽  
Insulin Infusion ◽  
Cardiovascular Responses ◽  
Glucose Disposal ◽  
Euglycaemic Clamp ◽  
Healthy Women ◽  
Hyperinsulinaemic Euglycaemic Clamp

The effect of underfeeding for 7 d (at 60 kJ/kg ideal body-weight) on the thermic and physiological responses to glucose and insulin infusions (hyperinsulinaemic euglycaemic clamp) was studied in six healthy women. Underfeeding had no significant effect on baseline metabolic rate, heart rate, forearm blood flow, diastolic blood pressure, blood intermediary metabolites, plasma insulin or catecholamines, but reduced both respiratory exchange ratio (RER; control (C) 0.86 (SE 0.02), underfed (U) 0.75 (SE 0.01)P< 0.01) and systolic blood pressure (by approximately 10 mmHg,P< 0.01). Baseline forearm glucose uptake and oxygen consumption were similar in both states. During the final 30 min of the glucose and insulin infusion, metabolic rate rose by 0.43 (SE 0.05) kJ/min in the C state, but no rise was seen in the U state (P< 0.01). Glucose disposal rate (C 47.9 (SE 1.8), U 47.3 (SE 4.1) μmol/kg per min) and storage rate (C 27.5 (SE 2.4), U 31.6 (SE 3.6) μmol/kg per min) were similar in both states, but glucose oxidation rate was reduced in the U state (C 20.5 (SE 1.7), U 15.4 (SE 0.7) μmol/kg per min;P< 0.05). RER rose to a higher value in the C state than in the U state (C 0.97 (SE 0.2), U 0.80 (SE 0.01);P< 0.01). During hyperinsulinaemia, the forearm glucose uptake and O2consumption rose in both states. No significant differences were seen in the cardiovascular responses to hyperinsulinaemia in either state. Thus underfeeding abolishes the rise in thermogenesis and reduces glucose oxidation during glucose and insulin infusions in healthy women, but does not affect the glucose disposal or storage rates or the other measured responses.

scholarly journals Hypothalamic Leptin Signaling Regulates Hepatic Insulin Sensitivity via a Neurocircuit Involving the Vagus Nerve

Endocrinology ◽  
2009 ◽  
Vol 150 (10) ◽  
pp. 4502-4511 ◽  
Author(s):  
Jonathan German ◽  
Francis Kim ◽  
Gary J. Schwartz ◽  
Peter J. Havel ◽  
Christopher J. Rhodes ◽  
...  
Keyword(s):  
Insulin Sensitivity ◽  
Vagus Nerve ◽  
Leptin Receptor ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Hepatic Insulin Sensitivity ◽  
Leptin Signaling ◽  
Peripheral Insulin Sensitivity ◽  
Hepatic Expression ◽  
Beneficial Effects

Abstract Recent evidence suggests that hormones such as insulin and leptin act in the hypothalamus to regulate energy balance and glucose metabolism. Here we show that in leptin receptor-deficient Koletsky (fak/fak) rats, adenovirally induced expression of leptin receptors in the area of the hypothalamic arcuate nucleus improved peripheral insulin sensitivity via enhanced suppression of hepatic glucose production, with no change of insulin-stimulated glucose uptake or disposal. This effect was associated with increased insulin signal transduction via phosphatidylinositol-3-OH kinase (as measured by pY-insulin receptor substrate-1 and pS-PKB/Akt) in liver, but not skeletal muscle, and with reduced hepatic expression of the gluconeogenic genes, glucose-6-phosphatase and phosphoenolpyruvate kinase. Moreover, the beneficial effects of hypothalamic leptin signaling on hepatic insulin sensitivity were blocked by selective hepatic vagotomy. We conclude that hypothalamic leptin action increases peripheral insulin sensitivity primarily via effects on the liver and that the mechanism underlying this effect is dependent on the hepatic branch of the vagus nerve.

scholarly journals Differential effects of hypercaloric choice diets on insulin sensitivity in rats

2017 ◽  
Vol 232 (1) ◽  
pp. 49-57 ◽  
Author(s):  
Charlene Diepenbroek ◽  
Leslie Eggels ◽  
Mariëtte T Ackermans ◽  
Eric Fliers ◽  
Andries Kalsbeek ◽  
...  
Keyword(s):  
Insulin Sensitivity ◽  
Glucose Intolerance ◽  
Free Choice ◽  
Saturated Fat ◽  
High Fat ◽  
Short Term ◽  
Sugar Water ◽  
Hepatic Insulin Sensitivity ◽  
Peripheral Insulin Sensitivity ◽  
High Sugar

We showed previously that rats on a free-choice high-fat, high-sugar (fcHFHS) diet become rapidly obese and develop glucose intolerance within a week. Interestingly, neither rats on a free-choice high-fat diet (fcHF), although equally obese and hyperphagic, nor rats on a free-choice high-sugar (fcHS) diet consuming more sugar water, develop glucose intolerance. Here, we investigate whether changes in insulin sensitivity contribute to the observed glucose intolerance and whether this is related to consumption of saturated fat and/or sugar water. Rats received either a fcHFHS, fcHF, fcHS or chow diet for one week. We performed a hyperinsulinemic–euglycemic clamp with stable isotope dilution to measure endogenous glucose production (EGP; hepatic insulin sensitivity) and glucose disappearance (Rd; peripheral insulin sensitivity). Rats on all free-choice diets were hyperphagic, but only fcHFHS-fed rats showed significantly increased adiposity. EGP suppression by hyperinsulinemia in fcHF-fed and fcHFHS-fed rats was significantly decreased compared with chow-fed rats. One week fcHFHS diet also significantly decreased Rd. Neither EGP suppression nor Rd was affected in fcHS-fed rats. Our results imply that, short-term fat feeding impaired hepatic insulin sensitivity, whereas short-term consumption of both saturated fat and sugar water impaired hepatic and peripheral insulin sensitivity. The latter likely contributed to glucose intolerance observed previously. In contrast, overconsumption of only sugar water affected insulin sensitivity slightly, but not significantly, in spite of similar adiposity as fcHF-fed rats and higher sugar intake compared with fcHFHS-fed rats. These data imply that the palatable component consumed plays a role in the development of site-specific insulin sensitivity.

Preserved direct hepatic insulin action in rats with diet-induced hepatic steatosis

2004 ◽  
Vol 286 (5) ◽  
pp. E828-E833 ◽  
Author(s):  
Roland Buettner ◽  
Iris Ottinger ◽  
Jürgen Schölmerich ◽  
L. Cornelius Bollheimer
Keyword(s):  
Insulin Sensitivity ◽  
Hepatic Steatosis ◽  
Insulin Action ◽  
Glycogen Synthase ◽  
Hepatic Glucose Output ◽  
Hepatic Insulin Sensitivity ◽  
Significant Difference ◽  
Hepatic Glucose ◽  
Glucose Output

Recent in vivo studies have demonstrated a strong negative correlation between liver triglyceride content and hepatic insulin sensitivity, but a causal relationship remains to be established. We therefore have examined parameters of direct hepatic insulin action on isolated steatotic livers from high-fat (HF)-fed rats compared with standard chow (SC)-fed controls. Direct hepatic action of insulin was assayed in Wistar rats after 6 wk of HF diet by measuring the insulin-induced suppression of epinephrine-induced hepatic glucose output in an isolated liver perfusion system. Insulin-induced activation of glycogen synthase was measured by quantifying the incorporation of radioactive UDP-glucose into glycogen in HF and SC liver lysates. HF diet induced visceral obesity, mild insulin resistance, and hepatic steatosis. Both suppression of epinephrine-induced glycogenolysis and activation of glycogen synthase by insulin were sustained in HF rats; no significant difference from SC controls could be detected. In conclusion , in our model, triglyceride accumulation into the liver was not sufficient to impair direct hepatic insulin action. The data argue for an important role of systemic factors in the regulation of hepatic glucose output and hepatic insulin sensitivity in vivo.

scholarly journals Longitudinal Changes in Insulin Resistance in Normal Weight, Overweight and Obese Individuals

2019 ◽  
Vol 8 (5) ◽  
pp. 623 ◽  
Author(s):  
Alice Tang ◽  
Adelle C. F. Coster ◽  
Katherine T. Tonks ◽  
Leonie K. Heilbronn ◽  
Nicholas Pocock ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Normal Weight ◽  
Liver Fat ◽  
Resonance Spectroscopy ◽  
Change Over Time ◽  
Euglycaemic Clamp ◽  
Hyperinsulinaemic Euglycaemic Clamp ◽  
Over Time

Background: Large cohort longitudinal studies have almost unanimously concluded that metabolic health in obesity is a transient phenomenon, diminishing in older age. We aimed to assess the fate of insulin sensitivity per se over time in overweight and obese individuals. Methods: Individuals studied using the hyperinsulinaemic-euglycaemic clamp at the Garvan Institute of Medical Research from 2008 to 2010 (n = 99) were retrospectively grouped into Lean (body mass index (BMI) < 25 kg/m2) or overweight/obese (BMI ≥ 25 kg/m2), with the latter further divided into insulin-sensitive (ObSen) or insulin-resistant (ObRes), based on median clamp M-value (M/I, separate cut-offs for men and women). Fifty-seven individuals participated in a follow-up study after 5.4 ± 0.1 years. Hyperinsulinaemic-euglycaemic clamp, dual-energy X-ray absorptiometry and circulating cardiovascular markers were measured again at follow-up, using the same protocols used at baseline. Liver fat was measured using computed tomography at baseline and proton magnetic resonance spectroscopy at follow-up with established cut-offs applied for defining fatty liver. Results: In the whole cohort, M/I did not change over time (p = 0.40); it remained significantly higher at follow-up in ObSen compared with ObRes (p = 0.02), and was not different between ObSen and Lean (p = 0.41). While BMI did not change over time (p = 0.24), android and visceral fat increased significantly in this cohort (ptime ≤ 0.0013), driven by ObRes (p = 0.0087 and p = 0.0001, respectively). Similarly, systolic blood pressure increased significantly over time (ptime = 0.0003) driven by ObRes (p = 0.0039). The best correlate of follow-up M/I was baseline M/I (Spearman’s r = 0.76, p = 1.1 × 10−7). Conclusions: The similarity in insulin sensitivity between the ObSen and the Lean groups at baseline persisted over time. Insulin resistance in overweight and obese individuals predisposed to further metabolic deterioration over time.

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