PPARα activation elevates blood pressure and does not correct glucocorticoid-induced insulin resistance in humans

Fibrates, activators of the nuclear receptor PPARα, improve dyslipidemia, but their effects on insulin resistance and vascular disease are unresolved. To test the hypothesis that PPARα activation improves insulin resistance and vascular function, we determined the effects of fenofibrate in healthy adults with insulin resistance induced by short-term glucocorticoid administration. Eighteen normal-weight subjects were studied in four stages: at baseline, after 21 days of fenofibrate (160 mg/day) alone, after 3 days of dexamethasone (8 mg/day) added to fenofibrate, and after 3 days of dexamethasone added to placebo (dexamethasone alone). Dexamethasone alone caused hyperinsulinemia, increased glucose, decreased glucose disposal, and reduced insulin-induced suppression of hepatic glucose production as determined by hyperinsulinemic euglycemic clamp and increased systolic blood pressure as determined by ambulatory monitoring, features associated with an insulin-resistant state. Fenofibrate improved fasting LDL and total cholesterol in the setting of dexamethasone treatment but had no significant effect on levels of insulin or glucose, insulin-stimulated glucose disposal, or insulin suppression of glucose production during clamps, or ambulatory monitored blood pressure. In the absence of dexamethasone, fenofibrate lowered fasting triglycerides and cholesterol but unexpectedly increased systolic blood pressure by ambulatory monitoring. These data suggest that PPARα activation in humans does not correct insulin resistance induced by glucocorticoids and may adversely affect blood pressure.

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P713Short term treatment of a low dose erythropoietin improves vascular function in a rat model of insulin resistance

European Heart Journal ◽

10.1093/eurheartj/ehz747.0318 ◽

2019 ◽

Vol 40 (Supplement_1) ◽

Author(s):

H Toba ◽

A Yamaoka ◽

S Sakurai ◽

Y Tanaka ◽

A Miyamoto ◽

...

Keyword(s):

Insulin Resistance ◽

Blood Pressure ◽

Vascular Function ◽

Insulin Signalling ◽

Term Treatment ◽

Protective Effects ◽

Insulin Resistant ◽

Induce Insulin Resistance ◽

Group A ◽

Group B

Abstract Background/Introduction Erythropoietin (EPO) exerts haematopoiesis-independent cardiovascular and renal protective effects by binding to EPO receptors expressed in hearts, arteries, and kidneys. We have reported that EPO inhibits vascular and renal injury in rat models of hypertension and type 1 diabetes. Recent studies report that EPO improves glucose tolerance in insulin resistant animals. Purpose This study investigated whether EPO would inhibit vascular and renal dysfunction in the setting of insulin resistance. Methods Rats were treated with sucrose (12% in drinking water) for 10 weeks to induce insulin resistance. EPO (3 times/week, s.c) was administered at the dose of 150U/kg for 10 weeks from the beginning (group A) or at the dose of 75U/kg for the last 4 weeks (group B) of sucrose treatment. Blood pressure was measured every second week by the tail-cuff method. HOMA-IR, haematocrit, and urinary protein excretion were measured. Using isolated aortas, acetylcholine-induced vasorelaxation under phenylephrine-induced pre-contraction was examined. Aortic sections were stained with haematoxylin-eosin. Results Both groups A and B showed higher haematocrit levels compared with the control and sucrose alone-treated groups. Sucrose treatment increased HOMA-IR (7.7±2.0 vs. 24±4.5, p<0.05), which was attenuated in groups A (3.6±0.9) and B (9.7±4.0). EPO treatment (150U/kg) had no effects on blood pressure for the first 4 weeks but caused time-dependent increases in blood pressure from the 6th week. Increased proteinuria and impaired aortic vasorelaxation in sucrose-treated rats were exacerbated by EPO (150U/kg) maybe because of hypertension (Control 122±2mmHg, Sucrose 125±2mmHg, group A 148±5mmHg), one of the major side effects of EPO. According to these results, we treated a half dose of EPO only for the last 4 weeks (group B). A lower dose of EPO treatment for a shorter period did not increase proteinuria (Control 15±2mg/day, Sucrose 25±3mg/day, group B 24±3mg/day) despite a mild increase in blood pressure (132±2mmHg). Impaired endothelium-dependent vasodilation and aortic thickening in the aorta of sucrose alone-treated rats were attenuated by lower and shorter EPO treatment (group B). Conclusions EPO inhibited insulin resistance and vascular injury in sucrose-induced insulin resistant rats. Further investigation into the mechanisms of tissue protective effects of EPO, especially focusing on the effects on insulin signalling in not only hepatic and muscle cell but also vascular and renal cells, will be needed.

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Peripheral and hepatic resistance to insulin and hepatic resistance to glucagon in uraemic subjects

Acta Endocrinologica ◽

10.1530/acta.0.1180125 ◽

1988 ◽

Vol 118 (1) ◽

pp. 125-134 ◽

Cited By ~ 18

Author(s):

Ole Schmitz

Keyword(s):

Insulin Resistance ◽

Insulin Infusion ◽

Serum Insulin ◽

Hepatic Glucose Production ◽

Glucose Production ◽

Endogenous Glucose Production ◽

Hepatic Insulin Resistance ◽

Glucose Disposal ◽

Peripheral Tissues ◽

Endogenous Glucose

Abstract. To characterize endogenous glucose production in uraemia, nondialyzed uraemic patients and controls were exposed to two major modulating hormones, insulin and glucagon. Nineteen uraemic and 15 healthy subjects underwent either a 2-step (insulin infusion rates: 0.45 and 1.0 mU·kg−1·min−1) or a 3-step (insulin infusion rates: 0.1, 0.2 and 0.3 mU·kg−1·min−1 sequential euglycaemic insulin clamp. Average steady state serum insulin concentrations were almost identical during all five infusion rates in uraemic patients (16,22, 26, 31 and 66 mU/l) and controls (15, 19, 24, 33 and 68 mU/l). At all steps, insulin infusion was accompanied by significantly lower glucose disposal rates ([3−3H]glucose) in uraemic patients compared with controls (P < 0.05 or less). Moreover, the restraining potency of insulin on endogenous glucose production was much more prominent in healthy than in uraemic subjects at the lowest three infusion rates (0.6 ± 1.0 versus 1.4 ± 0.3 (mean ± 1 sd), −0.3 ± 0.7 versus 0.7 ± 0.3, and −1.1 ± 0.7 versus 0.2 ± 0.6 mg·kg−1·min−1; P < 0.05, P < 0.01 and P < 0.01, respectively), implying a shift to the right of the dose-response curve in uraemia. In contrast, basal values were comparable (2.4 ± 0.3 versus 2.2 ± 0.6 mg·kg−1·min−1) as the difference vanished at higher infusion rates, i.e. peripheral insulinaemia above ≈30 mU/l. Another 7 uraemic patients and 7 controls were infused with glucagon at constant rates of 4 or 6 ng·kg−1·min−1, respectively, for 210 min concomitant with somatostatin (125 μg/h) and tritiated glucose. The ability of glucagon to elevate plasma glucose was markedly attenuated in uraemic patients compared with controls during the initial 60 min of glucagon exposure. This difference was entirely due to diminished hepatic glucose production (3.5 ± 0.8 versus 4.8 ± 1.0 mg·kg−1·min−1; P < 0.05). In conclusion, in addition to insulin resistance in peripheral tissues, uraemia is also associated with hepatic insulin resistance. Furthermore, glucagon challenge implies impaired early endogenous glucose release in uraemia suggesting a superimposed hepatic resistance to glucagon.

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Lowering plasma free fatty acid levels improves insulin action in conscious pregnant rabbits

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1993.264.4.e576 ◽

1993 ◽

Vol 264 (4) ◽

pp. E576-E582 ◽

Cited By ~ 6

Author(s):

M. Gilbert ◽

S. Basile ◽

A. Baudelin ◽

M. C. Pere

Keyword(s):

Insulin Resistance ◽

Insulin Action ◽

Hepatic Glucose Production ◽

Glucose Production ◽

Late Pregnancy ◽

Plasma Free Fatty Acid ◽

Glucose Disposal ◽

Hepatic Glucose ◽

Total Glucose ◽

Control Study

Acute elevation in plasma free fatty acid (FFA) levels in nonpregnant rabbits simulates some aspects of insulin resistance observed in late pregnancy. The aim of this study was therefore to evaluate whether lowered FFA induced by nicotinic acid (NA) infusion can improve insulin action in pregnant rabbits. To assess insulin sensitivity we applied euglycemic hyperinsulinemic clamp without (control study) or with concomitant NA infusion (NA study; infusion started 150 min before the glucose clamp) in conscious virgin and pregnant rabbits after an 18-h fast. A primed constant infusion of [3-3H]glucose was used to measure total glucose disposal and hepatic glucose production. Hyperinsulinemia, in association with NA infusion (NA study) brings about a significantly greater stimulation of total glucose disposal in both pregnant (approximately 30%) and nonpregnant (approximately 35%) rabbits compared with the control study. A more pronounced inhibition of hepatic glucose production occurred in NA study in pregnant rabbits (approximately 30 vs. approximately 10%) but it did not reach a statistical significance, whereas there was a total inhibition in nonpregnant rabbits. We conclude that acute decrease in plasma FFA levels mainly improves insulin action at the site of glucose utilization. These results therefore suggest that elevated FFA would contribute to the peripheral insulin resistance in late pregnancy.

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Acute activation of pyruvate dehydrogenase increases glucose oxidation in muscle without changing glucose uptake

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00386.2017 ◽

2018 ◽

Vol 315 (2) ◽

pp. E258-E266 ◽

Cited By ~ 11

Author(s):

Lewin Small ◽

Amanda E. Brandon ◽

Lake-Ee Quek ◽

James R. Krycer ◽

David E. James ◽

...

Keyword(s):

Glucose Uptake ◽

Pyruvate Dehydrogenase ◽

Glucose Oxidation ◽

Kinase Inhibitor ◽

Hepatic Glucose Production ◽

Glycogen Synthesis ◽

Glucose Production ◽

Glucose Disposal ◽

Acetyl Coa ◽

Insulin Resistant

Pyruvate dehydrogenase (PDH) activity is a key component of the glucose/fatty acid cycle hypothesis for the regulation of glucose uptake and metabolism. We have investigated whether acute activation of PDH in muscle can alleviate the insulin resistance caused by feeding animals a high-fat diet (HFD). The importance of PDH activity in muscle glucose disposal under insulin-stimulated conditions was determined by infusing the PDH kinase inhibitor dichloroacetate (DCA) into HFD-fed Wistar rats during a hyperinsulinemic-euglycemic clamp. Acute DCA infusion did not alter glucose infusion rate, glucose disappearance, or hepatic glucose production but did decrease plasma lactate levels. DCA substantially increased muscle PDH activity; however, this did not improve insulin-stimulated glucose uptake in insulin-resistant muscle of HFD rats. DCA infusion increased the flux of pyruvate to acetyl-CoA and reduced glucose incorporation into glycogen and alanine in muscle. Similarly, in isolated muscle, DCA treatment increased glucose oxidation and decreased glycogen synthesis without changing glucose uptake. These results suggest that, although PDH activity controls the conversion of pyruvate to acetyl-CoA for oxidation, this has little effect on glucose uptake into muscle under insulin-stimulated conditions.

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Increasing fructose 2,6-bisphosphate overcomes hepatic insulin resistance of type 2 diabetes

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.2002.282.1.e38 ◽

2002 ◽

Vol 282 (1) ◽

pp. E38-E45 ◽

Cited By ~ 28

Author(s):

Chaodong Wu ◽

David A. Okar ◽

Christopher B. Newgard ◽

Alex J. Lange

Keyword(s):

Gene Expression ◽

Insulin Resistance ◽

Type 2 Diabetes ◽

Hepatic Glucose Production ◽

Glucose Production ◽

Hepatic Insulin Resistance ◽

Insulin Resistant ◽

Kk Mice ◽

Hepatic Glucose

Hepatic glucose production is increased as a metabolic consequence of insulin resistance in type 2 diabetes. Because fructose 2,6-bisphosphate is an important regulator of hepatic glucose production, we used adenovirus-mediated enzyme overexpression to increase hepatic fructose 2,6-bisphosphate to determine if the hyperglycemia in KK mice, polygenic models of type 2 diabetes, could be ameliorated by reduction of hepatic glucose production. Seven days after treatment with virus encoding a mutant 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase designed to increase fructose 2,6-bisphosphate levels, plasma glucose, lipids, and insulin were significantly reduced in KK/H1J and KK.Cg-Ay/J mice. Moreover, high fructose 2,6-bisphosphate levels downregulated glucose-6-phosphatase and upregulated glucokinase gene expression, thereby reversing the insulin-resistant pattern of hepatic gene expression of these two key glucose-metabolic enzymes. The increased hepatic fructose 2,6-bisphosphate also reduced adiposity in both KK mice. These results clearly indicate that increasing hepatic fructose 2,6-bisphosphate overcomes the impairment of insulin in suppressing hepatic glucose production, and it provides a potential therapy for type 2 diabetes.

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Insulin resistance and reduced metabolic flexibility: cause or consequence of NAFLD?

Clinical Science ◽

10.1042/cs20170987 ◽

2017 ◽

Vol 131 (22) ◽

pp. 2701-2704 ◽

Cited By ~ 33

Author(s):

Amalia Gastaldelli

Keyword(s):

Insulin Resistance ◽

Liver Disease ◽

Hepatic Glucose Production ◽

Glucose Production ◽

Point Of View ◽

Glucose Disposal ◽

Protective Mechanism ◽

Metabolic Flexibility ◽

Alcoholic Fatty Liver ◽

Increased Risk

Whether non-alcoholic fatty liver disease (NAFLD) precedes insulin resistance (IR) or IR preludes/causes NAFLD has been long debated. Recent studies have shown that there are two phenotypes of NAFLD, ‘genetic’ vs ‘metabolic’ NAFLD. The former patients are more at risk of hepatocellular carcinoma and chronic liver disease the latter are more IR and at increased risk of type 2 diabetes (T2D). Even if they are not yet diabetics, from a metabolic point of view having NAFLD is equivalent to T2D with reduced peripheral glucose disposal and impaired suppression of hepatic glucose production, but without fasting hyperglycaemia. T2D develops only when hepatic autoregulation is lost and glucose production exceeds the capacity of muscle glucose disposal. In NAFLD adipocytes are resistant to the effect of insulin, lipolysis is increased and excess plasma free fatty acids (FFA) are taken up by other organs (mainly liver) where they are stored as lipid droplets or oxidized. Increased adiposity is associated with worsen severity of both ‘genetic’ and ‘metabolic’ NAFLD. FFA oxidative metabolism is increased in NAFLD and not shifted towards glucose during insulin infusion. Although this reduced metabolic flexibility is an early predictor of T2D, it can be seen also as a protective mechanism against excess FFA. In conclusion, IR precedes and causes ‘metabolic’ NAFLD, but not ‘genetic’ NAFLD. Reduced metabolic flexibility in NAFLD might be seen as a protective mechanism against FFA overflow, but together with IR remains a strong risk factor for T2D that develops with the worsening of hepatic regulation of glucose production.

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Ciliary Neurotrophic Factor Prevents Acute Lipid-Induced Insulin Resistance by Attenuating Ceramide Accumulation and Phosphorylation of c-Jun N-Terminal Kinase in Peripheral Tissues

Endocrinology ◽

10.1210/en.2005-1074 ◽

2006 ◽

Vol 147 (5) ◽

pp. 2077-2085 ◽

Cited By ~ 63

Author(s):

Matthew J. Watt ◽

Andrea Hevener ◽

Graeme I. Lancaster ◽

Mark A. Febbraio

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Insulin Sensitivity ◽

Hepatic Glucose Production ◽

Glucose Production ◽

Ciliary Neurotrophic Factor ◽

Glucose Disposal ◽

Hepatic Glucose ◽

Ceramide Accumulation ◽

Glucose Disposal Rate

Ciliary neurotrophic factor (CNTF) is a member of the gp130 receptor cytokine family recently identified as an antiobesity agent in rodents and humans by mechanisms that remain unclear. We investigated the impact of acute CNTF treatment on insulin action in the presence of lipid oversupply. To avoid confounding effects of long-term high-fat feeding or genetic manipulation on whole-body insulin sensitivity, we performed a 2-h Intralipid infusion (20% heparinized Intralipid) with or without recombinant CNTF pretreatment (Axokine 0.3 mg/kg), followed by a 2-h hyperinsulinemic-euglycemic clamp (12 mU/kg·min) in fasted, male Wistar rats. Acute Intralipid infusion increased plasma free fatty acid levels from 1.0 ± 0.1 to 2.5 ± 0.3 mm, which subsequently caused reductions in skeletal muscle (insulin-stimulated glucose disposal rate) and liver (hepatic glucose production) insulin sensitivity by 30 and 45%, respectively. CNTF pretreatment completely prevented the lipid-mediated reduction in insulin-stimulated glucose disposal rate and the blunted suppression of hepatic glucose production by insulin. Although lipid infusion increased triacylglycerol and ceramide accumulation and phosphorylation of mixed linage kinase 3 and c-Jun N-terminal kinase 1 in skeletal muscle, CNTF pretreatment prevented these lipid-induced effects. Alterations in hepatic and muscle insulin signal transduction as well as phosphorylation of c-Jun N-terminal kinase 1/2 paralleled alterations in insulin sensitivity. These data support the use of CNTF as a potential therapeutic means to combat lipid-induced insulin resistance.

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Neonatal exendin-4 treatment reduces oxidative stress and prevents hepatic insulin resistance in intrauterine growth-retarded rats

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00519.2009 ◽

2009 ◽

Vol 297 (6) ◽

pp. R1785-R1794 ◽

Cited By ~ 39

Author(s):

Elisabeth L. Raab ◽

Patricia M. Vuguin ◽

Doris A. Stoffers ◽

Rebecca A. Simmons

Keyword(s):

Oxidative Stress ◽

Insulin Resistance ◽

Hepatic Glucose Production ◽

Glucose Production ◽

Hepatic Insulin Resistance ◽

Glucose Disposal ◽

Intrauterine Growth ◽

Hepatic Glucose ◽

Neonatal Hepatocytes

Intrauterine growth retardation (IUGR) has been linked to the development of Type 2 diabetes in adulthood. We have developed an IUGR model in the rat whereby the animals develop diabetes later in life. Previous studies demonstrate that administration of the long-acting glucagon-like-peptide-1 agonist, Exendin-4, during the neonatal period prevents the development of diabetes in IUGR rats. IUGR animals exhibit hepatic insulin resistance early in life (prior to the onset of hyperglycemia), characterized by blunted suppression of hepatic glucose production (HGP) in response to insulin. Basal HGP is also significantly higher in IUGR rats. We hypothesized that neonatal administration of Exendin-4 would prevent the development of hepatic insulin resistance. IUGR and control rats were given Exendin-4 on days 1–6 of life. Hyperinsulinemic-euglycemic clamp studies showed that Ex-4 significantly reduced basal HGP by 20% and normalized insulin suppression of HGP in IUGR rats. While Ex-4 decreased body weight and fat content in both Control and IUGR animals, these differences were only statistically significant in Controls. Exendin-4 prevented development of oxidative stress in liver and reversed insulin-signaling defects in vivo, thereby preventing the development of hepatic insulin resistance. Defects in glucose disposal and suppression of hepatic glucose production in response to insulin were reversed. Similar results were obtained in isolated Ex-4-treated neonatal hepatocytes. These results indicate that exposure to Exendin-4 in the newborn period reverses the adverse consequences of fetal programming and prevents the development of hepatic insulin resistance.

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Insulin resistance but IGF-I sensitivity in chronic renal failure

AJP Renal Physiology ◽

10.1152/ajprenal.1996.271.1.f114 ◽

1996 ◽

Vol 271 (1) ◽

pp. F114-F119

Author(s):

R. H. Mak

Keyword(s):

Insulin Resistance ◽

Renal Failure ◽

Chronic Renal Failure ◽

Glucose Uptake ◽

Hepatic Glucose Production ◽

Glucose Production ◽

Insulin Resistant ◽

Igf I ◽

Total Body ◽

And Control

The effects of insulin-like growth factor I (IGF-I) and insulin on glucose metabolism were compared in awake, chronically catheterized rats with chronic renal failure (CRF) and sham-operated, pair-fed controls. In control rats, IGF-I (5 micrograms.kg-1.min-1) and insulin (2 mU.kg-1.min-1) infusions produced similar twofold increases in total body glucose uptake from fasting values under euglycemic conditions (euglycemic clamps). Total body glucose uptake during euglycemic IGF-I clamps at 5 and 10 micrograms.kg-1.min-1 was not different between CRF and control rats. Total body glucose uptake during euglycemic insulin clamps at 2 and 4 mU.kg-1.min-1 was significantly lower in CRF rats compared with corresponding values in control rats. Hepatic glucose production was suppressed by insulin equally but not by IGF-I in both groups. Correction of metabolic acidosis by NaHCO3 partially improved insulin resistance in rats with CRF, whereas an equimolar amount of NaCl had no effect. Thus the capacity of IGF-I infusion to stimulate total body glucose uptake is maintained in CRF rats that are insulin resistant.

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Biomarker-estimated flavan-3-ol intake is associated with lower blood pressure in cross-sectional analysis in EPIC Norfolk

Scientific Reports ◽

10.1038/s41598-020-74863-7 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Javier I. Ottaviani ◽

Abigail Britten ◽

Debora Lucarelli ◽

Robert Luben ◽

Angela A. Mulligan ◽

...

Keyword(s):

Blood Pressure ◽

Systolic Blood Pressure ◽

Vascular Function ◽

Cardiovascular Health ◽

Vascular Diseases ◽

Inverse Association ◽

Cvd Risk ◽

Lower Systolic Blood Pressure ◽

Cross Sectional ◽

Salt Reduction

Abstract Flavan-3-ols are a group of bioactive compounds that have been shown to improve vascular function in intervention studies. They are therefore of great interest for the development of dietary recommendation for the prevention of cardio-vascular diseases. However, there are currently no reliable data from observational studies, as the high variability in the flavan-3-ol content of food makes it difficult to estimate actual intake without nutritional biomarkers. In this study, we investigated cross-sectional associations between biomarker-estimated flavan-3-ol intake and blood pressure and other CVD risk markers, as well as longitudinal associations with CVD risk in 25,618 participants of the European Prospective Investigation into Cancer (EPIC) Norfolk cohort. High flavan-3-ol intake, achievable as part of an habitual diet, was associated with a significantly lower systolic blood pressure (− 1.9 (− 2.7; − 1.1) mmHg in men and − 2.5 (− 3.3; − 1.8) mmHg in women; lowest vs highest decile of biomarker), comparable to adherence to a Mediterranean Diet or moderate salt reduction. Subgroup analyses showed that hypertensive participants had stronger inverse association between flavan-3-ol biomarker and systolic blood pressure when compared to normotensive participants. Flavanol intake could therefore have a role in the maintenance of cardiovascular health on a population scale.

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