Aging is associated with myocardial insulin resistance and mitochondrial dysfunction

Aging is associated with insulin resistance, often attributable to obesity and inactivity. Recent evidence suggests that skeletal muscle insulin resistance in aging is associated with mitochondrial alterations. Whether this is true of the senescent myocardium is unknown. Twelve young (Y, 4 years old) and 12 old (O, 11 years old) dogs, matched for body mass, were instrumented with left-ventricular pressure gauges, aortic and coronary sinus catheters, and flow probes on left circumflex artery. Before surgery, all dogs participated in a 6-wk exercise program. Dogs underwent measurements of hemodynamics and plasma substrates before and during a 2-h hyperinsulinemic-euglycemic clamp to measure whole body and myocardial glucose and nonesterified fatty acid uptake. Following the protocol, myocardial and skeletal samples were obtained to measure components of the insulin-signaling cascade and mitochondrial structure. There was no difference in plasma glucose (Y, 90 ± 4 mg/dl; O, 87 ± 4 mg/dl), but old dogs had higher ( P < 0.02) nonesterified fatty acids (Y, 384 ± 48 μmol/l; O, 952 ± 97 μmol/l) and plasma insulin (Y, 39 ± 11 pmol/l; O, 108 ± 18 pmol/l). Old dogs had impaired total body glucose disposition (Y, 11.5 ± 1 mg·kg−1·min−1; O, 8.0 ± 0.5 mg·kg−1·min−1; P < 0.05) and insulin-stimulated myocardial glucose uptake (Y, 3.5 ± 0.3mg·min−1·g−1; O, 1.8 ± 0.3 mg·min−1·g−1; P < 0.05). The impaired insulin action was associated with altered insulin signaling and glucose transporter (GLUT4) translocation. There were myocardial mitochondrial structural changes observed in association with decreased expression of uncoupling protein-3. Aging is associated with both whole body and myocardial insulin resistance, independent of obesity and inactivity, but involving altered mitochondrial structure and impaired cellular insulin action.

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Abstract 15225: Post-ischemic Myocardial Insulin Resistance Induced by Tnf-α Overproduction Precipitates the Development of Heart Failure After Myocardial Infarction

Circulation ◽

10.1161/circ.130.suppl_2.15225 ◽

2014 ◽

Vol 130 (suppl_2) ◽

Author(s):

Feng Fu ◽

Jia Li ◽

Jie Xu ◽

Yuan Zhang ◽

Chao Gao ◽

...

Keyword(s):

Myocardial Infarction ◽

Insulin Resistance ◽

Insulin Sensitivity ◽

Insulin Signaling ◽

Left Ventricular ◽

Separate Experiment ◽

Tnf Α ◽

Lv Remodeling ◽

Myocardial Insulin Resistance

Objectives: Clinical evidence has demonstrated a decreased myocardial insulin response in HF patients. However, the role of myocardial insulin resistance and the underlying mechanisms in HF are largely unclear. Methods and Results: Sprague Dawley rats subjected to myocardial infarction (MI) resulted in a progressive left ventricular (LV) remodeling and dysfunction. Echocardiographic assessment showed preserved LV end-systolic dimension (LVESD 0.453 ± 0.027 cm) and ejection fraction (EF 57.03 ± 2.35%) at 1 wk after MI, and evident LV dilation (LVESD 0.612 ± 0.026 cm) and dysfunction (EF 40.21 ± 3.09%) at 4 wk after MI. Myocardial insulin sensitivity decreased significantly at 1 wk after MI as evidenced by reduced insulin-stimulated myocardial fluorodeoxyglucose uptake (Standardized Uptake Value: 2.71 ± 0.42 vs. 5.13 ± 0.51 of sham+insulin, n=6, P <0.01) and GLUT-4 translocation and altered insulin signaling, whereas systemic insulin sensitivity remained unchanged. Mechanistically, myocardial TNF-α production was increased following MI. Treatment with etanercept (a TNF-α inhibitor) post-MI improved myocardial insulin sensitivity, while adenovirus-mediated overexpression of TNF-α resulted in myocardial insulin resistance in non-MI hearts. In addition, TNF-α overexpressed rat hearts exhibited LV dysfunction (EF 41.32 ± 4.21%) and LV dilation as early as 1 wk after MI. Moreover, insulin treatment during the first week following MI suppressed myocardial TNF-α production and increased myocardial insulin sensitivity, resulting in alleviated cardiac dysfunction and remodeling at 4 wk after MI. Importantly, in a separate experiment, cardiomyocyte-specific insulin receptor knockout mice exhibited aggravated post-ischemic LV remodeling and dysfunction compared with littermate controls. Conclusions: Our data provide novel insights that myocardial insulin resistance, independently of systemic insulin resistance, precipitates the development of post-ischemic HF. Myocardial insulin resistance is an early event partly attributed to myocardial TNF-α overproduction following MI. This finding indicates the essential role of myocardial insulin signaling in protection against ischemic HF.

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Rat amylin-(8—37) enhances insulin action and alters lipid metabolism in normal and insulin-resistant rats

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1997.273.5.e859 ◽

1997 ◽

Vol 273 (5) ◽

pp. E859-E867 ◽

Cited By ~ 4

Author(s):

M. Hettiarachchi ◽

S. Chalkley ◽

S. M. Furler ◽

Y.-S. Choong ◽

M. Heller ◽

...

Keyword(s):

Insulin Resistance ◽

Lipid Metabolism ◽

Insulin Sensitivity ◽

Insulin Action ◽

Glycogen Synthesis ◽

Human Growth ◽

Whole Body ◽

Nonesterified Fatty Acids ◽

Insulin Resistant

To clarify roles of amylin, we investigated metabolic responses to rat amylin-(8—37), a specific amylin antagonist, in normal and insulin-resistant, human growth hormone (hGH)-infused rats. Fasting conscious rats were infused with saline or hGH, each with and without amylin-(8—37) (0.125 μmol/h), over 5.75 h. At 3.75 h, a hyperinsulinemic (100 mU/l) clamp with bolus 2-deoxy-d-[3H]glucose and [14C]glucose was started. hGH infusion led to prompt (2- to 3-fold) basal hyperamylinemia ( P < 0.02) and hyperinsulinemia. Amylin-(8—37) reduced plasma insulin ( P < 0.001) and enhanced several measures of whole body and muscle insulin sensitivity ( P < 0.05) in both saline- and hGH-infused rats. Amylin-(8—37) corrected hGH-induced liver insulin resistance, increased basal plasma triglycerides and lowered plasma nonesterified fatty acids in both groups, and reduced muscle triglyceride and total long-chain acyl-CoA content in saline-treated rats ( P < 0.05). In isolated soleus muscle, amylin-(8—37) blocked amylin-induced inhibition of glycogen synthesis but had no effect in the absence of amylin. Thus 1) hyperamylinemia accompanies insulin resistance induced by hGH infusion; 2) amylin-(8—37) increases whole body and muscle insulin sensitivity and consistently reduces basal insulin levels in normal and hGH-induced insulin-resistant rats; and 3) amylin-(8—37) elicits a significant alteration of in vivo lipid metabolism. These findings support a role of amylin in modulating insulin action and suggest that this could be mediated by effects on lipid metabolism.

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Endothelial insulin receptors differentially control insulin signaling kinetics in peripheral tissues and brain of mice

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1710625114 ◽

2017 ◽

Vol 114 (40) ◽

pp. E8478-E8487 ◽

Cited By ~ 37

Author(s):

Masahiro Konishi ◽

Masaji Sakaguchi ◽

Samuel M. Lockhart ◽

Weikang Cai ◽

Mengyao Ella Li ◽

...

Keyword(s):

Insulin Resistance ◽

Endothelial Cells ◽

Food Intake ◽

Insulin Signaling ◽

Insulin Action ◽

Insulin Receptors ◽

Brain Regions ◽

Peripheral Tissues ◽

Systemic Insulin Resistance

Insulin receptors (IRs) on endothelial cells may have a role in the regulation of transport of circulating insulin to its target tissues; however, how this impacts on insulin action in vivo is unclear. Using mice with endothelial-specific inactivation of the IR gene (EndoIRKO), we find that in response to systemic insulin stimulation, loss of endothelial IRs caused delayed onset of insulin signaling in skeletal muscle, brown fat, hypothalamus, hippocampus, and prefrontal cortex but not in liver or olfactory bulb. At the level of the brain, the delay of insulin signaling was associated with decreased levels of hypothalamic proopiomelanocortin, leading to increased food intake and obesity accompanied with hyperinsulinemia and hyperleptinemia. The loss of endothelial IRs also resulted in a delay in the acute hypoglycemic effect of systemic insulin administration and impaired glucose tolerance. In high-fat diet-treated mice, knockout of the endothelial IRs accelerated development of systemic insulin resistance but not food intake and obesity. Thus, IRs on endothelial cells have an important role in transendothelial insulin delivery in vivo which differentially regulates the kinetics of insulin signaling and insulin action in peripheral target tissues and different brain regions. Loss of this function predisposes animals to systemic insulin resistance, overeating, and obesity.

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Mechanisms of Insulin Action and Insulin Resistance

Physiological Reviews ◽

10.1152/physrev.00063.2017 ◽

2018 ◽

Vol 98 (4) ◽

pp. 2133-2223 ◽

Cited By ~ 276

Author(s):

Max C. Petersen ◽

Gerald I. Shulman

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

White Adipose Tissue ◽

Insulin Action ◽

Big Bang ◽

Whole Body ◽

Detailed Knowledge ◽

Bioactive Lipids ◽

Mechanistic Investigation ◽

The Impact

The 1921 discovery of insulin was a Big Bang from which a vast and expanding universe of research into insulin action and resistance has issued. In the intervening century, some discoveries have matured, coalescing into solid and fertile ground for clinical application; others remain incompletely investigated and scientifically controversial. Here, we attempt to synthesize this work to guide further mechanistic investigation and to inform the development of novel therapies for type 2 diabetes (T2D). The rational development of such therapies necessitates detailed knowledge of one of the key pathophysiological processes involved in T2D: insulin resistance. Understanding insulin resistance, in turn, requires knowledge of normal insulin action. In this review, both the physiology of insulin action and the pathophysiology of insulin resistance are described, focusing on three key insulin target tissues: skeletal muscle, liver, and white adipose tissue. We aim to develop an integrated physiological perspective, placing the intricate signaling effectors that carry out the cell-autonomous response to insulin in the context of the tissue-specific functions that generate the coordinated organismal response. First, in section II, the effectors and effects of direct, cell-autonomous insulin action in muscle, liver, and white adipose tissue are reviewed, beginning at the insulin receptor and working downstream. Section III considers the critical and underappreciated role of tissue crosstalk in whole body insulin action, especially the essential interaction between adipose lipolysis and hepatic gluconeogenesis. The pathophysiology of insulin resistance is then described in section IV. Special attention is given to which signaling pathways and functions become insulin resistant in the setting of chronic overnutrition, and an alternative explanation for the phenomenon of ‟selective hepatic insulin resistanceˮ is presented. Sections V, VI, and VII critically examine the evidence for and against several putative mediators of insulin resistance. Section V reviews work linking the bioactive lipids diacylglycerol, ceramide, and acylcarnitine to insulin resistance; section VI considers the impact of nutrient stresses in the endoplasmic reticulum and mitochondria on insulin resistance; and section VII discusses non-cell autonomous factors proposed to induce insulin resistance, including inflammatory mediators, branched-chain amino acids, adipokines, and hepatokines. Finally, in section VIII, we propose an integrated model of insulin resistance that links these mediators to final common pathways of metabolite-driven gluconeogenesis and ectopic lipid accumulation.

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Oxidative stress impairs insulin signal in skeletal muscle and causes insulin resistance in postinfarct heart failure

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.01185.2009 ◽

2011 ◽

Vol 300 (5) ◽

pp. H1637-H1644 ◽

Cited By ~ 34

Author(s):

Yukihiro Ohta ◽

Shintaro Kinugawa ◽

Shouji Matsushima ◽

Taisuke Ono ◽

Mochamad A. Sobirin ◽

...

Keyword(s):

Oxidative Stress ◽

Heart Failure ◽

Insulin Resistance ◽

Skeletal Muscle ◽

Insulin Signaling ◽

Glucose Transporter ◽

Diastolic Pressure ◽

Left Ventricular ◽

Serine Phosphorylation ◽

Glucose Transporter 4

Insulin resistance has been shown to occur as a consequence of heart failure. However, its exact mechanisms in this setting remain unknown. We have previously reported that oxidative stress is enhanced in the skeletal muscle from mice with heart failure after myocardial infarction (MI) ( 30 ). This study is aimed to investigate whether insulin resistance in postinfarct heart failure is due to the impairment of insulin signaling in the skeletal muscle caused by oxidative stress. Mice were divided into four groups: sham operated (sham); sham treated with apocynin, an inhibitor of NAD(P)H oxidase activation (10 mmol/l in drinking water); MI; and MI treated with apocynin. After 4 wk, intraperitoneal insulin tolerance tests were performed, and skeletal muscle samples were obtained for insulin signaling measurements. MI mice showed left ventricular dilation and dysfunction by echocardiography and increased left ventricular end-diastolic pressure and lung weight. The decrease in glucose level after insulin load significantly attenuated in MI compared with sham. Insulin-stimulated serine phosphorylation of Akt and glucose transporter-4 translocation were decreased in MI mice by 61 and 23%, respectively. Apocynin ameliorated the increase in oxidative stress and NAD(P)H oxidase activities measured by the lucigenin assay in the skeletal muscle after MI. It also improved insulin resistance and inhibited the decrease of Akt phosphorylation and glucose transporter-4 translocation. Insulin resistance was induced by the direct impairment of insulin signaling in the skeletal muscle from postinfarct heart failure, which was associated with the enhanced oxidative stress via NAD(P)H oxidase.

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Loss of PDGF-B activity increases hepatic vascular permeability and enhances insulin sensitivity

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00241.2011 ◽

2011 ◽

Vol 301 (3) ◽

pp. E517-E526 ◽

Cited By ~ 27

Author(s):

Summer M. Raines ◽

Oliver C. Richards ◽

Lindsay R. Schneider ◽

Kathryn L. Schueler ◽

Mary E. Rabaglia ◽

...

Keyword(s):

Insulin Sensitivity ◽

Insulin Signaling ◽

Insulin Action ◽

Basolateral Membrane ◽

Tolerance Test ◽

Whole Body ◽

Glucose Disposal ◽

Permeability Barrier ◽

Loss Of Function ◽

Transendothelial Transport

Hepatic vasculature is not thought to pose a permeability barrier for diffusion of macromolecules from the bloodstream to hepatocytes. In contrast, in extrahepatic tissues, the microvasculature is critically important for insulin action, because transport of insulin across the endothelial cell layer is rate limiting for insulin-stimulated glucose disposal. However, very little is known concerning the role in this process of pericytes, the mural cells lining the basolateral membrane of endothelial cells. PDGF-B is a growth factor involved in the recruitment and function of pericytes. We studied insulin action in mice expressing PDGF-B lacking the proteoglycan binding domain, producing a protein with a partial loss of function (PDGF-B ret/ ret). Insulin action was assessed through measurements of insulin signaling and insulin and glucose tolerance tests. PDGF-B deficiency enhanced hepatic vascular transendothelial transport. One outcome of this change was an increase in hepatic insulin signaling. This correlated with enhanced whole body glucose homeostasis and increased insulin clearance from the circulation during an insulin tolerance test. In obese mice, PDGF-B deficiency was associated with an 80% reduction in fasting insulin and drastically reduced insulin secretion. These mice did not have significantly higher glucose levels, reflecting a dramatic increase in insulin action. Our findings show that, despite already having a high permeability, hepatic transendothelial transport can be further enhanced. To the best of our knowledge, this is the first study to connect PDGF-B-induced changes in hepatic sinusoidal transport to changes in insulin action, demonstrating a link between PDGF-B signaling and insulin sensitivity.

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Modeling insulin resistance in rodents by alterations in diet: what have high-fat and high-calorie diets revealed?

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00337.2017 ◽

2018 ◽

Vol 314 (3) ◽

pp. E251-E265 ◽

Cited By ~ 11

Author(s):

Lewin Small ◽

Amanda E. Brandon ◽

Nigel Turner ◽

Gregory J. Cooney

Keyword(s):

Insulin Resistance ◽

High Fat Diet ◽

Insulin Action ◽

Whole Body ◽

Dietary Energy ◽

High Fat ◽

Large Heterogeneity ◽

Simple Carbohydrates ◽

Almost All ◽

High Calorie

For over half a century, researchers have been feeding different diets to rodents to examine the effects of macronutrients on whole body and tissue insulin action. During this period, the number of different diets and the source of macronutrients employed have grown dramatically. Because of the large heterogeneity in both the source and percentage of different macronutrients used for studies, it is not surprising that different high-calorie diets do not produce the same changes in insulin action. Despite this, diverse high-calorie diets continue to be employed in an attempt to generate a “generic” insulin resistance. The high-fat diet in particular varies greatly between studies with regard to the source, complexity, and ratio of dietary fat, carbohydrate, and protein. This review examines the range of rodent dietary models and methods for assessing insulin action. In almost all studies reviewed, rodents fed diets that had more than 45% of dietary energy as fat or simple carbohydrates had reduced whole body insulin action compared with chow. However, different high-calorie diets produced significantly different effects in liver, muscle, and whole body insulin action when insulin action was measured by the hyperinsulinemic-euglycemic clamp method. Rodent dietary models remain an important tool for exploring potential mechanisms of insulin resistance, but more attention needs to be given to the total macronutrient content and composition when interpreting dietary effects on insulin action.

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Insulin resistance and regulation of serum amino acid levels in myotonic dystrophy

Clinical Science ◽

10.1042/cs0710429 ◽

1986 ◽

Vol 71 (4) ◽

pp. 429-436 ◽

Cited By ~ 8

Author(s):

Richard T. Moxley ◽

William J. Kingston ◽

Kenneth L. Minaker ◽

Alastair J. Corbett ◽

John W. Rowe

Keyword(s):

Insulin Resistance ◽

Amino Acid ◽

Myotonic Dystrophy ◽

Insulin Infusion ◽

Normal Subjects ◽

Amino Acid Uptake ◽

Whole Body ◽

Glucose Disposal ◽

Acid Uptake ◽

Amino Acid Levels

1. To quantify the degree of whole body insulin resistance in patients with myotonic dystrophy and to determine if these same patients display signs of a whole body decrease in the action of insulin on amino acid uptake and glucose disposal, three separate 120 min studies employing the euglycaemic insulin clamp technique (20, 80 and 200 m-units min−1 m−2) were performed on five ambulatory patients with myotonic dystrophy. The results were compared with findings obtained in identical studies in 21 normal volunteers. 2. Myotonic dystrophy patients showed a slower, less marked decline in the serum concentration of insulin sensitive amino acids (threonine, valine, leucine, isoleucine, tyrosine, phenylalanine) during all three insulin infusions compared with normals. The greatest difference occurred at the low physiological elevations of insulin produced by the 20 m-units min−1 m−2 infusion. 3. Alanine levels fell significantly below baseline in patients with myotonic dystrophy after 60 and 120 min of insulin infusion with all three rates of insulin infusion. Normal subjects had only a minimal, insignificant decline in arterialized alanine concentrations during the three different insulin infusions. 4. Creatinine adjusted rates of whole body glucose disposal were 30–40% lower in the myotonic dystrophy group at all three doses of insulin compared with the normals. This demonstrates that their insulin resistance was not due simply to a reduction in muscle mass. 5. The overall pattern of findings in these studies of patients with myotonic dystrophy indicates that there is a whole body derangement in the regulation of circulating amino acid levels by insulin as well as a marked decrease in the action of this hormone in stimulating glucose uptake by target tissues.

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Short-term interval training alters brain glucose metabolism in subjects with insulin resistance

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x17734998 ◽

2017 ◽

Vol 38 (10) ◽

pp. 1828-1838 ◽

Cited By ~ 7

Author(s):

Sanna M Honkala ◽

Jarkko Johansson ◽

Kumail K Motiani ◽

Jari-Joonas Eskelinen ◽

Kirsi A Virtanen ◽

...

Keyword(s):

Insulin Resistance ◽

Insulin Sensitivity ◽

Interval Training ◽

Insulin Level ◽

Whole Body ◽

Moderate Intensity ◽

Acid Uptake ◽

Short Term ◽

Continuous Training ◽

Sedentary Subjects

Brain insulin-stimulated glucose uptake (GU) is increased in obese and insulin resistant subjects but normalizes after weight loss along with improved whole-body insulin sensitivity. Our aim was to study whether short-term exercise training (moderate intensity continuous training (MICT) or sprint interval training (SIT)) alters substrates for brain energy metabolism in insulin resistance. Sedentary subjects ( n = 21, BMI 23.7–34.3 kg/m2, age 43–55 y) with insulin resistance were randomized into MICT ( n = 11, intensity≥60% of VO2peak) or SIT ( n = 10, all-out) groups for a two-week training intervention. Brain GU during insulin stimulation and fasting brain free fatty acid uptake (FAU) was measured using PET. At baseline, brain GU was positively associated with the fasting insulin level and negatively with the whole-body insulin sensitivity. The whole-body insulin sensitivity improved with both training modes (20%, p = 0.007), while only SIT led to an increase in aerobic capacity (5%, p = 0.03). SIT also reduced insulin-stimulated brain GU both in global cortical grey matter uptake (12%, p = 0.03) and in specific regions ( p < 0.05, all areas except the occipital cortex), whereas no changes were observed after MICT. Brain FAU remained unchanged after the training in both groups. These findings show that short-term SIT effectively decreases insulin-stimulated brain GU in sedentary subjects with insulin resistance.

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(Pro)renin receptor in skeletal muscle is involved in the development of insulin resistance associated with postinfarct heart failure in mice

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00449.2013 ◽

2014 ◽

Vol 307 (6) ◽

pp. E503-E514 ◽

Cited By ~ 23

Author(s):

Arata Fukushima ◽

Shintaro Kinugawa ◽

Shingo Takada ◽

Shouji Matsushima ◽

Mochamad Ali Sobirin ◽

...

Keyword(s):

Oxidative Stress ◽

Heart Failure ◽

Insulin Resistance ◽

Skeletal Muscle ◽

Insulin Signaling ◽

Glucose Transporter ◽

Renin Angiotensin System ◽

Left Ventricular ◽

Serine Phosphorylation ◽

Superoxide Production

We previously reported that insulin resistance was induced by the impairment of insulin signaling in the skeletal muscle from heart failure (HF) via NAD(P)H oxidase-dependent oxidative stress. (Pro)renin receptor [(P)RR] is involved in the activation of local renin-angiotensin system and subsequent oxidative stress. We thus examined whether (P)RR inhibitor, handle region peptide (HRP), could ameliorate insulin resistance in HF after myocardial infarction (MI) by improving oxidative stress and insulin signaling in the skeletal muscle. C57BL6J mice were divided into four groups: sham operated (Sham, n = 10), Sham treated with HRP (Sham+HRP, 0.1 mg·kg−1·day−1, n = 10), MI operated (MI, n = 10), and MI treated with HRP (MI+HRP, 0.1 mg/kg/day, n = 10). After 4 wk, MI mice showed left ventricular dysfunction, which was not affected by HRP. (P)RR was upregulated in the skeletal muscle after MI (149% of sham, P < 0.05). The decrease in plasma glucose after insulin load was smaller in MI than in Sham (21 ± 2 vs. 44 ± 3%, P < 0.05), and was greater in MI+HRP (38 ± 2%, P < 0.05) than in MI. Insulin-stimulated serine phosphorylation of Akt and glucose transporter 4 translocation were decreased in the skeletal muscle from MI by 48 and 49% of Sham, both of which were ameliorated in MI+HRP. Superoxide production and NAD(P)H oxidase activities were increased in MI, which was inhibited in MI+HRP. HRP ameliorated insulin resistance associated with HF by improving insulin signaling via the inhibition of NAD(P)H oxidase-induced superoxide production in the skeletal muscle. The (P)RR pathway is involved in the development of insulin resistance, at least in part, via the impairment of insulin signaling in the skeletal muscle from HF.

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