Insulin at 100 years – is rebalancing its action key to fighting obesity-related disease?

ABSTRACT One hundred years ago, insulin was purified and administered to people with diabetes to lower blood glucose, suppress ketogenesis and save lives. A century later, insulin resistance (IR) lies at the heart of the obesity-related disease pandemic. Multiple observations attest that IR syndrome is an amalgamation of gain and loss of insulin action, suggesting that IR is a misnomer. This misapprehension is reinforced by shortcomings in common model systems and is particularly pronounced for the tissue growth disorders associated with IR. It is necessary to move away from conceptualisation of IR as a pure state of impaired insulin action and to appreciate that, in the long term, insulin can harm as well as cure. The mixed state of gain and loss of insulin action, and its relationship to perturbed insulin-like growth factor (IGF) action, should be interrogated more fully in models recapitulating human disease. Only then may the potential of rebalancing insulin action, rather than simply increasing global insulin signalling, finally be appreciated.

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Relation of insulin deficiency to impaired insulin action in NIDDM adult rats given streptozocin as neonates

Diabetes ◽

10.2337/diabetes.38.5.610 ◽

1989 ◽

Vol 38 (5) ◽

pp. 610-617 ◽

Cited By ~ 13

Author(s):

O. Blondel ◽

D. Bailbe ◽

B. Portha

Keyword(s):

Insulin Action ◽

Insulin Deficiency ◽

Adult Rats ◽

Impaired Insulin ◽

Impaired Insulin Action

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Antecedent protein restriction exacerbates development of impaired insulin action after high-fat feeding

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1999.276.1.e85 ◽

1999 ◽

Vol 276 (1) ◽

pp. E85-E93 ◽

Cited By ~ 18

Author(s):

Mark J. Holness ◽

Mary C. Sugden

Keyword(s):

Insulin Secretion ◽

Glucose Tolerance ◽

Insulin Action ◽

Protein Restriction ◽

Protein Diet ◽

Glucose Disposal ◽

High Fat ◽

Impaired Insulin ◽

Impaired Insulin Action ◽

Fat Feeding

The study investigated whether a persistent impairment of insulin secretion resulting from mild protein restriction predisposes to loss of glucoregulatory control and impaired insulin action after the subsequent imposition of the diabetogenic challenge of high-fat feeding. Offspring of dams provided with either control (20% protein) diet (C) or an isocaloric restricted (8%) protein diet (PR) were weaned onto the maintenance diet with which their mothers had been provided. At 20 wk of age, protein restriction enhanced glucose tolerance despite impaired insulin secretion and an augmented and sensitized lipolytic response to norepinephrine in adipocytes. C and PR rats were then transferred to a high-fat diet (HF, 19% protein, 22% lipid, 34% carbohydrate) and sampled after 8 wk. These groups are termed C-HF and PR-HF. Glucose tolerance was impaired in PR-HF, but not C-HF, rats. Insulin-stimulated glucose disposal rates were significantly lower (by 30%; P < 0.01) in the PR-HF group than in the C-HF group, and a specific impairment of antilipolytic response of insulin was unmasked in adipocytes from PR-HF, but not C-HF, rats. The study demonstrates that antecedent protein restriction accelerates and augments the development of impaired glucoregulation and insulin resistance after high-fat feeding.

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Impaired Insulin Action in Rats with Non-insulin-dependent Diabetes

Diabetes ◽

10.2337/diab.33.9.901 ◽

1984 ◽

Vol 33 (9) ◽

pp. 901-906 ◽

Cited By ~ 20

Author(s):

J. Levy ◽

J. R. Gavin ◽

A. Fausto ◽

R. L. Gingerich ◽

L. V. Avioli

Keyword(s):

Insulin Action ◽

Insulin Dependent Diabetes ◽

Impaired Insulin ◽

Insulin Dependent ◽

Impaired Insulin Action

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Cardiac-specific VEGFB overexpression reduces lipoprotein lipase activity and improves insulin action in rat heart

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00219.2021 ◽

2021 ◽

Author(s):

Rui Shang ◽

Nathaniel Lal ◽

ChaeSyng Lee ◽

Yajie Zhai ◽

Karanjit Puri ◽

...

Keyword(s):

Insulin Sensitivity ◽

Lipoprotein Lipase ◽

Insulin Action ◽

Insulin Signalling ◽

Isolated Heart ◽

Cardiac Metabolism ◽

Metabolic Reprogramming ◽

Flux Analysis

Cardiac muscle utilizes multiple sources of energy including glucose and fatty acid (FA). The heart cannot synthesize FA and relies on obtaining it from other sources, with lipoprotein lipase (LPL) breakdown of lipoproteins suggested to be a key source of FA for cardiac use. Recent work has indicated that cardiac vascular endothelial growth factor B (VEGFB) overexpression expands the coronary vasculature and facilitates metabolic reprogramming that favours glucose utilization. We wanted to explore whether this influence of VEGFB on cardiac metabolism involves regulation of LPL activity with consequent effects on lipotoxicity and insulin signalling. The transcriptomes of rats with and without cardiomyocyte-specific overexpression of human VEGFB were compared by using RNA-sequencing. Isolated perfused hearts or cardiomyocytes incubated with heparin were used to enable measurement of LPL activity. Untargeted metabolomic analysis was performed for quantification of cardiac lipid metabolites. Cardiac insulin sensitivity was evaluated using fast-acting insulin. Isolated heart and cardiomyocytes were used to determine transgene-encoded VEGFB isoform secretion patterns and mitochondrial oxidative capacity using high-resolution respirometry and extracellular flux analysis. In vitro, primary transgenic cardiomyocytes incubated overnight and thus exposed to abundantly secreted VEGFB isoforms in the absence of any in vivo confounding regulators of cardiac metabolism demonstrated higher basal oxygen consumption. In the whole heart, VEGFB overexpression induced an angiogenic response that was accompanied by limited cardiac LPL activity through multiple mechanisms. This was associated with a lowered accumulation of lipid intermediates, diacylglycerols and lysophosphatidylcholine, that are known to influence insulin action. In response to exogenous insulin, transgenic hearts demonstrated increased insulin sensitivity. In conclusion, the interrogation of VEGFB function on cardiac metabolism uncovered an intriguing and previously unappreciated effect to lower LPL activity and prevent lipid metabolite accumulation to improve insulin action. VEGFB could be a potential cardioprotective therapy to treat metabolic disorders, for example diabetes.

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Validating the Paradigm That Biomechanical Forces Regulate Embryonic Cardiovascular Morphogenesis and Are Fundamental in the Etiology of Congenital Heart Disease

Journal of Cardiovascular Development and Disease ◽

10.3390/jcdd7020023 ◽

2020 ◽

Vol 7 (2) ◽

pp. 23

Author(s):

Bradley B. Keller ◽

William J. Kowalski ◽

Joseph P. Tinney ◽

Kimimasa Tobita ◽

Norman Hu

Keyword(s):

Congenital Heart Disease ◽

Heart Disease ◽

Chick Embryo ◽

Congenital Heart ◽

Imaging Techniques ◽

Tissue Growth ◽

Model Systems ◽

Loading Conditions ◽

Biomechanical Loading ◽

Biomechanical Forces

The goal of this review is to provide a broad overview of the biomechanical maturation and regulation of vertebrate cardiovascular (CV) morphogenesis and the evidence for mechanistic relationships between function and form relevant to the origins of congenital heart disease (CHD). The embryonic heart has been investigated for over a century, initially focusing on the chick embryo due to the opportunity to isolate and investigate myocardial electromechanical maturation, the ability to directly instrument and measure normal cardiac function, intervene to alter ventricular loading conditions, and then investigate changes in functional and structural maturation to deduce mechanism. The paradigm of “Develop and validate quantitative techniques, describe normal, perturb the system, describe abnormal, then deduce mechanisms” was taught to many young investigators by Dr. Edward B. Clark and then validated by a rapidly expanding number of teams dedicated to investigate CV morphogenesis, structure–function relationships, and pathogenic mechanisms of CHD. Pioneering studies using the chick embryo model rapidly expanded into a broad range of model systems, particularly the mouse and zebrafish, to investigate the interdependent genetic and biomechanical regulation of CV morphogenesis. Several central morphogenic themes have emerged. First, CV morphogenesis is inherently dependent upon the biomechanical forces that influence cell and tissue growth and remodeling. Second, embryonic CV systems dynamically adapt to changes in biomechanical loading conditions similar to mature systems. Third, biomechanical loading conditions dynamically impact and are regulated by genetic morphogenic systems. Fourth, advanced imaging techniques coupled with computational modeling provide novel insights to validate regulatory mechanisms. Finally, insights regarding the genetic and biomechanical regulation of CV morphogenesis and adaptation are relevant to current regenerative strategies for patients with CHD.

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Current views on type 2 diabetes

Journal of Endocrinology ◽

10.1677/joe-09-0260 ◽

2009 ◽

Vol 204 (1) ◽

pp. 1-11 ◽

Cited By ~ 213

Author(s):

Yi Lin ◽

Zhongjie Sun

Keyword(s):

Type 2 Diabetes ◽

Animal Models ◽

Insulin Action ◽

Large Population ◽

Specific Aspect ◽

Multiple Organs ◽

Impaired Insulin ◽

Critical Components ◽

Impaired Insulin Action

Type 2 diabetes mellitus (T2DM) affects a large population worldwide. T2DM is a complex heterogeneous group of metabolic disorders including hyperglycemia and impaired insulin action and/or insulin secretion. T2DM causes dysfunctions in multiple organs or tissues. Current theories of T2DM include a defect in insulin-mediated glucose uptake in muscle, a dysfunction of the pancreatic β-cells, a disruption of secretory function of adipocytes, and an impaired insulin action in liver. The etiology of human T2DM is multifactorial, with genetic background and physical inactivity as two critical components. The pathogenesis of T2DM is not fully understood. Animal models of T2DM have been proved to be useful to study the pathogenesis of, and to find a new therapy for, the disease. Although different animal models share similar characteristics, each mimics a specific aspect of genetic, endocrine, metabolic, and morphologic changes that occur in human T2DM. The purpose of this review is to provide the recent progress and current theories in T2DM and to summarize animal models for studying the pathogenesis of the disease.

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059. POOR GROWTH BEFORE BIRTH IMPAIRS INSULIN SECRETION - WHAT WE HAVE LEARNT ABOUT THE MECHANISMS FROM THE PLACENTALLY-RESTRICTED SHEEP

Reproduction Fertility and Development ◽

10.1071/srb09abs059 ◽

2009 ◽

Vol 21 (9) ◽

pp. 14

Author(s):

K. L. Gatford

Keyword(s):

Insulin Resistance ◽

Insulin Secretion ◽

Beta Cell ◽

Insulin Action ◽

Cell Function ◽

Cell Mass ◽

Beta Cell Mass ◽

Poor Growth ◽

Impaired Insulin ◽

Impaired Insulin Action

Diabetes occurs when insulin secretion fails to increase sufficiently to compensate for developing insulin resistance. This implies that the increased risk of diabetes in adults who were small at birth reflects impaired insulin secretion as well as their well-known insulin resistance. More recently, direct evidence has been obtained that adults and children who were growth-restricted before birth secrete less insulin than they should, given their level of insulin resistance. Our research group is using the placentally-restricted (PR) sheep to investigate the mechanisms underlying impaired insulin action (sensitivity and secretion) induced by poor growth before birth. Like the intra-uterine growth-restricted (IUGR) human, the PR sheep develops impaired insulin action by adulthood, but has enhanced insulin sensitivity in infancy, associated with neonatal catch-up growth1, 2. Impaired insulin action begins to develop in early postnatal life, where although basal insulin action is high due to enhanced insulin sensitivity, maximal glucose-stimulated insulin action is already impaired in males3. Our cellular and molecular studies have identified impaired beta-cell function rather than mass as the likely cause of impaired insulin secretion, and we have reported a novel molecular defect in the calcium channels involved in the insulin secretion pathway in the pancreas of these lambs3. Upregulation of IGF-II and insulin receptor are implicated as key molecular regulators of beta-cell mass in the PR lamb3. By adulthood, both basal and maximal insulin action are profoundly impaired in the male lamb who was growth-restricted at birth2. These studies suggest therapies to prevent diabetes in the individual who grew poorly before birth should target beta-cell function, possibly in addition to further increasing beta-cell mass, to improve insulin secretion capacity, and its ability to increase in response to development of insulin resistance. We are now using the PR sheep to test potential therapies, since the timing of pancreatic development and hence exposure to a growth-restricting environment, is similar to that of the human.

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Impaired insulin action but normal insulin receptor activity in diabetic rat liver: effect of vanadate

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1990.258.3.e459 ◽

1990 ◽

Vol 258 (3) ◽

pp. E459-E467 ◽

Cited By ~ 1

Author(s):

O. Blondel ◽

J. Simon ◽

B. Chevalier ◽

B. Portha

Keyword(s):

Insulin Receptor ◽

Insulin Action ◽

Diabetic Rats ◽

Receptor Kinase ◽

Peripheral Tissues ◽

Impaired Insulin ◽

Insulin Dependent ◽

Insulin Receptor Kinase ◽

Impaired Insulin Action

In vivo insulin resistance is a characteristic of the liver and peripheral tissues in 10-wk-old female rats with non-insulin-dependent diabetes induced by streptozotocin given on day 5 after birth. Oral administration of vanadate (0.2 mg/ml) for 20 days in the diabetic rats lowered their plasma glucose levels to normal values without affecting their basal plasma insulin levels. In the basal state as well as after submaximal or maximal hyperinsulinemia (euglycemic clamp studies), peripheral glucose utilization and hepatic glucose production in vivo were normalized in the diabetic rats after the vanadate treatment. In wheat germ agglutinin purified receptors, 125I-labeled porcine insulin binding, basal and insulin-stimulated insulin receptor kinase activities for both the autophosphorylation of the beta-subunit and the phosphorylation of the artificial substrate poly (Glu-Tyr) 4:1, were found identical in diabetic and control rats, treated or not with vanadate. Liver phosphoenolpyruvate carboxykinase activity was significantly enhanced in untreated diabetic rats (P less than 0.01) as compared with control rats and returned to normal values after the 20-day vanadate treatment. Thus, in that model of non-insulin-dependent diabetes, 1) oral vanadate exerts a corrective insulin-like effect on impaired insulin action both at the level of liver and peripheral tissues, 2) impaired insulin action with no alteration of the insulin receptor tyrosine kinase is observed in the liver of untreated rats, and 3) corrective effect of vanadate on liver glucose metabolism is probably distal to the insulin receptor kinase activity.

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