Diabetes: Insulin resistance and derangements in lipid metabolism. Cure through intervention in fat transport and storage

Department of Medicine, Diabetes Center, Hadassah University Hospital, Jerusalem 91120, Israel.
Diabetes/Metabolism Research and Reviews (Impact Factor: 2.97). 01/2005; 21(1):3-14. DOI: 10.1002/dmrr.493
Source: PubMed

ABSTRACT We present multiple findings on derangements in lipid metabolism in type 2 diabetes. The increase in the intracellular deposition of triglycerides (TG) in muscles, liver and pancreas in subjects prone to diabetes is well documented and demonstrated to attenuate glucose metabolism by interfering with insulin signaling and insulin secretion. The obesity often associated with type 2 diabetes is mainly central, resulting in the overload of abdominal adipocytes with TG and reducing fat depot capacity to protect other tissues from utilizing a large proportion of dietary fat. In contrast to subcutaneous adipocytes, the central adipocytes exhibit a high rate of basal lipolysis and are highly sensitive to fat mobilizing hormones, but respond poorly to lipolysis restraining insulin. The enlarged visceral adipocytes are flooding the portal circulation with free fatty acids (FFA) at metabolically inappropriate time, when FFA should be oxidized, thus exposing nonadipose tissues to fat excess. This leads to ectopic TG accumulation in muscles, liver and pancreatic beta-cells, resulting in insulin resistance and beta-cell dysfunction. This situation, based on a large number of observations in humans and experimental animals, confirms that peripheral adipose tissue is closely regulated, performing a vital role of buffering fluxes of FFA in the circulation. The central adipose tissues tend to upset this balance by releasing large amounts of FFA. To reduce the excessive fat outflow from the abdominal depots and prevent the ectopic fat deposition it is important to decrease the volume of central fat stores or increase the peripheral fat stores. One possibility is to downregulate the activity of lipoprotein lipase, which is overexpressed in abdominal relatively to subcutaneous fat stores. This can be achieved by gastrointestinal bypass or gastroplasty, which decrease dietary fat absorption, or by direct means that include surgical removal of mesenteric fat. Indirect treatment consists of the compliant application of drastic lifestyle change comprising both diet and exercise and pharmacotherapy that reduces mesenteric fat mass and activity. The first step should be an attempt to effectively induce a lifestyle change. Next comes pharmacotherapy including acarbose, metformin, PPARgamma, or PPARgammaalpha agonists, statins and orlistat, estrogens in postmenopausal women or testosterone in men. Among surgical procedures, gastric bypass has been proven to produce beneficial results in advance of other surgical techniques, the evidence basis of which still needs strengthening.

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    • "Taking into account that high circulating levels of NEFA are known to impair insulin signalling, and interfere with GLUT4 expression (Armoni et al. 2007, Martins et al. 2012), and considering that we have detected a reduction of total GLUT4 protein content in SOL muscle, as well as a reduction of peripheral insulin sensitivity, we could point out the increased plasma NEFA levels as an additional mechanism for the establishment of insulin resistance in HMB-supplemented rats, a point which is supported by several studies (Kelley et al. 2002, Raz et al. 2005, Deng et al. 2012). Indeed, type 2 diabetic patients present an increased plasma NEFA levels which is associated with accumulation of lipid inside the muscle cells, compromising their glucose uptake (Phielix & Mensink 2008). "
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    ABSTRACT: AimInvestigate, in healthy sedentary rats, the potential mechanisms involved on the effects of beta hydroxy beta methylbutyrate (HMB) supplementation upon the glycemic homeostasis, by evaluating the insulin sensitivity in liver, skeletal muscle, and white adipose tissue.Methods Rats were supplemented with either beta hydroxy beta methylbutyrate (320 mg kg−1 BW) or saline by gavage for 4 weeks. After the experimental period, the animals were subjected to the glucose tolerance test (GTT) and plasma non-esterified fatty acids (NEFA) concentration measurements. The soleus skeletal muscle, liver and white adipose tissue were removed for molecular (western blotting and RT-PCR) and histological analysis.Results: The beta hydroxy beta methylbutyrate supplemented rats presented: 1) higher ratio between the area under the curve (AUC) of insulinemia and glycemia during glucose tolerance test; 2) impairment of insulin sensitivity on liver and soleus skeletal muscle after insulin overload; 3) reduction of glucose transporter 4 (GLUT 4) total and plasma membrane content on soleus; 4) increased hormone sensitive lipase (HSL) mRNA and protein expression on white adipose tissue and plasma non-esterified fatty acids (NEFA) levels and 5) reduction of fibre cross-sectional area of soleus muscle.Conclusion The data altogether indicate that beta hydroxy beta methylbutyrate supplementation impairs insulin sensitivity in healthy sedentary rats, which, in the long-term, could lead to an increased risk of developing type 2 diabetes.This article is protected by copyright. All rights reserved.
    Acta Physiologica 06/2014; 212(1). DOI:10.1111/apha.12336 · 4.25 Impact Factor
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    • "Metabolic disturbances in diabetes: implications for the heart Disturbances in energy metabolism of the heart have been implicated as important contributors to diabetic cardiac complications (Belke et al., 2000; Buchanan et al., 2005; Wang et al., 2006; Bugger & Abel, 2010; Lopaschuk et al., 2010). For the purpose of this review, we have provided a short summary on the changes in metabolism evident in diabetes [for an extensive review of altered substrate metabolism in diabetes , please refer to (Boden, 2003; Raz et al., 2005)]. At the cellular level, mitochondrial dysfunction in particular plays a significant contribution to the development and progression of both cardiac and vascular complications of diabetes. "
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    ABSTRACT: Cardiovascular disease is the primary cause of morbidity and mortality amongst the diabetic population. Both experimental and clinical evidence suggest that diabetic subjects are predisposed to a distinct cardiomyopathy, independent of concomitant macro- and microvascular disorders. 'Diabetic cardiomyopathy' is characterized by early impairments in diastolic function, accompanied by the development of cardiomyocyte hypertrophy, myocardial fibrosis and cardiomyocyte apoptosis. The pathophysiology underlying diabetes-induced cardiac damage is complex and multifactorial, with elevated oxidative stress a key contributor. We now review the current evidence of molecular disturbances present in the diabetic heart, and their role in the development of diabetes-induced impairments in myocardial function and structure. Our focus incorporates both the contribution of increased reactive oxygen species production and reduced antioxidant defenses to diabetic cardiomyopathy, together with modulation of protein signaling pathways and the emerging role of protein O-GlcNAcylation and miRNA dysregulation in the progression of diabetic heart disease. Lastly, we discuss both conventional and novel therapeutic approaches for the treatment of left ventricular dysfunction in diabetic patients, from inhibition of the renin-angiotensin-aldosterone-system, through recent evidence favoring supplementation of endogenous antioxidants for the treatment of diabetic cardiomyopathy. Novel therapeutic strategies, such as gene therapy targeting the phosphoinositide 3-kinase PI3K(p110α) signaling pathway, and miRNA dysregulation, are also reviewed. Targeting redox stress and protective protein signaling pathways may represent a future strategy for combating the ever-increasing incidence of heart failure in the diabetic population.
    Pharmacology [?] Therapeutics 01/2014; 142(3). DOI:10.1016/j.pharmthera.2014.01.003 · 7.75 Impact Factor
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    • "Furthermore, the hypolipidemic activity of both R. graveolens and rutin may also be mediated via inactivation of hepatic HMG-CoA reductase, a key enzyme, in cholesterol synthesis. Inhibitors of hepatic HMG-CoA reductase are well established drugs for the treatment of hypercholesterolemia and decrease the incidence of dyslipidemia in diabetic subjects (Raz et al., 2005). Flavonoids decrease liver HMG-CoA reductase activity in type II diabetic mice. "
    Journal of medicinal plant research 06/2012; 6(23). DOI:10.5897/JMPR12.040 · 0.88 Impact Factor
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