전문 번역가, 번역 회사, 웹 페이지 및 자유롭게 사용할 수 있는 번역 저장소 등을 활용합니다.
the sheer complexity of biological systems means that any effort to understand insulin resistance with a unified, succinct, and straightforward model may be a fool’s errand. certainly normal insulin action, despite sharing important effectors among different cell types, performs myriad functions that are not particularly amenable to encapsulation. in particular, understanding the intricate relationship between insulin control of both lipid and carbohydrate metabolism has proved a worthy challenge for generations of investigators (532). but in considering the several putative mediators of insulin resistance discussed in the preceding sections, it is tempting both to note potential areas of unification and to veer into teleological speculation. the fundamental element linking all putative mediators of insulin resistance is a relationship to nutrient oversupply. each mechanism discussed in this review is proposed to cause insulin resistance by either increasing nutrient-derived toxic metabolites (dag, ceramide, acylcarnitine, bcaa), overdriving nutrient utilization processes (er stress, oxidative stress), or responding to nutrient stressmediated cellular toxicity (inflammation). moreover, the pathophysiology of insulin resistance driven by cellular stress pathways and by inflammation shares common threads with the insulin resistance induced by bioactive lipids. er stress promotes de novo lipogenesis. the mitochondrial dysfunction of aged and insulin-resistant humans facilitates positive energy balance and ectopic lipid storage. adipose tissue inflammation drives lipolysis, increasing substrate delivery to nonadipose tissues. we therefore propose an integrated model of insulin resistance in which several simultaneous responses to nutrient oversupply converge and collide to facilitate ectopic lipid accumulation and consequent insulin resistance in skeletal muscle and liver (figure 19). if overnutrition is the central driver of all these metabolic defects, then the most obvious therapeutic option is calorie restriction. although the cellular effects of caloric restriction are complex and incompletely understood, the physiological effects of applying a hypocaloric diet to an obese insulin-resistant subject represent a useful test of the hypotheses presented in this review. recently, perry et al. (625) catalogued the metabolic consequences of a 3-day very-low-calorie diet (vlcd; 25% of normal caloric intake) in a rat model of insulin-resistant t2d (4 wk of high-fat feeding or western diet followed by low-dose streptozotocin/nicotinamide to achieve fasting hyperglycemia). without significantly reducing body weight, vlcd achieved near-normalization of plasma glucose and insulin levels. this was associated with reductions in ihtg, hepatic acetyl coa, hepatic membrane-associated dag, and hepatic pkc activation; parameters that did not change included hepatic ceramides, plasma glucagon, a panel of inflammatory cytokines, plasma fgf21, plasma bcaas, and hepatic er stress markers (625). in hyperinsulinemic-euglycemic clamp studies, vlcd resulted in increased akt activation and insulin suppression of hgp (625). interestingly, both direct and indirect components of hepatic insulin action were improved by vlcd; the improvements in hgp seen with vlcd could be abrogated by acetate infusion (to prevent vlcd-induced decreases in hepatic acetyl coa) or recapitulated by a glycogen phosphorylase inhibitor (to simulate vlcd-induced improvements in insulin-stimulated hepatic glycogen synthesis) (625). the utility of this rapid intervention is that it helps to distinguish the parameters that drive hyperglycemia from those that are secondary consequences or exacerbating factors. the results incriminate hepatic dag-pkc axis activation and metabolite-driven gluconeogenesis. yet all studies have limitations, and a major limitation of the above study is one shared by much of the work cited in this review: the use of a rodent model to draw inferences about human pathophysiology. one of the rodent-human differences most germane to the study of insulin resistance is the order in which tissues develop insulin resistance upon overnutrition. in rodents, just a few days of high-fat feeding is sufficient to cause hepatic steatosis and hepatic insulin resistance; skeletal muscle insulin resistance requires several weeks to develop (429). in those weeks, meanwhile, wat expands and eventually becomes inflamed, stimulating liinsulin action and insulin resistance physiol rev • vol 98 • october 2018 • www.prv.org 2193 downloaded from journals.physiology.org/journal/physrev (041.232.128.179) on april 13, 2021. polysis and in turn hepatic gluconeogenesis (620). in humans, available evidence points to skeletal muscle insulin resistance as the first defect; the young, healthy, lean offspring of type 2 diabetics display skeletal muscle insulin resistance but normal ihtg and normal hepatic insulin action (639). muscle insulin resistance promotes hepatic lipogenesis, however, and eventually nafld and hepatic insulin resistance develop. how adipose insulin resistance fits into this paradigm in humans remains relatively uncertain. indeed, adipose tissue insulin resistance is a particularly exciting topic of active exploration (176). wat is adapted to store excess energy and can do so prolifically without inducing metabolic derangements [evidenced most dramatically by the adiponectin transgenic ob/ob mouse, which remains normally insulin sensitive despite morbid obesity (408)]. as a result, some paradigms of nutrient stress well characterized in skeletal muscle and liver, such as lipidinduced insulin resistance, do not obviously translate to the white adipocyte. gross measurement of tissue lipids such as white adipose tissue liver insr hepatic glucose production muscle insulin resistance dag/pkcθ signaling gluconeogenesis dag/pkcε signaling insr acetyl coa β-oxidation β-oxidation pc glycogen synthesis imcl hepatic insulin resistance glycogen synthesis glucose transport skeletal muscle plasma glucose ihtg nefa nefa glycerol macrophage infiltration nutrient stress adipocyte death tnfα il-1β ? nefa overnutrition adipose insulin resistance insr rbp4 jnk glycerol tag nefa lipolysis glycerol acetyl coa β-oxidation figure 19. an integrated physiological perspective on tissue insulin resistance. chronic overnutrition is the ultimate cause of systemic insulin resistance and promotes insulin resistance by both tissue-autonomous and crosstalk-dependent mechanisms. chronic overnutrition promotes lipid accumulation in skeletal muscle and liver, which causes insulin resistance in those tissues. additionally, chronic overnutrition poses a nutrient stress to adipocytes, resulting in adipocyte insulin resistance and adipocyte death. increases in the adipokine rbp4 and other proinflammatory signals lead to the recruitment of macrophages to white adipose tissue. inflammatory signaling in macrophages, including activation of c-jun nh2-terminal kinase (jnk), leads to the elaboration of paracrine mediators such as tumor necrosis factor- (tnf), interleukin-1 (il-1), and others. these inflammatory cytokines may increase adipocyte lipolysis either directly or indirectly by impairing insulin signaling. the increased adipocyte lipolysis of inflammation increases nonesterified fatty acid (nefa) and glycerol turnover. this has direct (glycerol conversion to glucose) and indirect [nefa-derived acetyl coa activation of pyruvate carboxylase (pc)] stimulatory effects on gluconeogenesis, and also promotes accumulation of intrahepatic triglyceride (ihtg) and consequent lipid-induced hepatic insulin resistance, which impairs insulin stimulation of net hepatic glycogen synthesis. together, these effects increase hepatic glucose production. chronically increased lipolysis may also facilitate the accumulation of intramyocellular lipid (imcl) and consequent lipid-induced muscle insulin resistance. the decreased glucose disposal of muscle insulin resistance increases glucose availability for the liver, which in turn promotes ihtg accumulation and worsens
في حين أن الكربوهيدرات، التي توفر الجلوكوز للجسم لدعم عملية التمثيل الغذائي، هي حاسمة للنظام الغذائي، تناول غير مناسب يمكن أن يؤدي إلى ارتفاع السكر في الدم، ونقص السكر في الدم، وتقلبات نسبة السكر في الدم التي تضر النتائج الصحية (الشكل 2). الشكل 2- الأرباح التي يمكن أن تتراوح بين 2 و 2 عواقب عدم توازن الجلوكوز. a. فرط السكر في الدم (ارتفاع مستوى السكر في الدم) قد تسهم في تعزيز الدهون والعضلات الأيض; بالإضافة إلى ذلك ، يفضل فرط السكر في الدم مضاعفات في حالات الأمراض الحادة بما في ذلك الجراحة والأمراض الخطيرة.