Notes from the world congress on insulin resistance, diabetes, and cardiovascular disease

The 16th annual World Congress on Insulin Resistance, Diabetes, and Cardiovascular disease (WCIRDC) was held in Los Angeles, California, on November 29-December 1, 2018. It is fascinating that this topic has remained so important to our understanding and of the development of cardiometabolic conditions and to new therapeutic approaches. The Congress addressed a wide spectrum of conditions related to insulin resistance and new understandings of obesity: fat cells, diabetes, circadian related pathology, cardiovascular (CV), renal, and hepatic disease. This year the Congress honored and celebrated the science and life of its co-founder, Professor Gerald Reaven from Stanford University, who recently passed away.

Ronald Krauss, Oakland, CA reviewed new concepts of the relationship between diet and cardiovascular disease and dyslipidemia. He pointed out that population-based dietary studies are flawed by inaccuracies of recall, as well as by the challenge of incomplete ascertainment of confounders and covariates. Furthermore, simplistic attribution of changes in outcome to variations in one nutrient must take into account corresponding increases and decreases in others. Nevertheless, many studies now strongly suggest that dietary saturated fats (SFA) are not causally related to CVD.1 However, SFA from meat is associated with higher and from dairy with lower CVD risk,2, 3 suggesting additional mediators such as trimethylamine N-oxide, a byproduct of the microbiome in response to red meat.4 High intake of simple carbohydrates (CHO) appeared to be most strongly associated with mortality, most strongly shown in the PURE study, in which 135 335 persons from 18 countries were compared. In this study, both SFA and unsaturated fat intake were associated with lower mortality. Furthermore, higher dietary CHO were associated with lower LDL and HDL cholesterol and apolipoproteins B and A1, with the apoB/apoA1 ratio appearing to be a somewhat better predictor, decreasing with higher dietary SFA.5 A number of other studies suggest this ratio to be an important CVD risk marker,6 one which is associated with higher levels of small, dense LDL particles,7 which reflect lower insulin sensitivity.

Insulin resistance is associated with higher levels of inflammatory mediators such as C-reactive protein (CRP). Brendan Everett, Boston, MA discussed the role of inflammation in CVD, initially remarked upon with the “common soil hypothesis” that there is a linkage of both diabetes and CVD to an underlying condition, with inflammation, as well as insulin resistance, likely as the underlying explanatory mediator. The strong relationships between interleukin-6 and diabetes,8 and between CRP and both CVD and vascular death,9 suggests inflammation as a therapeutic target. This hypothesis was given further support in a large trial of rosuvastatin treatment of persons with elevated CRP, showing that along with reduction in LDL cholesterol was a nearly as great reduction in CRP, and with decrease in risk of a variety of CVD endpoints, including mortality,10 appearing to be linked to the lipid and CRP changes.11 A CVD outcome trial of administration of canakinumab, a human monoclonal antibody targeting interleukin-1β, to 10 061 patients with previous myocardial infarction and CRP ≥2 mg/L, showed reduction both in CRP and in CVD endpoints.12 Everett suggested, however, that “inflammation reduction is a catchall term that applies to a wide array of intricate biological processes,” so that anti-inflammatory treatments may or may not be disease-modifying, with a small study showing reduction in CVD with a low dose of colchicine,13 but a more recent trial of methotrexate not showing benefit.14 Whatever the contributory role of inflammation in the pathology of atherosclerosis, the outcome of the interventions studied to date suggest that treatment of established CVD with anti-inflammatory agents may be “too late” to reverse the damage. Along these lines, Sanjay Kaul, Los Angeles, CA argued that the results of the canakinumab study decidedly did not constitute “extraordinary proof [of the] extraordinary claim” that such an approach might be beneficial, going into the complexities of interpreting such complex interventions.

Timothy Garvey, Birmingham, AL discussed treatment of obesity as a crucial approach to stemming the diabetes epidemic, reviewing the large number of lifestyle and pharmacologic interventions, and the potential role of bariatric surgery, so that “we can do this,” but stressed the urgency of such approaches, with some 40% of the US population having either diabetes or prediabetes (and similar prevalences throughout the world). He suggested a risk stratification approach to select persons requiring intensive intervention, as those individuals having both prediabetes and metabolic syndrome have a many-fold greater likelihood of progressing to diabetes.15 Not only is obesity a factor in adults, but Stephen Daniels, Denver, CO discussed the evidence that childhood obesity is associated with CVD,16 and that with recovery from metabolic syndrome there may be improvement in endothelial function.17 Paul Zimmet, Melbourne, Australia, who was instrumental in the development of the concept and definition of the “harmonized” metabolic syndrome,18 suggested an alternative central mechanism of insulin resistance, what he termed the “Circadian Syndrome” of disruption of the normal diurnal rhythm with chronic sleep insufficiency, as well as continual caloric excess, appearing to lead to epigenetic modifications eventuating in hypertension, dyslipidemia, non-alcoholic fatty liver disease (NAFLD), sleep apnea, and perhaps depression and cognitive impairment.19-21

Richard Bergman, Los Angeles, CA discussed the control of hepatic glucose production, reviewing the notion that insulin does not act directly to lower hepatic glucose production (HGP), a concept dating to the 1950s,22 but rather that HGP is controlled indirectly by the antilipolytic effect of insulin on adipose tissue,23 with possible additional insulin signaling through the central nervous system. Bergman discussed the concept of “glucose effectiveness,” the direct effect of glucose on its own hepatic disposition, and then went on to address the important question of why approximately half of the insulin secreted into the portal vein is degraded by the liver without entering the systemic circulation, with the fascinating observation that hepatic insulin clearance is reduced by a high fat diet, and decreases in states of insulin resistance. Mediators of this phenomenon, ethnic variability, its consequences in pathogenesis of diabetes, and its potential therapeutic application to the treatment of diabetes are fascinating potential implications. Sun Kim, Stanford, CA further discussed the topic with a review of her studies of the role of insulin secretion and insulin clearance in the adaptation to insulin resistance.24 Gerald Shulman, New Haven, CT concluded a summary of his work on the central role of diacyl glycerol and protein kinase C in insulin resistance with the suggestion that the evolutionary basis of lipid-induced hepatic insulin resistance is starvation-induced increase in lipolysis, with consequent hepatic lipid accumulation, leading to hepatic insulin resistance to glycogen storage, preserving the liver's ability to produce glucose required by the brain.25

In a review of his remarkable studies of the function of fibroblast growth factor (FGF)1 as the metabolic mediator of the effect of peroxisome proliferator-activated receptor (PPAR)-γ, Ronald Evans, La Jolla, CA began by pointing out that fat is unique as the storage site of most of the body's energy, approximately 80 000 kcal as fat, with muscle protein and triglyceride having 30 000 kcal and 2500 kcal, muscle and liver glycogen having 1500 and 400 kcal, and only 80 kcal of energy being stored in blood glucose. Thus, it is logical that the control of adipocyte energy stores would play a crucial role in metabolism, and Evans discussed the evidence that activation of the PPARγ/retinoid X receptor heterodimer leads to FGF1 production,26 with FGF1 administration in an animal model having insulin sensitizing effect without thiazolidinedione side effects such as weight gain, bone loss, or edema.27 FGF1 and insulin may have parallel actions, insulin as an endocrine regulator produced in response to meals, while FGF1 acts physiologically as a local paracrine lipolysis regulator, an implication is that FGF1 or FGF1-mimetics may have therapeutic effects in insulin resistant states and in diabetes.

George King, Boston, MA further speculated on the molecular and CV implications of insulin resistance, noting that if approximately two thirds of CV risk is explained by recognized risk factors,28 one third of the causes must not be established, and might derive from insulin resistance, or, intriguingly, from deficiency of protective factors, such as insulin, vascular endothelial growth factor, platelet-derived growth factor, and antioxidant enzymes. Insulin acts on the vascular endothelium by regulating its own trafficking to underlying tissues, and as well by regulating vascular permeability, vascular tone, angiogenesis, and brown fat development and activation, as well as by reducing inflammation.29

2018年11月29日至12月1日在加利福尼亚州的洛杉矶市召开了第16届胰岛素抵抗、糖尿病与心血管疾病世界年会(World Congress on Insulin Resistance, Diabetes, and Cardiovascular disease,WCIRDC)。会议的主题对于我们了解与研究心脏代谢状况以及新的治疗方法非常重要。在大会上讨论了一系列与胰岛素抵抗相关的内容以及对肥胖的新认识:脂肪细胞、糖尿病、昼夜节律相关病理学、心血管(CV)、肾脏与肝脏疾病。今年在大会上表彰与缅怀了最近去世的大会共同创始人——斯坦福大学Gerald Reaven教授的科学生涯。

来自加利福尼亚州奥克兰市的Ronald Krauss回顾了饮食与心血管疾病以及血脂异常之间关系的新概念。他指出基于人群的饮食研究存在缺陷,  因为回忆往往并不准确,  除此之外针对混淆与共变的部分查证法也不可靠。此外,  不能简单地将结果变化归因于一种营养素的变化,  必须同时考虑到其他营养素是否有增加与减少。虽然如此,  目前许多研究明确表明,  饮食中的饱和脂肪(saturated fats,SFA)与CVD之间没有因果关系¹。然而,  来自肉类的SFA与更高的CVD风险相关,  而来自乳制品的SFA却与更低的CVD风险相关^2,3,这意味着进食红肉后产生的额外介质如三甲胺N-氧化物,  一种微生物产生的副产品,  可导致CVD风险升高⁴。过多摄入简单碳水化合物(simple carbohydrates,CHO)似乎与高死亡率密切相关,PURE研究对比了135335名来自18个国家的受试者,  发现这种相关性最强。在这项研究中,SFA以及不饱和脂肪的摄入都与更低的死亡率相关。此外,  更高的饮食CHO摄入与更低的LDL胆固醇、HDL胆固醇、载脂蛋白B以及载脂蛋白A1水平相关,  并且从某种程度上讲,apoB/apoA1比值似乎是一个更好的预测指标,  随着饮食SFA摄入量的增加而不断地下降⁵。其他许多研究也表明这项比值是一个重要的CVD风险指标⁶,其中的一个研究显示,  该比值与小而密的LDL颗粒水平的升高有关⁷,这反映出较低的胰岛素敏感性。

胰岛素抵抗与更高水平的炎症介质如C反应蛋白(C-reactive protein,CRP)具有相关性。来自马萨诸塞州波士顿市的Brendan Everett讨论了炎症对CVD的影响,  最初用“共同土壤学说”来解释,  糖尿病和CVD都与潜在的炎症状态有关,  除此之外还与胰岛素抵抗有关,  这些可以用来解释为可能潜在的中介物。白细胞介素-6与糖尿病之间⁸、CRP与CVD和血管死亡之间⁹的强烈相关性意味着可将炎症作为治疗目标。这一假说在一项大规模的瑞舒伐他汀治疗CRP升高患者的试验中得到了进一步的支持,  研究发现随着LDL胆固醇水平的下降,CRP的下降幅度几乎一样大,  并且各种CVD终点的风险也明显下降,  其中也包括死亡率¹⁰,这似乎与脂质以及CRP的变化有关¹¹。在一项使用卡纳单抗(一种以白细胞介素-1β为靶点的人单克隆抗体)治疗观察CVD结果的试验中,  发现10061名既往有心肌梗死并且CRP≥ 2 mg/L的患者在治疗后CRP与CVD终点都明显减少了¹²。然而,Everett认为,  “减少炎症是一个包罗万象的术语,  适用于各种复杂的生物过程”,  因此抗炎治疗可能会或可能不会改善疾病的预后,  在一项小规模的研究中发现低剂量秋水仙碱可以减少CVD的风险¹³,但在最近的一个甲氨蝶呤试验中却没有发现有益处¹⁴。无论炎症在动脉粥样硬化病理学中有何促进作用,  迄今为止所有的干预研究结果都表明,  使用抗炎药物治疗已经明确存在的CVD可能“太晚了”,  此时已经无法逆转疾病的进展。 来自加利福尼亚州洛杉矶市的Sanjay Kaul认为卡纳单抗研究的结果尚未达到这种方法带来 ” 非比寻常效益 “ 的说法，这种复杂的干预措施需要经过非一般的论证

来自阿拉巴马州伯明翰市的Timothy Garvey讨论了将治疗肥胖作为遏制糖尿病流行的重要方法,  他回顾了大量的生活方式与药物干预研究以及减肥手术(briatric surgery)的潜在作用,  以便“我们能够做到这一点”, 但强调了采用这类方法的紧迫性,  因为大约40%的美国人口患有糖尿病或者糖尿病前期(世界各地也有类似的患病率)。他建议采用风险分层的方法来选择需要强化干预的人,  因为同时患有糖尿病前期与代谢综合征的患者发展为糖尿病的可能性要比其他人大很多倍¹⁵。但并不仅仅只有成年人肥胖这个危险因素,  来自科罗拉多州丹佛市的Stephen Daniels讨论了儿童期肥胖与CVD相关的证据¹⁶,并且还提到了随着代谢综合征的缓解,  内皮功能也有可能得到改善¹⁷。来自澳大利亚墨尔本市的Paul Zimmet在“协调”代谢综合征的概念与定义方面具有重要的贡献¹⁸,他提出了另一种胰岛素抵抗的中枢机制,  他将慢性睡眠不足导致的正常昼夜节律紊乱称为“昼夜节律综合征”,  除此之外还有持续热量过剩,  似乎可以导致高血压、血脂异常、非酒精性脂肪肝、睡眠呼吸暂停、可能还有抑郁症与认知障碍的表观遗传变化^19-21。

来自加利福尼亚州洛杉矶市的Richard Bergman讨论了如何控制肝葡萄糖生成,  他回顾了并不是胰岛素的直接作用导致了肝葡萄糖生成减少的观点,  这个概念可以追溯到20世纪50年代²²,但是胰岛素可以作用在脂肪组织上,  有抗脂肪分解的作用,  从而间接控制肝葡萄糖²³,并且还有可能通过中枢神经系统传递额外的胰岛素信号。Bergman还讨论了“葡萄糖效应”的概念以及葡萄糖对自身肝脏葡萄糖处置能力的直接影响,  然后继续讨论了一个重要的问题——为什么分泌到门静脉的胰岛素大约有一半被肝脏降解而不是进入系统循环。一些令人感兴趣的观察研究结果表明,  高脂饮食可降低肝脏胰岛素清除率,  同时也改善胰岛素抵抗状态。这种现象的媒介、种族变异性、在糖尿病发病机制中的影响以及在糖尿病治疗中的潜在应用价值都非常令人感兴趣。来自加利福尼亚州斯坦福大学的Sun Kim进一步讨论了该主题,  回顾了她自己有关胰岛素分泌与胰岛素清除如何适应胰岛素抵抗的研究²⁴。来自康涅狄格州纽黑文市的Gerald Shulman总结了他自己关于甘油二酯与蛋白激酶C在胰岛素抵抗中有何重要作用的相关研究,  他认为脂质诱导的肝脏胰岛素抵抗的进化基础是饥饿诱导的脂肪分解增加,  随后发生的肝脏脂质蓄积导致肝脏胰岛素抵抗,  出现糖原贮积,  从而维持肝脏提供大脑所需葡萄糖的能力²⁵。

来自加利福尼亚州拉由拉市的Ronald Evans回顾了他的关于成纤维细胞生长因子(fibroblast growth factor,FGF)1作为代谢介质如何影响过氧化物酶体增殖物激活受体(peroxisome proliferator-activated receptor,PPAR)-γ的非凡研究,  指出了脂肪是人体独一无二的大部分能量的储存场所,  大约有80000 kcal的能量储存在脂肪中,  肌蛋白与甘油三酯中分别有30000 kcal和2500 kcal,肌糖原与肝糖原中分别有1500与400 kcal,只有80 kcal的能量储存在血糖中。因此,  在代谢中控制脂肪细胞的能量储存非常重要,  这也合乎逻辑,  并且Evans讨论了激活PPARγ/视黄醇X受体异二聚体可导致FGF1生成的证据²⁶,而在一个动物模型中给予FGF1治疗后,  发现具有胰岛素增敏作用,  并且没有噻唑烷二酮的副作用如体重增加、骨量丢失或者水肿²⁷。FGF1与胰岛素的作用可能是平行的,  胰岛素作为一种内分泌调节剂可对进食做出反应,  而FGF1在生理上是一种局部旁分泌的脂解调节剂,  这意味着对于胰岛素抵抗状态以及糖尿病来说,FGF1或者FGF1模拟物可能具有治疗作用。

来自麻萨诸塞州波士顿市的George King进一步推测了胰岛素抵抗的分子机制以及对CV的影响,  指出如果大约三分之二的CV风险可以用公认的危险因素来解释²⁸,那么三分之一的病因不可成立,  并且有可能就是由胰岛素抵抗导致的,  或者,  是由于缺乏保护性因子例如缺乏胰岛素、血管内皮生长因子、血小板衍生生长因子与抗氧化酶所导致的。胰岛素通过调节自身向下层组织的运输而作用于血管内皮,  并且还通过调节血管通透性、血管张力、血管生成以及棕色脂肪的发育与激活起作用,  除此之外还可以通过减少炎症而起作用²⁹。