The 21st annual World Congress on Insulin Resistance, Diabetes and Cardiovascular Disease, held in Los Angeles, California on December 7–9, 2023, included 69 presentations spanning a myriad of aspects of diabetes and its complications, of atherosclerosis, of renal disease, of liver disease, and of novel therapeutic approaches. For this summary, we will focus on presentations illustrating the current understanding of insulin resistance.

Giving an overview of insulin resistance, Ralph DeFronzo reviewed the complex pathways involved in glucose-handling. A total of 5%–10% of ingested glucose is ultimately removed in adipocytes, and the remainder in skeletal muscle. The insulin signal that regulates glucose disposal is associated with changes in adipocyte free fatty acid release, as well as in local vasodilatation via nitric oxide. In type 2 diabetes (T2D) all of these are abnormal.¹ T2D is associated with a defect in muscle glycogen synthesis and glucose oxidation,² with impaired muscle glycogen synthase, pyruvate dehydrogenase, and hexosekinase.³ The insulin signaling pathway involved in activating glucose transport is also involved in activating nitric oxide synthase, with both reduced in T2D, whereas several proinflammatory/atherosclerotic pathways, involving mitogen-activated protein kinase (MAPK) and the nuclear receptor small heterodimer partner, show unrestricted insulin response in T2D leading to vascular smooth muscle growth and inflammation. Lean offspring of two T2D parents who have normal glucose tolerance have hyperinsulinemia and show levels of insulin resistance similar to those of their parents, with the same defect in insulin receptor substrate and the same overactivity the MAPK pathway.⁴ Hepatic glucose output is increased in T2D,⁵ with the dose–response curve of hepatic glucose production vs portal insulin levels shifted to the right and evidence of decreased adipocyte insulin response,⁶ and muscle capillary bed insulin-induced vasodilatation⁷ also is impaired in T2D. DeFronzo observed that thiazolidinediones reverse all of these molecular defects in T2D, suggesting that use of these agents should be considered more strongly in clinical treatment.

Sam Klein asked which comes first, beta cell dysfunction, hyperinsulinemia, or insulin resistance? Answering this seemingly straightforward question, he observed, requires better understanding of the many underlying interrelationships. In a study comparing lean, normoglycemic persons with obese persons having varying degrees of glycemia, he found that the hyperinsulinemia of obesity is primarily associated with increased insulin secretion, as well as with reduction in cell surface insulin receptors in tissues responsible for insulin clearance.⁸ In this view, Klein considered that “it's the beta cell which tips you over into T2D,” citing studies showing that, with impaired glucose tolerance and diabetes, insulin secretion abnormality reflects impaired K-ATP channel density.⁹ However, he also reviewed a study of 24-hour insulin infusion causing physiologic hyperinsulinemia leading to impaired insulin-stimulated glycogen synthase activity and muscle insulin sensitivity¹⁰ and a study showing that individuals with higher insulin secretion rates progress to glucose intolerance.¹¹ Furthermore, a 6-month study of treatment with the K-ATP channel closing agent diazoxide in conjunction with weight loss improved hyperinsulinemia and insulin sensitivity.¹² His studies of dietary¹³ and bariatric surgery-induced¹⁴ weight loss suggest that the effect of weight loss on glucose-stimulated insulin secretion “depends on where you start,” leading to his proposal that obesity stimulated increase in insulin secretion should be considered the initiating cause of insulin resistance, leading to progressive dysglycemia.

Finally, Paul Zimmet reviewed the “historical milestones” leading to our present understanding of insulin resistance. He started with the Lancet publication in 1936 of Harold Himsworth's study differentiating insulin sensitive vs resistant diabetes.¹⁵ In 1949, Rachmiel Levine proposed that “insulin acts upon the cell membranes of certain tissues in such a manner that the transfer of hexoses (and perhaps other substances) from the extracellular fluid into the cell is facilitated,”¹⁶ and, in the same year, Joseph Bornstein developed the first insulin bioassay, confirming with R. D. Lawrence the existence of two types of diabetes “with and without available plasma insulin.”¹⁷ In 1960, the paper by Yalow and Berson describing the insulin immunoassay was finally published,¹⁸ after battling recommendations beginning in 1955 made by reviewers and by the editor of the Journal of Clinical Investigation to reject it. A number of important studies by Peter Bennett and colleagues began with the recognition of highly insulin-resistant diabetes among Pima Indians initially published in 1971,¹⁹ with Zimmet subsequently finding similar evidence of highly prevalent insulin resistant diabetes among Pacific islanders,²⁰ leading to his coining the term “Coca Colonization” to described adverse effects of adoption of Western lifestyles. Zimmet described what he termed “Starling's curve of the pancreas” in 1978, observing, “Compensatory hyperinsulinism may for some time prevent severe hyperglycaemia. However, once a critical level of hyperglycaemia is reached (ie, 2 h plasma glucose of approximately 280mg/100ml) beta cell function begins to fail and there is more rapid progression of hyperglycaemia. Thus, individuals might for some time remain in the ‘compensated’ phase of moderate hyperglycaemia and then move rapidly to a ‘decompensated’ phase of severe hyperglycaemia with a ‘falling’ insulin response.”²¹ Gerald Reaven's 1988 Banting Lecture described the constellation of risk factors based on insulin resistance as being more important than cholesterol in the development of cardiovascular disease,²² and Zimmet emphasized the multiple contributions of Jesse Roth in the understanding of the role of the cell membrane insulin receptor beginning in 1991.

第 21 届世界胰岛素抵抗、糖尿病和心血管疾病大会于 2023 年 12 月 7 日至 9 日在加利福尼亚州洛杉矶举行，会议包括 69 场演讲，涵盖糖尿病及其并发症、动脉粥样硬化、肾脏疾病、糖尿病等多个方面。肝病和新的治疗方法。在本总结中，我们将重点介绍说明当前对胰岛素抵抗的理解的演示。

拉尔夫·德弗龙佐 (Ralph DeFronzo) 概述了胰岛素抵抗，回顾了葡萄糖处理中涉及的复杂途径。总共 5%–10% 的摄入葡萄糖最终在脂肪细胞中被去除，其余的则在骨骼肌中被去除。调节葡萄糖处理的胰岛素信号与脂肪细胞游离脂肪酸释放的变化以及通过一氧化氮的局部血管舒张有关。在 2 型糖尿病 (T2D) 中，所有这些都是异常的。¹ T2D 与肌糖原合成和葡萄糖氧化缺陷有关，²与肌糖原合酶、丙酮酸脱氢酶和己糖激酶受损有关。³参与激活葡萄糖转运的胰岛素信号通路也参与激活一氧化氮合酶，两者在 T2D 中均减少，而涉及丝裂原激活蛋白激酶 (MAPK) 和核受体小异二聚体伴侣的几种促炎/动脉粥样硬化通路显示T2D 中胰岛素反应不受限制，导致血管平滑肌生长和炎症。两个具有正常糖耐量的 T2D 父母的瘦子后代患有高胰岛素血症，并且表现出与父母相似的胰岛素抵抗水平，具有相同的胰岛素受体底物缺陷和相同的 MAPK 通路过度活跃。⁴ T2D 中肝葡萄糖输出增加，⁵肝葡萄糖生成与门静脉胰岛素水平的剂量反应曲线向右移动，并且脂肪细胞胰岛素反应下降的证据，⁶和肌肉毛细血管床胰岛素诱导的血管舒张⁷在 T2D 中也受损T2D。 DeFronzo 观察到，噻唑烷二酮类药物可逆转 T2D 中的所有这些分子缺陷，这表明在临床治疗中应更强烈地考虑使用这些药物。

Sam Klein 问道，β 细胞功能障碍、高胰岛素血症或胰岛素抵抗，哪一个先发生？他指出，回答这个看似简单的问题需要更好地理解许多潜在的相互关系。在一项比较瘦、血糖正常的人和具有不同程度血糖的肥胖者的研究中，他发现肥胖的高胰岛素血症主要与胰岛素分泌增加以及负责胰岛素清除的组织中细胞表面胰岛素受体的减少有关。⁸根据这一观点，Klein 认为“是 β 细胞导致您患上 T2D”，并引用研究表明，在糖耐量受损和糖尿病的情况下，胰岛素分泌异常反映了 K-ATP 通道密度受损。⁹然而，他还回顾了一项研究，该研究涉及 24 小时胰岛素输注导致生理性高胰岛素血症，从而导致胰岛素刺激的糖原合成酶活性和肌肉胰岛素敏感性受损¹⁰以及一项显示胰岛素分泌率较高的个体会发展为葡萄糖耐受不良的研究。¹¹此外，一项为期 6 个月的 K-ATP 通道关闭剂二氮嗪治疗与减肥相结合的研究改善了高胰岛素血症和胰岛素敏感性。¹²他对饮食¹³和减肥手术引起的体重减轻^{14 的}研究表明，体重减轻对葡萄糖刺激的胰岛素分泌的影响“取决于你从哪里开始”，这导致他提出肥胖刺激胰岛素分泌增加应被视为最重要的因素。胰岛素抵抗的始因，导致进行性血糖异常。

最后，Paul Zimmet 回顾了导致我们目前对胰岛素抵抗的理解的“历史里程碑”。他首先于 1936 年在《柳叶刀》杂志上发表了 Harold Himsworth 区分胰岛素敏感性糖尿病和抵抗性糖尿病的研究。¹⁵ 1949 年，Rachmiel Levine 提出，“胰岛素作用于某些组织的细胞膜，促进己糖（或许还有其他物质）从细胞外液转移到细胞中” ¹⁶，同样，同年，Joseph Bornstein 开发了第一个胰岛素生物测定法，与 RD Lawrence 一起证实了“有或没有可用血浆胰岛素”的两种类型糖尿病的存在。¹⁷ 1960 年，Yalow 和 Berson 描述胰岛素免疫测定的论文终于发表，¹⁸在与审稿人和《临床研究杂志》编辑从 1955 年开始提出的拒绝该论文的建议进行了斗争之后。 Peter Bennett 及其同事的许多重要研究首先于 1971 年发表，首先认识到皮马印第安人中存在高度胰岛素抵抗的糖尿病，¹⁹ Zimmet 随后发现太平洋岛民中胰岛素抵抗糖尿病高度流行的类似证据，²⁰导致了他的创造“可口可乐殖民化”一词描述了采用西方生活方式的不利影响。 Zimmet 在 1978 年描述了他所谓的“胰腺斯塔林曲线”，并观察到，“代偿性高胰岛素血症可能会在一段时间内预防严重的高血糖。然而，一旦达到高血糖的临界水平（即，2小时血浆葡萄糖约为280mg/100ml），β细胞功能开始失效，并且高血糖进展更快。因此，个体可能会在一段时间内处于中度高血糖的“代偿”阶段，然后迅速进入严重高血糖的“失代偿”阶段，胰岛素反应“下降”。²¹ Gerald Reaven 在 1988 年班廷讲座中描述了基于胰岛素抵抗的一系列危险因素，这些因素在心血管疾病的发展中比胆固醇更重要，²²和 Zimmet 强调了 Jesse Roth 在理解细胞膜胰岛素作用方面的多重贡献受体从1991年开始。