Good afternoon. It’s an extraordinary honor and pleasure for me to be asked by the AAP to present the 2019 Kober Medal to Professor C. Ronald Kahn, my close friend and colleague for the past 45 years. I can think of no person more deserving of this prestigious award.

The early days

As some of you know, Ron grew up in Louisville, Kentucky, so my celebratory comments will have a Kentucky theme. Just as the Kentucky Derby begins with a call to the Derby, we might begin this event with a “Call to the Kober, 2019” (Supplemental Video 1; supplemental material available online with this article; https://doi.org/10.1172/JCI133156DS1).

At his core, those who know him well see Ron as basically “the boy from Louisville.” This is a city known for the Louisville Slugger baseball bat and the Kentucky Derby, but in the realm of medical science, it is also known as the birthplace of C. Ronald Kahn. Ron’s “Old Kentucky Home” was a house on Meadow Road. If it hasn’t yet, this house should someday be decorated with a prominent brass plaque to record this history.

The core Kahn family included his mom and dad, Reva and Dave, and his older brother Arnie (Figure 1). They were a source of great love and support during his childhood. Speaking of love, here is a wedding picture of Ron and Suzi from 1966 (Figure 2A). Fifty-three years later they are still happily together (Figure 2B).

Figure 1

The core Kahn family in front of their Louisville home. Left to right: Ron, Reva, Dave, and Arnie Kahn.

Figure 2

(A) The wedding of Ron and Suzi in 1966. (B) Ron and Suzi in 2019.

After graduating with highest honors from the University of Louisville, Ron set his sights on a medical career, and entered the University of Louisville Medical School. Ron performed at a high level in med school, and then matched at Barnes Hospital and Washington University in St. Louis for his medical residency. Suzi took this picture as Ron walked into the Hospital on the first day of his internship (Figure 3).

Figure 3

Ron entering Barnes Hospital on the first day of his internship.

The NIH days

Two years later, Ron set out for Bethesda to begin a glorious 11-year career at the NIH, working in the Clinical Center, Building 10. Ron set up home in the Diabetes Branch of the NIDDK as a fellow of Jesse Roth, the Branch Chief, who became my mentor three years later. When Ron arrived in 1970, Jesse had been working for several years to begin to define, characterize, and understand the biology and disease relevance of membrane receptors for peptide hormones. While these started with studies of ACTH, insulin receptors soon became the most critical model employed in the lab. Jesse and the people working with him during that period were really responsible for establishing this critical field, the precursor to what is now referred to as the field of signal transduction. Before this work, it was still debated whether insulin action began at the cell surface or began inside the cell, and if it began at the surface, what was the “second messenger” that mediated its action. Although they made fundamental discoveries, and established that the first step of insulin action was binding to a cell surface receptor, in retrospect what they actually understood then about the insulin receptor and insulin action was very limited. This is captured in an immortal cartoon drawn in 1979 by the scientist and cartoonist Pierre DeMeyts (Figure 4) showing that insulin binds to its receptor, then something happens, but what happened was really a black box! A long way since the black box concept!

Figure 4

Cartoon by Pierre DeMeyts from 1979, illustrating knowledge at the time on insulin action.

Phil Gorden, one of Ron’s early mentors, and a close collaborator of Jesse Roth, was a product of an even deeper place in the South — Mississippi (Supplemental Video 2)! The clinical associate who immediately preceded Ron in the lab was Bob Lefkowitz. Bob, or Lefko as he was called, was not from Kentucky or Mississippi, but from the Bronx. Bob attended the Bronx High School of Science, as I did a few years later. Bronx Science was and remains an amazing school that graduated many Nobel Laureates, of which Lefkowitz is one (Supplemental Video 3).

Jesse Roth was not from Kentucky, or the Bronx, but from Brooklyn. I asked him to say a few words (Supplemental Video 4).

To prepare for this talk, I actually did substantial research, aiming to uncover details on when and how Ron gained his interest in diabetes research. I went into the archives of the Banting and Best Institute in Toronto, where Banting and Best (and their experimental dog Margie) accomplished the impossible in 1921 — they discovered insulin. What I found, at the bottom of a box of old pictures, will astound you, as it did me (Figure 5). Somehow, Ron was actually there! Whether he was subsequently deleted from the picture and the story because he was not Canadian, or because he wore plaid pants like those seen here, will require more years of historical analysis.

Figure 5

Banting, Kahn, and Best in 1921, celebrating the earliest phase of insulin discovery.

Scientific contributions

To briefly review Ron’s scientific contributions, I will run through some of Ron’s greatest hits. Part one involves his contributions during the NIH years. In 1973, Ron and colleagues established that insulin receptor expression was altered in the severely insulin-resistant ob/ob mice (1). Although discovery that the cause of this obesity syndrome was a mutation in the gene for the fat cell hormone leptin would not be discovered until 1994 (2), this work established that receptor binding activity could be altered in an important disease model, increasing interest in receptor biology. In 1974, Ron published a paper characterizing in great detail the kinetics and specificity of liver membrane insulin receptors (3). In 1975 (4) and 1976 (5), Ron and colleagues identified two human syndromes of severe insulin resistance, and showed that these were in fact disorders of insulin receptors, one caused by antibodies against the receptor (work with me) (4, 5) and the other most likely due to genetic defects in the receptor. In 1978, the anti-receptor antibodies were shown to be capable of being agonists of insulin action in adipocytes, through receptor crosslinking (6). In 1982, Ron and colleagues showed for the first time that activating the insulin receptor would stimulate its own phosphorylation, a major breakthrough (7). In 1983 this was shown to be tyrosine phosphorylation (8).

Part 2 of Ron’s greatest hits continued in Boston. In 1991, he and associates identified and defined the first insulin receptor substrate, IRS-1 (9), and in 1994 this allowed them to expand and clarify understanding of downstream signaling pathways (10). Beginning in 1999, the Kahn lab used gene targeting to knock out insulin receptors in numerous tissues, including β cells (11), neurons (12), and adipocytes (13), producing many new insights into the complex biology of insulin. Not resting on his laurels, Ron has extended his research into new areas. Most recently, his work on the microbiome (14) and discovery of virally encoded insulin-like peptides (15) pushes our understanding of insulin action and the Kahn discovery envelope even further.

Now, sometimes Ron’s productivity creates problems for other scientists in the field. Mike Czech and his fellows explain this in this video (Supplemental Video 5).

Another way to capture Ron’s productivity is to graph his number of publications as a function of time. This plot reveals a nearly perfectly linear productivity from 1975 onwards (Figure 6A). We might then ask what effect this research has had on the prevalence of diabetes. Unfortunately, after an initial lag, there is a clear positive correlation between Ron’s scientific productivity and the prevalence of diabetes, which his research, as stated in numerous grant proposals, was aiming to reduce (Figure 6B). Fortunately, correlation doesn’t imply causation! In fact, my research reveals for the first time that diabetes prevalence would have been far greater if not for Ron’s scientific output, a point that Ron stresses in all grant proposals (Figure 6C).

Figure 6

Top: The number of papers by Ron Kahn over time. Bottom: Correlation between Ron Kahn’s publications and the prevalence of diabetes in the US.

Boston, Joslin, and Harvard

After 11 amazing years in Bethesda, including 4 when we closely interacted, Ron left the NIH, and was presented with his scientific symbol, a Louisville Slugger bat (Figure 7). The Harvard/Joslin Era began in 1981. I asked Dr. Eugene Braunwald, who recruited Ron to Boston, to offer a few comments. I asked him to inject some humor, but he replied — I don’t do humor (Supplemental Video 6).

Figure 7

Jesse Roth marks Ron’s departure from the NIH for Boston by presenting a Louisville Slugger bat.

Ron has assembled amazing lab groups over the years, a remarkable number of whom became leaders in the field of diabetes research, in the US and around the world. One of his legacies was outstanding mentorship of women scientists, one of whom was my wife, Terry Maratos-Flier (Supplemental Video 7).

Ron has won every award in the field of diabetes, and many outside the field. When he won the Banting award in 1993, he stood between Jesse Roth, who won it before he did, and me, who would go on to win this award (Figure 8).

Figure 8

Celebrating the presentation of the Banting Award from the American Diabetes Association to Ron Kahn in 1993. Left to right: Susan Roth, Suzi Kahn, Jesse Roth, Ron Kahn, Jeff Flier, Terry Maratos-Flier.

Turning back to his personal life, you can remove Ron from Louisville, but you can’t remove Louisville from Ron. Here’s the extended Kahn family in 2009, at Ron’s father Dave’s 100th birthday celebration (Figure 9). His daughter Stacy and son Jeff, doctor and lawyer, are the apple of their dad’s eye (Figure 10). And Ron with his four wonderful grandkids (Figure 11)!

Figure 9

The extended Kahn family celebrates Dave’s 100th birthday in 2009.

Figure 10

Ron Kahn with son Jeffrey and daughter Stacy.

Figure 11

Ron Kahn with his four grandkids.

With all of his success, Ron is still taking risks in both his research and his recreation (Figure 12). So much has been learned about insulin action since Pierre DeMeyts drew his famous cartoon in 1979 (Figure 4). Today, insulin signaling is no longer a black box. Instead, everything about insulin action is perfectly explained. To illustrate, I commissioned a new cartoon on the current state of insulin action by Pierre DeMeyts (Figure 13). Those of us there from the beginning confess that on some level, we do miss the simplicity of the black box. While a lot has been learned, not everything about insulin action is yet explained.

Figure 12

Ron Kahn skydiving.

Figure 13

Cartoon by Pierre DeMeyts, illustrating how far we have come since the “black box” in explaining insulin action pathways.

So, in the end, Ron Kahn is a man for the ages, and a true scientific Louisville slugger. His impact on the Joslin Diabetes Center, Harvard Medical School, and the international scientific community will last far into the future. In the end, I can say this: Through research conducted over the past 48 years at the NIH, Joslin, and Harvard, no one has contributed more than Ron Kahn to our understanding of insulin, insulin signal transduction, insulin’s complex multiorgan physiologic actions, and insulin’s role in human disease. He is most deserving of the 2019 Kober Medal, and it’s a great pleasure for me to present him to you today.

Supplemental material

View Supplemental Video 1

View Supplemental Video 2

View Supplemental Video 3

View Supplemental Video 4

View Supplemental Video 5

View Supplemental Video 6

View Supplemental Video 7

Footnotes

Copyright: © 2019, American Society for Clinical Investigation.

Reference information: J Clin Invest. 2019;129(12):5066–5070. https://doi.org/10.1172/JCI133156.

This article is adapted from a presentation at the AAP/ASCI/APSA Joint Meeting, April 6, 2019, in Chicago, Illinois, USA.

References

1. Kahn CR, Neville DM, Roth J. Insulin-receptor interaction in the obese-hyperglycemic mouse. A model of insulin resistance. J Biol Chem. 1973;248(1):244–250.View this article via: PubMedGoogle Scholar
2. Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM. Positional cloning of the mouse obese gene and its human homologue. Nature. 1994;372(6505):425–432.View this article via: PubMedCrossRefGoogle Scholar
3. Kahn CR, Freychet P, Roth J, Neville DM. Quantitative aspects of the insulin-receptor interaction in liver plasma membranes. J Biol Chem. 1974;249(7):2249–2257.View this article via: PubMedGoogle Scholar
4. Flier JS, Kahn CR, Roth J, Bar RS. Antibodies that impair insulin receptor binding in an unusual diabetic syndrome with severe insulin resistance. Science. 1975;190(4209):63–65.View this article via: PubMedCrossRefGoogle Scholar
5. Kahn CR, et al. The syndromes of insulin resistance and acanthosis nigricans. Insulin-receptor disorders in man. N Engl J Med. 1976;294(14):739–745.View this article via: PubMedCrossRefGoogle Scholar
6. Kahn CR, Baird KL, Jarrett DB, Flier JS. Direct demonstration that receptor crosslinking or aggregation is important in insulin action. Proc Natl Acad Sci U S A. 1978;75(9):4209–4213.View this article via: PubMedCrossRefGoogle Scholar
7. Kasuga M, Karlsson FA, Kahn CR. Insulin stimulates the phosphorylation of the 95,000-dalton subunit of its own receptor. Science. 1982;215(4529):185–187.View this article via: PubMedCrossRefGoogle Scholar
8. Kasuga M, Zick Y, Blithe DL, Crettaz M, Kahn CR. Insulin stimulates tyrosine phosphorylation of the insulin receptor in a cell-free system. Nature. 1982;298(5875):667–669.View this article via: PubMedCrossRefGoogle Scholar
9. Sun XJ, et al. Structure of the insulin receptor substrate IRS-1 defines a unique signal transduction protein. Nature. 1991;352(6330):73–77.View this article via: PubMedCrossRefGoogle Scholar
10. Araki E, et al. Alternative pathway of insulin signalling in mice with targeted disruption of the IRS-1 gene. Nature. 1994;372(6502):186–190.View this article via: PubMedCrossRefGoogle Scholar
11. Kulkarni RN, Brüning JC, Winnay JN, Postic C, Magnuson MA, Kahn CR. Tissue-specific knockout of the insulin receptor in pancreatic beta cells creates an insulin secretory defect similar to that in type 2 diabetes. Cell. 1999;96(3):329–339.View this article via: PubMedCrossRefGoogle Scholar
12. Brüning JC, et al. Role of brain insulin receptor in control of body weight and reproduction. Science. 2000;289(5487):2122–2125.View this article via: PubMedCrossRefGoogle Scholar
13. Blüher M, Kahn BB, Kahn CR. Extended longevity in mice lacking the insulin receptor in adipose tissue. Science. 2003;299(5606):572–574.View this article via: PubMedCrossRefGoogle Scholar
14. Ussar S, et al. Interactions between gut microbiota, host genetics and diet modulate the predisposition to obesity and metabolic syndrome. Cell Metab. 2015;22(3):516–530.View this article via: PubMedCrossRefGoogle Scholar
15. Altindis E, et al. Viral insulin-like peptides activate human insulin and IGF-1 receptor signaling: A paradigm shift for host-microbe interactions. Proc Natl Acad Sci U S A. 2018;115(10):2461–2466.View this article via: PubMedCrossRefGoogle Scholar

下午好。AAP要求我向过去45年来我的密友和同事C.Ronald Kahn教授颁发2019年Kober奖章，这对我来说是一种非凡的荣幸和荣幸。我认为没有人更应该得到这个享有盛誉的奖项。

初期

如您所知，罗恩（Ron）在肯塔基州路易斯维尔长大，因此我的庆祝言论将以肯塔基州为主题。就像肯塔基德比开始打德比一样，我们可能会以“打给Kober，2019”开始本活动（补充视频1；本文在线提供补充材料； https：//doi.org/10.1172 / JCI133156DS1）。

在他的核心处，那些非常了解他的人将罗恩（Ron）基本上说成是“路易斯维尔的男孩”。这是一个以路易斯维尔·斯拉格（Louisville Slugger）棒球棍和肯塔基德比（Kentucky Derby）闻名的城市，但在医学领域，它也被称为C.罗纳德·卡恩（C. Ronald Kahn）的出生地。罗恩（Ron）的“肯塔基故居”是一处位于梅多路（Meadow Road）的房子。如果还没有，这房子应该有朝一日用醒目的黄铜匾装饰起来，以记录这一历史。

Kahn的核心家庭包括他的父母，Reva和Dave，以及他的哥哥Arnie（图1）。在他的童年时期，他们是极大的爱与支持的源泉。说到爱情，这是1966年罗恩和苏兹的结婚照（图2A）。53年后，他们仍然幸福地在一起（图2B）。

图1

卡恩核心家庭在他们路易斯维尔的家门口。从左到右：Ron，Reva，Dave和Arnie Kahn。

图2

（A）罗恩和苏兹在1966年举行的婚礼。（B）罗恩和苏兹在2019年举行的婚礼。

罗恩（Ron）从路易斯维尔大学（University of Louisville）获得最高荣誉毕业后，将目光投向了医学事业，并进入了路易斯维尔大学医学院（University of Louisville Medical School）。罗恩（Ron）在医学院学习时表现出色，然后在圣路易斯的巴恩斯医院（Barnes Hospital）和华盛顿大学（Washington University）取得了医学上的居住权。Suzi在Ron实习的第一天走进医院时就拍了这张照片（图3）。

图3

罗恩在实习的第一天进入巴恩斯医院。

美国国立卫生研究院的日子

两年后，罗恩（Ron）前往贝塞斯达（Bethesda），开始了在NIH的光荣的11年职业生涯，在10号楼临床中心工作。院长，三年后成为我的导师。当罗恩（Ron）于1970年到达时，杰西（Jesse）从事了数年的工作，开始定义，表征和理解肽激素膜受体的生物学和疾病相关性。尽管这些都从ACTH的研究入手，但胰岛素受体很快成为实验室中采用的最关键的模型。在此期间，杰西（Jesse）和与他合作的人们真正负责建立这个关键领域，这是现在所谓的信号传导领域的前身。在开始这项工作之前，仍在争论胰岛素作用是从细胞表面开始还是在细胞内部开始，并且如果它开始于细胞表面，那么介导其作用的“第二信使”是什么。尽管他们做出了基本发现，并确定胰岛素作用的第一步是与细胞表面受体结合，但回想起来，他们对胰岛素受体和胰岛素作用的实际了解非常有限。科学家和漫画家Pierre DeMeyts（图4）在1979年绘制的不朽漫画中捕捉到了这一点（图4），图中显示胰岛素与受体结合，然后发生了一些事情，但实际上是黑匣子！自黑匣子概念以来很长的路要走！尽管他们做出了基本发现，并确定胰岛素作用的第一步是与细胞表面受体结合，但回想起来，他们对胰岛素受体和胰岛素作用的实际了解非常有限。科学家和漫画家Pierre DeMeyts（图4）在1979年绘制的不朽漫画中捕捉到了这一点（图4），图中显示胰岛素与受体结合，然后发生了一些事情，但实际上是黑匣子！自黑匣子概念以来很长的路要走！尽管他们做出了基本发现，并确定胰岛素作用的第一步是与细胞表面受体结合，但回想起来，他们对胰岛素受体和胰岛素作用的实际了解非常有限。科学家和漫画家Pierre DeMeyts（图4）在1979年绘制的不朽漫画中捕捉到了这一点（图4），图中显示胰岛素与受体结合，然后发生了一些事情，但实际上是黑匣子！自黑匣子概念以来很长的路要走！科学家和漫画家Pierre DeMeyts（图4）在1979年绘制的不朽漫画中捕捉到了这一点（图4），图中显示胰岛素与受体结合，然后发生了一些事情，但实际上是黑匣子！自黑匣子概念以来很长的路要走！科学家和漫画家Pierre DeMeyts（图4）在1979年绘制的不朽漫画中捕捉到了这一点（图4），图中显示胰岛素与受体结合，然后发生了一些事情，但实际上是黑匣子！自黑匣子概念以来很长的路要走！

图4

Pierre DeMeyts于1979年创作的漫画，阐释了当时有关胰岛素作用的知识。

罗恩（Ron）的早期导师之一，杰西·罗斯（Jesse Roth）的亲密合作者菲尔·高登（Phil Gorden），是南方更深的地方-密西西比州的产物（补充视频2）！在实验室中紧随罗恩之前的临床助理是鲍勃·莱夫科维茨（Bob Lefkowitz）。鲍勃（Bob）或莱夫科（Lefko）并非来自肯塔基州或密西西比州，而是布朗克斯区的人。鲍勃（Bob）和我几年后一样，就读于布朗克斯科学高中。布朗克斯科学曾经是而且现在仍然是一所令人惊叹的学校，毕业了许多诺贝尔奖得主，莱夫科维茨就是其中之一（补充视频3）。

杰西·罗斯（Jesse Roth）不是来自肯塔基州或布朗克斯区，而是布鲁克林区的人。我请他说几句话（补充视频4）。

为了准备这次演讲，我实际上进行了大量研究，旨在揭示Ron何时以及如何开始对糖尿病研究产生兴趣的详细信息。我进入了位于多伦多的Banting and Best Institute的档案，在那里，Banting和Best（以及他们的实验犬玛吉（Margie））在1921年实现了不可能的目标-他们发现了胰岛素。我发现，在一盒旧照片的底部，您会像我一样震惊（图5）。不知何故，罗恩实际上在那里！后来由于他不是加拿大人，还是因为他穿着这里看到的格子裤子而被从图片和故事中删除，都需要进行多年的历史分析。

图5

万灵（Banting），卡恩（Kahn）和贝斯特（Best）于1921年庆祝胰岛素研发的最早阶段。

科学贡献

为了简要回顾Ron的科学贡献，我将介绍Ron的一些热门作品。第一部分涉及他在NIH期间的贡献。1973年，罗恩（Ron）及其同事确定，在严重胰岛素抵抗的ob / ob小鼠中，胰岛素受体的表达发生了改变（1）。尽管直到1994年才发现这种肥胖症候群的原因是脂肪细胞激素瘦素的基因突变（2），这项工作确定了在重要的疾病模型中可以改变受体结合活性，从而增加了对受体生物学的兴趣。1974年，罗恩（Ron）发表了一篇论文，详细描述了肝膜胰岛素受体的动力学和特异性（3）。1975年（4）和1976（5），Ron和同事发现了两种严重的胰岛素抵抗的人类综合症，并表明它们实际上是胰岛素受体的疾病，一种是由针对该受体的抗体引起的（与我合作）（4，5）和另一个最有可能是由于受体的遗传缺陷。1978年，抗受体抗体通过受体交联被证明能够在脂肪细胞中发挥胰岛素激动剂的作用（6）。罗恩（Ron）及其同事在1982年首次证明激活胰岛素受体会刺激其自身的磷酸化，这是一个重大突破（7）。在1983年，这被证明是酪氨酸磷酸化（8）。

罗恩（Ron）的热门歌曲的第二部分在波士顿继续进行。1991年，他和同事们确定并定义了第一个胰岛素受体底物IRS-1（9），并在1994年使他们扩大并阐明了对下游信号传导途径的理解（10）。从1999年开始，卡恩（Kahn）实验室就开始使用基因定位技术敲除包括β细胞（11），神经元（12）和脂肪细胞（13），对胰岛素的复杂生物学产生了许多新见解。罗恩不为所欲，而是将研究范围扩展到新领域。最近，他在微生物组方面的工作（14）和发现病毒编码的胰岛素样肽（15）进一步推动了我们对胰岛素作用和卡恩发现范围的了解。

现在，有时罗恩（Ron）的生产力给该领域的其他科学家带来了麻烦。Mike Czech和他的同伴在此视频（补充视频5）中对此进行了解释。

捕捉罗恩生产力的另一种方法是绘制他的出版物数量作为时间的函数。该图显示了从1975年开始的几乎完美的线性生产率（图6A）。然后我们可能会问这项研究对糖尿病的流行有什么影响。不幸的是，在最初的滞后之后，罗恩的科学生产力与糖尿病的患病率之间存在明显的正相关性，正如他在众多赠款提案中指出的那样，他的研究旨在降低糖尿病的患病率（图6B）。幸运的是，关联并不表示因果关系！实际上，我的研究首次揭示，如果不是罗恩（Ron）的科学成果，糖尿病患病率将大大提高，这一点罗恩（Ron）在所有拨款申请中都强调了这一点（图6C）。

图6

顶部：Ron Kahn随时间推移发表的论文数量。下图：罗恩·卡恩（Ron Kahn）的出版物与美国糖尿病的患病率之间的相关性。

波士顿，乔斯林和哈佛

在贝塞斯达（Bethesda）经历了惊人的11年，包括我们密切互动的4年之后，罗恩（Ron）离开了美国国立卫生研究院（NIH），并被授予了他的科学符号路易斯维尔（Louisville Slugger）蝙蝠（图7）。哈佛大学/乔斯林时代始于1981年。我请招募罗恩（Ron）到波士顿的尤金·布劳恩瓦尔德（Eugene Braunwald）博士发表一些评论。我要求他注入幽默感，但他回答-我不幽默（补充视频6）。

图7

杰西·罗斯（Jesse Roth）展示了路易斯维尔（Louisville Slugger）球拍，标志着罗恩（Ron）从国立卫生研究院（NIH）离开波士顿。

多年来，罗恩（Ron）召集了许多了不起的实验室小组，其中相当多的人成为了美国乃至全球糖尿病研究领域的领导者。他的遗产之一是杰出的女科学家指导，其中之一是我的妻子特里·马拉托斯·弗利尔（Terry Maratos-Flier）（补充视频7）。

罗恩（Ron）赢得了糖尿病领域的每一个奖项，并且赢得了糖尿病领域之外的许多奖项。当他在1993年获得“ Banting”奖时，他介于曾获得过大奖的杰西·罗斯（Jesse Roth）和将继续获得该奖项的我之间（图8）。

图8

庆祝1993年美国糖尿病协会向罗恩·卡恩（Ron Kahn）颁发的Banting奖。从左到右：苏珊·罗斯（Susan Roth），苏兹·卡恩（Suzi Kahn），杰西·罗斯（Jesse Roth），罗恩·卡恩（Ron Kahn），杰夫·弗利尔（Jeff Flier），特里·马拉托斯·弗利尔（Terry Maratos-Flier）。

回到他的个人生活，您可以将Ron从路易斯维尔中删除，但不能将路易斯维尔从Ron中删除。这是2009年，在罗恩（Ron）的父亲戴夫（Dave）诞辰100周年庆典上，卡恩大家庭（图9）。他的女儿史黛西（Stacy）和儿子杰夫（Jeff），既是医生又是律师，是他们父亲的掌上明珠（图10）。罗恩（Ron）和他的四个出色的孙子孙女（图11）！

图9

卡恩（Kahn）大家庭在2009年庆祝戴夫（Dave）诞辰100周年。

图10

罗恩·卡恩（Ron Kahn）与儿子杰弗里（Jeffrey）和女儿史黛西（Stacy）。

图11

罗恩·卡恩（Ron Kahn）和他的四个孙子孙女。

尽管Ron取得了所有的成功，但他仍然在研究和娱乐方面都承担着风险（图12）。自从Pierre DeMeyts在1979年画出他著名的漫画以来，关于胰岛素作用的知识已经很多了（图4）。如今，胰岛素信号已不再是一个黑匣子。取而代之的是，关于胰岛素作用的一切都得到了很好的解释。为了说明这一点，我委托Pierre DeMeyts委托制作了一部有关胰岛素作用现状的新漫画（图13）。从一开始，我们当中的那些人就承认在某种程度上，我们确实怀念黑匣子的简单性。尽管已经学到了很多东西，但尚未解释有关胰岛素作用的所有内容。

图12

罗恩·卡恩（Ron Kahn）跳伞。

图13

皮埃尔·德梅特（Pierre DeMeyts）的漫画，阐释了自“黑匣子”以来我们在解释胰岛素作用途径方面走了多远。

因此，归根结底，罗恩·卡恩（Ron Kahn）是一个古老的人，也是真正的科学路易斯维尔（Louisville）拍手。他对乔斯林糖尿病中心，哈佛医学院和国际科学界的影响将持续到很长的将来。最后，我可以这样说：通过过去48年间在NIH，Joslin和哈佛进行的研究，没有人比Ron Kahn对我们对胰岛素，胰岛素信号转导，胰岛素复杂的多器官生理作用的理解有所帮助，和胰岛素在人类疾病中的作用。他是当之无愧的2019年Kober勋章的代言人，今天我很高兴将他介绍给您，这是我的荣幸。

补充材料

观看补充视频1

观看补充视频2

观看补充视频3

观看补充视频4

观看补充视频5

观看补充视频6

观看补充视频7

脚注

版权： ©2019，美国临床研究学会。

参考信息：J Clin Invest。2019; 129（12）：5066-5070。https://doi.org/10.1172/JCI133156。

本文改编自2019年4月6日在美国伊利诺伊州芝加哥举行的AAP / ASCI / APSA联席会议上的演讲。

参考

1. Kahn CR，Neville DM，Roth J.肥胖-高血糖小鼠中的胰岛素-受体相互作用。胰岛素抵抗模型。生物化学杂志。1973; 248（1）：244–250。查看此文章，网址为：PubMedGoogle Scholar
2. 张Y，Proenca R，Maffei M，Barone M，Leopold L，Friedman JM。小鼠肥胖基因及其人类同源物的位置克隆。大自然。1994; 372（6505）：425–432。查看此文章，网址为：PubMedCrossRefGoogle Scholar
3. Kahn CR，Freychet P，Roth J，Neville DM。肝脏质膜中胰岛素受体相互作用的定量方面。生物化学杂志。1974; 249（7）：2249–2257。查看此文章，网址为：PubMedGoogle Scholar
4. Flier JS，Kahn CR，Roth J，Bar RS。在具有严重胰岛素抵抗的不寻常糖尿病综合征中，损害胰岛素受体结合的抗体。科学。1975; 190（4209）：63–65。查看此文章，网址为：PubMedCrossRefGoogle Scholar
5. Kahn CR等。胰岛素抵抗和黑棘皮症的综合症。人体中的胰岛素受体疾病。新英格兰医学杂志。1976; 294（14）：739–745。查看此文章，网址为：PubMedCrossRefGoogle Scholar
6. Kahn CR，Baird KL，Jarrett DB，Flier JS。直接证明受体交联或聚集在胰岛素作用中很重要。美国国家自然科学委员会。1978; 75（9）：4209–4213。查看此文章，网址为：PubMedCrossRefGoogle Scholar
7. 春日男（Kasuga M），卡尔森（Karlsson），卡恩（Kahn）。胰岛素刺激其自身受体的95,000道尔顿亚基的磷酸化。科学。1982; 215（4529）：185–187。查看此文章，网址为：PubMedCrossRefGoogle Scholar
8. 春日男，Zick Y，布莱斯DL，克雷塔兹M，卡恩CR。胰岛素刺激无细胞系统中胰岛素受体的酪氨酸磷酸化。大自然。1982; 298（5875）：667–669。查看此文章，网址为：PubMedCrossRefGoogle Scholar
9. Sun XJ等。胰岛素受体底物IRS-1的结构定义了独特的信号转导蛋白。大自然。1991; 352（6330）：73–77。查看此文章，网址为：PubMedCrossRefGoogle Scholar
10. Araki E等。靶向IRS-1基因破坏的小鼠体内胰岛素信号传导的替代途径。大自然。1994; 372（6502）：186–190。查看此文章，网址为：PubMedCrossRefGoogle Scholar
11. Kulkarni RN，BrüningJC，Winnay JN，Postic C，Magnuson MA和Kahn CR。胰腺β细胞中胰岛素受体的组织特异性敲除会产生类似于2型糖尿病的胰岛素分泌缺陷。单元格。1999; 96（3）：329–339。查看此文章，网址为：PubMedCrossRefGoogle Scholar
12. BrüningJC等。脑胰岛素受体在控制体重和繁殖中的作用。科学。2000; 289（5487）：2122–2125。查看此文章，网址为：PubMedCrossRefGoogle Scholar
13. BlüherM，Kahn BB，Kahn CR。脂肪组织中缺乏胰岛素受体的小鼠的寿命延长。科学。2003; 299（5606）：572–574。查看此文章，网址为：PubMedCrossRefGoogle Scholar
14. Ussar S等。肠道菌群，宿主遗传学和饮食之间的相互作用调节了肥胖症和代谢综合征的易感性。细胞代谢。2015; 22（3）：516–530。查看此文章，网址为：PubMedCrossRefGoogle Scholar
15. Altindis E等。病毒胰岛素样肽激活人胰岛素和IGF-1受体信号传导：宿主-微生物相互作用的范式转变。美国国家自然科学委员会。2018; 115（10）：2461–2466。查看此文章，网址为：PubMedCrossRefGoogle Scholar