Gerald Reaven: A man for our times

Professor Gerald M Reaven 28 July 1928–12 February 2018.

Professor in Medicine, Stanford University, School of Medicine, Stanford, CA, USA.

2018 was a distinct year; on 12 February, Gerald M Reaven – Jerry – passed away, peacefully at home. The year was marked with anniversaries. It was the 30-year anniversary to Gerald Reaven’s Banting lecture 1988: Role of Insulin Resistance in Human Disease where he introduced ‘Syndrome X’, and when I saw Jerry for the first time – an occasion I’ll discuss later. It was the 20-year anniversary to our partnership in education and scientific initiatives. 2018 also marked the 15-year anniversary of the founding of The World Congress on Insulin Resistance Diabetes and Cardiovascular Disease (WCIRDC).

The 16th WCIRDC, 29 November–1 December 2018, was dedicated to honour and celebrate Jerry’s science and life. There was a special session ‘The Metabolic Syndrome Revisited: A Salute to Gerald Reaven, MD’ chaired by Ralph DeFronzo and Peter Grant and included a presentation by Peter Reaven, an endocrinologist – Jerry’s son, as well as lectures by Jerry’s colleges, corroborators and past fellows and the renamed award and keynote lecture: ‘Gerald Reaven Distinguished Leader in Insulin Resistance’.

The beginning

Jerry was born in Gary, IN, USA, grew up in Cleveland, OH, USA, where he developed his love for baseball. He attended the University of Chicago as an undergraduate and for medical school. After serving in the US Army Medical Corps in Europe, he completed his internal medicine residency at the University of Michigan in Ann Arbor. He joined the Stanford School of Medicine faculty in 1960, in the endocrinology division. He progressed to a full professorship in 1970. Jerry led endocrinology and gerontology eventually, after semi-retirement, he joined the cardiovascular division. Jerry was captivated by the findings of Himsworth, in the mid 1930s, that a large number of patients with diabetes are ‘insulin insensitive’, ¹ a finding that went dormant for many years. In 1970, Reaven argued for the existence of insulin resistance (IR), a diminished response to the hormone insulin, in people with type 2 diabetes mellitus (DM). At that time, a controversial concept was met with huge opposition. Jerry demonstrated, by a quantitative method to measure insulin-mediated glucose uptake in humans, that there are variable degrees of IR in healthy population and those with type 2 diabetes (T2D). In 1984, the National Diabetes Data Group endorsed the concept and referred to T2D as non-insulin-dependent diabetes mellitus (NIDDM) and that resistance to insulin-stimulated glucose uptake is a characteristic finding in patients with NIDDM and impaired glucose tolerance. Jerry did not stop there; he went further to show how IR and hyperinsulinaemia have a role in cardiovascular disease (CVD) in people who do not have diabetes.

When we met

I recently re-read the 1988 publication of Jerry’s Banting Lecture 1988: Role of Insulin Resistance in Human Disease. ² I was amazed at his vision and foresight. In today’s medical literature, where 3 years is already old news, this 30-year-old paper represents science which is as fresh and relevant today. In his lecture, Jerry introduced the novel idea of a link between IR and a cluster of metabolic abnormalities that together greatly increased the risk for CVD. He concluded that there is a series of related variables – which he named syndrome X – that tends to occur in the same individual and may be important in the aetiology of coronary artery disease (CAD). These changes included hyperglycaemia, hyperinsulinaemia (the corollary of IR), an increased triglyceride (TGL), a decreased high-density lipoprotein cholesterol (HDL-C) and high blood pressure. The common feature of the proposed syndrome is IR, and all other changes are secondary to it. All five of the proposed consequences have been shown to increase the risk of CAD.

I met Jerry at the Medical School of the University of Southern California where I was a first-year fellow in a unique diabetes-endocrinology programme. At our weekly endocrine fellows’ grand round, Jerry, following his 1988 Banting Award, lectured on the relationship of insulin to HTN. Like so many others, those days we just did not get it, we laughed. I actually thought that it was some kind of a hoax that he was just using his stature to lecture on issues regardless of how scientifically sound they were.

And yet, his lecture stuck with me. Couple of years later, when I was already in clinical practice, I started reading Jerry’s and others’ work on IR and suddenly everything clicked. I became a fan. In fact, I utilized the IR concepts – though primarily researched based, in my practice. As such, I was an early adopter of Metformin (introduced in the United States only in 1995) and thiazolidinediones (TZDs). Couple of years later, Jerry and I met at a small medical meeting in Palm Springs. Jerry was a speaker, and he came with his wife Eve. I was with my wife and our two small kids. Jerry had a name as a tyrant, a very hard person to work with, not pleasant to fellows, faculty and colleagues. People were fearful of him. I was not aware of any of it. I found his lecture to be great. At the end of the day, there was a group dinner. A whole ballroom for a mere 30 people or less. We were first with the kids; suddenly a woman comes down, she looked around, all the tables were empty and asked if she could join us. ‘Of course’. ‘I hope you won’t change your mind when my husband joins us’ – surely Eve was aware of Jerry’s reputation. When Jerry came, he and I went for a drink, turns out we both liked gin martini with olives – a good way to start a relationship with Jerry. Over drinks, I told him of what I had thought of him, and his work, when I heard him first. He laughed, and we became friends.

Developing education and initiatives

We shared similar views on the role of IR, Jerry as a researcher and I as a clinician. We named our first education meeting in 1998 ‘Syndrome X, Diabetes and beyond’ with a focus on CVD. In the following years, we kept searching our goals based on published data and ‘popular’ directions. In 1999, we called the meeting ‘Syndrome X, Diabetes, Obesity & The Heart’; in 2000, we added HTN to the name. In 2001, we changed to ‘The Metabolic- Insulin Resistance- Syndrome X’. At that time, the NCEP/ATPIII published their definition of the metabolic syndrome. In fact, following Jerry’s 1988 syndrome X, the World health Organization (WHO) published in 1998 their version of the syndrome which they already called metabolic syndrome, followed by the EGIR: European Group for Insulin Resistance that also used the name metabolic syndrome with similar definition. The AACE/ACE (American Association of Clinical Endocrinologists/American College of Endocrinology) convened a consensus to address syndrome X versus metabolic syndrome. I recruited Jerry to join ACCE and be a co-chair with Dan Einhorn and myself. The AACE/ACE elected to call it the insulin resistance syndrome (IRS) over the metabolic syndrome. ³ Although we recognized the clinical utility of metabolic syndrome, with criteria similar to the Metabolic Syndrome, to identify people at risk for Diabetes and CVD, we preferred the IRS not just because it presents the pathophysiologic role of IR, but, more importantly, it extends its clinical impact to many other conditions beyond DM and CVD.

The IRS

IR and hyperinsulinaemia presentations is often determined by the difference in resistance of various tissues and organs. Many, if not most, of the adverse events attributed to IR are secondary to the effects of compensatory hyperinsulinaemia (an attempt at preventing the decompensation of glucose homeostasis) on tissues that still have normal insulin sensitivity. Compensatory hyperinsulinaemia acts on the kidney to retain salt and water, which may explain the development of essential hypertension, and it decreases uric acid clearance by the kidneys, increases sympathetic nervous system activity and increases prevalence of certain cancers. It also impacts the ovaries where insulin stimulates testosterone secretion, as well as affecting other glands including the thyroid. Following Jerry’s research, he proved Himsworth’s concept that IR is part of the pathophysiology of T2DM. Jerry than extended the concept to syndrome X – linking IR to CVD, eventually demonstrating that the IRS leads to many other associated conditions: hypertension, coronary artery disease, polycystic ovarian syndrome (PCOS), non-alcoholic liver disease (NAFLD), certain forms of cancer and obstructive sleep apnoea, congestive heart failure and cognition. ⁴

Jerry was often misunderstood. Although he recognized the impact of obesity on IR, he also differentiated obesity from IR, specifically highlighting the risk of IR in normal-weight patients. He recognized the importance of the metabolic syndrome although he preferred the more inclusive IRS. He, and I and AACE included hyperglycaemia, but not diabetes as part of the syndrome. We believed that once diabetes develops, we have approved medications and guidelines to manage the condition, while there are currently no approved medications for the IRS. Our concern was to be able to identify them early, intervene and prevent the development of DM and CVD. However, because of Jerry’s combative – debate like – preaching of his concepts, he was wrongly accused for discounting obesity and metabolic syndrome. The criticism did not sway him, and he has always fought for his – pure – science and data-based principles. ⁵

The world congress of IR diabetes and CVD

In 2003, we agreed that we should elevate our education efforts. There was a great need to understand the many faces of IR. To both myself, a community physician, and Jerry, from academia, there was a need to extend the impact of IR from the research arena to clinical practice. To be able to cover all the fields which relate to IR, we founded the International Committee for Insulin Resistance (ICIR) with experts in diabetes, cardiology, obesity, lipids, cancer, PCOS, liver, paediatrics as well as researchers and clinicians. At Jerry’s suggestion, we started an abstract programme, initially with the journal Diabetes and Vascular Disease Research, followed by Endocrine Practice. Jerry provided vision and leadership, teaching me the unwavering search for truth, to be scientifically honest and follow the data. The World Congress on Insulin Resistance Syndrome DM & CVD has become the main stage where globally recognized scientists and clinicians present and share their knowledge. As the congress progressed, its strength became from its fabulous international faculty. A lot of this success was due to following Jerry’s principle ‘if the speaker does not have anything of value to say- why should he or she say it here?’ Scientifically, the congress developed from a mere ‘Getting to the Heart of the Matter’ to ‘Exploring New Frontiers in Metabolism- Tomorrow’s Clinical Science Today’.

Friendship

Jerry proved to be a renaissance man, knowledgeable, witty and with an exquisite taste in food, drinks, music and life. He had the reputation of being rough and unkind, and though he could be difficult and demanding at times, I actually found him to be warm, generous, social and helpful. His intelligence and analytical mind contributed greatly to the many conversations we had. We typically met several times a year. Two of these yearly meetings became a tradition. I would fly to San Francisco and Jerry would pick me up at the airport. His car was the only car one could buy which was all ‘no power’: stick shift, no automatic windows, no power breaks nor steering, a regular lock and obviously no navigation. Generally, he left his cell phone at home. We would drive around till we found a decent looking fast food place. We would sit for about 5 h on coffee and food. Jerry had an incredible knowledge of the literature while I updated him on leadership changes within medical societies and academia. At the end of the meeting, we would create the framework for the next congress. The second meeting was the evening before the World Congress. We met over a couple of gin martinis updating each other in a more relaxing social atmosphere getting ready for the conference. Jerry was most happy when Eve joined him. Eve was a scientist with specialty in electronic microscopy, who turned an artist. She created beautiful ties and scarfs from photos she took with the electronic microscope. Jerry often negotiated for her to get a booth in large meetings, where he was lecturing, allowing her to sell her art. At times, he would replace her and himself sell the ties and scarfs. My wife Nava is a painter artist herself, and we added another dimension to the congress, an art and science exhibition displaying both Nava and Eve’s work.

Jerry Reaven is one of America’s Scientific Giants, I was fortunate to be associated with him for 20 years, learn from him, adopt him as my mentor and had the privilege to call him my friend or in Jerry’s language ‘buddy’.