Daniel Porte Jr., 13 August 1931–13 May 2023

Introduction

Few scientists can lay claim to a string of discoveries that fundamentally changed how we view a common disease process. Fewer still are also phenomenal mentors. Yet both are the legacy of Daniel Porte Jr., who on 13 May 2023 died peacefully at the age of 91.

As Dan’s scientific achievements were reviewed in detail in recent publications in both Diabetes Care and Diabetologia (1,2), we have opted in this remembrance to highlight those qualities that distinguished him as a scientist, a mentor, and a person. Our hope is that this glimpse into the making of an exceptional leader of our field will offer a road map for others, and for younger readers in particular. For those interested in learning more about Dan’s remarkable contributions to the field of diabetes over a four-decade span, his scientific achievements are summarized in Table 1.

Table 1.

Summary of Scientific Achievements of Daniel Porte, Jr.

Area of interest	Implications
Physiology and pathophysiology of islet function
Adrenergic regulation/stress hyperglycemia	1. Catecholamines cause sustained hyperglycemia in humans by inhibiting basal and glucose-stimulated insulin secretion (6–8) 2. Catecholamines may contribute to the impairment of insulin secretion in type 2 diabetes (9) 3. Direct neural stimulation influences the secretion of islet hormones (10,11) 4. Impaired insulin secretion contributes to the hyperglycemia induced by stresses in humans (12–16)
Obesity and aging	1. Body fat influences basal and stimulated insulin secretion (17–19) 2. Obesity-related insulin resistance enhances islet sensitivity to glucose (20) 3. High-fat diet–induced obesity in dogs leads to impaired islet function (21) 4. Impaired islet adaptation to insulin resistance contributes to glucose intolerance in aging humans (22–24)
Type 2 diabetes	1. Complete loss of the acute insulin secretory response to glucose is a fundamental characteristic of people with type 2 diabetes (25,26) 2. Acute insulin secretory responses to nonglucose secretagogues are variably reduced in type 2 diabetes, are maintained in part by hyperglycemia, and are modulated by sulfonylureas (27,28) 3. Type 2 diabetes is characterized by diminished β-cell secretory capacity (29) 4. β-cell dysfunction is present in individuals at increased risk of developing type 2 diabetes (30,31)
Multiphasic responses to glucose, nonglucose secretagogues and glucose potentiation	1. Insulin secretory responses to glucose in humans are multiphasic, mimicking in vitro islet studies (32,33) 2. Voltage and ATP dependency of glucose-stimulated potassium channels in islets (5,34–35) 3. Secretin, arginine, and β-adrenergic agonists stimulate acute insulin secretion in humans (27,36,37) 4. Increasing glucose levels in vivo potentiate insulin responses to nonglucose secretagogues, mimicking in vitro islet studies; increased insulin secretion is a physiological adaptation to both insulin resistance and prolonged glucose infusion (28,38,39) 5. Glucose levels and epinephrine interact to modulate insulin and glucagon secretion in human (40,41)
Islet and peripheral adaptations to insulin resistance	1. Islet sensitivity to glucose is increased in drug-induced insulin resistance in humans (42) 2. The relationship between insulin sensitivity and insulin secretion in humans is hyperbolic (43) 3. Glucose effectiveness is a major determinant of glucose tolerance in humans (44,45) 4. Distinguishing impact of insulin-dependent and insulin-independent glucose disposal in humans (44,45)
Proinsulin/IAPP	1. Proinsulin processing is impaired in type 2 diabetes (46–49) 2. IAPP is a normal β-cell secretory product (50)
Central regulation of energy balance
Insulin	1. Administering insulin directly into the brain influences pancreatic insulin secretion, indicating that pancreatic β-cells are under the influence of insulin-sensitive cells in the CNS (51,52) 2. Vagal input from the brain stimulates insulin secretion (53–55) 3. Insulin and insulin receptors are located in brain areas influencing metabolism and pancreatic insulin secretion (56–58) 4. Administering insulin directly into the brain lowers food intake and body weight, consistent with the hypothesis that insulin functions as an “adiposity negative feedback” signal to inform the brain regarding the status of body fat stores (59,60) 5. Evidence that plasma insulin enters CSF suggests the existence of a feedback loop between the CNS and insulin secretion (61,62) 6. Entry of insulin from plasma to CSF can be quantified in a dog model and is saturable: evidence of an insulin receptor–mediated regulated transport system into brain interstitial fluid (63–66) 7. Insulin inhibits hypothalamic Npy gene expression, a potential mechanism to explain how insulin action in the brain reduces food intake (62,67–69)
Leptin	1. Leptin both reduces food intake and inhibits Npy gene expression in ob/ob mice but not in db/db mice, identifying hypothalamic NPY-containing neurons (later shown to also express AgRP) as key brain targets for leptin and showing that inhibition of these neurons requires a functional leptin receptor (70)
Discovery of hypothalamic Agouti-related protein (AgRP) neurons	1. First identification of AgRP neurons, a major neuronal target for the actions of both leptin and insulin (71)
A feasible and testable model for how energy homeostasis works	1. A pioneering review on a complex physiological process (cited >7,600 times) (72)
Regulation of basal and postprandial glucose homeostasis	1. The effect of glucose itself to enhance glucose uptake is impaired in type 2 diabetes (73,74) 2. Published at the time of his passing, this perspectives article provides evidence that basal and postprandial glucose are regulated via distinct mechanisms (75)
Diabetic neuropathy
Metabolic effects on peripheral nerve function	1. Hyperglycemia affects nerve conduction in type 2 diabetes (76–78) 2. Proof of concept clinical trial showing improved nerve function with metabolic intervention in type 2 diabetes (79)
Quantitative measurements of autonomic neuropathy	1. Abnormal cardiac and iris regulation are present in type 2 diabetes and correlate with abnormal peripheral nerve function (80–83)

CNS, central nervous system; CSF, cerebrospinal fluid.

A Unique Combination of Attributes

Perhaps Dan’s most distinctive quality was that he was always asking questions. He had an insatiable curiosity about physiology and pathophysiology and was continuously assembling a “big picture” understanding from the sea of information available to him. There were never too many questions for Dan to ponder, and as the answers came, he would fit them together like some kind of jigsaw puzzle master. He also realized that answering one question invariably led to others, and he was not bound to a particular scientific approach. While much of his work could be described as “bench-to-bedside” translation of basic science to clinical research, things were just as likely to move in the opposite direction, i.e., a clinical observation leading to a hypothesis that was tested at the bench. To Dan, asking the right question is what mattered most, and he was open to any approach with the potential to answer it.

Dan was also skeptical but not closed-minded. He was always open to new ideas but had a knack for quickly gauging their merit, and he would not accept them until the evidence in favor was compelling. His trainees and colleagues knew that if you could convince him of the legitimacy of your ideas, you could convince anybody. And if you could convince him that they were worth testing, you were given the green light. And of course, there were the odd occasions when he was not completely convinced, but the green light was still available to generate the data needed to convince him.

Dan firmly embraced the philosophy that good ideas need to be supported. Once convinced of the merit of a scientific idea or research proposal, he would set about obtaining the necessary funds, believing deeply that for projects with merit that was plain for him to see, such funds should be committed. Dan’s grantsmanship was reflective of this commitment—his philosophy was that once he was certain that a project was meritorious, it was simply a matter of “bringing the reviewer around” to his perspective, understanding that this might take some time.

Another of Dan’s unique qualities was that once convinced of the legitimacy and importance of a set of findings or ideas, his confidence was unassailable—When you’re right, you’re right! He understood that there will always be doubters, as there should be, but this did not trouble him in the least. He had absolute certainty that, given time, the world will eventually come around to his way of seeing things. Indeed, there are many examples of Dan’s work and ideas that were met initially with skepticism but were ultimately validated and are now part of our textbook understanding.

Dan also had a long career as a physician at the Veterans Affairs Medical Center in Seattle and later in San Diego. When it came to his clinical duties, Dan was committed to both patient care and science in medicine. In addition to ensuring that the best possible decisions were made for each of his patients, Dan’s compulsion to understand mechanistic underpinnings of disease processes was of enormous value in teaching. In this way, his approach in the clinic—both in patient care decisions and in clinical teaching—was predicated on understanding how the underlying disease process works. His clinical trainees learned that therapeutic decision-making should be informed by understanding the relationship between a patient’s clinical presentation and the underlying cellular, molecular, and physiological processes that have gone awry.

Unwavering Commitment to Scientific Advancement Ahead of Other Considerations

Dan seamlessly married each of the qualities above with an unwavering commitment to scientific advancement, ahead of other considerations. To better understand this philosophy, we provide five specific examples:

1. Dan never hesitated to share new information, technology, or resources with colleagues and the world. His feeling was that the desire for ownership of one’s discoveries cannot be allowed to interfere with the goal of advancing science.

2. Dan had a remarkable ability to identify and support worthy new ideas outside of his area of expertise. Examples include mathematical modeling of physiological processes (e.g., two-pool compartment modeling of insulin secretion, Bergman minimal model method) (3) and investigation into specific diabetes complications, e.g., diabetic neuropathy (4). Despite having no specific prior expertise in these areas, Dan’s work with others enabled important breakthroughs that remain highly relevant today. A useful illustration of this point relates to the discovery of the crucial role played by K_ATP channels in glucose-induced insulin secretion by pancreatic β-cells. This landmark finding was published in Nature in 1984 by Daniel Cook and Nick Hales (5). A few years earlier, Daniel Cook had been recruited to Seattle to join the Porte group. Although Dan was not listed as a coauthor on the 1984 Nature article, Dan’s mentorship, support, and guidance were essential to the success of this project.

3. Dan was his own toughest scientific critic, and he taught his trainees to be the same. His approach was to identify any flaws in a study design or outcomes before the work was published rather than leaving it to others to find them. Typically, this meant that a new observation would be thoroughly replicated and/or confirmed with use of an alternative method before it was submitted for publication.

4. Dan encouraged younger scientists to “find their lane.” While being enthusiastic in his support for productive collaborations and a team approach, he recognized the importance of creating opportunities for independence for junior investigators working within a larger collaborative group such as his own. He also had a unique ability to advance research progress and academic career development in disciplines distinct from his own. He frequently assisted others in their pursuit of research ideas and directions (such as diabetic neuropathy) that he was not directly involved in. His success in this area stemmed from his unwavering commitment to scientific advancement, his desire to see others succeed, and his deep understanding of “how to make it in science”—his mastery of how to navigate the many challenges inherent in academic success was unparalleled.

5. Dan always felt that a negative outcome could be just as or even more important than a positive one. Inherent in Dan’s drive to answer questions and piece together the “big picture” was the conviction of the importance of research that, while being guided by a set of hypotheses, was not invested in a particular outcome; the answer is the answer, you need to accept it, incorporate it into the big picture, and move on appropriately.

Unwavering Commitment to Others

One of Dan’s most distinctive qualities was that his commitment to science was balanced with an equally strong commitment to the success and well-being of his colleagues and trainees. He was self-contained without being self-possessed, which enabled him to see a situation through the eyes of others who were involved. These qualities are illustrated by his outstanding career as an administrator, woven seamlessly into his extraordinary scientific career. Dan served for over two decades as the associate chief of staff for research at the VA Puget Sound Health Care System, during which time he also directed the National Institutes of Health–funded Diabetes Research Center at the University of Washington. Perhaps most impressive is that he remains one of only two individuals in the 80-plus year history of the American Diabetes Association to have served as its president while also receiving the organization’s highest recognition for both mentorship (Albert Renold Award, 1995) and scientific achievement (Outstanding Scientific Achievement Award, 1970, and Banting Medal for Lifetime Scientific Achievement, 1990).

Concluding Remarks

By highlighting how a unique combination of attributes combined to create a unique scientific legacy, we hope that this tribute to Daniel Porte Jr. will enable others to find success in their journey. In addition to a series of fundamental discoveries, Dan was a uniquely empowering mentor whose legacy guides us still.

Funding Statement

This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health, grants DK101997 and DK083042 (to M.W.S.) and by the NIDDK-funded Diabetes Research Center (P30DK017047) and Nutrition Obesity Research Center (P30DK035816) at the University of Washington. S.E.K. was supported by the VA Puget Sound Health Care System and the Department of Veterans Affairs (I01 BX001060).