Hormones, the Pancreas and Obesity

November 2010
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The path to an anti-obesity drug may be through the stomach. By focusing on hormones in the gut, veteran researcher Laurence Miller, M.D., and colleagues hope to find new treatments for pancreas and digestive problems — and perhaps obesity itself.

Dr. Miller working.

Laurence Miller, M.D.

The next time your restaurant server poses the annoying question, "Are you still working on your meal?" you will know to thank your gut hormones for your answer. Gastroenterologist and physician-researcher Laurence Miller, M.D., is an expert in this area, his particular expertise is pancreatic disease.

In a typical week, Dr. Miller frequently shifts his attention from the immediate needs of his patients to a fascinating submicroscopic and molecular research world. For 30 years the National Institutes of Health has funded Dr. Miller's research. His lab probes the secrets of what happens when you eat — specifically, how hormones released when you eat a meal can transmit signals to control the process of digestion, primarily by regulating pancreatic secretion.

Building compounds with broad application

Digestion 101

The pancreas is an unobtrusive, yellowish, glandular organ, about 7 inches long. It lies deep in the abdomen, hidden behind the stomach and upper intestine and serves a pivotal role in digesting food.

As food moves through the intestine, the pancreas secretes enzymes that break down complex nutrients into small absorbable pieces (glucose, fatty acids and amino acids) that can move across the intestinal wall and into the bloodstream where they provide nourishment. All this is carefully orchestrated and coordinated by a variety of gastrointestinal hormones that are secreted by single cells scattered throughout the gastrointestinal tract. These hormones are responsible for moving the meal and its components through the gut at an optimal rate to allow digestion and absorption, while minimizing symptoms such as painful distension, gas, or diarrhea.

Diseases of the pancreas are often seriously debilitating, causing diabetes, malabsorption, weight loss, diarrhea and, especially in patients with pancreatic cancer, severe abdominal pain.

Delia I. Pinon.

Delia Pinon, an expert in peptide chemistry and photochemistry, synthesizes a receptor probe to explore molecular activity of cholecystokinin.

Dr. Miller has focused much of his research on the hormone cholecystokinin (CCK). CCK is released into the bloodstream after eating a meal by endocrine cells located in the intestine.

"We're trying to come up with more selective, more potent, more active drugs that can meet needs that aren't met today," Dr. Miller says. "One of our major efforts is in the CCK receptor field. That receptor today is very important as a potential target for the management of obesity."

The CCK receptor is a protein that resides within the surface membrane of distinct cell types in the body. When CCK in the bloodstream binds to its receptor on a target cell, a signal is transmitted to the interior of that cell. Depending on which cells are receiving the CCK signal, the result can be either that digestive enzymes are delivered into the intestine, the gallbladder empties and food is shuttled faster through the intestine, or the person stops eating because they feel full.

Dr. Miller has established a variety of photochemical and fluorescence approaches, where light signals are emitted and measured with very high precision each time a CCK molecule docks to its receptor. The emitted light signals are then interpreted using complex computer programs that have allowed Dr. Miller to gain extraordinary molecular insights into the structure of the CCK receptor and the molecular basis of its interactions with CCK. These insights have contributed to the development and refinement of new drugs targeting this receptor.

As might be expected, Dr. Miller has a very well established network of prominent scientific collaborators, a group that includes Ruben Abagyan, Ph.D., from the University of California San Diego, and Arthur Christopoulos, Ph.D., and Patrick Sexton, Ph.D., both from Monash University in Australia. This multi-institutional team of scientists shares an interest in the CCK receptor as well as other members of the same receptor family, known as G protein-coupled receptors (GPCRs). And the pharmaceutical industry loves this area of research. Why? Because GPCRs have proven time and time again to be wonderful drug targets.

The fact that research of other GPCRs has led to the discovery of many blockbuster drugs is a huge motivator for Dr. Miller. His goal is to develop compounds that can mimic or interfere with the actions of these hormones. His expertise leads him to believe that such compounds will provide the framework and rationale for drug development, not just for the treatment of pancreatic disease, but also for the treatment of gastrointestinal motility and metabolic disorders. In addition, because of the CCK's role in the feeling of fullness, the group is very excited about their potential for controlling obesity — currently a super sized public health issue facing modern America.

As he says, "We want to provide a more individualized approach to maintenance and treatment than we've ever had before."

Energetic leadership

Dr. Kaleeckal G. Harikumar.

Kaleeckal Harikumar, Ph.D., uses fluorescence microscopy to evaluate the lipid composition of the cell membrane and its influence on receptor function.

Because of his conviction of the enormous health benefits that can come from the detailed study of hormones and their receptors, Dr. Miller has built one of the most advanced research programs in the world focusing intensively on the molecular basis of their interactions.

Given the central role of the pancreas in medicine, physiology and biomedical discovery, it is hardly surprising that Dr. Miller has been at the heart of some of the major collaborative initiatives undertaken in recent years at Mayo Clinic. For example, in 1998 he spearheaded the effort to recruit Stephen Russell, M.D., Ph.D., to develop and lead the highly successful Molecular Medicine Program. In 2001, he helped initiate a pancreatic cancer SPORE (Specialized Program of Research Excellence), which became the first major collective grant in pancreatic cancer research to be awarded to Mayo Clinic. Gloria Petersen, Ph.D., now directs it. Her own project studies the molecular epidemiology of pancreatic cancer to identify genetic risk and gene-environment interactions. Dr. Petersen is a member of leadership teams of the NCI-based PanScan studies, and the Pancreatic Cancer Case-Control Consortium (PANC4).

In 2002, Dr, Miller took on the dual research leadership positions of Deputy Director of the Cancer Center, and Research Dean for Mayo Clinic in Arizona, where he was tasked to build the biomedical research effort. These appointments, together with his research achievements during the subsequent eight years bear witness to his extraordinary ability to grow the research enterprise, attracting and recruiting outstanding faculty while expanding facilities and infrastructure, and orchestrating their integration into a comprehensive research program spanning the three Mayo Clinic Campuses in Rochester, Arizona and Florida.

Energy and enthusiasm may be the key qualities underpinning Dr. Miller's remarkable contributions as a leader and builder of new research initiatives. Five minutes with him and it is impossible to imagine that he will ever lose his irrepressible enthusiasm for science and medicine. It is not surprising, then, that having recently stepped down from his demanding role as Research Dean at Mayo Clinic in Arizona, he is already deeply embroiled in the next big initiative — an extraordinarily ambitious statewide health program in collaboration with Lawrence Mandarino, Ph.D., an endocrinology researcher with duel appointments at Mayo Clinic in Arizona and Arizona State University. Dr. Mandarino directs the ASU/Mayo Center for Metabolic and Vascular Biology. The mega-collaboration between the two centers is focused on the metabolic syndrome; a combination of obesity, heart disease and diabetes that is fast becoming one of the most pressing health issues of our time. Watch this space!