George Grunberger, M.D., Named Director of CMMG

The CMMG was established in 1994 within the School of Medicine to serve as the catalyst for basic scientists and clinical investigators as they collaborate to unravel the molecular and genetic basis of human disease. The CMMG emerged from the integration of the Department of Molecular Biology and Genetics and the Center for Molecular Biology. Dr. Grunberger's insight as a basic scientist and as a clinician together with his vast administrative expertise makes him exceptionally qualified to lead the CMMG on its mission. He sees the CMMG as the pivotal force generating enthusiasm and expertise in genetics as both a basic science and a clinical specialty.

Dr. Grunberger attended medical school at the New York University School of Medicine and completed a residency in internal medicine at Case Western Reserve University. Upon completing his residency, Dr. Grunberger sought to study an area of medicine in which there were still many mysteries and unanswered questions. He turned to the field of endocrinology to tackle the question of how insulin works.

"Dr. Grunberger was recruited to establish and direct the Diabetes Program at Wayne State University/Detroit Medical Center."

In 1980, he joined the Diabetes Branch of the National Institutes of Arthritis, Diabetes, Digestive, and Kidney Diseases at the National Institutes of Health where he completed a fellowship in endocrinology and metabolism in 1983. After completing his fellowship, Dr. Grunberger continued to work at the NIH where he was the first to describe an actual biochemical defect in the insulin receptors of an insulin-resistant patient with normal insulin binding but deficient protein tyrosine kinase activity. This report was published in Science in March, 1984.

In 1986, Dr. Grunberger was recruited to establish and direct the Diabetes Program at Wayne State University/Detroit Medical Center. Because of his motivation to take care of patients and pursue a basic science component in his career, he was jointly appointed in the Department of Internal Medicine and the Department of Molecular Biology and Genetics. The Department of Molecular Biology and Genetics had just been founded prior to Dr. Grunberger's arrival at WSU and he was only the third faculty member to be recruited into this department. Today the CMMG has over 60 faculty members. Dr. Grunberger has had the opportunity to witness the evolution of genetics as a major emphasis within the School of Medicine at WSU.

For the past 11 years Dr. Grunberger has functioned as Director of the Diabetes Program where he continues to be intimately involved in patient care. His dedication to patient care is evident from his article published in Diabetes Care in March, 1997. He and his colleagues were able to demonstrate in a controlled study it is safe and convenient for patients to inject insulin directly through their clothing. This finding certainly has made life just a little easier for people who have diabetes. In 1995 Dr. Grunberger was awarded the Outstanding Leadership Award by the American Diabetes Association. This year he was named President of the Michigan Affiliate of the American Diabetes Association.

Dr. Grunberger continues to support two active diabetes research groups-basic research laboratories at the Elliman Building and the Clinical Diabetes Research Center at the Harper Professional Office Building. He currently has $1.5 million in grant support. He also is committed to teaching and is involved in graduate and medical student education as well as mentoring medical residents and endocrinology fellows. One of his graduate students successfully defended her Ph.D. thesis last year and another will hopefully finish her Ph.D. program in his laboratory next year. As he has done over the past 10 years, Dr. Grunberger is again directing the CMMG graduate course on molecular biology of cellular signaling.

Dr. Grunberger is certainly well-known to the CMMG and we welcome him as our new leader. Everyone in the School of Medicine is sure to continue to benefit from his enthusiasm, expertise, and wisdom.

The speakers:

Rintaro Nakaya, M.D., Dr. Med. Sci., Professor emeritus, Tokyo Medical and Dental University: "Etiological agents of infectious enteritis in Japan and their antibiotic resistance."

Yoshiro Terawaki, M.D., Professor, Department of Bacteriology, Shinshu University School of Medicine, Matsumoto, Japan: "Analysis of functional domains of replication initiator protein RepA of plasmid Rts1 by means of hybrid proteins with phage P1 RepA."

Bernard Weisblum, M.D., Professor, Department of Pharmacology, University of Wisconsin Medical School, Madison: "New insights into macrolide antibiotic action from studies of their ability to induce resistance."

Stanley N. Cohen, M.D., K.-T. Li Professor of Genetics and Professor of Medicine, Stanford University School of Medicine: "New ways of searching for tumor suppressor genes."

Simon Silver, Ph.D., Professor, Department Microbiology & Immunology, University of Illinois College of Medicine: "Mechanisms of bacterial toxic metal resistances: Lessons for genomics."

Sydney Brenner, Ph.D., President and Director of Science, The Molecular Sciences Institute, Inc., La Jolla: "Fishing for genes."

Vainutis Vaitkevicius, M.D., Professor, WSU and Karmanos Cancer Institute: "Molecular markers of pancreatic carcinoma and their clinical correlations."

Harvey Pass, M.D., Professor, WSU and Karmanos Cancer Institute: "Molecular biology and related carcinogenesis of malignant pleural mesothelioma."

Harumi Kasamatsu, Ph.D., Professor, Molecular, Cell and Developmental Biology, University of California, Los Angeles: "Nuclear entry of a DNA tumor virus."

Lawrence G. Lum, M.D., Scientific Director, Immunotherapy Research and Therapy Institute, St. Luke's Medical Center, Milwaukee: "Immunotherapy on the road to gene therapy."

Katrina T. Trevor, Ph.D., Principal Investigator, Lombardi Gene Therapy Laboratory, Immunotherapy Research and Therapy Institute, St. Luke's Medical Center, Milwaukee: "Gene modification of T cells for cancer immunotherapy."

John Zaia, M.D., Professor, Department of Pediatrics, City of Hope National Medical Center, Duarte: "Gene therapy for AIDS-the problems and the possibilities."

R. Michael Blaese, M.D., Chief, Clinical Gene Therapy Branch , National Center for Human Genome Research, NIH: "Gene therapy: Early lessons and prospects for the future."

Type 1 diabetes is caused by an autoimmune destruction of the beta cells in the pancreas. The beta cells function to produce insulin, which is necessary for the proper metabolism of glucose. 60-85% of patients with type 1 diabetes have pancreatic islet cell antibodies, and 30-60% have antibodies to insulin before therapy is instituted. Prior to the disease onset, these antibodies can be noted. Patients typically are not obese and require insulin throughout their life. The incidence of this condition is about 10-20% in North America and Europe and accounts for 5-10% of all diabetic cases. The age of onset is usually before 30 years. Type 1 diabetes is less frequent among people of Asian or African-American descent.

"Diabetes mellitus is a heterogeneous group of disorders characterized by glucose intolerance."

The progression of this condition spans a period of years. In the beginning stage of type 1 diabetes, as few as 10% of the beta cells survive, while after several years, none remain. Therefore, if therapy is to be effective, it should be started prior to the onset of the acute diabetic syndrome.

There appears to be a genetic component to this condition. However, studies of monozygous twins have shown the concordance rate to be 30-50%, which indicates that other factors play a role in the development of type 1 diabetes. Empiric studies have shown the following recurrence risks: siblings of an affected individual, 5-10%, children of affected fathers, 4-6%, and children of affected mothers, 1-3%. It is believed that there are a number of genes involved in the development of this condition.

Although it is difficult to determine an exact number, there does appear to be reduced penetrance of the type 1 diabetic genotype. It has been estimated that approximately 1/3 of those with a genetic susceptibility will develop the disease. Therefore, what an individual inherits is a genetic susceptibility for type 1 diabetes.

One area that is associated and linked to type 1 diabetes is the HLA region on chromosome 6. An increased incidence of certain HLA haplotypes have been associated with type 1 diabetes. Caucasian type 1 diabetes patients have been found to have an increased frequency of the class II HLA antigens DR3 and/or DR4 (95% compared to 50% of non-diabetics). Interestingly, the relative risk is higher for those patients who have both DR3 and DR4 than for those who are homozygous for either DR3 or DR4. If a patient with type 1 diabetes has a sibling with a DR3 or a DR4, the sibling's risk for developing the disease increases (12-24%). Affected siblings share two HLA haplotypes about 55-60% of the time, which is increased above the expected 25%. However, it still remains unknown if the class II genes are the cause of the type 1 diabetes risk, or if the true genes have yet to be discovered.

"One area that is associated and linked to type 1 diabetes is the HLA region on chromosome 6."

A few other non-HLA regions are candidates for type 1 diabetes susceptibility. At least 10 loci have been identified as sites of possible type 1 diabetes genes. Their locations include chromosome 2q, 3q, 4q, 6, 11, 13q, 15q, and 18q. Once the responsible genes are identified and cloned, the roles of and the interactions between the loci will be better understood.

The genetics involved with this condition are complex and not well understood. Evidence has shown that some loci confer susceptibility or protection, while interactions between loci may also occur.

Type 2 diabetes usually appears in obese individuals over the age of 50. Patients can be successfully treated with dietary modification and/or oral drugs. Type 2 diabetes is not an autoimmune disorder and there is not an HLA association. Genetic factors play a strong role in the occurrence of type 2 diabetes, as concordance rates for identical twins exceed 90%. The recurrence risk for first degree relatives is 10-15% for clinical diabetes and 20-30% for impaired glucose tolerance

Although a few candidate genes have been identified for type 2 diabetes, none have been found to play a definitive role A small number of cases may be explained by mutations found in some of the candidate genes. A few loci that may play a role in type 2 diabetes have recently been identified.

There are two current theories regarding the etiology of type 2 diabetes. The initial event has been suggested to be primary insulin resistance of the peripheral tissues. Other studies have shown that insulin secretion abnormalities are the primary cause. It is quite possible that both factors play a role in this disorder.

A subset of type 2 diabetes, MODY (maturity onset diabetes of the young), can be inherited as an autosomal dominant trait. Mutations in the glucokinase (GCK) gene on chromosome 7p have been identified in approximately 60%? of French families. Glucokinase converts glucose to glucose-6-phosphate in the pancreas. Individuals with GCK mutations tend to have either a mild form of diabetes or impaired glucose tolerance and rarely require insulin. In other families, linkage has been found to chromosome 20q and 12q. Individuals with a disease that has been linked to one of these regions tend to have a more serious clinical course.

Congenital anomalies occur with a higher frequency in infants born to diabetic mothers. The risk of a birth defect in the general population is about 2-3%, while the risk to women with type 1 diabetes is 6-10%. There is also an increased risk for congenital malformations in women with type 2 diabetes, although it is lower than for women with type1diabetes. The risk is related to the degree of control throughout the pregnancy. Malformations involving the skeletal, renal, cardiovascular and central nervous system are the most common. Some of the higher risks include transposition of the great vessels (8%), and the caudal regression syndrome (16%).

A diabetes subtype, coined Maternally Inherited Diabetes and Deafness (MIDD), has been identified. Approximately 1-1.5% of diabetic cases in Japan and the Netherlands are due to this subtype. The diabetes associated with this condition can be either type1or type 2. The average age of onset of diabetes is 25-35 years. The hearing impairment, which often does not develop into deafness, usually precedes the onset of diabetes. Most individuals, regardless of the type of diabetes, were not obese.

Analysis of pedigrees with the triad of diabetes, maternal inheritance and impaired hearing found a distinct mutation in the mitochondrial DNA that has been associated with this disease. The responsible mutation, located at position 3243, is a G à A substitution in one of the two genes for the transfer RNA for leucine (tRNA-Leu, UUR)). Although a few point mutations have been found in certain individuals, none have been identified in multiple pedigrees. The finding of the mitochondrial mutation demonstrates the importance of mitochondria in maintaining glucose homeostasis.

Long term complications of the disease can include retinopathy, nephropathy and neuropathy. An increase in atherosclerotic disease of large vessels, including cerebral cardiac and peripheral vascular disease, is also seen.

This year's event was considered a big success and attracted some of Michigan's most prestigious car collectors. Seventy-two cars with values up to $250,000 were on display next to Hutzel Hospital. There were 10 different classes of cars ranging from antique/vintage cars to muscle and modified cars.

Throughout the day there was an ongoing program that included celebrities such as WOMC radio announcer, Mark "Doc" Andrews and "Top Hat John" Jendza III, host of Motor City Wheels on Comcast Cablevision. Red Wing alumni Gary Bergman and Bob Evo signed autographs and chatted with the crowd. Lila Orbach-Lazarus, medical reporter and news anchor from WDIV, Channel 4 participated in the award presentations. The highlight of the day, however, was the presence of several healthy children who are alive today because of the efforts of the members of the DMC's Center for Fetal Diagnosis and Therapy.

This year the show again exceeded its goal and raised more than $50,000 which is expected to support the visits of approximately 25 families to Detroit. This will eliminate the biggest obstacle for families who need to drop everything and come to Detroit for prenatal evaluation and possible surgical treatment. Anyone wishing to contribute to this program or volunteer to help with next year's show can contact the WSU School of Medicine Development Office at 313-577-1495. Congratulations Dr. Johnson on another successful show!

The CMMG is also pleased to announce that the following faculty members have recently been appointed to adjunct or associate positions in the CMMG: Joseph D. Artiss, M.D. (pathology), Donald J. DeGracia, Ph.D. (emergency medicine), Felix Fernandez-Madrid, M.D. (internal medicine), Ahmad R. Heydari, Ph.D. (nutrition and food science), Gregory P. Kalemkerian, M.D. (internal medicine), Gary S. Kraus, M.D. (emergency medicine), Jack Lilien, Ph.D. (biological sciences), Adhip N. Majumdar, Ph.D. (internal medicine, biochemistry), Robert W. Neumar, M.D., Ph.D. (emergency medicine), Brian J. O''Neil, M.D. (emergency medicine), Heimo Riedel, Ph.D. (biological sciences), Rick J. Schiebinger, M.D. (internal medicine), Bonnie F. Sloane, Ph.D. (pharmacology), P. R. Srinivas, Ph.D. (internal medicine), Wei-Zen Wei, Ph.D. (Karmanos Cancer Institute), and Blain C. White, M.D. (emergency medicine).

Faculty interested in a CMMG appointment should send an application letter and curriculum vitae to the director at 3216 Scott Hall (telephone 313-577-5323).