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PubMed1997

Merrill C. Sosman Lecture. Surviving managed care.

Managed care has arrived, especially on the West Coast. This tsunami is moving eastward at a rapid rate. Perhaps the experience with killer bees will be repeated with managed care, with decreased virulence as this wave moves across the country. Institutions would be wise to prepare for these changes with improved efficiency and cost-effectiveness. Radiologists are particularly at risk and need to aggressively adapt to managed care by becoming informed, developing a clear strategy for coping, and then executing their plan. Evolution will demonstrate once again the survival of the fittest.

California↗
PubMed1996

Lilly lecture 1995. Glucose transport: pivotal step in insulin action.

The effect of insulin to acutely stimulate glucose uptake into muscle and adipose tissue is essential for normal glucose homeostasis. The GLUT4 glucose transporter is a major mediator of this action, and insulin recruits GLUT4 from an intracellular pool to the plasma membrane. An important pathologic feature of obesity, NIDDM, and to a lesser extent IDDM is resistance to insulin-stimulated glucose uptake. Investigations of the mechanisms have revealed tissue-specific regulation of GLUT4 with decreased gene expression in adipose cells but not in skeletal muscle. This has led to the hypothesis that alterations in the trafficking of the GLUT4 vesicle or in the exposure or activation of the GLUT4 transporter may cause insulin resistance in skeletal muscle in obesity and diabetes. Exercise training increases GLUT4 expression in muscle in association with enhanced glucose tolerance in vivo. Transgenic mice have been created to investigate other approaches to improve insulin action on glucose transport. Overexpression of GLUT4 in adipocytes of transgenic mice increases the proportion of GLUT4 on the plasma membrane and enhances insulin sensitivity in vivo. Altering insulin signaling by overexpressing p21ras in adipocytes of transgenic mice results in increased GLUT4 on the plasma membrane in the absence of insulin and increases insulin sensitivity in vitro and in vivo. Thus, glucose transport is a pivotal step in whole-body insulin action. Strategies to increase the number of GLUT4 transporters that are functionally inserted in the plasma membrane in muscle and adipocytes may lead to new therapies to treat or prevent NIDDM.

Adipose Tissue↗
PubMed2002

While tinkering with the beta-cell...metabolic regulatory mechanisms and new therapeutic strategies: American Diabetes Association Lilly Lecture, 2001.

A common feature of the two major forms of human diabetes is the partial or complete loss of insulin secretion from beta-cells in the pancreatic islets of Langerhans. In this article, we review the development of a set of tools for studying beta-cell biology and their application to understanding of fuel-mediated insulin secretion and enhancement of beta-cell survival. Insights into these basic issues are likely to be useful for the design of new drug and cell-based diabetes therapies.

Animals↗
PubMed2004

Lilly lecture 2003: the struggle for mastery in insulin action: from triumvirate to republic.

Type 2 diabetes arises from a combination of impaired insulin action and defective pancreatic beta-cell function. Classically, the two abnormalities have been viewed as distinct yet mutually detrimental processes. The combination of impaired insulin-dependent glucose metabolism in skeletal muscle and impaired beta-cell function causes an increase of hepatic glucose production, leading to a constellation of tissue abnormalities that has been referred to as the diabetes "ruling triumvirate." Targeted mutagenesis in mice has led to a critical reappraisal of the integrated physiology of insulin action. These studies indicate that insulin resistance in skeletal muscle and adipose tissue does not necessarily lead to hyperglycemia, so long as insulin sensitivity in other tissues is preserved. Additional data suggest a direct role of insulin signaling in beta-cell function and regulation of beta-cell mass, thus raising the possibility that insulin resistance may be the overarching feature of diabetes in all target tissues. I propose that we replace the original picture of a ruling triumvirate with that of a squabbling republic in which every tissue contributes to the onset of the disease.

Animals↗
PubMed2001

From policemen to policies: what is the future for 2-h glucose? The Kelly West Lecture, 2000.

OBJECTIVE: To describe the characteristics and vital prognosis of men with diabetes diagnosed by one fasting plasma glucose (FPG) concentration > or =7.0 mmol/l, with diabetes diagnosed by one isolated postchallenge hyperglycemia (IPH) (FPG <7.0 mmol/l and a 2-h plasma glucose concentration > or =11.1 mmol/l), or with impaired glucose tolerance (IGT). RESEARCH DESIGN AND METHODS: This study involved a cohort of 6,881 Caucasian nondiabetic men from the Paris Prospective Study, aged 44-55 years, who were followed for cause of death for 20 years. RESULTS: Diabetes was diagnosed in 4.3% of the men (1.0% diabetes diagnosed by IPH), and IGT was diagnosed in 9% of the men. At baseline, the men with diabetes diagnosed by IPH had a lower cardiovascular risk profile than those with diabetes diagnosed by FPG, as did the men with IGT and a normal fasting glucose level (<6.1 mmol/l, IGT and normal fasting glucose), compared with men with impaired fasting glucose (6.1-6.9 mmol/l, IGT and impaired fasting glucose [IFG]). At 20 years of follow-up, all-cause and cancer death rates were higher in men with diabetes diagnosed by IPH than in men with diabetes diagnosed by FPG (55 vs. 44%, P < 0.1 and 31 vs. 17%, P < 0.01, respectively) but were not significantly different for coronary causes (6 vs. 11%). Men with IGT and normal fasting glucose also had significantly higher cancer death rates than men with IGT and IFG. CONCLUSIONS: The most likely explanation for the high cancer and low coronary death rates is that men with diabetes diagnosed by IPH consumed alcohol; the men in this study drank 49 g of pure alcohol on average per day, equivalent to 0.6 l of wine. If these results are confirmed by other prospective studies, screening subjects for isolated postchallenge hyperglycemia may not be worthwhile.

Adult↗
PubMed1997

The Eugene M. Landis Award Lecture 1996. Delivery of molecular and cellular medicine to solid tumors.

To reach cancer cells in a tumor, a blood-borne therapeutic molecule or cell must make its way into the blood vessels of the tumor and across the vessel wall into the interstitium and finally migrate through the interstitium. Unfortunately, tumors often develop in ways that hinder each of these steps. Our research goals are to analyze each of these steps experimentally and theoretically and then integrate the resulting information in a unified theoretical framework. This paradigm of analysis and synthesis has allowed us to obtain a better understanding of physiologic barriers in solid tumors and to develop novel strategies to exploit and/or to overcome these barriers for improved cancer detection and treatment.

Animals↗
PubMed2002

Tomorrow's challenges - today's realities making the leap, 2002 Ryley-Jeffs Memorial Lecture.

The premise of the presentation is a challenge to health care providers to examine the quality of services currently provided in health care facilities across the country. While the Canadian health care system is under scrutiny with numerous reviews and commissions, the underlying question is: are the structural changes making a difference? We need to consider the recommendations in the latest report from the Institute of Medicine, Crossing the Quality Chasm. The report calls for a sweeping redesign and suggests a set often new rules to guide patient/clinician relationships. Dietitians must take the lead on implementation of systematic changes, model the way and get involved in the necessary changes. As the report suggests, the gap between where we are and where we need to go in providing quality health care services is not just a crack, it is in fact a chasm.

Canada↗