HHMI's Graeme Bell on the Molecular Genetics of Diabetes

Why are certain ethnic and racial groups more commonly afflicted with diabetes?

Bell: The eminent human geneticist James Neel of the University of Michigan proposed that genes that increase our risk of developing diabetes today conferred an advantage in the past. He suggested that under conditions of feast and famine--a situation presumably not uncommon throughout human history--people with the so-called thrifty gene were better able to store food as fat during the feast periods. Diabetes would only develop under the modern scenario of plentiful food supplies and low physical activity. The thrifty gene then became disadvantageous. If the thrifty genotype hypothesis is correct, it suggests that populations with a history of less-stable food supplies may have a higher risk of developing diabetes, and this may explain the increased prevalence of diabetes in certain ethnic and racial groups.

High Impact Papers from Graeme Bell
Published Since 1990
(Ranked by average citations per year)

Rank	Paper	Total citations	Average cites per year
1	G.I. Bell, et al., "Molecular biology of mammalian glucose transporters," Diabetes Care, 13(3):198-208, 1990.	497	62
2	Y. Yamada, et al., "Cloning and functional characterization of a family of human and mouse somatostatin receptors expressed in brain, gastrointestinal tract, and kidney," Proc. Natl. Acad. Sci. USA, 89(1):251-5, 1992.	371	62
3	K. Yasuda, et al., "Cloning and functional comparison of KAPPA-opioid and DELTA-opioid receptors from mouse brain," Proc. Natl. Acad. Sci. USA, 90(14):6736-40, 1993.	298	60
4	I.A. Drummond, et al., "Repression of the insulin-like growth factor II gene by the Wilms tumor suppressor WT1," Science, 257(5070):674-8, 1992.	267	45
5	G.I. Bell, T. Reisine, "Molecular biology of somatostatin recep- tors," Trends Neurosci., 16(1):34-8, 1993.	226	45
6	N. Vionnet, et al., "Nonsense mutation in the glucokinase gene causes early-onset non-insulin-dependent diabetes mellitus," Nature, 356(6371):721-2, 1992.	256	43
7	P. Froguel, et al., "Familial hyperglycemia due to mutations in glucokinase: Definition of a subtype of diabetes mellitus," New Engl. J. Med., 328(10):697-702, 1993.	207	41

SOURCE: ISI's Science Indicators Database, 1990-97

Clinical Studies

After locating a gene responsible for diabetes, how do you determine how mutations in the gene cause disease?

Bell: We can do this by carrying out clinical studies of patients with mutations in different diabetes genes. In the Clinical Research Center at the University of Chicago, we can measure the effect of the mutation on insulin secretion by the pancreatic b-cells, insulin action on muscle and fat tissue, and regulation of glucose metabolism by the liver. These clinical studies can indicate the primary tissue that is affected in patients with mutations in different diabetes genes, thereby forming the basis for more comprehensive studies in mouse models having mutations in the same diabetes genes.

Do you think that we are closer to understanding the genetics of one type of diabetes versus another?

Bell: I would say that of all the forms of diabetes, we now have the clearest understanding of MODY. We now know that mutations in five different genes can cause this form of diabetes. We can identify pre-diabetic individuals in MODY families by genetic testing and follow those patients for the first sign of diabetes. Prompt treatment can prevent the development of diabetic complications. We can now also begin to consider ways of preventing or delaying the onset of diabetes in these patients.

As for the other types of diabetes?

Bell: In the other types of diabetes, the genetics are much more difficult because we're looking at multiple genes that interact with one another and with unknown factors in the environment. Moreover, for both insulin-dependent and non-insulin-dependent forms of diabetes, we're going to be dealing with relatively common polymorphisms that have a subtle effect on the function of the gene or encoded protein rather than mutations as in MODY. Thus, identifying the susceptibility genes for the common for forms of diabetes and discovering which variation in these genes is relevant to the disease state is going to be very difficult.

Neurobiology Connection

Let's turn for a moment to your neurobiology research: How did neurobiology become part of your work, and how does it relate to your investigation of diabetes?

Bell: The insulin-secreting pancreatic b-cell is in many respects a hybrid between a liver cell and a neuron, showing many of the features of each. As we characterize the genes and proteins expressed in the b-cell, occasionally we find that some of the molecules that we have identified are relevant to neurobiology.
Our work on somatostatin and somatostatin receptors represents one such foray into neurobiology. Somatostatin inhibits insulin and growth hormone secretion and also affects the function of neurons in the brain. Our studies showed that there is a family of somatostatin receptors with different functional properties and distinct patterns of expression. This research on somatostatin receptors and our related work on opioid receptors opened up a whole field that others were better qualified to study than I was. So we came back to diabetes.