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James H Warram, MD, ScD
Investigator
Joslin Diabetes Center
 
10/17/1977 -  
 
 Epidemiologic Methods

Epidemiologic methods are the most useful tools for studying the etiology of the late complications of diabetes such as kidney disease - a multistage disease process progressing from microalbuminuria to overt proteinuria and finally to end-stage renal failure. Based on his long term follow-up studies, conducted in collaboration with Drs. Krolewski and Laffel, Dr. Warram developed a model of the natural history of diabetic nephropathy that postulates the existence of different sets of environmental and genetic factors influencing the development of each stage of renal disease. For example, the onset of microalbuminuria is determined primarily by the level of glycemic control and cigarette smoking. The risk is very low if the glycohemoglobin is less than 8% and increases rapidly as the level of hemoglobin rises above 8%. In contrast, progression of microalbuminuria to overt proteinuria is strongly related to the serum triglyceride level independently of the level of glycemic control. Moreover, the dose response relationship with glycemic control is different. The risk of progression increases as the glycohemoglobin increases from 6.0 to 8.5% but does not increase further above this value. Currently, the interactions between these exposures and DNA polymorphisms in genes that have been shown to be involved in predisposition to diabetic nephropathy are being examined. The overall goal of Dr. Warram's research is to identify risk factors for the development of each of the three stages of renal complications and to apply this knowledge for optimizing patient care to prevent or postpone kidney disease in patients with diabetes.



Studies of non-diabetic relatives of patients with diabetes are an important means of identifying diabetes risk factors. Dr. Warram's research capitalizes on his access to a large population of such relatives and the long tradition of family studies at the Joslin. In a study that is a continuation of observations begun in the 1960's by Dr. Stuart Soeldner on a large cohort of offspring of parents with type 2 diabetes, he and his co-workers showed that the major predictors of the development of type 2 diabetes in these offspring are two components of glucose disposal: impaired glucose clearance in the presence of basal insulin (glucose resistance) and unresponsiveness of the glucose clearance rate to increased insulin (insulin resistance). He and his collaborators are also studying the development of obesity in this cohort and determinants of the level of insulin secretion.



In a series of studies of the risk of diabetes in the offspring of parents with type 1 diabetes, Dr. Warram found a significant difference between the offspring of diabetic mothers and fathers. The low risk of diabetes in the offspring of diabetic mothers indicates that exposure in utero to maternal type 1 diabetes has a profound protective effect against the development of diabetes in the child. Recently, he has done similar research examining the determinants of the risk of diabetes in siblings and offspring of index cases with type 2 diabetes. The risk to siblings of index cases is primarily determined by the diabetes status of the parents, thus the pattern of occurrence in families is most consistent with an autosomal dominant mode of inheritance. The transmission of diabetes risk through an affected parent may be slightly higher if that parent is the mother rather than the father, but the difference is quite small and may be an artifact due to incomplete information on parental diabetes status.



Selected References:



Krolewski AS, L Laffel L, Krolewski M, Quinn M, Warram JH. Glycosylated hemoglobin and the risk of microalbuminuria in patients with insulin-dependent diabetes mellitus. N Eng J Med 1995; 332:1251-1255



Warram JH, Gearin G, Laffel L, Krolewski AS. Effect of duration of IDDM on the prevalence of stages of diabetic nephropathy defined by urinary albumin creatinine ratio. J Am Soc Nephrol 1996; 7:930-37



Warram JH, Scott LJ, Hanna LS, Cohen SE, Laffel LMB, Ryan L, Krolewski AS. Progression of microalbuminuria to proteinuria in type 1 diabetes: Nonlinear relationship with hyperglycemia. Diabetes 2000; 49:94-100



Warram JH, Martin BC, Krolewski AS, Soeldner JS, Kahn CR. Slow glucose removal rate and hyperinsulinemia precede the development of Type II diabetes in offspring with diabetic parents. Ann Intern Med 1990; 113: 909-915



Martin BC, Warram JH, Krolewski AS, Bergman RN, Soeldner JS, Kahn CR. Role of glucose and insulin resistance in development of type 2 diabetes mellitus: results of a 25-year follow-up study. Lancet 1992; 340:925-929



Warram JH, Kopczynski J, Janka HU, Krolewski AS. Epidemiology of non-insulin-dependent diabetes mellitus and its macrovascular complications. A basis for the development of cost-effective programs. Endocrin Metab Clin N Am 1997; 26:165-188



Sigal RJ, El-Hashimy M, Martin BC, Soeldner JS, Krolewski AS, Warram JH. Acute postchallenge hyperinsulinemia predicts weight gain. A prospective study. Diabetes 1997; 46:1025-1029



El-Hashimy M, Angelico MC, Martin BC, Krolewski AS, Warram JH. Factors modifying the risk of insulin dependent diabetes mellitus in children of an IDDM parent. Diabetes 1995; 44:295-299



Biographical Sketch:



Dr. Warram is a Senior Investigator in the Section on Epidemiology and Genetics and a Lecturer in the Department of Epidemiology at Harvard School of Public Health. He received his medical degree from Harvard Medical School and his doctorate in epidemiology from Harvard School of Public Health as well. Before coming to Joslin in 1977, he was a member of the faculty in the Department of Biostatistics at the Harvard School of Public Health.