Stopping Type 1 Diabetes
Stopping Type 1 Diabetes
Type 1 diabetes—or, more accurately, type 1A diabetes—is thought to arise from selective immunologically mediated destruction of the insulin-producing β-cells in the pancreatic islets of Langerhans with consequent insulin deficiency. This occurs in individuals in whom genetic susceptibility outweighs genetic protection and is probably initiated by environmental factors not yet clearly defined. The disease arises via a cellular-mediated immune process, presumably a specific reaction to one or more β-cell proteins (autoantigens). There is consequent progressive impairment of β-cell function and apparent decline in β-cell mass. A secondary humoral immune response is characterized by the appearance of autoantibodies that serve as markers of the immune damage to β-cells. This insidious type 1 diabetes disease process generally evolves over a variable period of years (Fig. 1). The decline in β-cell function—and presumably in mass—is evidenced metabolically by loss of first-phase insulin response to an intravenous glucose challenge and later by the appearance of impairment in glycemic regulation, which is manifested as dysglycemia either as impaired glucose tolerance, impaired fasting glucose, or "indeterminate" glucose levels (values >200 mg/dl [11.1 mmol/l] at 30, 60, or 90 min during an oral glucose tolerance test). Ultimately, the clinical syndrome of type 1 diabetes becomes evident when the majority of β-cell function has been lost and presumably most β-cells have been destroyed; at this juncture, frank hyperglycemia supervenes. Although that broad sequence can be articulated, there are still gaps in many of the details. Further understanding of the nature of the disease process will facilitate the design of intervention strategies aimed at abrogating β-cell destruction and ultimately at prophylaxis of type 1 diabetes.
(Enlarge Image)
Figure 1.
Progression of the type 1 diabetes disease process. This is a cellular autoimmune process occurring in individuals with a genetic predisposition to the disease, presumably triggered by some environmental factor. Humoral antibodies indicate that the disease process is underway, and there is then progressive impairment of β-cell function manifested by progressive deterioration of glucose metabolism. The time frame is variable, so the x-axis is dimensionless. IAA, insulin autoantibody; ICA, islet cell antibody; IVGTT, intravenous glucose tolerance test; OGTT, oral glucose tolerance test.
It should be evident from the above sequence of events that if type 1 diabetes is to be conquered, it is necessary 1) to stop immune destruction of β-cells, 2) to replace or regenerate β-cells, and 3) to preserve β-cell function and mass. In regards to all three of these, much has been accomplished in animal models of type 1 diabetes. Yet in human beings, success has been elusive. That is not to say that progress has not been made, for indeed it has. In this Perspectives in Diabetes article, written in honor of the 40th anniversary of the Juvenile Diabetes Research Foundation (JDRF), we review the progress that has been made, indicate the challenges that have confronted investigators in these efforts, and propose a vision for how such research efforts might unfold in the future. We also note that several important consortia are addressing various aspects of this sequence, and these are listed in Table 1. These consortia have been supported by several institutes of the National Institutes of Health (NIH), JDRF, and the American Diabetes Association (ADA).
Abstract and Introduction
Introduction
Type 1 diabetes—or, more accurately, type 1A diabetes—is thought to arise from selective immunologically mediated destruction of the insulin-producing β-cells in the pancreatic islets of Langerhans with consequent insulin deficiency. This occurs in individuals in whom genetic susceptibility outweighs genetic protection and is probably initiated by environmental factors not yet clearly defined. The disease arises via a cellular-mediated immune process, presumably a specific reaction to one or more β-cell proteins (autoantigens). There is consequent progressive impairment of β-cell function and apparent decline in β-cell mass. A secondary humoral immune response is characterized by the appearance of autoantibodies that serve as markers of the immune damage to β-cells. This insidious type 1 diabetes disease process generally evolves over a variable period of years (Fig. 1). The decline in β-cell function—and presumably in mass—is evidenced metabolically by loss of first-phase insulin response to an intravenous glucose challenge and later by the appearance of impairment in glycemic regulation, which is manifested as dysglycemia either as impaired glucose tolerance, impaired fasting glucose, or "indeterminate" glucose levels (values >200 mg/dl [11.1 mmol/l] at 30, 60, or 90 min during an oral glucose tolerance test). Ultimately, the clinical syndrome of type 1 diabetes becomes evident when the majority of β-cell function has been lost and presumably most β-cells have been destroyed; at this juncture, frank hyperglycemia supervenes. Although that broad sequence can be articulated, there are still gaps in many of the details. Further understanding of the nature of the disease process will facilitate the design of intervention strategies aimed at abrogating β-cell destruction and ultimately at prophylaxis of type 1 diabetes.
(Enlarge Image)
Figure 1.
Progression of the type 1 diabetes disease process. This is a cellular autoimmune process occurring in individuals with a genetic predisposition to the disease, presumably triggered by some environmental factor. Humoral antibodies indicate that the disease process is underway, and there is then progressive impairment of β-cell function manifested by progressive deterioration of glucose metabolism. The time frame is variable, so the x-axis is dimensionless. IAA, insulin autoantibody; ICA, islet cell antibody; IVGTT, intravenous glucose tolerance test; OGTT, oral glucose tolerance test.
It should be evident from the above sequence of events that if type 1 diabetes is to be conquered, it is necessary 1) to stop immune destruction of β-cells, 2) to replace or regenerate β-cells, and 3) to preserve β-cell function and mass. In regards to all three of these, much has been accomplished in animal models of type 1 diabetes. Yet in human beings, success has been elusive. That is not to say that progress has not been made, for indeed it has. In this Perspectives in Diabetes article, written in honor of the 40th anniversary of the Juvenile Diabetes Research Foundation (JDRF), we review the progress that has been made, indicate the challenges that have confronted investigators in these efforts, and propose a vision for how such research efforts might unfold in the future. We also note that several important consortia are addressing various aspects of this sequence, and these are listed in Table 1. These consortia have been supported by several institutes of the National Institutes of Health (NIH), JDRF, and the American Diabetes Association (ADA).
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