Transcription factor abnormalities as a cause of beta cell dysfunction in diabetes: a hypothesis
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G C Weir1, A Sharma, D H Zangen
1Joslin Diabetes Center, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA.
Abstract:
Well-characterized defects in insulin secretion, most notably a loss of glucose-induced insulin secretion, are found in virtually all forms of NIDDM, as well as in early IDDM. Similar abnormalities have been found in all animal models of diabetes in which they have been studied. A novel hypothesis is being proposed to explain the mechanisms responsible for these alterations. Many abnormalities in the various steps of glucose-induced insulin secretion have been identified in rodent models of diabetes, but none by itself seems sufficient to explain the defects. These include a loss of GLUT2, glycogen accumulation, glucose recycling, abnormal glucokinase or hexokinase, altered mitochondrial glycerol phosphate dehydrogenase (mGPDH) activity, abnormal ion channel function and beta cell degranulation. We propose that optimal secretory function is dependent upon the unique differentiation of beta cells that is maintained by a set of transcription factors and that this control is disrupted by the diabetic state. Therefore, we propose that key transcription factors are affected even when beta cells are stressed by insulin resistance in very earliest stages of diabetes and that the abnormality becomes more severe as full-blown diabetes develops, which leads to loss of beta cell differentiation and a resultant derangement of insulin secretion.
Insights
Defects in glucose-induced insulin secretion in diabetes stem from disrupted beta cell differentiation. Key transcription factors are affected early, leading to impaired insulin secretion as diabetes progresses.
Area of Science:
- Endocrinology
- Molecular Biology
- Diabetes Research
Background:
- Insulin secretion defects, particularly reduced glucose-induced insulin secretion, characterize both non-insulin-dependent diabetes mellitus (NIDDM) and early insulin-dependent diabetes mellitus (IDDM).
- Similar secretory abnormalities are observed in animal models of diabetes.
Purpose of the Study:
- To propose a novel hypothesis explaining the mechanisms behind impaired glucose-induced insulin secretion in diabetes.
- To investigate the role of beta cell differentiation and transcription factors in diabetes-related secretory dysfunction.
Main Methods:
- Review and synthesis of existing data on abnormalities in glucose-induced insulin secretion in rodent models of diabetes.
- Hypothesizing the central role of transcription factor disruption in beta cell differentiation and function.
Main Results:
- Identified numerous abnormalities in glucose-induced insulin secretion (e.g., GLUT2 loss, altered enzyme activity, ion channel dysfunction, degranulation) in diabetes models, none sufficient alone to explain defects.
- Proposed that disruption of transcription factor-mediated beta cell differentiation underlies these defects.
Conclusions:
- Optimal insulin secretion relies on specialized beta cell differentiation maintained by transcription factors.
- Diabetic states, even in early insulin resistance, disrupt these key transcription factors, leading to progressive loss of beta cell differentiation and impaired insulin secretion.