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Beta Cell Functional Adaptation and Dysfunction in Insulin Resistance and the Role of Chronic Kidney Disease

Background: Beta cells are central in the pathophysiology of diabetes, since their functional adaptation maintains euglycemia in insulin-resistant individuals and beta cell dysfunction is required for the clinical picture of frank diabetes. The pathophysiological mechanisms driving compensation and decompensation are incompletely understood and little is known about the influence of chronic kidney disease (CKD) on beta cell function. Summary: In compensated insulin resistance, beta cells enhance their function at all stages in the stimulus-secretion coupling cascade, from the most proximal membrane depolarization to the intermediate increase in intracellular calcium concentration and the most distal granule fusion. Intercellular coupling is not disrupted at this early stage during disease progression. Later during progression, when hyperglycemia becomes more apparent owing to insufficient beta cell compensation, intracellular stimulus-secretion coupling becomes enhanced to an even larger degree, but intercellular coupling becomes disrupted, indicating that ineffective cell-to-cell signal transmission may be the earliest event in progression to frank diabetes. CKD can negatively affect beta cell function through increased levels of urea that reduce beta cell glucose utilization and impair insulin secretion, and possibly also through factors other than urea. It remains to be investigated whether urea and other factors of CKD can also affect intercellular coupling. Key messages: Beta cells enhance intracellular stimulus-secretion coupling in early insulin resistance. With worsening insulin resistance, intracellular coupling enhances even more, but intercellular coupling becomes disrupted. CKD negatively impacts beta cell function, but its influence on intercellular coupling awaits further studies.