Peptide hormones are first produced as larger precursor prohormones that require endoproteolytic cleavage to liberate the mature hormones. A structurally conserved but functionally distinct family of nine prohormone convertase enzymes (PCs) are responsible for cleavage of protein precursors of which PC1/3 and PC2 are known to be exclusive to neuroendocrine cells and responsible for prohormone cleavage. Differential expression of PCs within tissues define prohormone processing; whereas glucagon is the major product liberated from proglucagon via PC2 in pancreatic α-cells, proglucagon is preferentially processed by PC1/3 in intestinal L cells to produce glucagon-like peptides 1 and 2 (GLP-1, GLP-2). Beyond our understanding of processing of islet prohormones in healthy islets, there is convincing evidence that proinsulin, proIAPP, and proglucagon processing is altered during prediabetes and diabetes. There is predictive value of elevated circulating proinsulin or proinsulin : C-peptide ratio for progression to type 2 diabetes and elevated proinsulin or proinsulin : C-peptide is predictive for development of type 1 diabetes in at risk groups. After onset of diabetes, patients have elevated circulating proinsulin and proIAPP and proinsulin may be an autoantigen in type 1 diabetes. Further, preclinical studies reveal that α-cells have altered proglucagon processing during diabetes leading to increased GLP-1 production. We conclude that despite strong associative data, current evidence is inconclusive on the potential causal role of impaired prohormone processing in diabetes, and suggest that future work should focus on resolving the question of whether altered prohormone processing is a causal driver or merely a consequence of diabetes pathology.

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胰岛激素原加工改变：糖尿病的原因还是后果？

肽激素首先作为较大的前体激素原产生，需要内切蛋白水解来释放成熟激素。九种激素原转化酶 (PC) 的结构保守但功能不同的家族负责蛋白质前体的裂解，其中已知 PC1/3 和 PC2 是神经内分泌细胞独有的，并负责激素原的裂解。组织内 PC 的差异表达定义了激素原加工；胰高血糖素是胰高血糖素原通过胰腺 α 细胞中的 PC2 从胰高血糖素原释放的主要产物，而胰高血糖素原在肠 L 细胞中优先被 PC1/3 加工以产生胰高血糖素样肽 1 和 2（GLP-1、GLP-2）。除了我们对健康胰岛中胰岛激素原加工的理解之外，还有令人信服的证据表明，胰岛素原、proIAPP、在糖尿病前期和糖尿病期间，胰高血糖素原的加工过程会发生改变。循环胰岛素原或胰岛素原：C-肽比率升高对发展为 2 型糖尿病具有预测价值，而胰岛素原或胰岛素原：C-肽升高对高危人群发展为 1 型糖尿病具有预测价值。糖尿病发作后，患者的循环胰岛素原和 proIAPP 升高，胰岛素原可能是 1 型糖尿病的自身抗原。此外，临床前研究表明，α 细胞在糖尿病期间改变了胰高血糖素原的加工过程，导致 GLP-1 的产生增加。我们得出的结论是，尽管有强有力的关联数据，但目前的证据对于糖尿病中激素原加工受损的潜在因果作用尚无定论，