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Genetics of Endocrine Disorders and Diabetes Mellitus
Published in George H. Gass, Harold M. Kaplan, Handbook of Endocrinology, 2020
Bess Adkins Marshall, Abby Solomon Hollander
In addition, a few families have been found in which a mutation in the insulin gene prevents cleavage of proinsulin to insulin and causes familial hyperproinsulinemia.22–24 These patients have elevated immunoreactive insulin measurable in their serum, but the majority is proinsulin rather than insulin. They are normoglycemic or mildly hyperglycemic.
Diabetes Mellitus
Published in Victor A. Bernstam, Pocket Guide to GENE LEVEL DIAGNOSTICS in Clinical Practice, 2019
Relative hyperproinsulinemia and the presence of amyloid deposits in the islets of NIDDM patients have been related to the inappropriate release of unprocessed proinsulin. The islet amyloid is composed of a peptide, called islet amyloid polypeptide (IAPP), or amylin. This 37-amino acid neuropeptide-like molecule has 50% homology with the neuropeptide calcitonin gene-related peptide (CGRP). Structural similarity with CGRP points to possible modulating effects of IAPP on adenylate cyclase.
Noninsulin-Dependent Animal Models of Diabetes Mellitus
Published in John H. McNeill, Experimental Models of Diabetes, 2018
Christopher H. S. McIntosh, Raymond A. Pederson
The animal models used to date have provided a wealth of information regarding individual obesity genes, which can also result in NIDDM. It has only recently been possible to identify specific human gene mutations, which ultimately result in defined subtypes of diabetes. The earliest example of this was insulin itself. Families have been identified in several populations in which one or more members have single-point mutations in insulin genes resulting in amino acid substitutions in their proinsulin.364 Some of these mutations result in the secretion of peptide with reduced biological activity due to functionally important changes in the A or B chain. Individuals in which insulin demonstrates reduced receptor binding are mildly diabetic or hyperglycemic, and hyperinsulinemic. Other mutations result in hyperproinsulinemia. The prevalence of such mutations is rare.1 Two major approaches to the identification of further diabetogenic genes in humans have been taken. The first of these, the candidate gene approach,2,12,14 involves the characterization of molecules involved in normal insulin secretion and action, and determining whether or not patients with inherited forms of diabetes have genetic defects in these molecules. Many of the studies discussed earlier involved this approach in the study of animal diabetes. The second approach, random gene searching,12,14 is based on the identification of families with inherited forms of diabetes and mapping to the human genome. By using positional cloning, defective genes can then be identified. By using these two approaches, specific single-gene disorders have been identified (Table 14.3), and these have generally been associated with early-onset NIDDM or severe insulin resistance.1
Improvement in the proinsulin/C-peptide ratio during treatment with ipragliflozin in Japanese patients with type 2 diabetes mellitus
Published in Expert Opinion on Pharmacotherapy, 2018
Takahiro Takase, Akinobu Nakamura, Chiho Yamamoto, Tatsuya Atsumi, Hideaki Miyoshi
Proinsulin is synthesized by the secreting granule of pancreatic beta cells and is a precursor molecule for insulin and C-peptide. Physiologically, almost all proinsulin molecules are intracellularly cleaved into insulin and C-peptide [1]. Therefore, serum proinsulin levels are greatly lower than those of insulin and C-peptide in healthy people. Presumably hyperproinsulinemia might be caused by inefficient proinsulin processing within the beta cell secretory granule, leading to an increased release of immature insulin precursors, or alternatively caused by an increased secretary demand on beta cells, leading to an increased insulin secretion from the reserve insulin granule pool, which could contain greater amounts of immature insulin precursors [2,6]. Our findings would support the latter explanation, since our results suggest that treatment with ipragliflozin ameliorated the increased demand for insulin, resulting in a decrease in the proinsulin/C-peptide ratio. Therefore, ipragliflozin treatment could improve beta cell function by reducing beta cell overload.