Pancreatic islet amyloidosis, β-cell apoptosis, and α-cell proliferation are determinants of islet remodeling in type-2 diabetic baboons

Abstract

␤-Cell dysfunction is an important factor in the development of hyperglycemia of type-2 diabetes mellitus, and pancreatic islet amyloidosis (IA) has been postulated to be one of the main contributors to impaired insulin secretion. The aim of this study was to evaluate the correlation of IA with metabolic parameters and its effect on islets of Langerhans remodeling and relative endocrine-cell volume in baboons. We sequenced the amylin peptide, determined the fibrillogenic propensities, and evaluated pancreatic histology, clinical and biochemical characteristics, and endocrine cell proliferation and apoptosis in 150 baboons with different metabolic status. Amylin sequence in the baboon was 92% similar to humans and showed superimposable fibrillogenic propensities. IA severity correlated with fasting plasma glucose (FPG) (r ‫؍‬ 0.662, P < 0.001) and HbA1c (r ‫؍‬ 0.726, P < 0.001), as well as with free fatty acid, glucagon values, decreased homeostasis model assessment (HOMA) insulin resistance, and HOMA-B. IA severity was associated with a decreased relative ␤-cell volume, and increased relative ␣-cell volume and hyperglucagonemia. These results strongly support the concept that IA and ␤-cell apoptosis in concert with ␣-cell proliferation and hypertrophy are key determinants of islets of Langerhans ''dysfunctional remodeling'' and hyperglycemia in the baboon, a nonhuman primate model of type-2 diabetes mellitus. The most important determinants of IA were age and FPG (R 2 ‫؍‬ 0.519, P < 0.0001), and different FPG levels were sensitive and specific to predict IA severity. Finally, a predictive model for islet amyloid severity was generated with age and FPG as required variables.amyloid deposits ͉ non-human primates ͉ insulin resistance ͉ islet of Langerhans ͉ type-2 diabetes mellitus T ype-2 diabetes mellitus (T2DM) is a chronic metabolic disorder characterized by insulin resistance in liver, muscle, and adipose tissue, as well as progressive ␤-cell dysfunction leading to hyperglycemia (1-3). Hyperglycemia and islet amyloidosis (IA) have been implicated in the progressive loss of ␤ cells in T2DM (4, 5). The prevalence of IA has been reported to range from 40 to 90% in T2DM individuals, and from 7% to 33% in nondiabetic controls (6 -11). Islet amyloid pancreatic polypeptide (IAPP) is the major constituent of pancreatic amyloid deposits (12, 13). In humans, monkeys, and cats, but not in mice and rats, IAPP has an amyloidogenic-promoting region, which resides within amino acids 20 to 29. Abnormalities in IAPP processing and secretion have been proposed as important contributors to the formation of IA (14 -17). Of note, IA and ␤-cell apoptosis have been observed in normal human islets transplanted into diabetic nude mice, as well as in the liver of type-1 diabetic patients transplanted with human islets (18,19).IA can cause ␤-cell death by occupying extracellular space, thereby impairing nutrients and oxygen uptake. In addition, small IAPP oligomers can form nonselective ion-permeable membrane pores, leading to increased...

The regulation of pre- and post-maturational plasticity of mammalian islet cell mass

“…Ageing was positively correlated with the severity of islet amyloidosis, and increased amyloidosis was associated with an increased rate of alpha cell replication and beta cell apoptosis [128].…”

β-Cell regeneration: the pancreatic intrinsic faculty

“…More precise-ly, some investigators suggested the potential involvement of a-cells in b-cell regeneration after observing cells coexpressing glucagon and insulin in several pancreatic regeneration models. Another interesting observation is that diabetic patients have an increased a-cell mass [69,70]; similarly, a-cell proliferation was increased in STZ-treated rats, and a-cells expressed b-cell markers such as Pdx1, Glut2 (Slc2a2) and insulin [31,66,71]. In the same way, bcell ablation induced by DOX in Ins2-rtTA; TetO-DTA mice was followed by the appearance of a very small number of glucagon+/insulin+ bihormonal cells, although these cells were not lineage-traced and their contribution to the formation of new b-cells was not explored [50].…”

End Sequence Analysis Toolkit (ESAT) expands the extractable information from single-cell RNA-seq data

“…6C,D). Since dysregulation of amylin has been associated with β-cell death in type 2 diabetes (Huang et al 2007;Guardado-Mendoza et al 2009), it will be interesting to know in which cells and the exact portion of cells where amylin becomes dysregulated during diabetes onset.…”