Pancreatic Nonhormone Expressing Endocrine Cells in Children With Type 1 Diabetes.

It has been proposed that the deficit in ß-cell mass in type 1 diabetes (T1D) may be due, in part, to ß-cell degranulation to chromogranin-positive hormone-negative (CPHN) cells. The frequency and distribution of pancreatic CPHN cells were investigated in 19 children with T1D compared with 14 non-diabetic (ND) children. We further evaluated these cells for replication and expression of endocrine lineage markers Nkx6.1 and Nkx2.2, and compared these frequencies with those previously reported in CPHN cells in adults with T1D. In contrast to adults' cells, pancreatic CPHN cells were comparably abundant (percentage of endocrine cells ± standard error of the mean, 1.4 ± 0.2 vs 1.0 ± 0.2 in patients with T1D vs ND subjects, respectively; P = not significant) and comparably distributed in children with T1D vs ND donors. Replication of CPHN cells was detected but unchanged in children with T1D vs ND children, as was the percentage of CPHN cells expressing Nkx6.1 or NKx2.2. In children with T1D, the frequency of pancreatic CPHN cells was not increased, and this differed from adults with T1D.

Increased Frequency of Hormone Negative and Polyhormonal Endocrine Cells in Lean Individuals With Type 2 Diabetes.

CONTEXT: It has been suggested that beta cell loss in type 2 diabetes (T2D) may be due to beta cell degranulation and/or altered cell identity. While shown to have a minor role in obese T2D, this has not been evaluated in lean T2D. OBJECTIVE: To establish the contribution of altered beta cell identity in lean T2D and, using a rodent model of lean T2D, whether changes in beta cell identity precede hyperglycemia. DESIGN, SETTING, AND PARTICIPANTS: We investigated the frequency of chromogranin A positive hormone negative (CPHN) and polyhormonal endocrine cells in pancreas from 10 lean nondiabetic and 10 lean T2D subjects and in pancreas from wild-type and human IAPP transgenic rats at the prediabetic and diabetic stages. RESULTS: CPHN cells and polyhormonal-expressing cells were comparably increased in lean T2D and human IAPP transgenic rats, in the latter both before and at onset of diabetes. However, the extent of these cells could only account for approximately 2% of beta cell loss. CONCLUSION: Degranulation and altered identity play at most a minor role in the beta cell deficit in lean T2D. Because the increase in CPHN and polyhormonal cells precede diabetes onset, these changes are likely a response to stress rather than hyperglycemia, and may reflect attempted regeneration.

Increased Hormone-Negative Endocrine Cells in the Pancreas in Type 1 Diabetes.

CONTEXT AND OBJECTIVE: Type 1 diabetes (T1D) is characterized by a ß-cell deficit due to autoimmune inflammatory-mediated ß-cell destruction. It has been proposed the deficit in ß-cell mass in T1D may be in part due to ß-cell degranulation to chromogranin-positive, hormone-negative (CPHN) cells. DESIGN, SETTING, AND PARTICIPANTS: We investigated the frequency and distribution of CPHN cells in the pancreas of 15 individuals with T1D, 17 autoantibody-positive nondiabetic individuals, and 17 nondiabetic controls. RESULTS: CPHN cells were present at a low frequency in the pancreas from nondiabetic and autoantibody-positive, brain-dead organ donors but are more frequently found in the pancreas from donors with T1D (islets: 1.11% ± 0.20% vs 0.26% ± 0.06 vs 0.27% ± 0.10% of islet endocrine cells, T1D vs autoantibody positive [AA+] vs nondiabetic [ND]; T1D vs AA+, and ND, P < .001). CPHN cells are most commonly found in the single cells and small clusters of endocrine cells rather than within established islets (clusters: 18.99% ± 2.09% vs 9.67% ± 1.49% vs 7.42% ± 1.26% of clustered endocrine cells, T1D vs AA+ vs ND; T1D vs AA+ and ND, P < .0001), mimicking the distribution present in neonatal pancreas. CONCLUSIONS: From these observations, we conclude that CPHN cells are more frequent in T1D and, as in type 2 diabetes, are distributed in a pattern comparable with the neonatal pancreas, implying a possible attempted regeneration. In contrast to rodents, CPHN cells are insufficient to account for loss of ß-cell mass in T1D.

One-day high-fat diet induces inflammation in the nodose ganglion and hypothalamus of mice.

A high-fat diet (HFD) induces inflammation in systemic organs including the hypothalamus, resulting in obesity and diabetes. The vagus nerve connects the visceral organs and central nervous system, and the gastric-derived orexigenic peptide ghrelin transmits its starvation signals to the hypothalamus via the vagal afferent nerve. Here we investigated the inflammatory response in vagal afferent neurons and the hypothalamus in mice following one day of HFD feeding. This treatment increased the number of macrophages/microglia in the nodose ganglion and hypothalamus. Furthermore, one-day HFD induced expression of Toll-like receptor 4 in the goblet cells of the colon and upregulated mRNA expressions of the proinflammatory biomarkers Emr1, Iba1, Il6, and Tnfα in the nodose ganglion and hypothalamus. Both subcutaneous administration of ghrelin and celiac vagotomy reduced HFD-induced inflammation in these tissues. HFD intake triggered inflammatory responses in the gut, nodose ganglion, and subsequently in the hypothalamus within 24 h. These findings suggest that the vagal afferent nerve may transfer gut-derived inflammatory signals to the hypothalamus via the nodose ganglion, and that ghrelin may protect against HFD-induced inflammation.

Diet-induced obesity causes peripheral and central ghrelin resistance by promoting inflammation.

Ghrelin, a stomach-derived orexigenic peptide, transmits starvation signals to the hypothalamus via the vagus afferent nerve. Peripheral administration of ghrelin does not induce food intake in high fat diet (HFD)-induced obese mice. We investigated whether this ghrelin resistance was caused by dysfunction of the vagus afferent pathway. Administration (s.c.) of ghrelin did not induce food intake, suppression of oxygen consumption, electrical activity of the vagal afferent nerve, phosphorylation of ERK2 and AMP-activated protein kinase alpha in the nodose ganglion, or Fos expression in hypothalamic arcuate nucleus of mice fed a HFD for 12 weeks. Administration of anti-ghrelin IgG did not induce suppression of food intake in HFD-fed mice. Expression levels of ghrelin receptor mRNA in the nodose ganglion and hypothalamus of HFD-fed mice were reduced. Inflammatory responses, including upregulation of macrophage/microglia markers and inflammatory cytokines, occurred in the nodose ganglion and hypothalamus of HFD-fed mice. A HFD blunted ghrelin signaling in the nodose ganglion via a mechanism involving in situ activation of inflammation. These results indicate that ghrelin resistance in the obese state may be caused by dysregulation of ghrelin signaling via the vagal afferent.