Diagnosis, treatment and genetic analysis of a case with fibrocalculous pancreatic diabetes.

Fibrocalculous pancreatic diabetes (FCPD) is a rare type of diabetes mellitus with both impaired endocrine and exocrine functions of the pancreas. In this report, we presented a case with FCPD, who had recurrent abdominal pain since early childhood and was diagnosed with diabetes mellitus at the age of 25, with pancreatic calcification on abdominal computed tomography (CT) scan. Genetic testing revealed two homozygous mutations in the SPINK1 gene (c.194+2T>C and -191-24G>A). Both the homozygous variants were shared by his unaffected sibling, and the heterozygous variants had been verified on their unaffected parents. Based on this case and 90 other reported cases in China, we retrospectively analyzed the clinical characteristics of FCPD. It is recommended that unclassified diabetic patients with a lean body type, no ketosis tendency but poor islet function should be considered for the possibility of FCPD. Pancreatic imaging and genetic testing may be beneficial for the differential diagnosis. This study improves our understanding and management of FCPD, and also enriches clinical evidence for subsequent research on pathogenic mechanisms and drug target screening.

Anti-inflammatory Effect of Astaxanthin on the Sickness Behavior Induced by Diabetes Mellitus.

Chronic inflammation appears to play a critical role in sickness behavior caused by diabetes mellitus. Astaxanthin has been used in treating diabetes mellitus and diabetic complications because of its neuroprotective and anti-inflammatory actions. However, whether astaxanthin can improve sickness behavior induced by diabetes and its potential mechanisms are still unknown. The aim of this study was to investigate the effects of astaxanthin on diabetes-elicited abnormal behavior in mice and its corresponding mechanisms. An experimental diabetic model was induced by streptozotocin (150 mg/kg) and astaxanthin (25 mg/kg/day) was provided orally for 10 weeks. Body weight and water consumption were measured, and the sickness behavior was evaluated by the open field test (OFT) and closed field test (CFT). The expression of glial fibrillary acidic protein (GFAP) was measured, and the frontal cortical cleaved caspase-3 positive cells, interleukin-6 (IL-6), and interleukin-1ß (IL-1ß) expression levels were also investigated. Furthermore, cystathionine ß-synthase (CBS) in the frontal cortex was detected to determine whether the protective effect of astaxanthin on sickness behavior in diabetic mice is closely related to CBS. As expected, we observed that astaxanthin improved general symptoms and significantly increase horizontal distance and the number of crossings in the OFT and CFT. Furthermore, data showed that astaxanthin could decrease GFAP-positive cells in the brain and down-regulate the cleaved caspase-3, IL-6, and IL-1ß, and up-regulate CBS in the frontal cortex. These results suggest that astaxanthin provides neuroprotection against diabetes-induced sickness behavior through inhibiting inflammation, and the protective effects may involve CBS expression in the brain.

Receptor for advanced glycation end products aggravates cognitive deficits in type 2 diabetes through binding of C-terminal AAs 2-5 to mitogen-activated protein kinase kinase 3 (MKK3) and facilitation of MEKK3-MKK3-p38 module assembly.

In this study, we explored the precise mechanisms underlying the receptor for advanced glycation end products (RAGE)-mediated neuronal loss and behavioral dysfunction induced by hyperglycemia. We used immunoprecipitation (IP) and GST pull-down assays to assess the interaction between RAGE and mitogen-activated protein kinase kinase 3 (MKK3). Then, we investigated the effect of specific mutation of RAGE on plasticity at hippocampal synapses and behavioral deficits in db/db mice through electrophysiological recordings, morphological assays, and behavioral tests. We discovered that RAGE binds MKK3 and that this binding is required for assembly of the MEKK3-MKK3-p38 signaling module. Mechanistically, we found that activation of p38 mitogen-activated protein kinase (MAPK)/NF-κB signaling depends on mediation of the RAGE-MKK3 interaction by C-terminal RAGE (ctRAGE) amino acids (AAs) 2-5. We found that ctRAGE R2A-K3A-R4A-Q5A mutation suppressed neuronal damage, improved synaptic plasticity, and alleviated behavioral deficits in diabetic mice by disrupting the RAGE-MKK3 conjugation. High glucose induces direct binding of RAGE and MKK3 via ctRAGE AAs 2-5, which leads to assembly of the MEKK3-MKK3-p38 signaling module and subsequent activation of the p38MAPK/NF-κB pathway, and ultimately results in diabetic encephalopathy (DE).

Inhibition of iNOS alleviates cognitive deficits and depression in diabetic mice through downregulating the NO/sGC/cGMP/PKG signal pathway.

Diabetes mellitus often results in a number of complications involving impaired brain function, including cognitive deficits and depression. However, the potential mechanisms for diabetes-related cognitive deficits and depression are not fully understood. Neurons in the hippocampal, cortical and amygdala functional regions are more susceptible to damage during hyperglycemia. Neuroprotection in the brain can rescue cognitive deficits and depression induced by hyperglycemia. This study investigated the potential mechanisms underlying diabetes-related congnitive deficits and depression, determined whether the inflammatory factor inducible nitric oxide synthase (iNOS) and the nitric oxide (NO)/soluble guanylyl cyclases (sGC)/cyclic guanosine monophosphate (cGMP)/protein kinase G (PKG) pathway, play key roles in cognitive deficits and depression associated. In the present study, diabetic animal models were induced by streptozotocin (STZ, 150mg/kg) in mice, and aminoguanidine (AG), a selective inhibitor of iNOS, was given by intraperitoneal injection for 10 weeks. Blood glucose, activities of NOS and the levels of NO in serum and brain regions were measured. The spatial memory was detected using the Morris water maze test, depressive behavior was evaluated by the tail suspension test (TST), forced swimming test (FST), closed field test (CFT) and open field test (OFT). We also detected neuronal survival and cleaved caspase-3 positive ratios in three brain regions and the levels of iNOS, sGC, cGMP and PKG in hippocampus and frontal cortex. Data indicated that diabetic mice exerted impairments in spatial memory, decreased locomotor activity and increased immobile time in diabetic mice. In addition, diabetic mice had significantly decreased surviving neuronal density and showed signs of obvious neuronal injury in the hippocampus, frontal cortex and amygdala. iNOS overexpression and its associated signaling pathway NO/sGC/cGMP/PKG in the hippocampus and frontal cortex were implicated during hyperglycemia. However, AG improved the behavior disorders, reduced the activity of iNOS, protected nerve cells and inhibited the level of iNOS, sGC, PKG and cleaved caspase-3 in the hippocampus and cortex. These results suggested that iNOS/NO/sGC/cGMP/PKG signal pathway is a key feature of cognitive deficits and depression associated with diabetes. AG ameliorated cognitive deficits and depression in diabetic mice by exerting anti-inflammatory and neuroprotective effects by suppressing iNOS-associated signaling pathways.