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A 34‐year‐old man visited our Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan, because of dry mouth and weight loss. His plasma glucose level was 32.8 mmol/L and serum levels of ketone bodies were increased, but with metabolic alkalemia. He was also suffering from renal tubular hypomagnesemia and hypokalemia. Abdominal computed tomography showed bilateral renal cysts. These findings were suggestive of maturity‐onset diabetes of the young type 5. Genetic testing showed heterozygous hepatocyte nuclear factor 1 beta gene deletion. In the present case, it seemed reasonable to view hepatocyte nuclear factor 1 beta gene deletion as the common cause of maturity‐onset diabetes of the young type 5‐associated diabetic ketoacidosis and tubular malfunction‐induced hypokalemic alkalosis. This case exemplifies the importance of hepatocyte nuclear factor 1 beta gene abnormality as a potential cause of diabetic ketoacidosis with alkalemia. [ABSTRACT FROM AUTHOR]

Patients with long-standing diabetes commonly develop cognitive impairment and dementia, defined as diabetic encephalopathy. Enhanced susceptibility of brain neurons to oxidative and carbonyl stress is a contributing factor. Glucagon-like peptide (GLP)-1 is a brain-gut peptide, and recently became an attractive treatment modality for patients with diabetes. GLP-1 readily enters the brain, prevents neuronal cell apoptosis, and improves learning and memory impairment in Alzheimer's disease. Therefore, in the current study, we investigated whether GLP-1 could protect against hyperglycemic- and carbonyl stress- induced neuronal cell apoptosis. Rat pheochromocytoma cell line (PC12), which is used commonly as a neuronal cell model, was exposed to 25 mM glucose and/or 500 µM methylglyoxal (MG) with or without 0.1 nM GLP-1, and cell apoptosis, protein expression and phosphorylation of epidermal growth factor receptor (EGFR)/Akt/mTOR/glutamate-L-cysteine ligase (GCL) were determined. The mechanism of GLP-1-mediated EGFR transactivation was also examined. Hyperglycemia and MG induced PC 12 apoptosis as well as mitochondrial cytochrome c release, caspase-9 and -3 activation, and PARP cleavage. GLP-1 protected against hyperglycemic- and MG- induced PC12 apoptosis, which corresponded to the phosphorylation of EGFR, PI3K, Akt, mTOR, and the upregulation of GCL. Inhibitors of EGFR (14C10), EGFR ligands (anti-HB-EGF-Ab, anti-amphiregulin (AR)-Ab), a metalloproteinase which acts as EGFR ligand shedding (KB-R7785), PI3K (wortmannin, LY294002), Akt (AktI), and mTOR (rapamycin) abrogated the GLP-1 cytoprotective effect. In sum, hyperglycemic and carbonyl stress induces neuronal cell apoptosis through mitochondrial apoptotic signaling. GLP-1 treatment affords neuroprotection by enhancing PI3K/Akt/mTOR/GCL signaling through EGFR transactivation via GLP-1 receptor-mediated EGFR ligand (HB-EGF, AR) shedding, and thus represents a promising treatment modality for diabetic encephalopathy. [ABSTRACT FROM AUTHOR]

Patients with long-standing diabetes commonly develop cognitive impairment and dementia, recognized as primary diabetic encephalopathy. Brain insulin deficiency, the impairment of brain insulin signaling, and oxidative stress in the brain have been thought as the contributing factors. Additionally, multiple lines of evidence suggest that reactive carbonyl compounds, which are products of oxidative damage to sugar, lipids, and amino acids, are closely involved in the pathogenesis of various neurodegenerative disorders including diabetic encephalopathy. Therefore, in the current study, we investigated the oxidative susceptibility of neuronal cells to methylglyoxal (MG), a model of carbonyl stress, under chronic high glucose, and its protection by insulin. Human brain endothelial cells (IHEC) and rat pheochromocytoma cells (PC 12), both of which are used commonly as neuronal cell models, were exposed to 25 mM glucose for 7 days with or without 500 µM MG and/or 100 nM insulin. Cell apoptosis, cellular redox status, protein expressions of PI3K/Akt/mTOR/glutamate-L-cysteine ligase (GCL) and S-glutathionylation were determined. Carbonyl and hyperglycemic stress exacerbated IHEC and PC12 apoptosis, as well as redox shifts, mitochondrial cytochrome c release, caspase-9 and -3 activation, and PARP cleavage. Insulin protected against carbonyl and hyperglycemic stress-induced apoptosis through the improvement of redox status via PI3K/Akt/mTOR/Nrf2/GCL signaling. MG potentiated insulin-induced GCL expression through Nrf2 nuclear translocation independent of PI3/Akt/mTOR pathway. Additionally, MG and chronic high glucose induced Keap1-glutathionylation. In summary, human brain endothelial cells and neurons exhibit vulnerability to carbonyl and hyperglycemic stress in conjunction with cellular redox shifts and mitochondrial apoptotic signaling. Insulin treatment affords neuroprotection by reversing redox shifts through activating PI3K/Akt/mTOR/Nrf2/GCL signaling. MG potentiates the anti-apoptotic effect of insulin as a compensatory response. Keap1 glutathionylation induced by MG and chronic high glucose seems to act as inducers of Nrf2/GCL signaling as an adaptive response. Thus, the enhanced vulnerability of neuronal cells to carbonyl and hyperglycemic stress, and its neuroprotective mechanisms of insulin will have important implications for understanding primary diabetic encephalopathy. [ABSTRACT FROM AUTHOR]

It is well-known that diabetes exacerbates brain damage after cerebral stroke in patients with diabetes and in experimental diabetic animal models. Increased apoptosis in ischemic and penumbra regions of diabetic brain is a contributing factor in the exacerbation of cerebral infarct volume after ischemic insults. Administration of insulin can reduce neurological disability in cerebral stroke, accompanied by inhibition of neuronal apoptosis. It has been demonstrated that peripheral insulin is transported into the brain through circumventricular organs or blood-brain barrier, and that brain insulin can confer cytoprotection of neuronal cells against oxidative stress. However, the molecular mechanisms underlying the vulnerability of diabetic neuronal cells to chronic oxidative challenge and protective action of brain insulin have not been elucidated. Therefore, in the current study, we investigated the oxidative susceptibility of brain endothelial cells and neurons using human brain endothelial cells (IHEC) and rat pheochromocytoma cells (PC12), both of which are used commonly as neuronal cell models, to chronic hyperglycemic stress and neuroprotective action of insulin. IHEC and PC12 were treated with 25 mM glucose for 7 days with or without 100 nM insulin. Cell apoptosis, cellular redox status, protein expression and phosphorylation of PBK/Akt/mTOR pathway, as well as Nrf2-dependent upregulation of ghitamate-L-cysteine ligase (GCL) were determined. Chronic hyperglycemia exacerbated IHEC and PC12 apoptosis, which corresponded to decreased PI3K/Akt/mTOR/Nrf2/GCL signaling, exaggerated redox imbalance, and enhanced actin/Keap-1 S-glutathionylation. Insulin reversed the impaired PI3K/Akt/mTOR/Nrf2 signaling, and enhanced Nrf2-mediated GCL expression. Consequently, insulin restored redox balance and attenuated apoptosis. Inhibitors of insulin receptor tyrosine kinase, PI3K, Akt and mTOR abrogated insulin-induced Nrf2-mediated GCL expression, redox balance restoration, and IHEC and PC12 survival. In summary, human brain endothelial cells and neurons exhibit vulnerability to hyperglycemic stress which is associated with marked redox shifts and impaired PI3K/Akt/mTOR/Nrf2/GCL signaling. Insulin treatment affords neuroprotection by reversing cellular redox shifts through activating PI3K/Akt/mTOR/Nrf2/GCL signaling. [ABSTRACT FROM AUTHOR]

It is well known that insulin resistance affects osteodystrophy, and there is an important relationship between insulin resistance and hepato-biliary disease. It is also well known that hepato-biliary and pancreatic disease is associated with osteodystrophy. In the present review, we describe the mechanism of diabetes and osteodystrophy due to hepato-biliary and pancreatic disease. Hepatic osteodystrophy is associated with malabsorption, abnormalities of vitamin D metabolism, inflammatory cytokines, receptor activator of NF-kappaB ligand, and insulin-like growth factor-1. In particular, tumor necrosis factor-alpha and malabsorption are important factors for viral and alcoholic hepatitis, respectively. Malabsorption due to steatorrhea is important for cholestatic disease and chronic pancreatitis. A greater focus on non-alcoholic steatohepatitis (NASH) and further investigations to clarify the relationship between osteodystrophy and NASH are needed.