ABSTRACT
INTRODUCTION: Diabetic ketoacidosis (DKA) is an acute life-threatening complication in patients with type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM). Causes, underlying pathophysiology, and mortality differ significantly by diabetes type, which initial treatment is dependent on, but few reports on these differences are available. This study aimed to clarify differences in clinical characteristics between the diabetes types to extract important clinical clues for preventing DKA and ensuring appropriate initial treatment in the emergency room. METHODS: We retrospectively analyzed the clinical presentation of 24 T1DM patients and 13 T2DM patients admitted with DKA to Kobe City Medical Center West Hospital between April 2006 and December 2018. RESULTS: In T1DM, the main causes were insulin omission and new onset, and important factors were also misdiagnosis with consequent inappropriate insulin prescription and older age with dementia. In T2DM, the main causes were infection and excessive soft drink consumption. For all soft drink ketosis patients, this was the first presentation of diabetes. The main complaint differed between diabetes types. Vomiting was a characteristic symptom in T1DM DKA; most T2DM DKA patients presented with generalized malaise or decreased level of consciousness. On blood examination, serum potassium level was higher and HbA1c was lower in T1DM DKA. CONCLUSIONS: To prevent DKA, it is important to provide social support for elderly patients with T1DM DKA and lifestyle intervention for younger T2DM or obese patients. Vomiting and serum potassium levels contribute to the classification of diabetes type and subsequent initial treatment in the emergency room. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13340-021-00539-w.
ABSTRACT
Misfolding of proteins during endoplasmic reticulum (ER) stress results in the formation of cytotoxic aggregates. The ER-associated degradation pathway counteracts such aggregation through the elimination of misfolded proteins by the ubiquitin-proteasome system. We now show that SHP substrate-1 (SHPS-1), a transmembrane glycoprotein that regulates cytoskeletal reorganization and cell-cell communication, is a physiological substrate for the Skp1-Cullin1-NFB42-Rbx1 (SCF(NFB42)) E3 ubiquitin ligase, a proposed mediator of ER-associated degradation. SCF(NFB42) mediated the polyubiquitination of immature SHPS-1 and its degradation by the proteasome. Ectopic expression of NFB42 both suppressed the formation of aggresome-like structures and the phosphorylation of the translational regulator eIF2alpha induced by overproduction of SHPS-1 as well as increased the amount of mature SHPS-1 at the cell surface. An NFB42 mutant lacking the F box domain had no such effects. Our results suggest that SCF(NFB42) regulates SHPS-1 biosynthesis in response to ER stress.
Subject(s)
Antigens, Differentiation/biosynthesis , Endoplasmic Reticulum/metabolism , Membrane Glycoproteins/biosynthesis , Neural Cell Adhesion Molecule L1/biosynthesis , Receptors, Immunologic/biosynthesis , Ubiquitin/metabolism , Amino Acid Sequence , Antigens, Differentiation/genetics , Antigens, Differentiation/metabolism , Base Sequence , Cell Cycle Proteins/metabolism , Cell Line , Cysteine Endopeptidases/metabolism , DNA Primers , Fluorescent Antibody Technique , Membrane Glycoproteins/genetics , Membrane Glycoproteins/metabolism , Molecular Sequence Data , Multienzyme Complexes/metabolism , Mutagenesis, Site-Directed , Nerve Tissue Proteins/metabolism , Neural Cell Adhesion Molecule L1/genetics , Neural Cell Adhesion Molecule L1/metabolism , Proteasome Endopeptidase Complex , Receptors, Immunologic/genetics , Receptors, Immunologic/metabolism , S-Phase Kinase-Associated Proteins/metabolismABSTRACT
The adhesion receptor SHPS-1 activates the protein-tyrosine-phosphatase SHP-2 and thereby promotes integrin-mediated reorganization of the cytoskeleton. SHPS-1 also contributes to cell-cell communication through association with CD47. Although functional alteration of SHPS-1 is implicated in cellular transformation, the role of the CD47-SHPS-1 interaction in carcinogenesis has been unclear. A soluble SHPS-1 ligand (CD47-Fc) has now been shown to bind to Melan-a non-tumorigenic melanocytes but not to syngeneic B16F10 melanoma cells. Treatment of B16F10 cells with 1-deoxymannojirimycin, which prevents N-glycan processing, restored the ability of SHPS-1 derived from these cells to bind CD47-Fc in vitro, indicating that aberrant N-glycosylation of SHPS-1 impairs CD47 binding in B16F10 cells. CD47-Fc inhibited the migration of Melan-a cells but not that of B16F10 cells. However, a monoclonal antibody that reacts with SHPS-1 on both Melan-a and B16F10 cells inhibited the migration of both cell types similarly. CD47 binding induced proteasome-mediated degradation of SHPS-1 in a tyrosine phosphorylation-independent manner. Furthermore, overexpression of SHPS-1 reduced the level of tyrosine phosphorylation of focal adhesion kinase, and this effect was reversed by CD47 binding. These results suggest that CD47 binds to and thereby down-regulates SHPS-1 on adjacent cells, resulting in inhibition of cell motility. Resistance to this inhibitory mechanism may contribute to the highly metastatic potential of B16 melanoma.
