A Case Series of Ketoacidosis After Coronavirus Disease 2019 Vaccination in Patients With Type 1 Diabetes.

Introduction: We report a case series of severe ketoacidosis after COVID-19 vaccination in a type 1 diabetes patients treated with insulin and an SGLT-2 inhibitor. Case Report: We present two cases of type 1 diabetes mellitus. One patient was treated with insulin therapy and an SGLT-2 inhibitor, and the other patient was treated with insulin therapy alone. Both patients became ill after coronavirus disease-2019 vaccination, making it difficult to continue their diet or insulin injections. On admission, they developed severe diabetic ketoacidosis. This is the first report of ketoacidosis after coronavirus disease-2019 vaccination. Conclusion: The vaccine should be carefully administered to type 1 diabetes patients receiving intensive insulin therapy and a sodium-glucose transporter due to the high risk ketoacidosis. It is important to instruct patients to drink sufficient fluids and to continue insulin injections when they become sick.

The association between impaired proinsulin processing and type 2 diabetes mellitus in non-obese Japanese individuals.

We aimed to examine the association between impaired proinsulin processing in pancreatic beta cells and type 2 diabetes mellitus in non-obese Japanese patients. Participants were divided into groups for normal glucose tolerance, prediabetes, and type 2 diabetes based on the oral glucose tolerance test (OGTT). Activities of prohormone convertase (PC) 1/3 and PC2 in fasting states were estimated. Multiple regression analysis was undertaken to ascertain if alteration of the activities of these enzymes contributes to the development of impaired glucose tolerance by comparison with HOMA-ß and the oral disposition index (DI(O)). Overall, 452 subjects were included. PC1/3 activity tended to decrease in type 2 diabetes compared with normal glucose tolerance. PC2 activity showed no difference among the three groups. Decreased estimated PC1/3 activity was significantly associated with type 2 diabetes after adjustment for sex, age, creatinine, triglycerides, HOMA-ß and DI(O). Odds ratios (95% CI) of PC1/3, HOMA-ß, and DI(O) were 2.16 (1.12-4.19), 3.44 (1.82-6.52) and 14.60 (7.87-27.11), respectively. Furthermore, decreased PC1/3(≤1.7) combined with decreased HOMA-ß (≤30) had a sensitivity of 73% and specificity of 62%. Decreased PC1/3 activity may be a useful measurement of beta-cell function alongside decreased HOMA-ß or DI(O). A combined decrease in estimated fasting PC1/3 activity and HOMA-ß measurement led to suspicion of type 2 diabetes in the non-obese Japanese population studied.

Estimated proinsulin processing activity of prohormone convertase (PC) 1/3 rather than PC2 is decreased in pancreatic ß-cells of type 2 diabetic patients.

Type 2 diabetic (T2D) patients exhibit fasting relative hyperproinsulinemia owing to pancreatic ß-cell dysfunction. To clarify the mechanism underlying this hyperproinsulinemic state, we evaluated the activities of the endopeptidases prohormone convertase (PC) 1/3 and PC2 in T2D patients. Fasting blood levels of intact proinsulin (IPI), total proinsulin (t-PI) and C-peptide were measured simultaneously, and intravenous glucagon loading was performed to investigate the dynamics of circulating proinsulin-related molecules released from pancreatic ß-cells in 12 healthy volunteers and 18 T2D patients. Taking advantage of the 95% cross-reactivity between proinsulin and des-31,32-proinsulin (des-31,32-PI) with the human proinsulin radioimmunoassay kit used in this study, we estimated PC1/3 and PC2 activities using the following formulas: des-31,32-PI = (t-PI-IPI)/0.95; PC1/3 activity = des-31,32-PI/IPI; and PC2 activity = C-peptide/des-31,32-PI. C-peptide responses to glucagon were slightly lower among T2D patients. IPI and the IPI/C-peptide ratio were significantly higher in T2D patients (p<0.05 and p<0.01, respectively). There was no difference in des-31,32-PI levels or PC2 activity between the two groups. However, PC1/3 activity was significantly lower in T2D patients than in the control group (p<0.01). We propose that decreased activity of PC1/3 rather than PC2 in pancreatic ß-cells is involved in the impaired proinsulin processing, resulting in elevated IPI levels in T2D patients.

Activators of AMP-activated protein kinase enhance GLUT4 translocation and its glucose transport activity in 3T3-L1 adipocytes.

To determine whether the increase in glucose uptake following AMP-activated protein kinase (AMPK) activation in adipocytes is mediated by accelerated GLUT4 translocation into plasma membrane, we constructed a chimera between GLUT4 and enhanced green fluorescent protein (GLUT4-eGFP) and transferred its cDNA into the nucleus of 3T3-L1 adipocytes. Then, the dynamics of GLUT4-eGFP translocation were visualized in living cells by means of laser scanning confocal microscopy. It was revealed that the stimulation with 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR) and 2,4-dinitrophenol (DNP), known activators of AMPK, promptly accelerates its translocation within 4 min, as was found in the case of insulin stimulation. The insulin-induced GLUT4 translocation was markedly inhibited after addition of wortmannin (P < 0.01). However, the GLUT4 translocation through AMPK activators AICAR and DNP was not affected by wortmannin. Insulin- and AMPK-activated translocation of GLUT4 was not inhibited by SB-203580, an inhibitor of p38 mitogen-activated protein kinase (MAPK). Glucose uptake was significantly increased after addition of AMPK activators AICAR and DNP (P < 0.05). AMPK- and insulin-stimulated glucose uptake were similarly suppressed by wortmannin (P < 0.05-0.01). In addition, SB-203580 also significantly prevented the enhancement of glucose uptake induced by AMPK and insulin (P < 0.05). These results suggest that AMPK-activated GLUT4 translocation in 3T3-L1 adipocytes is mediated through the insulin-signaling pathway distal to the site of activated phosphatidylinositol 3-kinase or through a signaling system distinct from that activated by insulin. On the other hand, the increase of glucose uptake dependent on AMPK activators AICAR and DNP would be additionally due to enhancement of the intrinsic activity in translocated GLUT4 protein, possibly through a p38 MAPK-dependent mechanism.

PPAR-gamma overexpression selectively suppresses insulin secretory capacity in isolated pancreatic islets through induction of UCP-2 protein.

Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) regulates several cellular functions, but its physiological role in pancreatic islet cells remains to be investigated. In this study, we confirmed the presence of PPAR-gamma in rat isolated islets and examined its role on insulin and glucagon secretion by using PPAR-gamma-overexpressed islets. PPAR-gamma overexpression significantly suppressed insulin secretion induced by stimulatory concentration of glucose (p<0.05). In addition, insulin secretion evoked by high potassium depolarization also was significantly decreased from PPAR-gamma-overexpressed islets (p<0.05). On the other hand, no significant change in glucagon release was observed after high potassium depolarization between PPAR-gamma-overexpressed and control islets. Insulin and glucagon content in islets was not statistically different between the two groups. In addition, the expression of uncoupling protein-2 (UCP-2) was found to be induced in PPAR-gamma-overexpressed islets. This result clearly indicates that the deteriorative effect of PPAR-gamma overexpression on the secretory machinery is selective for pancreatic beta-cells. And it is possible that its site of action can be located in the energy-consuming exocytotic process of insulin secretory granules, and that the reduction of ATP production through increased UCP-2 reduces insulin exocytosis.

Pioglitazone improves insulin secretory capacity and prevents the loss of beta-cell mass in obese diabetic db/db mice: Possible protection of beta cells from oxidative stress.

In order to assess the beneficial effect of the peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonist pioglitazone on reduction of mass and alteration of function of pancreatic beta cells under diabetic conditions, diabetic C57BL/KsJ db/db mice were treated with pioglitazone for 6 weeks, and insulin secretory capacity and insulin content of isolated pancreatic islets were evaluated. In addition, the expression of oxidative stress markers, 4-hydroxy-2-nonenal (HNE)-modified proteins and heme oxygenase-1, in endocrine pancreas was examined to measure reduction of oxidative stress in pancreatic beta cells. The capacity for glucose-induced insulin secretion from isolated islets and their insulin content were improved by pioglitazone treatment (P <.01). When beta cells were stained with anti-insulin antibodies, those of db/db mice treated with pioglitazone exhibited strong staining, as also observed in their lean littermates. The density of immunostaining for oxidative stress markers was significantly reduced in pancreatic islets of pioglitazone-treated db/db mice (P <.05). This study clearly demonstrates the benefit of long-term treatment with pioglitazone in decreasing hyperglycemia and improving glucose-induced insulin secretory capacity in diabetic db/db mice. The results of immunocytochemical examination suggest that this treatment reduces oxidative stress and thereby preserves beta-cell mass. Treatment with pioglitazone thus protects against beta-cell damage and would be useful for restoration of insulin secretory capacity in obese diabetes individuals.

Insulinotropic action of glutamate is dependent on the inhibition of ATP-sensitive potassium channel activities in MIN 6 beta cells.

To investigate the cellular mechanism of insulinotropic effect of glutamate in pancreatic beta cells, we utilized patch-clamp technique to monitor directly the activities of ATP-sensitive potassium channels (K(ATP) channels). Dimethylglutamate (5mM), a membrane-permeable analog of glutamate, augmented the insulin release induced by the stimulatory concentrations of glucose (p<0.05-0.01). In the cell-attached configurations, dimethylglutamate reversibly and significantly suppressed the K(ATP) channel activities (p<0.01). On the other hand, no significant effect was observed when glutamate itself was applied to the inside-out patches, whereas the prompt and reversible suppression was recorded in the case of ATP (p<0.01). These results indicate that the insulinotropic action of glutamate in beta cells could be derived from the inhibition of K(ATP) channel activities, probably due to generation of messengers via intracellular metabolism such as ATP.

Pancreatic endocrine function and glucose transporter (GLUT)-2 expression in rat acute pancreatitis.

INTRODUCTION: Impairment in pancreatic endocrine function is believed to play an important role in the development of glucose intolerance in acute pancreatitis. AIM: To investigate the functional aspects of endocrine cells in acute pancreatitis and the expression of glucose transporter (GLUT) 2 in the pancreatitis islet. METHODOLOGY: A mild form of acute pancreatitis was induced in rats by an injection of a sodium taurocholate solution via a cannulated biliopancreatic duct. Isolated islets were stimulated by glucose, and insulin secretion was analyzed by radioimmunoassay. Immunohistochemical detection of GLUT2 with use of a specific antibody was attempted to determine GLUT2 expression in pancreatic islets. RESULTS: A marked elevation of glucose levels observed in the current rat pancreatitis model confirmed that glucose intolerance can occur even in a mild form of pancreatitis. The architecture of the islets, however, remained intact despite marked inflammatory changes in the neighboring exocrine region. Insulin secretion studies revealed that the ability of islets to secrete insulin in response to glucose was markedly reduced in pancreatitis islets. GLUT2 immunoreactivity in endocrine cells was found to be intact in pancreatitis islets. CONCLUSION: The amount of insulin released from isolated islets following glucose stimulation is reduced in acute edematous pancreatitis, although pancreatic islets remain histologically intact. On the basis of the present findings, it appears that although the mechanisms responsible for this functional deficiency remain to be determined, the decrease in insulin secretion is possibly caused by impairment of some pancreatic B-cell functions rather than GLUT2-mediated glucose transportation.