Comparison of Prevailing Insulin Regimens at Different Time Periods in Hospitalized Patients: A Real-World Experience from a Tertiary Hospital

Background@#Prevailing insulin regimens for glycemic control in hospitalized patients have changed over time. We aimed to determine whether the current basal-bolus insulin (BBI) regimen is superior to the previous insulin regimen, mainly comprising split-mixed insulin therapy. @*Methods@#This was a single tertiary center, retrospective observational study that included non-critically ill patients with type 2 diabetes mellitus who were treated with split-mixed insulin regimens from 2004 to 2007 (period 1) and with BBI from 2008 to 2018 (period 2). Patients from each period were analyzed after propensity score matching. The mean difference in glucose levels and the achievement of fasting and preprandial glycemic targets by day 6 of admission were assessed. The total daily insulin dose, incidence of hypoglycemia, and length of hospital stay were also evaluated. @*Results@#Among 244 patients from each period, both fasting glucose (estimated mean±standard error, 147.4±3.1 mg/dL vs. 129.4±3.2 mg/dL, P<0.001, day 6) and preprandial glucose (177.7±2.8 mg/dL vs. 152.8±2.8 mg/dL, P<0.001, day 6) were lower in period 2 than in period 1. By day 6 of hospital admission, 42.6% and 67.2% of patients achieved a preprandial glycemic target of <140 mg/dL in periods 1 and 2, respectively (relative risk, 2.00; 95% confidence interval, 1.54 to 2.59), without an increased incidence of hypoglycemia. Length of stay was shorter in period 2 (10.23±0.26 days vs. 8.70±0.26 days, P<0.001). @*Conclusion@#BBI improved glycemic control in a more efficacious manner than a split-mixed insulin regimen without increasing the risk of hypoglycemia in a hospital setting.

Efficacy and Safety of Self-Titration Algorithms of Insulin Glargine 300 units/mL in Individuals with Uncontrolled Type 2 Diabetes Mellitus (The Korean TITRATION Study): A Randomized Controlled Trial

Background@#To compare the efficacy and safety of two insulin self-titration algorithms, Implementing New Strategies with Insulin Glargine for Hyperglycemia Treatment (INSIGHT) and EDITION, for insulin glargine 300 units/mL (Gla-300) in Korean individuals with uncontrolled type 2 diabetes mellitus (T2DM). @*Methods@#In a 12-week, randomized, open-label trial, individuals with uncontrolled T2DM requiring basal insulin were randomized to either the INSIGHT (adjusted by 1 unit/day) or EDITION (adjusted by 3 units/week) algorithm to achieve a fasting self-monitoring of blood glucose (SMBG) in the range of 4.4 to 5.6 mmol/L. The primary outcome was the proportion of individuals achieving a fasting SMBG ≤5.6 mmol/L without noct urnal hypoglycemia at week 12. @*Results@#Of 129 individuals (age, 64.1±9.5 years; 66 [51.2%] women), 65 and 64 were randomized to the INSIGHT and EDITION algorithms, respectively. The primary outcome of achievement was comparable between the two groups (24.6% vs. 23.4%, P=0.876). Compared with the EDITION group, the INSIGHT group had a greater reduction in 7-point SMBG but a similar decrease in fasting plasma glucose and glycosylated hemoglobin. The increment of total daily insulin dose was significantly higher in the INSIGHT group than in the EDITION group (between-group difference: 5.8±2.7 units/day, P=0.033). However, body weight was significantly increased only in the EDITION group (0.6±2.4 kg, P=0.038). There was no difference in the occurrence of hypoglycemia between the two groups. Patient satisfaction was significantly increased in the INSIGHT group (P=0.014). @*Conclusion@#The self-titration of Gla-300 using the INSIGHT algorithm was effective and safe compared with that using the EDITION algorithm in Korean individuals with uncontrolled T2DM (ClinicalTrials.gov number: NCT03406663).

Endoplasmic Reticulum Stress and Dysregulated Autophagy in Human Pancreatic Beta Cells

Pancreatic beta cell homeostasis is crucial for the synthesis and secretion of insulin; disruption of homeostasis causes diabetes, and is a treatment target. Adaptation to endoplasmic reticulum (ER) stress through the unfolded protein response (UPR) and adequate regulation of autophagy, which are closely linked, play essential roles in this homeostasis. In diabetes, the UPR and autophagy are dysregulated, which leads to beta cell failure and death. Various studies have explored methods to preserve pancreatic beta cell function and mass by relieving ER stress and regulating autophagic activity. To promote clinical translation of these research results to potential therapeutics for diabetes, we summarize the current knowledge on ER stress and autophagy in human insulin-secreting cells.

Letter: Early Assessment of the Risk for Gestational Diabetes Mellitus: Can Fasting Parameters of Glucose Metabolism Contribute to Risk Prediction? (Diabetes Metab J 2019;43:785–93)

No abstract available.

Response: Favorable Glycemic Control with Once-Daily Insulin Degludec/Insulin Aspart after Changing from Basal Insulin in Adults with Type 2 Diabetes (Endocrinol Metab 2019; 34:382-9, Han Na Jang et al.)

No abstract available.

Favorable Glycemic Control with Once-Daily Insulin Degludec/Insulin Aspart after Changing from Basal Insulin in Adults with Type 2 Diabetes

BACKGROUND: Conflicting results have been reported on the efficacy of insulin degludec/insulin aspart (IDegAsp) compared to basal insulin in type 2 diabetes. We investigated the effects of changing basal insulin to IDegAsp on glycemic control and sought to identify factors related to those effects.METHODS: In this retrospective study of patients from three referral hospitals, patients with type 2 diabetes using basal insulin with hemoglobin A1c (HbA1c) levels less than 11.0% were enrolled. Basal insulin was replaced with IDegAsp, and data were analyzed from 3 months before to 3 months after the replacement.RESULTS: Eighty patients were recruited (52.5% male; mean age, 67.0±9.8 years; mean duration of diabetes, 18.9±8.5 years; mean HbA1c, 8.7%±1.0%). HbA1c levels increased during 3 months of basal insulin use, but significantly decreased after changing to IDegAsp (8.28%±1.10%, P=0.0001). The reduction was significant at 6 months in 35 patients whose longer-term data were available. Patients with a measured fasting plasma glucose (m-FPG) lower than their predicted FPG (p-FPG) by regression from HbA1c showed a significant HbA1c reduction caused by the change to IDegAsp, even without a significantly increased insulin dose. However, patients whose m-FPG was higher than their p-FPG did not experience a significant HbA1c reduction, despite a significantly increased insulin dose. Furthermore, the HbA1c reduction caused by IDegAsp was significant in patients with low fasting C-peptide levels and high insulin doses.CONCLUSION: We observed a significant glucose-lowering effect by replacing basal insulin with IDegAsp, especially in patients with a lower m-FPG than p-FPG.

F-box only protein 9 is an E3 ubiquitin ligase of PPARγ

Peroxisome proliferator-activated receptor gamma (PPARγ) is a critical regulator of carbohydrate and lipid metabolism, adipocyte differentiation and inflammatory response. Post-translational modification of PPARγ and its degradation involve several pathways, including the ubiquitin–proteasome system. Here, we identified F-box only protein 9 (FBXO9) as an E3 ubiquitin ligase of PPARγ. We screened interacting partners of PPARγ using immunoprecipitation and mass spectrometric analysis and identified FBXO9 as an E3 ubiquitin ligase of PPARγ. FBXO9 directly interacted with PPARγ through the activation function-1 domain and ligand-binding domain. FBXO9 decreased the protein stability of PPARγ through induction of ubiquitination. We found that the F-box motif of FBXO9 was required for its ubiquitination function. The activity of PPARγ was significantly decreased by FBXO9 overexpression. Furthermore, FBXO9 overexpression in 3T3-L1 adipocytes resulted in decreased levels of endogenous PPARγ and suppression of adipogenesis. These results suggest that FBXO9 is an important enzyme that regulates the stability and activity of PPARγ through ubiquitination.

Prediction of Diabetes Using Serum C-Peptide

No abstract available.

1,5-Anhydro-D-Glucitol Could Reflect Hypoglycemia Risk in Patients with Type 2 Diabetes Receiving Insulin Therapy

BACKGROUND: The identification of a marker for hypoglycemia could help patients achieve strict glucose control with a lower risk of hypoglycemia. 1,5-Anhydro-D-glucitol (1,5-AG) reflects postprandial hyperglycemia in patients with well-controlled diabetes, which contributes to glycemic variability. Because glycemic variability is related to hypoglycemia, we aimed to evaluate the value of 1,5-AG as a marker of hypoglycemia. METHODS: We enrolled 18 adults with type 2 diabetes mellitus (T2DM) receiving insulin therapy and assessed the occurrence of hypoglycemia within a 3-month period. We measured 1,5-AG level, performed a survey to score the severity of hypoglycemia, and applied a continuous glucose monitoring system (CGMS). RESULTS: 1,5-AG was significantly lower in the high hypoglycemia-score group compared to the low-score group. Additionally, the duration of insulin treatment was significantly longer in the high-score group. Subsequent analyses were adjusted by the duration of insulin treatment and mean blood glucose, which was closely associated with both 1,5-AG level and hypoglycemia risk. In adjusted correlation analyses, 1,5-AG was negatively correlated with hypoglycemia score, area under the curve at 80 mg/dL, and low blood glucose index during CGMS (P=0.068, P=0.033, and P=0.060, respectively). CONCLUSION: 1,5-AG level was negatively associated with hypoglycemia score determined by recall and with documented hypoglycemia after adjusting for mean glucose and duration of insulin treatment. As a result, this level could be a marker of the risk of hypoglycemia in patients with well-controlled T2DM receiving insulin therapy.

Clinical Characteristics of Subjects with Sulfonylurea-Dependent Type 2 Diabetes

BACKGROUND: Even though several oral anti-diabetic drugs (OAD) with various modes of action are replacing sulfonylurea (SU), some patients seem to be dependent on SU for adequate glycemic control. Therefore, we evaluated the clinical characteristics of such patients. METHODS: We selected the patients with type 2 diabetes who met following criteria from 2009 to 2014 at Seoul National University Hospital: glycated hemoglobin (HbA1c) was maintained below 7.5% for at least 6 months under small dose of SU (glimepiride or =1.2% within 3 months or > or =1.5% within 6 months; and after resuming SU, HbA1c reduction was > or =0.8% or reduction of fasting plasma glucose was > or =40 mg/dL within 3 months. Patients with impaired hepatic or renal function, and steroid users were excluded. RESULTS: Nineteen subjects were enrolled: after averaged 4.8+/-1.5 months of SU-free period, HbA1c increased from 6.7%+/-0.4% to 8.8%+/-0.8% even though adding other OAD such as gliptins. However, HbA1c decreased to 7.4%+/-0.7% after resuming SU within 2.4+/-0.8 months. There was no sexual predominance. Despite their old age (67+/-11 years) and long duration of diabetes (18+/-10 years), fasting C-peptide was relatively well-reserved (3.9+/-2.6 ng/mL), and nephropathy was not observed (albumin-creatinine ratio 21.2+/-16.6 mg/g and estimated glomerular filtration rate 75.8+/-18.0 mL/min/1.73 m2). Strong family history was also noted (73.7%). CONCLUSION: Despite hypoglycemia risk of SU, it seemed indispensable for a subset of patients with regard to insulin secretion. Genetic influences would be evaluated.

Response: Normal Glucose Tolerance with a High 1-Hour Postload Plasma Glucose Level Exhibits Decreased beta-Cell Function Similar to Impaired Glucose Tolerance (Diabetes Metab J 2015;39:147-53)

No abstract available.

Association of HLA Genotype and Fulminant Type 1 Diabetes in Koreans

Fulminant type 1 diabetes (T1DM) is a distinct subtype of T1DM that is characterized by rapid onset hyperglycemia, ketoacidosis, absolute insulin deficiency, and near normal levels of glycated hemoglobin at initial presentation. Although it has been reported that class II human leukocyte antigen (HLA) genotype is associated with fulminant T1DM, the genetic predisposition is not fully understood. In this study we investigated the HLA genotype and haplotype in 11 Korean cases of fulminant T1DM using imputation of whole exome sequencing data and compared its frequencies with 413 participants of the Korean Reference Panel. The HLA-DRB1*04:05-HLA-DQB1*04:01 haplotype was significantly associated with increased risk of fulminant T1DM in Fisher's exact test (odds ratio [OR], 4.11; 95% confidence interval [CI], 1.56 to 10.86; p = 0.009). A histidine residue at HLA-DRbeta1 position 13 was marginally associated with increased risk of fulminant T1DM (OR, 2.45; 95% CI ,1.01 to 5.94; p = 0.054). Although we had limited statistical power, we provide evidence that HLA haplotype and amino acid change can be a genetic risk factor of fulminant T1DM in Koreans. Further large-scale research is required to confirm these findings.

Identification of Two Cases of Ciliopathy-Associated Diabetes and Their Mutation Analysis Using Whole Exome Sequencing

BACKGROUND: Alstrom syndrome and Bardet-Biedl syndrome are autosomal recessively inherited ciliopathies with common characteristics of obesity, diabetes, and blindness. Alstrom syndrome is caused by a mutation in the ALMS1 gene, and Bardet-Biedl syndrome is caused by mutations in BBS1-16 genes. Herein we report genetically confirmed cases of Alstrom syndrome and Bardet-Biedl syndrome in Korea using whole exome sequencing. METHODS: Exome capture was done using SureSelect Human All Exon Kit V4+UTRs (Agilent Technologies). HiSeq2000 system (Illumina) was used for massive parallel sequencing. Sanger sequencing was used for genotype confirmation and familial cosegregation analysis. RESULTS: A 21-year old Korean woman was clinically diagnosed with Alstrom syndrome. She had diabetes, blindness, obesity, severe insulin resistance, and hearing loss. Whole exome sequencing revealed a nonsense mutation in exon 10 of ALMS1 (c.8776C>T, p.R2926X) and a seven base-pair deletion resulting in frameshift mutation in exon 8 (c.6410_6416del, p.2137_2139del). A 24-year-old Korean man had Bardet-Biedl syndrome with diabetes, blindness, obesity, and a history of polydactyly. Whole exome sequencing revealed a nonsynonymous mutation in exon 11 of the BBS1 gene (c.1061A>G, p.E354G) and mutation at the normal splicing recognition site of exon 7 of the BBS1 gene (c.519-1G>T). CONCLUSION: We found novel compound heterozygous mutations of Alstrom syndrome and Bardet-Biedl syndrome using whole exome sequencing. The whole exome sequencing successfully identified novel genetic variants of ciliopathy-associated diabetes.

Normal Glucose Tolerance with a High 1-Hour Postload Plasma Glucose Level Exhibits Decreased beta-Cell Function Similar to Impaired Glucose Tolerance

BACKGROUND: Subjects with normal glucose tolerance (NGT) who have a high 1-hour postload plasma glucose level (> or =155 mg/dL; NGT 1 hour-high) have been shown to be at higher risk for type 2 diabetes than subjects with NGT 1 hour-low postload plasma glucose level (<155 mg/dL). We compared beta-cell function in subjects with NGT 1 hour-high, NGT 1 hour-low, and impaired glucose tolerance (IGT). METHODS: We classified subjects into NGT 1 hour-low (n=149), NGT 1 hour-high (n=43), and IGT (n=52). The beta-cell function was assessed based on insulinogenic index (IGI), oral disposition index (DI), and insulin secretion-sensitivity index-2 (ISSI-2). RESULTS: Insulin sensitivity was comparable between the subjects with NGT 1 hour-high and NGT 1 hour-low. The beta-cell function with/without adjusting insulin sensitivity was significantly different among the three groups. The IGI (pmol/mmol) was 116.8+/-107.3 vs. 64.8+/-47.8 vs. 65.8+/-80.6 (P=0.141), oral DI was 3.5+/-4.2 vs. 1.8+/-1.4 vs. 1.8+/-3.1 (P<0.001), and ISSI-2 was 301.2+/-113.7 vs. 213.2+/-67.3 vs. 172.5+/-87.5 (P<0.001) in NGT 1 hour-low, NGT 1 hour-high, and IGT, respectively. Post hoc analyses revealed that oral DI and ISSI-2 were significantly different between NGT 1 hour-low and NGT 1 hour-high but comparable between NGT 1 hour-high and IGT. CONCLUSION: Among Korean subjects with NGT, those who have a higher 1-hour postload glucose level have a compromised insulin-sensitivity adjusted beta-cell function to a similar degree as IGT subjects.

Mitochondrial Complexes I and II Are More Susceptible to Autophagy Deficiency in Mouse beta-Cells

BACKGROUND: Damaged mitochondria are removed by autophagy. Therefore, impairment of autophagy induces the accumulation of damaged mitochondria and mitochondrial dysfunction in most mammalian cells. Here, we investigated mitochondrial function and the expression of mitochondrial complexes in autophagy-related 7 (Atg7)-deficient beta-cells. METHODS: To evaluate the effect of autophagy deficiency on mitochondrial function in pancreatic beta-cells, we isolated islets from Atg7(F/F):RIP-Cre+ mice and wild-type littermates. Oxygen consumption rate and intracellular adenosine 5'-triphosphate (ATP) content were measured. The expression of mitochondrial complex genes in Atg7-deficient islets and in beta-TC6 cells transfected with siAtg7 was measured by quantitative real-time polymerase chain reaction. RESULTS: Baseline oxygen consumption rate of Atg7-deficient islets was significantly lower than that of control islets (P<0.05). Intracellular ATP content of Atg7-deficient islets during glucose stimulation was also significantly lower than that of control islets (P<0.05). By Oxygraph-2k analysis, mitochondrial respiration in Atg7-deficient islets was significantly decreased overall, although state 3 respiration and responses to antimycin A were unaffected. The mRNA levels of mitochondrial complexes I, II, III, and V in Atg7-deficient islets were significantly lower than in control islets (P<0.05). Down-regulation of Atg7 in beta-TC6 cells also reduced the expression of complexes I and II, with marginal significance (P<0.1). CONCLUSION: Impairment of autophagy in pancreatic beta-cells suppressed the expression of some mitochondrial respiratory complexes, and may contribute to mitochondrial dysfunction. Among the complexes, I and II seem to be most vulnerable to autophagy deficiency.

Clinical Implications of Glucose Variability: Chronic Complications of Diabetes

Glucose variability has been identified as a potential risk factor for diabetic complications; oxidative stress is widely regarded as the mechanism by which glycemic variability induces diabetic complications. However, there remains no generally accepted gold standard for assessing glucose variability. Representative indices for measuring intraday variability include calculation of the standard deviation along with the mean amplitude of glycemic excursions (MAGE). MAGE is used to measure major intraday excursions and is easily measured using continuous glucose monitoring systems. Despite a lack of randomized controlled trials, recent clinical data suggest that long-term glycemic variability, as determined by variability in hemoglobin A1c, may contribute to the development of microvascular complications. Intraday glycemic variability is also suggested to accelerate coronary artery disease in high-risk patients.

Bone marrow stem/progenitor cell mobilization in C57BL/6J and BALB/c mice / 한국실험동물학회지

Bone marrow (BM) has been considered as a reservoir of stem/progenitor cells which are able to differentiate into ectodermal, endodermal, and mesodermal origins in vitro as well as in vivo. Following adequate stimulation, such as granulocyte stimulating factor (G-CSF) or AMD3100, BM resident stem/progenitor cells (BMSPCs) can be mobilized to peripheral blood. Several host-related factors are known to participate in this mobilization process. In fact, a significant number of donors are resistant to G-CSF induced mobilization protocols. AMD3100 is currently used in combination with G-CSF. However, information regarding host-related factors which may influence the AMD3100 directed mobilization is extremely limited. In this study, we were to get some more knowledge on the host-related factors that affect the efficiency of AMD3100 induced mobilization by employing in vivo mobilization experiments. As a result, we found that C57BL/6J mice are more sensitive to AMD3100 but less sensitive to G-CSF which promotes the proliferation of BMSPCs. We excluded S1P as one of the host related factor which influences AMD3100 directed mobilization because pre-treatment of S1P receptor antagonist FTY720 did not inhibit BMSPC mobilization. Further in vitro experiments revealed that BALB/c mice, compared to C57BL/6J mice, have less BMSPCs which migrate in response to host related factors such as sphingosine-1-phosphate (S1P) and to CXCL12. We conclude that AMD3100-directed mobilization depends on the number of BMSPCs rather than on the host-related factors. These results suggest that the combination of AMD3100 and G-CSF is co-operative and is optimal for the mobilization of BMSPCs.

Letter: A1c Variability Can Predict Coronary Artery Disease in Patients with Type 2 Diabetes with Mean A1c Level Greater than 7 (Endocrinol Metab 2013;28:125-32, Eun Ju Lee et al.)

No abstract available.

Clinical Characteristics of the Responders to Dipeptidyl Peptidase-4 Inhibitors in Korean Subjects with Type 2 Diabetes

We investigated characteristics associated with the efficacy of dipeptidyl peptidase-4 inhibitors (DPP4i) in Korean patients with type 2 diabetes. We reviewed medical records of 477 patients who had taken sitagliptin or vildagliptin longer than 40 weeks. Response to DPP4i was evaluated with HbA1c change after therapy (DeltaHbA1c). The Student's t-test between good responders (GR: DeltaHbA1c > 1.0%) and poor responders (PR: DeltaHbA1c < 0.5%), a correlation analysis among clinical parameters, and a linear multivariate regression analysis were performed. The mean age was 60 yr, duration of diabetes 11 yr and HbA1c was 8.1%. Baseline fasting plasma glucose (FPG), HbA1c, C-peptide, and creatinine were significantly higher in the GR compared to the PR. Duration of diabetes, FPG, HbA1c, C-peptide and creatinine were significantly correlated with DeltaHbA1c. In the multivariate analysis, age (r2 = 0.006), duration of diabetes (r2 = 0.019), HbA1c (r2 = 0.296), and creatinine levels (r2 = 0.024) were independent predictors for the response to DPP4i. Body mass index and insulin resistance were not associated with the response to DPP4i. In conclusion, better response to DPP4i would be expected in Korean patients with type 2 diabetes who have higher baseline HbA1c and creatinine levels with shorter duration of diabetes.

Transformation of Nonfunctioning Pancreatic Neuroendocrine Carcinoma Cells into Insulin Producing Cells after Treatment with Sunitinib

We report a rare case of severe hypoglycemia after sunitinib treatment for pancreatic neuroendocrine carcinoma. We describe the initial clinical presentation, laboratory results, pathologic findings, and managment in a patient with a nonfunctioning pancreatic neuroendocrine carcinoma with liver metastases who developed life threatening hypoglycemia after 2 months of sunitinib therapy. A 46-year-old woman presented to the emergency department with loss of consciousness from hypoglycemia. Serum C-peptide and insulin levels at fasting state revealed that the hypoglycemia resulted from endogenous hyperinsulinemia. She had been diagnosed with nonfunctioning pancreatic neuroendocrine carcinoma based on a biopsy of metastatic cervical lymph node and was being treated with sunitinib, a small molecule tyrosine kinase inhibitor. Immunohistochemical stain of the metastatic liver mass demonstrated that the initially nonfunctioning neuroendocrine carcinoma cells had changed into insulin-producing cells after sunitinib therapy. Transarterial chemoembolization of the liver masses and systemic chemotherapy with streptozotocin/adriamycin relieved the hypoglycemia. A nonfunctioning pancreatic neuroendocrine carcinoma was transformed into an insulin-producing tumor after treatment with sunitinib, causing endogenous hyperinsulinemia and severe hypoglycemia.