Eun Ky Kim

Prevalence and Clinical Characteristics of Recently Diagnosed Type 2 Diabetes Patients with Positive Anti-Glutamic Acid Decarboxylase Antibody

Background Latent autoimmune diabetes in adults (LADA) refers to a specific type of diabetes characterized by adult onset, presence of islet auto-antibodies, insulin independence at the time of diagnosis, and rapid decline in β-cell function. The prevalence of LADA among patients with type 2 diabetes varies from 2% to 20% according to the study population. Since most studies on the prevalence of LADA performed in Korea were conducted in patients who had been tested for anti-glutamic acid decarboxylase antibody (GADAb), a selection bias could not be excluded. In this study, we examined the prevalence and clinical characteristics of LADA among adult patients recently diagnosed with type 2 diabetes. Methods We included 462 patients who were diagnosed with type 2 diabetes within 5 years from the time this study was performed. We measured GADAb, fasting insulin level, fasting C-peptide level, fasting plasma glucose level, HbA1c, and serum lipid profiles and collected data on clinical characteristics. Results The prevalence of LADA was 4.3% (20/462) among adult patients with newly diagnosed type 2 diabetes. Compared with the GADAb-negative patients, the GADAb-positive patients had lower fasting C-peptide levels (1.2±0.8 ng/mL vs. 2.0±1.2 ng/mL, P=0.004). Other metabolic features were not significantly different between the two groups. Conclusion The prevalence of LADA is 4.3% among Korean adult patients with recently diagnosed type 2 diabetes. The Korean LADA patients exhibited decreased insulin secretory capacity as reflected by lower C-peptide levels.

Decreasing Trends of the Prevalence of Diabetes and Obesity in Korean Women Aged 30–59 Years Over the Past Decade: Results From the Korean National Health and Nutrition Examination Survey, 2001–2010

The prevalence of diabetes in South Korea reached 9 to ∼10% in adults aged ≥30 years and remained stable in the 2000s (1,2). Even though the Korean population is rapidly aging, the proportion of the elderly population aged ≥65 years has been increasing over the past 10 years from 7.2% of the total population in 2000 to 11.0% in 2010 (3). We investigated the change in the prevalence of diabetes in Korean adults aged ≥30 years with respect to age, using data from the Korean National Health and Nutritional Examination Survey (KNHANES) 2001–2010. Subjects with diabetes were defined as users of antidiabetic medication, including insulin, at the point of the survey or as individuals with an 8-h fasting plasma glucose …

Identification and Functional Characterization of P159L Mutation in HNF1B in a Family with Maturity-Onset Diabetes of the Young 5 (MODY5)

Mutation in HNF1B, the hepatocyte nuclear factor-1β (HNF-1β) gene, results in maturity-onset diabetes of the young (MODY) 5, which is characterized by gradual impairment of insulin secretion. However, the functional role of HNF-1β in insulin secretion and glucose metabolism is not fully understood. We identified a family with early-onset diabetes that fulfilled the criteria of MODY. Sanger sequencing revealed that a heterozygous P159L (CCT to CTT in codon 159 in the DNA-binding domain) mutation in HNF1B was segregated according to the affected status. To investigate the functional consequences of this HNF1B mutation, we generated a P159L HNF1B construct. The wild-type and mutant HNF1B constructs were transfected into COS-7 cells in the presence of the promoter sequence of human glucose transporter type 2 (GLUT2). The luciferase reporter assay revealed that P159L HNF1B had decreased transcriptional activity compared to wild-type (p < 0.05). Electrophoretic mobility shift assay showed reduced DNA binding activity of P159L HNF1B. In the MIN6 pancreatic β-cell line, overexpression of the P159L mutant was significantly associated with decreased mRNA levels of GLUT2 compared to wild-type (p < 0.05). However, INS expression was not different between the wild-type and mutant HNF1B constructs. These findings suggests that the impaired insulin secretion in this family with the P159L HNF1B mutation may be related to altered GLUT2 expression in β-cells rather than decreased insulin gene expression. In conclusion, we have identified a Korean family with an HNF1B mutation and characterized its effect on the pathogenesis of diabetes.

Radiographic Characteristics of Adrenal Masses in Oncologic Patients

Background We aimed to assess the usefulness of pre-contrast Hounsfield unit (HU) and mass size on computed tomography to differentiate adrenal mass found incidentally in oncologic patients. Methods From 2000 to 2012, 131 oncologic patients with adrenal incidentaloma were reviewed retrospectively. Receiver operating characteristic (ROC) curves were applied to determine the optimal cut-off value of the mean HU and size for detecting adrenal metastasis. Results The median age was 18 years, and 80 patients were male. The initial mass size was 18 mm, and 71 (54.2%) of these were on the left side. A bilateral adrenal mass was found in 11 patients (8.4%). Biochemically functional masses were observed in 9.2% of patients. Thirty-six out of 119 patients with nonfunctional masses underwent adrenalectomy, which revealed metastasis in 13. The primary cancers were lung cancer (n=4), renal cell carcinoma (n=2), lymphoma (n=2), hepatocellular carcinoma (n=2), breast cancer (n=1), and others (n=2). The area under the curve for the size and HU for clinically suspicious metastasis were 0.839 (95% confidence interval [CI], 0.761 to 0.900; P<0.001) and 0.959 (95% CI, 0.898 to 0.988; P<0.001), respectively. The cut-off value to distinguish between metastasis and benign masses were 22 mm for size and 20 for HU. Conclusion ROC curve results suggest that pre-contrast HU >20 can be used as a diagnostic reference to suggest metastasis in oncologic patients with adrenal masses.

Feasibility of a Patient-Centered, Smartphone-Based, Diabetes Care System: A Pilot Study

Background We developed a patient-centered, smartphone-based, diabetes care system (PSDCS). This study aims to test the feasibility of glycosylated hemoglobin (HbA1c) reduction with the PSDCS. Methods This study was a single-arm pilot study. The participants with type 2 diabetes mellitus were instructed to use the PSDCS, which integrates a Bluetooth-connected glucometer, digital food diary, and wearable physical activity monitoring device. The primary end point was the change in HbA1c from baseline after a 12-week intervention. Results Twenty-nine patients aged 53.9±9.1 years completed the study. HbA1c and fasting plasma glucose levels decreased significantly from baseline (7.7%±0.7% to 7.1%±0.6%, P<0.0001; 140.9±39.1 to 120.1±31.0 mg/dL, P=0.0088, respectively). The frequency of glucose monitoring correlated with the magnitude of HbA1c reduction (r=–0.57, P=0.0013). The components of the diabetes self-care activities, including diet, exercise, and glucose monitoring, were significantly improved, particularly in the upper tertile of HbA1c reduction. There were no severe adverse events during the intervention. Conclusion A 12-week application of the PSDCS to patients with inadequately controlled type 2 diabetes resulted in a significant HbA1c reduction with tolerable safety profiles; these findings require confirmation in a future randomized controlled trial.

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

Background Subjects with normal glucose tolerance (NGT) who have a high 1-hour postload plasma glucose level (≥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 β-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 β-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 β-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 β-cell function to a similar degree as IGT subjects.

Effect of carnitine-orotate complex on glucose metabolism and fatty liver: A double-blind, placebo-controlled study

Effective medicines have not been introduced for insulin resistance‐related fatty liver. The efficacy and safety of treatment between a combination of metformin and carnitine‐orotate complex and metformin alone in a 12‐week, double‐blind, randomized, placebo‐controlled study on drug‐naïve patients with impaired glucose metabolism and fatty liver were compared.

Effects of gemigliptin, a dipeptidyl peptidase-4 inhibitor, on lipid metabolism and endotoxemia after a high-fat meal in patients with type 2 diabetes

We aimed to investigate the effects of gemigliptin, a dipeptidyl peptidase‐4 inhibitor, on postprandial lipoprotein levels and endotoxemia in a randomized, double‐blind, placebo‐controlled, crossover study. Ten people with type 2 diabetes mellitus (T2DM), inadequately controlled with oral antidiabetic medications and/or lifestyle modification, were randomized to gemigliptin or placebo for 4 weeks. At the end of each treatment phase, the study participants underwent a high‐fat meal tolerance test and needle aspiration of abdominal subcutaneous adipose tissue. The median (range) fasting and total area under the curve of apolipoprotein B48 (ApoB48) were significantly lower with gemigliptin than with placebo (2.9 [1.5‐15.8] µg/mL vs 4.2 [1.3‐23.4] µg/mL; P = .020; 35.3 [14.4‐87.4] µg/mL × hour vs 42.2 [17.5‐109.0] µg/mL × hour; P = .020, respectively), whereas apolipoprotein B100 showed no significant difference. Serum endotoxin levels were undetectable in 70% of the samples, so we were not able to evaluate the effect of gemigliptin on endotoxemia. The gene expression of inflammatory cytokines in subcutaneous adipose tissue was not affected by gemigliptin. Gemigliptin reduced ApoB48 levels after a high‐fat meal in participants with T2DM. Whether systemic endotoxin levels can be reduced by gemigliptin requires further investigation.

Improving Effect of the Acute Administration of Dietary Fiber-Enriched Cereals on Blood Glucose Levels and Gut Hormone Secretion

Dietary fiber improves hyperglycemia in patients with type 2 diabetes through its physicochemical properties and possible modulation of gut hormone secretion, such as glucagon-like peptide 1 (GLP-1). We assessed the effect of dietary fiber-enriched cereal flakes (DC) on postprandial hyperglycemia and gut hormone secretion in patients with type 2 diabetes. Thirteen participants ate isocaloric meals based on either DC or conventional cereal flakes (CC) in a crossover design. DC or CC was provided for dinner, night snack on day 1 and breakfast on day 2, followed by a high-fat lunch. On day 2, the levels of plasma glucose, GLP-1, glucose-dependent insulinotropic polypeptide (GIP), and insulin were measured. Compared to CC, DC intake exhibited a lower post-breakfast 2-hours glucose level (198.5±12.8 vs. 245.9±15.2 mg/dL, P<0.05) and a lower incremental peak of glucose from baseline (101.8±9.1 vs. 140.3±14.3 mg/dL, P<0.001). The incremental area under the curve (iAUC) of glucose after breakfast was lower with DC than with CC (P<0.001). However, there were no differences in the plasma insulin, glucagon, GLP-1, and GIP levels. In conclusion, acute administration of DC attenuates postprandial hyperglycemia without any significant change in the representative glucose-regulating hormones in patients with type 2 diabetes (ClinicalTrials.gov. NCT 01997281).

An insulinoma with an aberrant feeder from the splenic artery detected by super-selective arterial calcium stimulation with venous sampling

To the Editor, A pancreatic insulinoma is a rare endocrine neoplasm with an estimated incidence of four cases per million person-years. Because the typical size of an insulinoma is < 2 cm, computed tomography (CT) or magnetic resonance imaging (MRI) may not detect the location of the tumor. The sensitivity of detecting an insulinoma is 70% to 80% for CT, 85% for MRI, and 85% to 90% for endoscopic ultrasound (EUS) [1]. Selective arterial calcium stimulation with hepatic venous sampling (ASVS) is a good complementary tool that increases the sensitivity to 84% to 100% [2]. However, ASVS does not always locate the insulinoma, and equivocal findings are reported frequently. We hereby report a case of an insulinoma in the pancreatic head with an aberrant feeder artery arising from the splenic artery, which was detected by angiography and super-selective ASVS. A 50-year-old woman, who had never been diagnosed with diabetes mellitus, was admitted to a local emergency department for loss of consciousness. Her capillary blood glucose level was 41 mg/dL, and she recovered consciousness immediately after intravenous glucose administration. An abdominal CT scan did not indicate any definite pancreatic mass (Fig. 1A). Therefore, she was referred to our hospital for further evaluation. Figure 1 (A) Abdominal computed tomography image. (B) No definite mass was found. Celiac arteriography shows the tumor (arrow) and the feeding artery (arrowheads) originating from the proximal splenic artery. Her medical history was unremarkable, and she had no family history of endocrine disease. She had suffered from fatigue and dizziness for the last 6 months. No specific findings were revealed on a physical examination. Laboratory results, including a complete blood cell count and basic chemistry tests, were within normal ranges. A 72-hour fasting test was performed but was terminated after 2 hour due to symptomatic hypoglycemia. Her serum glucose level was 51 mg/dL, and she felt severe fatigue. Serum insulin (9.9 mIU/mL) and C-peptide (2.2 ng/mL) levels were elevated sufficiently to diagnose inappropriate endogenous hyperinsulinemia. Because we thought that the size of the potential insulinoma was very small, no further imaging studies, including EUS, were performed. ASVS was performed to identify and localize the insulin-secreting tumor. First, celiac and superior mesenteric arteriography was performed. A small hypervascular tumor in the pancreatic head and a feeding artery originating from the proximal portion of the splenic artery were observed (Fig. 1B). Blood samples were obtained from the hepatic vein 0, 30, 60, and 120 seconds after injecting 5 mL calcium gluconate diluted in normal saline (0.025 mEq/kg) via the superior mesenteric artery, gastroduodenal artery, splenic artery, and the feeder artery originating from the splenic artery. Serum insulin and C-peptide levels are shown in Fig. 2. Figure 2 Insulin (A) and C-peptide (B) levels in hepatic venous blood samples after selective arterial calcium stimulation of three major pancreatic arteries and the feeder artery. Insets depict insulin and C-peptide levels after calcium stimulation of three major ... Insulin and C-peptide levels in the splenic artery during conventional ASVS were higher than those in the superior mesenteric or gastroduodenal arteries. We took a step further using super-selective ASVS on the aberrant feeder artery from the splenic artery. The results showed remarkable increases in insulin and C-peptide secretion (Fig. 2), indicating that the tumor stained in the pancreatic head was an insulinoma. A pylorus-preserving pancreaticoduodenectomy was performed without complications. The pathology was consistent with a well-differentiated benign endocrine tumor based on the 2000 World Health Organization Classification for Pancreatic Endocrine Neoplasms. The tumor was 1.4 × 0.7 × 0.5 cm3 in size, the mitotic count was < 1/10 at a high power field, and Ki-67 was positive in 0.27% (15/5,524) of the tumor cells. Immunohistochemical studies revealed that most of the tumor cells were positive for chromogranin, synaptophysin, insulin, and CD56, but negative for glucagon, somatostatin, carcinoembryonic antigen, and mucin-1 (Fig. 3). The premeal capillary blood glucose level recovered after surgery and was maintained within 100 to 150 mg/dL. Her fasting plasma glucose level was 89 mg/dL at the 3-month follow-up. Serum insulin and C-peptide levels decreased to 1.4 mIU/mL and 1.2 ng/mL, respectively. She did not experience hypoglycemic symptoms. Figure 3 (A-F) Immunohistochemical staining of the insulinoma (×200). Hematoxylin and eosin staining of the insulinoma is consistent with a neuroendocrine tumor (A). The proportion of Ki-67-positive cells (arrowheads) was 0.27% (15/5,524) of tumor cells ... This was a case of a pancreatic head insulinoma supplied by an aberrant artery from the splenic artery. Conventional ASVS assumes two distinctive portions of the pancreas: the pancreatic head portion supplied by the superior mesenteric or gastroduodenal artery and the pancreatic body to tail portion supplied by the splenic artery. However, many variations in pancreatic vascular anatomy have been reported, particularly in the head portion. Okahara et al. [3] found that 36% of inferior pancreaticoduodenal arteries arose from branches other than the superior mesenteric artery, and that 2% of the superior pancreaticoduodenal arteries arose from branches other than the gastroduodenal artery. An insulinoma with an aberrant feeder artery, as in our case, has not yet been reported. Two studies on super-selective ASVS have been published [4,5]. However, these studies performed intra-arterial calcium stimulation through the splenic artery divided into proximal, middle, and distal portions, whereas we selected the tumor feeding artery specifically. Notably, the results of conventional ASVS indicated that the insulinoma could be in the pancreatic body or the tail portion, because higher insulin and C-peptide levels were obtained via the splenic artery compared with the superior mesenteric or gastroduodenal arteries. However, peak insulin levels 60 seconds after the calcium injection via the feeder artery was in hundreds of basal insulin levels of the three major arteries supplying the pancreas. We could have resected the pancreatic body and tail if we had not found tumor staining in the pancreatic head and its feeder artery. As such, super-selective ASVS was necessary to localize and functionally diagnose the insulinoma accurately. Interestingly, baseline insulin and C-peptide levels were highly elevated compared with those of the three major arteries supplying the pancreas during super-selective ASVS for the feeder artery. One study reported elevated insulin levels in tumor-supplying arteries before calcium stimulation, as in our case [4]. This finding can be explained by delayed calcium perfusion into the insulinoma from prior stimulation tests or by the radiocontrast media used during angiography. A 15-minute interval between stimulations has been suggested to avoid this delayed effect [4]. In conclusion, this case report emphasizes the importance of careful angiography and super-selective ASVS to diagnose suspicious insulinomas that are difficult to locate using conventional imaging methods.