The increase in the number of patients with diabetes has become a worldwide healthcare issue, with numbers predicted to reach approximately 600 million by 2035. In Asia-Pacific region, the prevalence of type 2 diabetes has increased dramatically in recent decades, of which the major causes are believed to be modern lifestyle changes, e.g., Western dietary pattern and reduced physical activity, on their genetic basis of lower insulin secretory capacity. Particularly, in East Asian countries, the amount of fat intake has increased nearly three-fold over this half of century; dietary fat appears to be the major culprit of type 2 diabetes pandemic in East Asia. However, convincing evidence has not yet been provided as to whether high-fat diet causes type 2 diabetes in epidemiological cohort studies. Here, we summarize clinical studies regarding fat intake and type 2 diabetes, and animal studies on high-fat diet-induced diabetes including our recent works on the novel mouse lines (selectively bred diet-induced glucose intolerance-prone [SDG-P] and -resistant [SDG-R]) to address the etiology of high-fat diet-induced diabetes. These epidemiological and experimental findings would provide further insight into the etiology of type 2 diabetes under the modern nutritional environment, namely in the context of increased fat intake.

View full abstract

The impact of postchallenge glucose on the relationship between insulin sensitivity (SI) and secretion (β) is unknown. We analyzed data from 2,264 health examinees (male/female 1,524/740, median age 54 yrs) with normal glucose tolerance (NGT, n = 1,623), non-diabetic hyperglycemia (NDH, n = 555), or diabetes (DM, n = 86) using OGTT-derived indices of SI (insulin sensitivity index [ISI]-Matsuda, 1/HOMA-IR, and 1/fasting IRI) and β (δIRI_0-30/δPG_0-30, and Stumvoll 1st [Stumvoll-1] and 2nd [Stumvoll-2] phases). The combination of 1/HOMA-IR and Stumvoll-1 recapitulated the hyperbolic SI-β relationship with the slope of the fitted line -1.000 in NGT subjects, and therefore it was utilized in the following analysis of the SI-β correlation. In multiple regression analysis of the relationship between SI and β, an independent correlation was found for 1 h-plasma glucose (PG; PG₆₀) but not for 2 h-PG. When the NGT subjects were grouped by PG₆₀ quartile (Q), the fitted line was flat in Q1 but progressively steeper from Q2 to Q4, with a slope (95%CI) of -0.663 (-0.726~-0.605), -0.680 (-0.745~-0.622), -0.847 (-0.922~-0.779), and -1.259 (-1.370~-1.158) (P for trend < 0.05). The fitted line steepened further in the NDH and DM groups, with a slope of -1.545 and -1.915, respectively (P < 0.01 for the difference). The intercept of the fitted line for SI-β correlation was also progressively lower across the PG₆₀ Q for NGT, NDH, and DM. In conclusion, using the 1/HOMA-IR-Stumvoll-1 pair for an analysis of the SI-β relationship, elevated PG₆₀ was associated with steepening and downward shifting of the fitted line for the SI-β correlation. The finding suggests impaired beta cell function.

View full abstract

Although elevated serum gamma-glutamyl transferase activity (GGT) has been linked with metabolic risk factors for sarcopenia, including non-alcoholic fatty liver disease, adiposity, and insulin resistance, whether GGT independently associated with sarcopenia and sarcopenic obesity has not yet been investigated. We analyzed cross-sectional data of 3,193 community-dwelling adults (42.2% men, age 63.4 ± 8.7) aged ≥50 years from the Fifth Korean National Health and Nutrition Examination Survey, 2010-2011. Sarcopenia was defined as a calculated value of the appendicular skeletal muscle mass divided by body weight (ASM/Wt, %) <1 standard deviation below the sex-specific mean for healthy young adults. Sarcopenic obesity was defined as sarcopenia combined with a waist circumference ≥90 cm for men and ≥85 cm for women. The prevalence of sarcopenia and sarcopenic obesity increased stepwise from the lowest to highest GGT quintiles (sarcopenia, 20.2-39.7%; sarcopenic obesity, 7.5-27.3%; P for trend, <0.001). Serum GGT activity was associated negatively with ASM and positively with waist circumference. In multivariate logistic regression analyses, participants in the highest GGT quintile had a 2.3-fold increased risk of sarcopenia and 3.4-fold risk of sarcopenic obesity versus those in the lowest quintile, whereas each single-unit increase in natural log-GGT associated independently with a 35% increased risk of sarcopenia and 62% increased risk of sarcopenic obesity after adjusting for age, sex, body mass index, and other confounders. Elevated serum GGT activity was independently associated with sarcopenia and sarcopenic obesity in community-dwelling older adults.

View full abstract

Luseogliflozin, a selective sodium glucose cotransporter 2 inhibitor, was demonstrated in a previous 24-week study of type 2 diabetic patients to be efficacious and well tolerated. This study mainly aimed to evaluate the long-term safety of luseogliflozin monotherapy in Japanese type 2 diabetic patients based on the Japanese guidelines. Additionally, long-term efficacy was also evaluated. Patients on diet and exercise therapy alone with an HbA1c of 6.9-10.5% received luseogliflozin 2.5 mg once daily for 52 weeks. For patients with insufficient glycemic control, this dose was able to be increased to 5 mg at Week 24. Adverse events (AEs), clinical laboratory tests, vital signs and 12-lead electrocardiograms were used to assess safety. Efficacy endpoints consisted of changes in HbA1c, fasting plasma glucose (FPG), and body weight from baseline. Of 299 patients who received luseogliflozin, 279 completed the study. Most AEs were mild in severity with incidences of AEs and adverse drug reactions at 75.3% and 16.7%, respectively. Although hypoglycemia was observed in 7 patients (2.3%), no major hypoglycemic episodes occurred. The incidences of AEs of special interest, including pollakiuria, volume depletion and urinary tract/genital infections, were at acceptable levels. Luseogliflozin significantly lowered HbA1c (-0.50%, P< 0.001), FPG (-16.3 mg/dL, P< 0.001) and body weight (-2.68 kg, P< 0.001) at Week 52 compared to baseline. Up-titration to 5 mg further improved glycemic control. In this long-term study of Japanese type 2 diabetic patients, luseogliflozin monotherapy was well tolerated for 52 weeks and provided a sustained glycemic lowering effect and reduced body weight.

View full abstract

Patients with hypogonadism have poor cardiovascular and metabolic outcomes, and the effect of testosterone replacement therapy (TRT) is not clear. We investigated the presence of inflammation, insulin resistance and endothelial dysfunction in an unconfounded population of congenital hypogonadotrophic hypogonadism (CHH) and the effect of TRT on these subjects. A total of 60 patients with CHH (mean age 21.82±2.22 years) and 70 healthy control subjects (mean age 21.32±1.13 years) were enrolled. The demographic parameters, Asymmetric dimethylarginine (ADMA), TNF-like weak inducer of apoptosis (TWEAK), high sensitive C reactive protein (hs-CRP) and homeostatic model assessment of insulin resistance (HOMA-IR) levels were measured before and after TRT. The patients had higher Waist Circumferences (WC) (p=0.009), Diastolic Blood Pressures (p=0.02), Triglycerides (p=0.03), ADMA, insulin and HOMA-IR levels (p<0.001 for all) and lower TWEAK levels (p<0.001), compared to the healthy controls. After 5.56 ± 2.04 months of TRT, the patients had significantly elevated systolic blood pressures (p=0.01), body mass indexes and WC (p<0.001 and p=0.001 respectively) and decreased total and HDL cholesterol levels (p=0.032 and p<0.001 respectively). ADMA levels significantly increased (p=0.003), while the alterations in TWEAK, hsCRP and HOMA-IR were not significant. The results of the present study show that endothelial dysfunction, inflammation and insulin resistance are prevalent even in the very young subjects with CHH, who have no metabolic or cardiac problems at present. This increased cardiometabolic risk however, do not improve but even get worse after six months of TRT. Long term follow-up studies are warranted to investigate the unfavorable cardiometabolic effects of TRT.

View full abstract

The objective of this study was to reveal the exact role of Kupffer cells in the diet-induced insulin resistance, inflammation and liver autophagy. C57BL/6j male mice were fed with either chow diet or high-fat diet (HFD) for 12 weeks. Meanwhile, HFD feeding mice received an intraperitoneal injection of either 0.2% GdCl₃ solution (20mg/kg) twice a week to deplete Kupffer cells or natural saline (5mL/kg) as control. The mRNA expressions of Kupffer cells markers (CD68 and F4/80), insulin sensitivity, TNF-α concentration and NF-κB activation and parameters of autophagy were assessed. Results demonstrated that CD68 and F4/80 mRNA expressions in the liver were up-regulated in HFD fed animals, while significantly reduced after GdCl₃ administration. HFD feeding led to insulin resistance and TNF-α level and activation of NF-κB in insulin-sensitive tissues (liver, adipose tissue and skeletal muscle) were significantly elevated. Interestingly, alterations above were reversed by varying degrees but significantly after Kupffer cells depletion. Furthermore, western blot showed hepatic LC3-II as well as phosphorylation of AMPK in liver and skeletal muscle were significantly lower in mice fed HFD, and these changes dramatically ameliorated by GdCl₃ treating. In conclusion, selective depletion of Kupffer cells significantly attenuated diet-induced insulin resistance, inflammation and promoted liver autophagy. Strategies targeting Kupffer cells function or autophagic processes could be a promising approach to counteract diet induced obesity and related metabolic disorders.

View full abstract

Hyperparathyroidism-jaw tumor syndrome (HPT-JT) is a rare autosomal dominant hereditary tumor syndrome characterized by synchronous or metachronous occurrence of primary hyperparathyroidism (PHPT), ossifying fibroma of the maxilla and/or mandible, renal tumor and uterine tumors. Early diagnosis of this syndrome is essential because it is associated with increased risk of parathyroid cancer. A 30-year-old man with urolithiasis had severe hypercalcemia (15.0 mg/dL after correction) induced by inappropriate parathyroid hormone (PTH) secretion (intact PTH 1390 pg/mL), indicating severe PHPT. An underlying parathyroid tumor was surgically removed and was histologically confirmed to be an adenoma. However, PHPT due to another parathyroid tumor reoccurred two years after the surgery. Although no HPT-JT-associated manifestations other than PHPT were detected, HPT-JT was strongly suspected based on the exclusion of multiple endocrine neoplasia (MEN) and the young age of disease occurrence. Genetic analysis revealed a novel nonsense mutation (p.Arg91X; c.271C>T) in exon 3 of the causative gene, CDC73, which encodes the tumor suppressor protein parafibromin. The residual parathyroid glands were all removed without autotransplantation of parathyroid gland taking into consideration prospective parathyroid carcinogenesis. The resected parathyroid tumor was also an adenoma. The present case highlights that HPT-JT should be considered and CDC73 mutation analysis should be performed, especially in cases of early-onset PHPT, recurrent PHPT, PHPT with polyglandular parathyroid involvement, and PHPT presenting with severe hypercalcemia even if there is no positive family history.

View full abstract

Peroxisome proliferator-activated receptor gamma, co-activator-related 1 (Pprc1) is the third member of the Pgc1 family. Other than the well-characterized Pgc1a and Pgc1b that act as regulators of mitochondrial biogenesis and oxidative metabolism, the function of Pprc1 in vivo is rarely reported, due to embryonic lethality of whole-body Pprc1 knockout mice. To investigate the biological and physiological function of Pprc1 in metabolic processes, male Pprc1^+/- mice fed with a high fat diet (HFD) showed resistance to diet-induced obesity with a decrease of adipose tissue in Pprc1^+/- mice, which was a result of elevated energy expenditure. In skeletal muscle of Pprc1^+/- mice, Pprc1 level showed haplo-insufficiency with down-regulation of Pgc1b and Pgc1a, whereas in adipose tissue, Pprc1 expression remained normal, with significant compensatory increase of other Pgc1 family members to induce an up-regulation of respiratory chain genes. Taken together, as the first report on the metabolic roles of Pprc1 in vivo, these results indicated an elevated basal metabolic rate and lipid metabolic alteration of male Pprc1^+/- mice on HFD, suggesting the significant role of Pprc1 in controlling mitochondrial gene expression and energy metabolic processes, synergistically with Pgc1a and Pgc1b.

View full abstract

Cushing’s disease is primarily caused by pituitary corticotroph adenomas, which autonomically secrete adrenocorticotropic hormone (ACTH). ACTH production may be associated with tumor cell proliferation; however, the effects of cell cycle progression on ACTH production and cell proliferation are little known in corticotroph tumor cells. A DNA polymerase inhibitor, aphidicolin, arrests cells at the entrance to the S phase and blocks the cell cycle; aphidicolin also induces apoptosis in tumor cells. In the present study, we determined ACTH production and cell proliferation of AtT-20 corticotroph tumor cells following treatment with aphidicolin. Aphidicolin decreased proopiomelanocortin mRNA levels in AtT-20 cells and the levels of ACTH in the culture medium of these cells. Aphidicolin also decreased cell proliferation and induced apoptosis in AtT-20 cells. Fluorescence-activated cell sorting analyses revealed that this agent increased the percentage of G0/G1 phase cells, and decreased S phase cells. Aphidicolin decreased the phosphorylation of cyclic adenosine monophosphate response element-binding protein and Akt. Aphidicolin increased the levels of tumor protein 27 (p27) and 53 (p53), while it decreased cyclin E levels. Aphidicolin also increased the mRNA levels of the stress response gene growth arrest and DNA damage-inducible 45β (GADD45β), a putative downstream target of p53. The p53 knockdown increased GADD45β mRNA levels. The GADD45β knockdown inhibited the decreases in cell proliferation. Thus, aphidicolin inhibits cell proliferation via the p53-GADD45β pathway in AtT-20 cells.

View full abstract

The purpose of this study was to determine the ultrasonographic (US) appearance of focal Hashimoto’s thyroiditis (FHT). Thirty-seven FHT patients and 60 consecutive patients with 60 papillary thyroid carcinomas (PTC) that were confirmed by cytology or histopathology between January 2011 and December 2013 were analyzed. Using the results of color Doppler imaging, US findings were retrospectively reviewed. Inter-group differences in size, internal content, echogenicity, echo texture, shape, boundary, margin, calcifications, fine echogenic septa, and blood flow were statistically assessed. The US appearances of the FHTs examined were: solid (100%), hypoechoic (97%), heterogeneous (68%), ovoid-to-round shape (73%), well-defined boundary (95%), smooth margin (89%), and hypervascular (46%). Ovoid-to-round shape, well-defined boundary, fine echogenic septa, and hypervascularity were significantly more prevalent for FHTs than for PTCs (p < 0.05). Ovoid-to-round shape and fine echogenic septa have a higher specificity and positive predictive value. FHTs show a spectrum of US appearances, making FHT diagnosis cumbersome. Fine echogenic septa are highly specific for FHT. Ovoid-to-round shape, well-defined boundary and hypervascularity may possibly be associated with FHT.

View full abstract