Insulin secretion with respect to pH environments has been investigated for a long time but its mechanism remains largely unknown. Extracellular pH is usually maintained at around 7.4 and, its change has been thought to occur in non-physiological situations. Acidification takes place under ischemic and inflammatory microenvironments, where stimulation of anaerobic glycolysis results in the production of lactic acid. In addition to ionotropic ion channels, such as transient receptor potential V1 (TRPV1) and acid-sensing ion channels (ASICs), metabotropic proton-sensing G protein-coupled receptors (GPCRs) have also been identified recently as proton-sensing machineries. While ionotropic ion channels usually sense strong acidic pH, proton-sensing GPCRs sense pH of 7.6 to 6.0 and have been shown to mediate a variety of biological actions in neutral and mildly acidic pH environments. Studies with receptor knockout mice have revealed that proton-sensing receptors, including ovarian cancer G protein-coupled receptor 1 (OGR1), a proton-sensing GPCRs, play a role in the regulation of insulin secretion and glucose metabolism under physiological conditions. Small molecule 3,5-disubstituted isoxazoles have recently been identified as OGR1 agonists working at neutral pH and have been shown to stimulate pancreatic β-cell differentiation and insulin synthesis. Thus, proton-sensing OGR1 may be an important player for insulin secretion and a potential target for improving β-cell function.
Previous studies from our and other labs have shown that insulin resistance is associated with an inositol imbalance of excess myo-inositol and deficient chiro-inositol together with a deficiency of myo-inositol to chiro-inositol epimerase in vivo and in vitro. In this report, we utilized well characterized theca cells from normal cycling women, with normal insulin sensitivity, and theca cells from women with polycystic ovary syndrome (PCOS), with increased insulin sensitivity to examine the myo-inositol to chiro-inisitol (M/C) ratio and the myo-inositol to chiro-inositol epimerase activity. PCOS theca cells with increased insulin sensitivity were specifically used to investigate whether the inositol imbalance and myo-inositol to chiro-inositol epimerase are regulated in a similar or the opposite direction than that observed in insulin resistant cells. The results of these studies are the first to demonstrate that in insulin sensitive PCOS theca cells the inositol imbalance goes in the opposite direction to that observed in insulin resistant cells, and there is a decreased M/C ratio and an increased myo-inositol to chiro-inositol epimerase activity. Further biochemical and genetic studies will probe the mechanisms involved.
A homodimer of taste type 1 receptor 3 (T1R3) functions as a sweet taste-sensing receptor in pancreatic β-cells. This receptor is activated by various sweet molecules including sugars such as glucose. To determine the role of this receptor in glucose-induced insulin secretion, we addressed whether or not this receptor modulates glucose metabolism in MIN6 cells. We measured changes in intracellular ATP ([ATP]i) in MIN6 cells expressing luciferase. Sucralose, an agonist of T1R3, induced immediate and sustained elevation of [ATP]i in the presence of 5.5 mM glucose. The effect of sucralose was dose-dependent and, at 5 mM, was greater than that induced by 25 mM glucose. In contrast, carbachol, GLP-1 or high concentration of potassium did not reproduce the sucralose action. Sucralose facilitated the increase in [ATP]i induced by a mitochondrial fuel methylsuccinate, and potentiated glucose-induced elevation of [ATP]i. Administration of a non-metabolizable glucose analogue, 3-O-methylglucose, which acts as an agonist of T1R3, induced a small and transient increase in [ATP]i. 3-O-Methylglucose augmented elevation of [ATP]i induced by methylsuccinate, and also enhanced glucose-induced increase in [ATP]i. Knock down of T1R3 by using shRNA attenuated [ATP]i-response to high concentration of glucose and also reduced the glucose-induced insulin secretion. These results indicate that activation of the homodimer of T1R3 facilitates the metabolic pathway in mitochondria and augments ATP production. The results obtained by using 3-O-methylglucose suggest that glucose, by acting on the homodimer of T1R3, promotes its own metabolism.
Previous studies have identified several common genetic variants in VDR, GC and CYP2R1 to be associated with circulating levels of 25-hydroxyvitamin D [25(OH)D] and vitamin D deficiency in Western populations. We aimed to investigate the associations of these variants with serum levels of 25(OH)D and vitamin D status in 1,199 Chinese. Nine common variants of VDR, GC and CYP2R1 were genotyped using multiple SNaPshot assay, and serum 25(OH)D was detected by radioimmunoassay. The prevalence of vitamin D deficiency (<50 nmol/L) was 38.8%, which is higher in women (46.2%) than in men (34.3%, P<0.0001). The risk alleles of three common variants of GC (rs7041, rs4588, and rs2282679) were significantly associated with a lower serum levels of 25(OH)D (-1.789 ≤β ≤-3.549, P ≤0.006), while common variants in VDR and CYP2R1 were not associated with serum levels of 25(OH)D after adjusted for covariates (P ≥0.30). None of the nine common variants were associated with the presence of vitamin D deficiency in multivariable adjusted logistic regression analyses (P ≥0.17). Haplotype-based analyses of GC-rs7041 and rs4588 showed that the haplotype Gc2-2 (rs7041 AA and rs4588 TT) had the lowest levels of 25(OH)D compared with other haplotypes that contained at least one copy of Gc1 allele (Ptrend <0.0001). Our results suggest that the common variants of GC are genetic determinants of serum 25(OH)D in Chinese.
Central diabetes insipidus (CDI) is caused by deficiency of arginine vasopressin, an antidiuretic hormone. Patients with CDI manifest polyuria which is usually compensated for by increases in water intake. However, some patients are not able to sense thirst due to the destruction of osmoreceptors in the hypothalamus. These adipsic CDI patients are easily dehydrated and the consequent dehydration could be life-threatening. The objective of this study was to investigate the prognosis of adipsic CDI patients. We have reviewed 149 patients with CDI in three hospitals using databases of the electronic medical recording systems, and examined whether adipsia could affect the morbidity and mortality in CDI patients with multivariable analyses. Twenty-three patients with CDI were adipsic while the remaining 126 patients were non-adipsic. The multivariate analyses showed that the incidence of serious infections which required hospitalization was significantly higher in the adipsic CDI patients compared to that in non-adipsic CDI patients (p <0.001). A total of 6 patients with CDI died during the follow-up (median duration; 60 months, range 1 to 132 months). Four of them were adipsic, three of whom died of infection. The statistical analyses revealed that the risk of death in adipsic CDI patients was significantly higher than in non-adipsic patients (p =0.007). It is thus suggested that adipsic CDI patients were susceptible to serious infections which could be the causes of death.
The aim of this study was to clarify the relationship between baseline beta cell function and future glycated albumin (GA) to glycated hemoglobin ratio (GA/HbA1c) in patients with type 2 diabetes. In our retrospective cohort, 210 type 2 diabetic patients who had been admitted to our hospital and in whom HbA1c and GA had been measured at baseline and 2 years after admission were included in this study. Baseline beta cell function was assessed by postprandial C-peptide immunoreactivity index (PCPRI) during admission. With intensification of treatment during admission, HbA1c and GA were significantly decreased 1 year and 2 years after admission. While baseline HbA1c was not significantly correlated with HbA1c after 2 years, baseline GA/HbA1c was strongly correlated with GA/HbA1c after 2 years (r = 0.575, P <0.001). When the patients were divided into two groups according to median PCPRI, patients with low PCPRI showed higher GA/HbA1c both at baseline and after 2 years compared to those with high PCPRI. There was a significant negative correlation between PCPRI and GA/HbA1c after 2 years (r = -0.379, P <0.001). Multiple regression analysis revealed that PCPRI was an independent predictor of GA/HbA1c after 2 years. In conclusion, our findings suggest that lower beta cell function is associated with sustained higher GA/HbA1c ratio in patients with type 2 diabetes.
Dipeptidyl peptidase-4 (DPP-4) inhibitor is a new class of anti-diabetic drug which exerts its glucose-lowering action by suppressing the degradation of a gut incretin hormone glucagon-like peptide-1 (GLP-1). To elucidate whether treatment with stronger DPP-4 inhibitor on top of angiotensin II type 1 receptor blocker (ARB) provides greater renal protective effects, we performed a crossover study with two DPP-4 inhibitors, sitagliptin and alogliptin, in twelve type 2 diabetic patients with incipient nephropathy taking ARBs. This study consisted of three treatment periods: sitagliptin 50 mg/day for 4 weeks (first period), alogliptin 25 mg/day for 4 weeks (second period), and sitagliptin 50 mg/day for 4 weeks (third period). Significant changes in body mass index, blood pressure, serum lipids, serum creatinine, estimated glomerular filtration rate, and HbA1c were not observed among the three treatment periods. Reduced urinary levels of albumin and an oxidative stress marker 8-hydroxy-2’-deoxyguanosine (8-OHdG), increased urinary cAMP levels, and elevated plasma levels of stromal cell-derived factor-1α (SDF-1α) which is a physiological substrate of DPP-4 were observed after the switch from sitagliptin to a stronger DPP-4 inhibitor alogliptin. Given a large body of evidence indicating anti-oxidative action of cAMP and up-regulation of cellular cAMP production by SDF-1α, the present results suggest that more powerful DPP-4 inhibition on top of angiotensin II type 1 receptor blockade would offer additional protection against early-stage diabetic nephropathy beyond that attributed to glycemic control, via reduction of renal oxidative stress by SDF-1α-cAMP pathway activation.
Epidemiologic studies have shown that low vitamin D levels are associated with reduced insulin sensitivity and increased risk of developing type 2 diabetes mellitus (T2DM). However, there is little evidence that vitamin D supplementation improves glucose intolerance. We evaluated the glucose-lowering effect of vitamin D in Korean T2DM subjects. We enrolled 158 T2DM patients who had stable glycemic control [hemoglobin A1c (HbA1c) <8.5%] and vitamin D levels less than 20 ng/mL. The participants were randomized into two groups: Placebo (100 mg daily of elemental calcium administered twice a day) or Vitamin D (1000 IU daily of cholecalciferol combined with 100 mg of elemental calcium administered twice a day). We compared outdoor physical activity, glycemic control, homeostasis model of assessment - insulin resistance (HOMA-IR), and parathyroid hormone (PTH), during the 24-week intervention. We analyzed the data of 129 participants (placebo =65, vitamin D =64) who completely followed the protocol. Outdoor physical activity and oral anti-diabetic drugs did not differ between the groups. While there were significant differences in the vitamin D levels (15.6 ± 7.1 ng/mL vs 30.2 ± 10.8 ng/mL, P<0.001) and change in PTH levels (1.4 ± 15.3 pg/mL vs -5.5 ± 9.8 pg/mL, P=0.003) between the placebo and vitamin D groups, there were no differences in HbA1c (7.27 ± 0.87% vs 7.40 ± 0.90%) (P=0.415) and HOMA-IR. Serum calcium and kidney function results showed that the vitamin D supplementation was safe. While vitamin D supplementation is safe and effective in the attainment of vitamin D sufficiency, it had no effect on long-term glycemic control for T2DM in our study.
To examine how elevated alanine aminotransferase (ALT) could be associated with newly diagnosed diabetes mellitus. We conducted a cross-sectional analysis on a mass health examination. The odds ratios (ORs) for diabetes mellitus and newly diagnosed diabetes mellitus were compared between people with and without abdominal obesity, together with and without elevated ALT levels. 5499 people were included in this study. Two hundred fifty two (4.6%) fulfilled the diagnosis of diabetes mellitus with 178 (3.2%) undiagnosed before. Metabolic syndrome was vigorously associated with diabetes mellitus and newly diagnosed diabetes mellitus (12.4% vs. 1.4% and 9.0% vs. 0.9%), but elevated ALT alone was not. However, coexisting with obesity, elevated ALTs were robustly associated with diabetes mellitus and newly diagnosed diabetes mellitus. For the incidence of newly diagnosed diabetes mellitus, in comparison to non-obese people with normal ALT (1.7%, OR = 1), obese people especially with elevated ALT levels had significantly higher ORs (obese with ALT ≤ 40 U/L: 4.7%, OR 1.73, 95% CI 1.08-2.77, P 0.023; ALT 41-80 U/L: 6.8%, OR 2.06, 95% CI 1.20-3.55, P 0.009; ALT 81-120 U/L: 8.8%, OR 3.07, 95% CI 1.38-6.84, P 0.006; ALT > 120 U/L: 18.2%, OR 7.44, 95% CI 3.04-18.18, P < 0.001). Abdominal obesity validates the association between elevated alanine aminotransferase and diabetes mellitus and newly diagnosed diabetes mellitus. People with abdominal obesity, especially with coexisting elevated ALT levels should be screened for undiagnosed diabetes mellitus.
An early thirties man diagnosed with Erdheim-Chester disease (ECD) was simultaneously disclosed to have hypogonadotropic hypogonadism, central adrenal insufficiency, and GH deficiency in addition to central diabetes insipidus (CDI). Pituitary magnetic resonance imaging (MRI) showed swelling in the stalk, enlargement of the anterior lobe with delayed enhancement, and loss of high intensity of the posterior lobe on T1-weighted images, suggesting of pituitary involvement of ECD. Three months after starting treatment with interferon α and zoledronic acid, polyuria and polydipsia were ameliorated without DDAVP, accompanied with improvement of MRI. Simultaneously technetium-99m bone scintigraphy showed improvement, accompanied with a relief of bone pain and high fever. In contrast, he developed secondary hypothyroidism with slight enlargement of anterior pituitary gland without relapse of CDI, suggesting of different responses to treatment with interferon α between anterior pituitary lobe and posterior one. So far he continues to be replaced with deficient hormone replacement therapy. As for bone pain, it remains to be controlled with the decreased levels of bone resorption marker with decreased abnormal uptake in bone scintigraphy although zoledronic acid was discontinued for osteonecrosis of the jaw. For four years, he has not showed new involvement at other organs besides bones and the pituitary. While CDI is known to be very common in ECD, improvement of CDI has been reported in a few cases. Other endocrine manifestations, especially with detailed endocrine status, have been also reported in limited cases. Thus we report this case and review the literature.
In 2011 a 76 year-old man with a medical history of diabetes, hypertension and autoimmune pancreatitis was admitted to our hospital because of anorexia, general malaise and repeated hypoglycemia. When he was 72 years old, he suffered from pancreatitis, and pancreas head tumor was operated. IgG4-related pancreatitis was diagnosed histopathologically. On admission anterior pituitary function test revealed impaired response of ACTH and cortisol to CRH, and no response of GH, TSH and gonadotropin to GHRH, TRH and LHRH, respectively. Baseline PRL level was elevated. Serum IgG and IgG4 levels were markedly elevated. Pituitary MRI showed significant enlargement of pituitary gland and stalk. Chest CT suggested IgG4-related lung disease. IgG4-related infundibulo-hypophysitis was diagnosed based on the above mentioned past history and results of present examinations. Twenty mg of hydrocortisone, followed by 20 mg of prednisolone (PSL) and 25 μg of levothyroxine markedly reduced serum IgG4 levels and ameliorated the symptom, the size of pituitary and stalk, and anterior pituitary function (TSH, GH and gonadotropin), although diabetes insipidus became apparent due to glucocorticoid administration. This is a typical case of IgG4-related hypophysitis in which PSL causes marked improvement of pituitary mass and pituitary function along with the reduction of serum IgG4 levels.