Efficacy and Safety of Metformin and Atorvastatin Combination Therapy vs. Monotherapy with Either Drug in Type 2 Diabetes Mellitus and Dyslipidemia Patients (ATOMIC): Double-Blinded Randomized Controlled Trial.

Background: It is well known that a large number of patients with diabetes also have dyslipidemia, which significantly increases the risk of cardiovascular disease (CVD). This study aimed to evaluate the efficacy and safety of combination drugs consisting of metformin and atorvastatin, widely used as therapeutic agents for diabetes and dyslipidemia. Methods: This randomized, double-blind, placebo-controlled, parallel-group and phase III multicenter study included adults with glycosylated hemoglobin (HbA1c) levels >7.0% and <10.0%, low-density lipoprotein cholesterol (LDL-C) >100 and <250 mg/dL. One hundred eighty-five eligible subjects were randomized to the combination group (metformin+atorvastatin), metformin group (metformin+atorvastatin placebo), and atorvastatin group (atorvastatin+metformin placebo). The primary efficacy endpoints were the percent changes in HbA1c and LDL-C levels from baseline at the end of the treatment. Results: After 16 weeks of treatment compared to baseline, HbA1c showed a significant difference of 0.94% compared to the atorvastatin group in the combination group (0.35% vs. -0.58%, respectively; P<0.0001), whereas the proportion of patients with increased HbA1c was also 62% and 15%, respectively, showing a significant difference (P<0.001). The combination group also showed a significant decrease in LDL-C levels compared to the metformin group (-55.20% vs. -7.69%, P<0.001) without previously unknown adverse drug events. Conclusion: The addition of atorvastatin to metformin improved HbA1c and LDL-C levels to a significant extent compared to metformin or atorvastatin alone in diabetes and dyslipidemia patients. This study also suggested metformin's preventive effect on the glucose-elevating potential of atorvastatin in patients with type 2 diabetes mellitus and dyslipidemia, insufficiently controlled with exercise and diet. Metformin and atorvastatin combination might be an effective treatment in reducing the CVD risk in patients with both diabetes and dyslipidemia because of its lowering effect on LDL-C and glucose.

Characterization of variable presentations of diabetic ketoacidosis based on blood ketone levels and major society diagnostic criteria: a new view point on the assessment of diabetic ketoacidosis.

AIM: We aimed to evaluate the clinical utility of blood ketone measurement and to test the performance of the diagnostic criteria for diabetic ketoacidosis (DKA) issued by the American Diabetes Association, the Joint British Diabetes Societies, and the American Association of Clinical Endocrinologists and the American College of Endocrinology. METHODS: This retrospective analysis included 278 patients with suspected DKA who were hospitalized at 4 university hospitals and aged ≥16 years with a blood glucose level of >200 mg/dL and a blood ketone level of ≥1.0 mmol/L as well as other biochemical data. The patients were categorized into four subgroups (ketosis, typical DKA, atypical DKA, and DKA + lactic acidosis). Atypical DKA in each analysis was defined by our supplementary criteria if the biochemical data did not meet each set of diagnostic criteria from the aforementioned societies. RESULTS: Blood ketone levels in patients with diabetic ketosis and those with DKA varied widely, 1.05-5.13 mmol/L and 1.02-15.9 mmol/L, respectively. Additionally, there were significant discrepancies between the guidelines in the diagnosis of DKA. Thus, the proportion of patients with atypical DKA ranged from 16.5% to 42.4%. Notably, the in-hospital mortality was comparable between patients with typical and atypical DKA, with a very high mortality in patients with DKA + lactic acidosis (blood lactate >5 mmol/L). CONCLUSIONS: Our results showed that considering variable presentations of DKA, blood ketone data need to be interpreted cautiously along with other biochemical data and suggested that a new system is required to better characterize DKA.

Resolution of Metabolic Disorders and Overweight in a Patient with ACTH-independent Cushing's Syndrome after Unilateral Adrenalectomy.

Excessive production of cortisol by abnormal adrenocortical tissue causes clinical manifestations of Cushing's syndrome and is associated with metabolic abnormalities including abdominal obesity, hyperglycemia, dyslipidemia, and hypertension, which increase the risk for type 2 diabetes mellitus as well as vascular morbidity and mortality. Removing the cause of hypercortisolism is initially required to resolve metabolic disorders in patients with adrenal Cushing's syndrome. A 38-year-old woman with diabetes mellitus and hypertension, which were not well controlled by medications, complained of abdominal obesity, rounded face, thin limbs, and bruising. Based on clinical manifestations and laboratory findings, she was diagnosed with Cushing's syndrome due to unilateral cortisol-producing adrenal adenoma. After left adrenalectomy, the patient's blood glucose improved to a satisfactory level, and she rapidly discontinued insulin and oral glucose-lowering agent therapy. Her body mass index decreased to the normal range, and her other metabolic symptoms, dyslipidemia and hypertension, also improved significantly. She has maintained resolution of metabolic disorders and overweight for eight years since surgery without recurrence of Cushing's syndrome.

Protective Effects of Vildagliptin against Pioglitazone-Induced Bone Loss in Type 2 Diabetic Rats.

Long-term use of thiazolidinediones (TZDs) is associated with bone loss and an increased risk of fracture in patients with type 2 diabetes (T2DM). Incretin-based drugs (glucagon-like peptide-1 (GLP-1) agonists and dipeptidylpeptidase-4 (DPP-4) inhibitors) have several benefits in many systems in addition to glycemic control. In a previous study, we reported that exendin-4 might increase bone mineral density (BMD) by decreasing the expression of SOST/sclerostin in osteocytes in a T2DM animal model. In this study, we investigated the effects of a DPP-4 inhibitor on TZD-induced bone loss in a T2DM animal model. We randomly divided 12-week-old male Zucker Diabetic Fatty (ZDF) rats into four groups; control, vildagliptin, pioglitazone, and vildagliptin and pioglitazone combination. Animals in each group received the respective treatments for 5 weeks. We performed an intraperitoneal glucose tolerance test (IPGTT) before and after treatment. BMD and the trabecular micro-architecture were measured by DEXA and micro CT, respectively, at the end of the treatment. The circulating levels of active GLP-1, bone turnover markers, and sclerostin were assayed. Vildagliptin treatment significantly increased BMD and trabecular bone volume. The combination therapy restored BMD, trabecular bone volume, and trabecular bone thickness that were decreased by pioglitazone. The levels of the bone formation marker, osteocalcin, decreased and that of the bone resorption marker, tartrate-resistant acid phosphatase (TRAP) 5b increased in the pioglitazone group. These biomarkers were ameliorated and the pioglitazone-induced increase in sclerostin level was lowered to control values by the addition of vildagliptin. In conclusion, our results indicate that orally administered vildagliptin demonstrated a protective effect on pioglitazone-induced bone loss in a type 2 diabetic rat model.

Genetic Analysis of Multiple Endocrine Neoplasia Type 1 (MEN1) Leads to Misdiagnosis of an Extremely Rare Presentation of Intrasellar Cavernous Hemangioma as MEN1.

BACKGROUND: Multiple endocrine neoplasia type 1 (MEN1) is a rare inherited disorder characterized by the simultaneous occurrence of endocrine tumors in target tissues (mainly the pituitary, endocrine pancreas, and parathyroid glands). MEN1 is caused by mutations in the MEN1 gene, which functions as a tumor suppressor and consists of one untranslated exon and nine exons encoding the menin protein. This condition is usually suspected when we encounter patients diagnosed with tumors in multiple endocrine organs, as mentioned above. METHODS: A 65-year-old woman who underwent surgery for a pancreatic tumor (serous cystadenoma) 5 years previously was referred to our hospital due to neurologic symptoms of diplopia and left ptosis. Brain magnetic resonance imaging revealed a 3.4-cm lesion originating from the cavernous sinus wall and extending into the sellar region. It was thought to be a nonfunctioning tumor from the results of the combined pituitary function test. Incidentally, we found that she also had a pancreatic tumor, indicating the necessity of genetic analysis for MEN1. RESULTS: Genomic analysis using peripheral leukocytes revealed a heterozygous c.1621G>A mutation in the MEN1 gene that was previously reported to be either a pathogenic mutation or a simple polymorphism. We pursued a stereotactic approach to the pituitary lesion, and microscopic findings of the tumor revealed it to be an intrasellar cavernous hemangioma, a rare finding in the sellar region and even rarer in relation to oculomotor palsy. The patient recovered well from surgery, but refused further evaluation for the pancreatic lesion. CONCLUSION: There is great emphasis placed on genetic testing in the diagnosis of MEN1, but herein we report a case where it did not assist in diagnosis, hence, further discussion on the role of genetic testing in this disease is needed. Also, in cases of pituitary tumor with cranial nerve palsy, despite its low prevalence, intrasellar cavernous hemangioma could be suspected.

Genetic and clinical characteristics of korean patients with isolated hypoparathyroidism: from the Korean hypopara registry study.

Isolated hypoparathyroidism (IH) shows heterogeneous phenotypes and can be caused by defects in a variety of genes. The goal of our study was to determine the clinical features and to analyze gene mutations in a large cohort of Korean patients with sporadic or familial IH. We recruited 23 patients. They showed a broad range of onset age and various values of biochemical data. Whole exome sequencing was performed on two affected cases and one unaffected individual in a family. All coding exons and exon-intron borders of GCMB, CASR, and prepro-PTH were sequenced using PCR-amplified DNA. In one family who underwent the whole exome sequencing analysis, approximately 300 single nucleotide changes emerged as candidates for genetic alteration. Among them, we identified a functional mutation in exon 2 of GCMB (C106R) in two affected cases. Besides, heterozygous gain-of-function mutations in the CASR gene were found in other subjects; D410E and P221L. We also found one single nucleotide polymorphism (SNP) in the prepro-PTH gene, five SNPs in the CASR gene, and four SNPs in the GCMB gene. The current study represents a variety of biochemical phenotypes in IH patients with the molecular genetic diagnosis of IH.

Direct and indirect effects of the temperament and character on alexithymia: a pathway analysis with mood and anxiety.

OBJECTIVE: We aimed to assess the pathway from personality to alexithymia through mood and anxiety as mediators. METHOD: Three hundred thirty-four subjects (130 male), whose psychiatric health was verified by Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Axis I disorders, completed the Toronto Alexithymia Scale-20 (TAS-20), the Temperament and Character Inventory, the State-Trait Anxiety Inventory (STAI), and the Center for Epidemiological Studies-Depression scale (CES-D). The schematic models for the pathway analysis from Temperament and Character Inventory (TCI) to TAS-20 scores were made. RESULTS: Low reward dependence (RD), low self-directedness (S-D), and high cooperativeness (CO) had paths to TAS-20 total (P = .000, P = .000, and P = .042, respectively). S-D had also an indirect path via STAI-state to TAS total. On TAS-20 factor 1, low RD, low S-D, and high self-transcendence (ST) had direct effects (P = .004, P = .000, and P = .000, respectively). S-D had also an indirect path via STAI-state and (CES-D) on TAS-20 factor 1. On TAS factor 2, low novelty seeking (NS), high harm avoidance (HA), low RD, low S-D, and high cooperativeness (CO) had direct effects (P = .005, P = .011, P = .000, P = .000, and P = .004, respectively). On TAS-20 factor 3, low RD and S-D had direct effects (P = .002 and P = .000, respectively). CONCLUSION: Current results suggest that although alexithymia is affected by the personality, state-dependent mood and anxiety may mediate the relationship between alexithymia and personality.