Effectiveness and Safety of Adding Basal Insulin Glargine in Patients with Type 2 Diabetes Mellitus Exhibiting Inadequate Response to Metformin and DPP-4 Inhibitors with or without Sulfonylurea.

BACKGROUND: We aimed to investigate the effectiveness and safety of adding basal insulin to initiating dipeptidyl peptidase-4 (DPP-4) inhibitor and metformin and/or sulfonylurea (SU) in achieving the target glycosylated hemoglobin (HbA1c) in patients with type 2 diabetes mellitus (T2DM). METHODS: This was a single-arm, multicenter, 24-week, open-label, phase 4 study in patients with inadequately controlled (HbA1c ≥7.5%) T2DM despite the use of DPP-4 inhibitor and metformin. A total of 108 patients received insulin glargine while continuing oral antidiabetic drugs (OADs). The primary efficacy endpoint was the percentage of subjects achieving HbA1c ≤7.0%. Other glycemic profiles were also evaluated, and the safety endpoints were adverse events (AEs) and hypoglycemia. RESULTS: The median HbA1c at baseline (8.9%; range, 7.5% to 11.1%) decreased to 7.6% (5.5% to 11.7%) at 24 weeks. Overall, 31.7% subjects (n=33) achieved the target HbA1c level of ≤7.0%. The mean differences in body weight and fasting plasma glucose were 1.2±3.4 kg and 56.0±49.8 mg/dL, respectively. Hypoglycemia was reported in 36 subjects (33.3%, 112 episodes), all of which were fully recovered. There was no serious AE attributed to insulin glargine. Body weight change was significantly different between SU users and nonusers (1.5±2.5 kg vs. -0.9±6.0 kg, P=0.011). CONCLUSION: The combination add-on therapy of insulin glargine, on metformin and DPP-4 inhibitors with or without SU was safe and efficient in reducing HbA1c levels and thus, is a preferable option in managing T2DM patients exhibiting dysglycemia despite the use of OADs.

Expression and regulation of osteoprotegerin in adipose tissue.

PURPOSE: Osteoprotegerin (OPG), a potent inhibitor of osteoclastic bone resorption, has a variety of biological functions that include anti-inflammatory effects. Adipocytes and osteoblasts share a common origin, and the formation of new blood vessels often precedes adipogenesis in developing adipose tissue microvasculature. We examined whether OPG is secreted from adipocytes, therefore contributing to the prevention of neovascularization and protecting the vessels from intimal inflammation and medial calcification. MATERIALS AND METHODS: The mRNA expression of OPG and receptor activator of NF-kappaB ligand (RANKL) was measured in differentiated 3T3L1 adipocytes and adipose tissues. RESULTS: OPG mRNA expression increased with the differentiation of 3T3L1 adipocytes, while RANKL expression was not significantly altered. OPG mRNA was expressed at higher levels in white adipose tissue than in brown adipose tissue and was most abundant in the epididymal portion. In differentiated 3T3L1 adipocytes, Rosiglitazone and insulin reduced the OPG/RANKL expression ratio in a dose- and time- dependent manner. In contrast, tumor necrosis factor-alpha (TNF-alpha) increased the expression of both OPG and RANKL in a time-dependent manner. The OPG/RANKL ratio was at a maximum two hours after TNF-alpha treatment and then returned to control levels. Furthermore, OPG was abundantly secreted into the media after transfection of OPG cDNA with Phi C31 integrase into 3T3L1 cells. CONCLUSION: Our results indicate that OPG mRNA is expressed and regulated in the adipose tissue. Considering the role of OPG in obesity-associated inflammatory changes in adipose tissue and vessels, we speculate that OPG may have both a protective function against inflammation and anti-angiogenic effects on adipose tissue.

Peripheral effect of alpha-melanocyte-stimulating hormone on fatty acid oxidation in skeletal muscle.

To study the peripheral effects of melanocortin on fuel homeostasis in skeletal muscle, we assessed palmitate oxidation and AMP kinase activity in alpha-melanocyte-stimulating hormone (alpha-MSH)-treated muscle cells. After alpha-MSH treatment, carnitine palmitoyltransferase-1 and fatty acid oxidation (FAO) increased in a dose-dependent manner. A strong melanocortin agonist, NDP-MSH, also stimulated FAO in primary culture muscle cells and C2C12 cells. However, [Glu6]alpha-MSH-ND, which has ample MC4R and MC3R agonistic activity, stimulated FAO only at high concentrations (10(-5) M). JKC-363, a selective MC4R antagonist, did not suppress alpha-MSH-induced FAO. Meanwhile, SHU9119, which has both antagonistic activity on MC3R and MC4R and agonistic activity on both MC1R and MC5R, increased the effect of alpha-MSH on FAO in both C2C12 and primary muscle cells. Small interference RNA against MC5R suppressed the alpha-MSH-induced FAO effectively. cAMP analogues mimicked the effect of alpha-MSH on FAO, and the effects of both alpha-MSH and cAMP analogue-mediated FAO were antagonized by a protein kinase A inhibitor (H89) and a cAMP antagonist ((Rp)-cAMP). Acetyl-CoA carboxylase activity was suppressed by alpha-MSH and cAMP analogues by phosphorylation through AMP-activated protein kinase activation in C2C12 cells. Taken together, these results suggest that alpha-MSH increases FAO in skeletal muscle, in which MC5R may play a major role. Furthermore, these results suggest that alpha-MSH-induced FAO involves cAMP-protein kinase A-mediated AMP-activated protein kinase activation.

Duodenal somatostatinoma associated with diabetic ketoacidosis presumably caused by somatostatin-28 hypersecretion.

CONTEXT: Extrapancreatic somatostatinoma is very rare and clinically distinguished from its pancreatic counterpart because somatostatinoma syndrome with mild diabetes is rare in extrapancreatic somatostatinoma because of poor secretion of somatostatin. Moreover, because somatostatin inhibits the secretion of insulin and glucagon simultaneously, true diabetic ketoacidosis (DKA) seldom ensues. PATIENT: A 23-yr-old woman presented with DKA and an abdominal mass. A computed tomography scan showed a huge, encapsulated mass in a duodenal submucous portion. A high circulating level of somatostatin was detected (67.2 pmol/liter; reference range, 0.6-7.3 pmol/liter). INTERVENTION: The tumor mass was successfully removed with Whipple's procedure, and the patient gradually recovered both clinically and biochemically. RESULTS: Immunohistochemical staining of the tumor tissue exhibited diffusely positive for somatostatin and somatostatin-28 but negative for insulin, glucagon, calcitonin, serotonin, and S-100. CONCLUSION: As far as we know, this is the first case report of gastrointestinal somatostatinoma associated with DKA.

Characteristics of type 2 diabetes in terms of insulin resistance in Korea.

The aim of this study was to assess the implications of insulin resistance on the clinical and biochemical profiles of Korean type 2 diabetic patients. 122 patients with type 2 diabetes underwent a short insulin tolerance test to assess insulin resistance. Subjects were classified in tertiles according to ISI (insulin sensitivity index), and the tertile I (the insulin- resistant group) and tertile III (the insulin-sensitive group) clinical and biochemical parameters were compared. Age, waist circumference (WC), systolic blood pressure (SBP), HbA1c, body fat content, and fasting plasma glucose were significantly higher in tertile I than tertile III (all p < 0.05). The frequency of hypertension and family history of cerebrovascular disease (CVD) were greater in tertile I than III (p < 0.05). To evaluate the factors affecting ISI, multiple regression was performed, and age, WC, SBP, HbA1c, and body fat content were found to be independently related to insulin resistance (p < 0.05). Old age, hypertension, central obesity, and poor glycemic control were identified as clinical parameters of insulin resistance in Korean type 2 diabetic patients.

The correlation between insulin resistance and the visceral fat to skeletal muscle ratio in middle-aged women.

Central obesity with visceral fat accumulation and the amount of skeletal muscle mass may influence insulin sensitivity via its capacity for glucose load uptake. We investigated the relationships among the following metabolic variables: ratio of fat area to skeletal muscle area (VMR), percent ideal body weight, body mass index, waist-to-hip circumference (WHR) and visceral fat to subcutaneous fat ratio (VSR) in 114 nondiabetic middle-aged women. Anthropometric parameters, lipid profiles and sex hormone- binding globulin were measured. Visceral and subcutaneous fat areas at the umbilical level and the skeletal muscle area at the mid-thigh level were measured and computed. 75-gram OGTT tests were performed, along with measuring plasma glucose, insulin and free fatty acid levels, according to which area under the curve of glucose (Glu-AUC), insulin (Ins-AUC), free fatty acid (FFA-AUC) and glucose/insulin ratio (GIR=Glu- AUC/Ins-AUC), were calculated. 1) Triglyceride was more correlated with VSR than VMR. 2) The independent anthropometric parameters for each metabolic variable were In conclusion, VMR for Ins-AUC, WHR for Glu-AUC and total cholesterol, and VSR for triglyceride. 3) For subjects with higher VMR, age, Ins-AUC and triglyceride were significantly higher. 4) Subjects with higher VMR were older and showed higher Ins-AUC and lower GIR than the subjects with lower VMR. In conclusion, VMR is an anthropometric parameter that reflects insulin resistance concerning glucose metabolism, and VSR is thought to be a good parameter that that reflects the serum lipid levels. Further prospective studies are necessary to reevaluate the visceral fat vs. skeletal muscle relationship.

Graves' disease associated with Klinefelter's syndrome.

Klinefelter's syndrome is one of the most common forms of primary hypogonadism and infertility in males. It is characterized by small and firm testes, gynecomastia, azoospermia, and an elevated gonadotropin level. The frequencies of diabetes mellitus, breast cancer, and germ cell neoplasia increases in Klinefelter's syndrome. We report upon a 35 year-old male patient with Graves' disease in association with Klinefelter's syndrome; as confirmed by chromosome analysis. The patient is being treated with antithyroid medication for Graves' disease and by testosterone replacement for Klinefelter's syndrome.

The effect of iodine restriction on thyroid function in patients with hypothyroidism due to Hashimoto's thyroiditis.

Lifelong thyroid hormone replacement is indicated in patients with hypothyroidism as a result of Hashimoto's thyroiditis. However, previous reports have shown that excess iodine induces hypothyroidism in Hashimoto's thyroiditis. This study investigated the effects of iodine restriction on the thyroid function and the predictable factors for recovery in patients with hypothyroidism due to Hashimoto's thyroiditis. The subject group consisted of 45 patients who had initially been diagnosed with hypothyroidism due to Hashimoto's thyroiditis. The subjects were divided randomly into two groups. One group was an iodine intake restriction group (group 1) (iodine intake: less than 100 micro g/day) and the other group was an iodine intake non-restriction group (group 2). The thyroid-related hormones and the urinary excretion of iodine were measured at the baseline state and after 3 months. After 3 months, a recovery to the euthyroid state was found in 78.3 % of group 1 (18 out of 23 patients), which is higher than the 45.5% from group 2 (10 out of 22 patients). In group 1, mean serum fT4 level (0.80 +/- 0.27 ng/dL at the baseline, 0.98 +/- 0.21 ng/dL after 3 months) and the TSH level (37.95 +/- 81.76 micro IU/mL at the baseline, 25.66 +/- 70.79 micro IU/mL after 3 months) changed significantly during this period (p < 0.05). In group 2, the mean serum fT4 level decreased (0.98 +/- 0.17 ng/dL at baseline, 0.92 +/- 0.28 ng/dL after 3 months, p < 0.05). In the iodine restriction group, the urinary iodine excretion values were higher in the recovered patients than in non-recovered patients (3.51 +/- 1.62 mg/L vs. 1.21 +/- 0.39 mg/ L, p=0.006) and the initial serum TSH values were lower in the recovered patients than in the non-recovered patients (14.28 +/- 12.63 micro IU/mL vs. 123.14 +/- 156.51 micro IU/mL, p=0.005). In conclusion, 78.3% of patients with hypothyroidism due to Hashimoto's thyroiditis regained an euthyroid state iodine restriction alone. Both a low initial serum TSH and a high initial urinary iodine concentration can be predictable factors for a recovery from hypothyroidism due to Hashimoto's thyroiditis after restricting their iodine intake.

A case of thyroid storm due to thyrotoxicosis factitia.

We describe a case of thyroid storm due to thyrotoxicosis factitia, which was caused by the ingestion of excessive quantities of exogenous thyroid hormone for the purpose of reducing weight. An 18-year-old female was admitted to the hospital 24 hours after taking up to 50 tablets of synthyroid (1 tablet of synthyroid : levothyroxine 100 microg). Because of her stuporous mental state and acute respiratory failure, she was intubated and treated in the intensive care unit. After reviewing her history carefully and examining plasma thyroid hormone levels, we diagnosed this case as a thyroid storm due to thyrotoxicosis factitia. Her thyroid function test revealed that T3 was 305 ng/dL, T4 was 24.9 microg/dl, FT4 was 7.7 ng/dL, TSH was 0.05 micro IU/mL and TBG was 12.84 microg/mL (normal range: 11.3 - 28.9). TSH receptor antibody, antimicrosomal antibody, and antithyroglobulin antibody were negative. She was recovered by treatment, namely, steroid and propranolol, and was discharged 8 days after admission. Thyroid storm due to thyrotoxicosis factitia caused by the ingestion of excessive thyroid hormone is rarely reported worldwide. Therefore, we now report a case of thyroid storm that resulted from thyrotoxicosis factitia caused by the ingestion of a massive amount of thyroid hormone over a period of 6 months.