Therapeutic Efficacy of Twin-Block and Fixed Oral Appliances in Patients with Obstructive Sleep Apnea Syndrome.

PURPOSE: To compare the efficacy of twin-block (i.e., allows mouth opening) and fixed (i.e., maintains mouth closure) mandibular advancement splints (MASs) for the treatment of obstructive sleep apnea-hypopnea syndrome (OSA). MATERIALS AND METHODS: From 2011 to 2013, 23 patients with OSA in the twin-block group, and from 2013 to 2015, 29 patients in the fixed MAS group were included. All patients underwent polysomnography before and after 3 months of treatment. The two sets of polysomnographic and cephalometric variables were compared. RESULTS: A significant difference (p < 0.001) was observed in the apnea-hypopnea index before and after MAS treatment in both groups (twin-block group: 20.6 ± 11.5 vs. 14.7 ± 9.4; fixed group: 21.4 ± 15.2 vs. 11.2 ± 9.7). In the twin-block group, 5 patients (21.7%) were complete responders, 9 (39.1%) were fair responders, and 9 (39.1%) were nonresponders; the corresponding figures for the fixed group were 14 (48.3%), 9 (31.0%), and 6 (20.7%) patients. A significant between-group difference was observed in the distribution of responders (p = 0.046). The fixed group showed a significant improvement in the snoring index (p = 0.003), arousal index (p = 0.036), and desaturation rate (p = 0.012). Finally, the change in incisal overjet was larger in the fixed group than in the twin-block group (p < 0.001). CONCLUSIONS: These results suggest that fixed oral appliances are superior in treating OSA, based on their ability to prevent mouth opening and reduce incisal overjet.

Circulating betatrophin is elevated in patients with type 1 and type 2 diabetes.

There is evidence that betatrophin, a hormone derived from adipose tissue and liver, affects the proliferation of pancreatic beta cells in mice. The aim of this study was to examine circulating betatrophin concentrations in Japanese healthy controls and patients with type 1 and type 2 diabetes. A total of 76 subjects (12 healthy controls, 34 type 1 diabetes, 30 type 2 diabetes) were enrolled in the study. Circulating betatrophin was measured with an ELISA kit and clinical parameters related to betatrophin were analyzed statistically. Circulating betatrophin (Log transformed) was significantly increased in patients with diabetes compared with healthy subjects (healthy controls, 2.29 ± 0.51; type 1 diabetes, 2.94 ± 0.44; type 2 diabetes, 3.17 ± 0.18; p<0.001, 4.1 to 5.4 times in pg/mL order). Age, HbA1c, fasting plasma glucose and Log triglyceride were strongly associated with Log betatrophin in all subjects (n=76) in correlation analysis. In type 1 diabetes, there was a correlation between Log betatrophin and Log CPR. These results provide the first evidence that circulating betatrophin is significantly elevated in Japanese patients with diabetes. The findings of this pilot study also suggest a possibility of association between the level of betatrophin and the levels of glucose and triglycerides.

Crucial role of a long-chain fatty acid elongase, Elovl6, in obesity-induced insulin resistance.

Insulin resistance is often associated with obesity and can precipitate type 2 diabetes. To date, most known approaches that improve insulin resistance must be preceded by the amelioration of obesity and hepatosteatosis. Here, we show that this provision is not mandatory; insulin resistance and hyperglycemia are improved by the modification of hepatic fatty acid composition, even in the presence of persistent obesity and hepatosteatosis. Mice deficient for Elovl6, the gene encoding the elongase that catalyzes the conversion of palmitate to stearate, were generated and shown to become obese and develop hepatosteatosis when fed a high-fat diet or mated to leptin-deficient ob/ob mice. However, they showed marked protection from hyperinsulinemia, hyperglycemia and hyperleptinemia. Amelioration of insulin resistance was associated with restoration of hepatic insulin receptor substrate-2 and suppression of hepatic protein kinase C epsilon activity resulting in restoration of Akt phosphorylation. Collectively, these data show that hepatic fatty acid composition is a new determinant for insulin sensitivity that acts independently of cellular energy balance and stress. Inhibition of this elongase could be a new therapeutic approach for ameliorating insulin resistance, diabetes and cardiovascular risks, even in the presence of a continuing state of obesity.

TFE3 transcriptionally activates hepatic IRS-2, participates in insulin signaling and ameliorates diabetes.

Using an expression cloning strategy, we have identified TFE3, a basic helix-loop-helix protein, as a transactivator of metabolic genes that are regulated through an E-box in their promoters. Adenovirus-mediated expression of TFE3 in hepatocytes in culture and in vivo strongly activated expression of IRS-2 and Akt and enhanced phosphorylation of insulin-signaling kinases such as Akt, glycogen synthase kinase 3beta and p70S6 kinase. TFE3 also induced hexokinase II (HK2) and insulin-induced gene 1 (INSIG1). These changes led to metabolic consequences, such as activation of glycogen and protein synthesis, but not lipogenesis, in liver. Collectively, plasma glucose levels were markedly reduced both in normal mice and in different mouse models of diabetes, including streptozotocin-treated, db/db and KK mice. Promoter analyses showed that IRS2, HK2 and INSIG1 are direct targets of TFE3. Activation of insulin signals in both insulin depletion and resistance suggests that TFE3 could be a therapeutic target for diabetes.

Endocrine, inflammatory and immune responses and individual differences in acute hypobaric hypoxia in lowlanders.

When lowlanders are exposed to environments inducing hypobaric hypoxia (HH) such as high mountains, hemodynamic changes occur to maintain oxygen levels in the body. However, changes to other physiological functions under such conditions have yet to be clarified. This study investigated changes in endocrine, inflammatory and immune parameters and individual differences during acute HH exposure using a climatic chamber (75 min of exposure to conditions mimicking 3500 m) in healthy lowlanders. Aldosterone and cortisol were significantly decreased and interleukin (IL)-6, IL-8 and white blood cell (WBC) counts were significantly increased after HH. Lower peripheral oxygen saturation (SpO2) was associated with higher IL-6 and WBC counts, and higher IL-8 was associated with higher cortisol. These findings suggest that endocrine, inflammatory and immune responses are evoked even with a short 75-min exposure to HH and individuals with lower SpO2 seemed to show more pronounced responses. Our results provide basic data for understanding the physiological responses and interactions of homeostatic systems during acute HH.

Granuphilin is activated by SREBP-1c and involved in impaired insulin secretion in diabetic mice.

Granuphilin is a crucial component of the docking machinery of insulin-containing vesicles to the plasma membrane. Here, we show that the granuphilin promoter is a target of SREBP-1c, a transcription factor that controls fatty acid synthesis, and MafA, a beta cell differentiation factor. Potassium-stimulated insulin secretion (KSIS) was suppressed in islets with adenoviral-mediated overexpression of granuphilin and enhanced in islets with knockdown of granuphilin (in which granuphilin had been knocked down). SREBP-1c and granuphilin were activated in islets from beta cell-specific SREBP-1c transgenic mice, as well as in several diabetic mouse models and normal islets treated with palmitate, accompanied by a corresponding reduction in insulin secretion. Knockdown- or knockout-mediated ablation of granuphilin or SREBP-1c restored KSIS in these islets. Collectively, our data provide evidence that activation of the SREBP-1c/granuphilin pathway is a potential mechanism for impaired insulin secretion in diabetes, contributing to beta cell lipotoxicity.

SREBPs suppress IRS-2-mediated insulin signalling in the liver.

Insulin receptor substrate 2 (IRS-2) is the main mediator of insulin signalling in the liver, controlling insulin sensitivity. Sterol regulatory element binding proteins (SREBPs) have been established as transcriptional regulators of lipid synthesis. Here, we show that SREBPs directly repress transcription of IRS-2 and inhibit hepatic insulin signalling. The IRS-2 promoter is activated by forkhead proteins through an insulin response element (IRE). Nuclear SREBPs effectively replace and interfere in the binding of these transactivators, resulting in inhibition of the downstream PI(3)K/Akt pathway, followed by decreased glycogen synthesis. These data suggest a molecular mechanism for the physiological switching from glycogen synthesis to lipogenesis and hepatic insulin resistance that is associated with hepatosteatosis.

[A case of hospital-acquired pneumonia caused by intermediately susceptible carbapenem Acinetobacter baumannii].

The incidence of Acinetobacter baumannii pneumonia in hospital-acquired pneumonia in Japan is rare. We report a case of ventilator-associated A. baumanii pneumonia. A 69-year-old man admitted for fever was diagnosed with Streptococcus pneumoniae pneumonia based on chest radiography, urine antigen, and sputum examination. Despite appropriate antibiotics, the pneumonia progressed, necessitating intensive respiratory management. Ten days there after, he suffered sudden septic shock and superimposed pneumonia despite both carbapenem and fluoroquinolone administration. A. baumanii was detected from blood and sputum. Piperacilline/tazobactam, amikacin, and intensive care saved his life.

An increase in serum retinol-binding protein 4 in the type 2 diabetic subjects with nephropathy.

UNLABELLED: The present study was undertaken to determine retinol-binding protein 4 (RBP4) levels in subjects with diabetic nephropathy. A total of 149 type 2 diabetic subjects and 19 control subjects were enrolled. Serum levels of RBP4 were measured by a method of ELISA. Serum RBP4 levels were significantly greater in the subjects with type 2 diabetes mellitus than the controls (70.5 +/- 35.3 vs. 40.1 +/- 13.0 microg/ml, mean +/- SD, p<0.01). Serum RBP4 levels were gradually increased according to the progression of diabetic nephropathy (p value in trend test: <0.001). Its elevation was significantly greater in the diabetic subjects with stages 1, 3B and 4 than the control subjects (Stage 1: 64.6 +/- 29.7, Stage 3B: 123.3 +/- 71.8, Stage 4: 91.4 +/- 33.8 vs. CONTROL: 40.1 +/- 13.0 microg/ml, p<0.01). Similar results were obtained in the subjects based on the amount of albuminuria (Normo-: 64.6 +/- 29.7, Micro-: 63.7 +/- 29.4, and Marcoalbuminuria: 90.3 +/- 44.6 microg/ml, p <0.001). Serum RBP4 levels had a positive correlation with serum creatinine levels(r = 0.377, p<0.001), and a negative correlation with 1/creatinine (r = -0.420, p<0.001). Also, there was a negative correlation between serum RBP4 and the estimated glomerular filtration rate(r = -0.436, p<0.001). Multiple regression analysis showed that estimated glomerular filtration rate was an independent determinant for increased serum RBP4 levels. There was no difference in serum RBP4 levels between the advanced nephropathy with and without macrovascular diseases. These results indicate an increase in serum RBP4 levels in the type 2 diabetic subjects, particularly complicated with advanced renal impairment.

Incomplete deficiency of hypothalamic hormones in hypothalamic hypopituitarism associated with an old traumatic brain injury.

A 62 year-old man was admitted to determine the pathogenesis of his hypoglycemia. He was unconscious and his plasma glucose level was 26 mg/dL. When he was 31 years old, he had a traffic accident and was unconscious for several days. Physical findings on admittance showed that the patient's BMI was 17.8 and blood pressure, 114/70 mmHg. He was alert. He had a hypogonadal face with a lack of beard, and he had an atrophic testis with a volume of 1 to 2 ml. Laboratory findings showed that his fasting plasma glucose was 73 mg/dL; serum sodium, 133 mmol/l; potassium, 4.1 mmol/l; serum insulin, less than 1.0 muU/ml.; plasma ACTH, 45.8 pg/ml; serum cortisol, 5.2 microg/dL; and free cortisol urinary excretion, less than 4.5 microg/day; serum LH, 0.8 mIU/ml; serum testosterone, less than 0.05 ng/ml; serum TSH, 2.0 uIU/ml; free T(4), 0.7 ng/dL; free T(3), 1.5 pg/ml; and serum prolactin, 29.0 ng/ml. The levels of all the pituitary hormones were elevated in response to a mixture of exogenous corticotrophin-releasing hormone (CRH), luteinizing hormone-releasing hormone (LH-RH), thyrotropin-releasing hormone (TRH), and growth hormone-releasing hormone (GRH). However, there was no increased secretion of adrenocorticotropic hormone (ACTH) in response to hypoglycemia (induced by the administration of insulin) and there was no increased secretion of luteinizing hormone (LH) and follicle stimulating hormone (FSH) in response to the administration of clomiphene. Magnetic resonance imaging revealed an atrophied pituitary gland with an empty sella, but there were no abnormal findings of the hypothalamus. Hydrocortisone replacement at a dosage of 20 mg/day increased the patient's plasma glucose from 73 to 100 mg/dL and his serum sodium from 133 to 138 mmol/l. These findings therefore indicate a partial impairment in hypothalamic hormone release, resulting from a traumatic brain injury that the patient had received 31 years ago.

Risk Factors of Hypoglycemic Encephalopathy and Prolonged Hypoglycemia in Patients With Severe Hypoglycemia.

BACKGROUND: The aim of the study was to investigate risk factors of hypoglycemic encephalopathy (HE) in patients with severe hypoglycemia. METHODS: We retrospectively enrolled patients with severe hypoglycemia who were transported to the emergency department in an ambulance. We defined severe hypoglycemia as plasma glucose level < 60 mg/dL (or capillary levels < 50 mg/dL). HE was defined as severe hypoglycemia with altered level of consciousness (Glasgow coma scale < 12) and prolonged HE as coma or stupor lasting > 24 h after glucose administration. We compared several parameters between patients with and without HE and between prolonged and recovered patients. RESULTS: Included were 173 patients with severe hypoglycemia; of them, 94 were diagnosed with HE, with 12 of them prolonged HE. Glucose level in HE patients was lower than that in those without HE (P < 0.001). Moreover, we noted a significant difference in glucose levels between the prolonged and recovered groups. Furthermore, body temperature was higher in prolonged versus recovered patients (P = 0.0017). CONCLUSION: Blood glucose level may be correlated with severity of altered level of consciousness. In addition, body temperature may be related to coma or prolonged stupor.

Lipid synthetic transcription factor SREBP-1a activates p21WAF1/CIP1, a universal cyclin-dependent kinase inhibitor.

Sterol regulatory element-binding proteins (SREBPs) are membrane-bound transcription factors that regulate lipid synthetic genes. In contrast to SREBP-2, which regulates cellular cholesterol level in normal cells, SREBP-1a is highly expressed in actively growing cells and activates entire programs of genes involved in lipid synthesis such as cholesterol, fatty acids, triglycerides, and phospholipids. Previously, the physiological relevance of this potent activity of SREBP-1a has been thought to regulate the supply of membrane lipids in response to cell growth. Here we show that nuclear SREBP-1a and SREBP-2 bind directly to a novel SREBP binding site in the promoter of the p21(WAF1/CIP1) gene, the major cyclin-dependent kinase inhibitor, and strongly activate its promoter activity. Only the SREBP-1a isoform consistently causes induction of p21 at both the mRNA and protein levels. Colony formation assays and polyploidy of livers from transgenic mice suggest that activation of p21 by SREBP-1a could inhibit cell growth. Activation of endogenous SREBPs in lipid deprivation conditions was associated with induction of p21 mRNA and protein. Expression of p21 was reduced in SREBP-1 null mice. These data suggest a physiological role of SREBP-1a in p21 regulation. Identification of p21 as a new SREBP target might implicate a new paradigm in the link between lipid synthesis and cell growth.

Suppression of centrosome amplification after DNA damage depends on p27 accumulation.

The centrosome plays a fundamental role in cell division, cell polarity, and cell cycle progression. Centrosome duplication is mainly controlled by cyclin-dependent kinase 2 (CDK2)/cyclin E and cyclin A complexes, which are inhibited by the CDK inhibitors p21Cip1 and p27Kip1. It is thought that abnormal activation of CDK2 induces centrosome amplification that is frequently observed in a wide range of aggressive tumors. We previously reported that overexpression of the oncogene MYCN leads to centrosome amplification after DNA damage in neuroblastoma cells. We here show that centrosome amplification after gamma-irradiation was caused by suppression of p27 expression in MYCN-overexpressing cells. We further show that p27-/- and p27+/- mouse embryonic fibroblasts and p27-silenced human cells exhibited a significant increase in centrosome amplification after DNA damage. Moreover, abnormal mitotic cells with amplified centrosomes were frequently observed in p27-silenced cells. In response to DNA damage, the level of p27 gradually increased in normal cells independently of the ataxia telangiectasia mutated/p53 pathway, whereas Skp2, an F-box protein component of an SCF ubiquitin ligase complex that targets p27, was reduced. Additionally, p27 levels in MYCN-overexpressing cells were restored by treatment with Skp2 small interfering RNA, indicating that down-regulation of p27 by MYCN was due to high expression of Skp2. These results suggest that the accumulation of p27 after DNA damage is required for suppression of centrosome amplification, thereby preventing chromosomal instability.

[A case of multidrug-resistant squamous cell lung carcinoma responding to S-1 plus CPT-11 combination chemotherapy].

The patient was a 63-year-old man who consulted our hospital with complaints of a cough and breathing difficulties. His chest CT revealed a 25-mm mass in his right S1 hilar area with spiculation, disseminated nodule in right lung, and pericardial effusions. Also, bronchoscope and TBLB revealed squamous cell carcinoma. This patient was diagnosed as lung cancer (cT4N3M1, stage IV), and chemotherapy was initiated. The chemotherapy was given in the order of CBDCA (AUC3) +GEM (1,000 mg/m(2)), DOC (60 mg/m(2)), and VNR (25 mg/m(2)), and the tumor response was PD. S- 1 (120 mg/body/day, continuous administration for 2 weeks followed by 1 week of rest) was chosen as fourth-line treatment, and a breast CT detected tumor size reduction following completion of the first course. However, after completion of three courses, the breast CT found tumor-enlargement again. Then the chemotherapy was changed to amrubicin (35 mg/m(2)), but the treatment was discontinued due to skin rash. We once experienced a size reduction with S-1, so S-1 (100 mg/body/day, day 1-14) plus CPT-11 (60 mg/m(2), day 1, 7, 14) combination chemotherapy was conducted at 4-week intervals. After two courses were completed, tumor size reduction was observed by breast XP and CT. The response rate was 40.0%. Currently, seven courses were completed, and we will continue this treatment due to the tumor response of SD. The S-1 single treatment and S-1+CPT-11 combination chemotherapy showed efficacy for this difficult case of NSCLC with refractoriness to multiple cancer drug chemotherapy. This combination treatment should be investigated further for its therapeutic benefit.

A transcription factor of lipid synthesis, sterol regulatory element-binding protein (SREBP)-1a causes G(1) cell-cycle arrest after accumulation of cyclin-dependent kinase (cdk) inhibitors.

Sterol regulatory element-binding protein (SREBP)-1a is a unique membrane-bound transcription factor highly expressed in actively growing cells and involved in the biosynthesis of cholesterol, fatty acids, and phospholipids. Because mammalian cells need to synthesize membrane lipids for cell replication, the functional relevance of SREBP-1a in cell proliferation has been considered a biological adaptation. However, the effect of this potent lipid-synthesis activator on cell growth has never been explored. Here, we show that induction of nuclear SREBP-1a, but not SREBP-2, completely inhibited cell growth in inducible Chinese hamster ovary (CHO) cell lines. Growth inhibition occurred through G(1) cell-cycle arrest, which is observed in various cell types with transient expression of nuclear SREBP-1a. SREBP-1a caused the accumulation of cyclin-dependent kinase (cdk) inhibitors such as p27, p21, and p16, leading to reduced cdk2 and cdk4 activities and hypophosphorylation of Rb protein. In contrast to transactivation of p21, SREBP-1a activated p27 by enhancing stabilization of the protein through inhibition of SKP2 and KPC1. In vivo, SREBP-1a-expressing livers of transgenic mice exhibited impaired regeneration after partial hepatectomy. SREBP-1-null mouse embryonic fibroblasts had a higher cell proliferation rate than wild-type cells. The unexpected cell growth-inhibitory role of SREBP-1a provides a new paradigm to link lipid synthesis and cell growth.

Identification of ISG12b as a putative interferon-inducible adipocytokine which is highly expressed in white adipose tissue.

AIM: A number of adipocytokines have been suggested to be involved in the disruption of glucose metabolism, and also in the development of various diabetic complications. We attempted to identify and analyze additional adipocytokines, to better understanding the roles of adipocytes and adipocytokines. METHODS: An oligo-capping signal sequence trap, developed in our laboratory for screening the cDNAs of secretory proteins, was used to sreen cDNAs expressed in mouse white adipose tissue. Profiles of the genes identified in mice and cultured cells were further investigated by northern blotting and luciferase assay. RESULTS: A cDNA fragment of interferon-stimulated gene 12b (ISG12b) was obtained in the search. A northern blot analysis revealed ISG12b to be highly expressed in white adipose tissue. Interferon alpha (IFNalpha) was shown to induce ISG12b expression in the adipose tissue of BL6 mice in vivo, and also in a 3T3-L1 preadipocyte cell line in vitro. The level of ISG12b was higher in mature adipocytes than in preadipocytes. A promoter analysis demonstrated that the 369bp upstream from the transcription initiation site of ISG12b mRNA contain strong promoter activity, and the interferon-stimulated response elements (ISREs) were not present within the 5593bp upstream region. CONCLUSION: ISG12b is an additional candidate for a adipocytokine induced to express in adipose tissue by interferon.

Targeted deletion of both thymidine phosphorylase and uridine phosphorylase and consequent disorders in mice.

Thymidine phosphorylase (TP) regulates intracellular and plasma thymidine levels. TP deficiency is hypothesized to (i) increase levels of thymidine in plasma, (ii) lead to mitochondrial DNA alterations, and (iii) cause mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). In order to elucidate the physiological roles of TP, we generated mice deficient in the TP gene. Although TP activity in the liver was inhibited in these mice, it was fully maintained in the small intestine. Murine uridine phosphorylase (UP), unlike human UP, cleaves thymidine, as well as uridine. We therefore generated TP-UP double-knockout (TP(-/-) UP(-/-)) mice. TP activities were inhibited in TP(-/-) UP(-/-) mice, and the level of thymidine in the plasma of TP(-/-) UP(-/-) mice was higher than for TP(-/-) mice. Unexpectedly, we could not observe alterations of mitochondrial DNA or pathological changes in the muscles of the TP(-/-) UP(-/-) mice, even when these mice were fed thymidine for 7 months. However, we did find hyperintense lesions on magnetic resonance T(2) maps in the brain and axonal edema by electron microscopic study of the brain in TP(-/-) UP(-/-) mice. These findings suggested that the inhibition of TP activity caused the elevation of pyrimidine levels in plasma and consequent axonal swelling in the brains of mice. Since lesions in the brain do not appear to be due to mitochondrial alterations and pathological changes in the muscle were not found, this model will provide further insights into the causes of MNGIE.

Transgenic mice overexpressing SREBP-1a under the control of the PEPCK promoter exhibit insulin resistance, but not diabetes.

Sterol regulatory element-binding protein-1 (SREBP-1) is a transcription factor which regulates genes involved in the synthesis of fatty acids and triglycerides. The overexpression of nuclear SREBP-1a in transgenic mice under the control of the PEPCK promoter (TgSREBP-1a) caused a massively enlarged fatty liver and disappearance of peripheral white adipose tissue. In the current study, we estimated the impact of this lipid transcription factor on plasma glucose/insulin metabolism in vivo. TgSREBP-1a exhibited mild peripheral insulin resistance as evidenced by hyperinsulinemia both at fasting and after intravenous glucose loading, and retarded glucose reduction after insulin injection due to decreased plasma leptin levels. Intriguingly, hyperinsulinemia in TgSREBP-1a mice was markedly exacerbated in a fed state and sustained after intravenous glucose loading, and paradoxically decreased after the portal injection of glucose. TgSREBP-1a mice consistently showed very small plasma glucose increases after portal glucose loading because of a large capacity for hepatic glucose uptake. These data suggested that hepatic insulin resistance emerges postprandially. In addition, pancreatic islets from TgSREBP-1a were enlarged. These data demonstrate that SREBP-1a activation in the liver has a strong impact on plasma insulin levels, implicating the potential role of SREBPs in hepatic insulin metabolism relating to insulin resistance.

Transgenic mice overexpressing nuclear SREBP-1c in pancreatic beta-cells.

Influx of excess fatty acids and the resultant accumulation of intracellular triglycerides are linked to impaired insulin secretion and action in the pathogenesis of type 2 diabetes. Sterol regulatory element-binding protein (SREBP)-1c is a transcription factor that controls cellular synthesis of fatty acids and triglycerides. SREBP-1c is highly expressed in high-energy and insulin-resistant states. To investigate effects of this synthetic lipid regulator on insulin secretion, we generated transgenic mice overexpressing nuclear SREBP-1c under the insulin promoter. beta-Cell-specific expression of SREBP-1c caused reduction in islet mass and impaired glucose-stimulated insulin secretion and was associated with accumulation of triglycerides, suppression of pancreas duodenal homeobox-1, and upregulation of uncoupling protein 2 gene expression. The mice presented with impaired glucose tolerance that was exacerbated by a high-energy diet. Taken together with enhanced insulin secretion from SREBP-1-null islets, these data suggest that SREBP-1c and endogenous lipogenesis could be involved in beta-cell dysfunction and diabetes.