Once-weekly glucagon-like peptide-1 receptor agonist dulaglutide significantly decreases glycated haemoglobin compared with once-daily liraglutide in Japanese patients with type 2 diabetes: 52 weeks of treatment in a randomized phase III study.

AIMS: To examine the efficacy and safety of once-weekly dulaglutide 0.75 mg monotherapy compared with once-daily liraglutide 0.9 mg in Japanese patients with type 2 diabetes (T2D) for 52 weeks. METHODS: We conducted a phase III, randomized, 52-week (26-week primary endpoint), active- and placebo-controlled trial comparing 492 Japanese patients (dulaglutide, n = 281; liraglutide, n = 141; and placebo, n = 70). Participants and investigators were blinded to treatment assignment for dulaglutide and placebo but not for liraglutide (open-label comparator); after 26 weeks, patients randomized to placebo were switched to once-weekly dulaglutide 0.75 mg (open-label). The present paper reports results for patients treated with dulaglutide and patients treated with liraglutide for 52 weeks. RESULTS: At week 52, dulaglutide decreased HbA1c significantly from baseline compared with liraglutide [least squares mean difference: -0.20; 95% confidence interval (CI) -0.39, -0.01; p = 0.04]. At week 52 (last observation carried forward), dulaglutide significantly decreased pre- and post-dinner blood glucose (BG) levels, the mean of seven-point self-monitored BG profiles, the mean of all postprandial BG levels and circadian variation compared with liraglutide. Body weight was generally stable in both groups through 52 weeks. The most frequently reported adverse events were nasopharyngitis, constipation, nausea and diarrhoea. Eight dulaglutide-treated (2.9%) and four liraglutide-treated (2.9%) patients reported hypoglycaemia, with no event being severe. CONCLUSIONS: Monotherapy with once-weekly dulaglutide 0.75 mg was effective and safe in Japanese patients with T2D, with better glycaemic control compared with once-daily liraglutide 0.9 mg.

Once-weekly glucagon-like peptide-1 receptor agonist dulaglutide is non-inferior to once-daily liraglutide and superior to placebo in Japanese patients with type 2 diabetes: a 26-week randomized phase III study.

AIMS: To examine the efficacy and safety of once-weekly dulaglutide monotherapy (0.75 mg) compared with placebo and once-daily liraglutide (0.9 mg) in Japanese patients with type 2 diabetes. METHODS: This was a phase III, 52-week (26-week primary endpoint), randomized, double-blind, placebo-controlled, open-label comparator (liraglutide) trial comparing 492 Japanese patients with type 2 diabetes (dulaglutide, n = 281; liraglutide, n = 141; and placebo, n = 70) who were aged ≥20 years. Patients and investigators were blinded to treatment assignment for dulaglutide and placebo but not for liraglutide. The primary objective evaluated the superiority of dulaglutide versus placebo on change from baseline in glycated haemoglobin (HbA1c) at 26 weeks. Analyses were performed on the full analysis set. RESULTS: At 26 weeks, once-weekly dulaglutide was superior to placebo and non-inferior to once-daily liraglutide for HbA1c change from baseline [least squares mean difference: dulaglutide vs placebo -1.57% (95% confidence interval -1.79 to -1.35); dulaglutide vs liraglutide -0.10% (95% confidence interval -0.27 to 0.07)]. The most frequently reported adverse events were nasopharyngitis, constipation, diarrhoea, nausea, abdominal distension and decreased appetite; only decreased appetite was different between the dulaglutide and liraglutide groups [dulaglutide, n = 2 (0.7%); liraglutide, n = 8 (5.8%); p = 0.003]. Nine (1.8%) patients experienced hypoglycaemia [dulaglutide, n = 6 (2.1%); liraglutide, n = 2 (1.5%); placebo, n = 1 (1.4%)], with no event being severe. CONCLUSIONS: In Japanese patients with type 2 diabetes, once-weekly dulaglutide (0.75 mg) was superior to placebo and non-inferior to once-daily liraglutide (0.9 mg) for reduction in HbA1c at 26 weeks. Dulaglutide was safe and well tolerated.

Human diabetes associated with a mutation in the tyrosine kinase domain of the insulin receptor.

Insulin receptor complementary DNA has been cloned from an insulin-resistant individual whose receptors have impaired tyrosine protein kinase activity. One of this individual's alleles has a mutation in which valine is substituted for Gly996, the third glycine in the conserved Gly-X-Gly-X-X-Gly motif in the putative binding site fo adenosine triphosphate. Expression of the mutant receptor by transfection into Chinese hamster ovary cells confirmed that the mutation impairs tyrosine kinase activity.

Citrullinated antigens as C1q-binding and monoclonal rheumatoid factor (mRF)-binding peptides in synovial fluids from rheumatoid arthritis patients.

OBJECTIVE: Previous studies have demonstrated that immune complexes (ICs) may be involved in the pathogenesis of rheumatoid arthritis (RA). However, autoantigens contained in rheumatoid ICs remain to be elucidated. In the present study, we investigated whether the peptides captured by C1q and monoclonal rheumatoid factor (mRF), presumably associated with ICs, were citrullinated in synovial fluids from patients with RA. METHODS: Sixteen rheumatoid arthritis synovial fluids (RASFs), 7 osteoarthritis synovial fluids (OASFs), and 20 sera from RA patients were used for experiments. ICs were measured using commercially available kits based on the C1q-binding (C1q-IC) and mRF-binding (mRF-IC) assays. Citrullination of the peptides captured by C1q and mRF was detected by anti-modified citrulline antibody (Senshu Ab) after chemical modification. RESULTS: There was a significant correlation between levels of citrullination of C1q-binding peptides and those of mRF-binding peptides in RASFs (r=0.77), both of which were significantly higher than those in OASFs. No citrullinated Ags captured by C1q and mRF were detected in sera from patients with RA. CONCLUSIONS: We have demonstrated the presence of citrullinated Ags as C1q- and mRF-binding peptides in RASF. We suggest that citrullinated Ags may contribute to the pathogenesis of RA through IC formation in the joint.

Diabetes with the 3243 mitochondrial tRNALeu(UUR) mutation. Characteristic neuroimaging findings.

OBJECTIVE: To investigate the basis of central nervous system dysfunction in diabetes associated with the 3243 mitochondrial tRNA mutation, we studied neuroimaging findings in patients with this disease. RESEARCH DESIGN AND METHODS: We screened 205 diabetic patients. Those patients who had the 3243 mutation in leukocytes or muscle were enrolled. All the subjects underwent computed tomography (CT), magnetic resonance imaging (MRI), magnetic resonance angiography (MRA), and N-isopropyl-p-[123I]iodoamphetamine ([123I]IMP) single-photon emission computed tomography (SPECT) of the brain. RESULTS: None of the nine subjects with the 3243 mutation had the typical clinical picture of mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes, and none had neurological focal signs. CT or MRI revealed diffuse brain atrophy in three patients (33%) and cerebellar atrophy in one (11%). Abnormal high intensity areas were observed on MRI in five patients (56%). The overall prevalence of brain abnormalities was 56% (5 of 9) on CT and 78% (7 of 9) on MRI scans. MRA revealed no stenotic lesions. SPECT showed reduced accumulation of [123I]IMP in the right or left parieto-occipital region in eight patients (89%). CONCLUSIONS: Reduced accumulation of [123I]IMP in the parieto-occipital cortex was found in a high proportion of our subjects on SPECT. This imaging finding might be characteristic of diabetes associated with the 3243 mitochondrial tRNA mutation and may be a sign of latent central nervous system dysfunction.

Paraoxonase polymorphism (Gln192-Arg) is associated with coronary heart disease in Japanese noninsulin-dependent diabetes mellitus.

Serum paraoxonase/arylesterase (PONA) is associated with high-density lipoprotein and may prevent oxidation of low-density lipoprotein by hydrolyzing lipid peroxides. A recent report suggested an association of glutamine (A type)/arginine (B type) polymorphism at position 192 of PONA gene with coronary heart disease (CHD) among Caucasian patients with noninsulin-dependent diabetes mellitus (NIDDM). However, conflicting results have also been reported. To investigate the significance of this polymorphism in the pathogenesis of CHD, we performed an association study of this polymorphism with CHD in Japanese NIDDM patients. We genotyped 164 patients with NIDDM, 42 with CHD, and 122 without CHD. Other known risk factors for CHD were matched between the 2 groups. AB+BB isoforms were detected in 41 of 42 diabetic patients with CHD. The proportion of B allele carriers (AB+BB) was significantly higher than that of AA carriers among diabetic patients with CHD compared with those without CHD (chi 2 = 7.68, P = 0.003). Multivariate logistic regression analyses showed a markedly increased odds ratio (OR: 8.823, CI, 1.13-68.7) in B allele carriers, while ORs of other risk factors remained between 1.01 and 1.92. Carriers of the B allele of the Gln192Arg polymorphism in the PONA gene proved to be at increased risk for developing CHD in Japanese NIDDM patients. This association was independent of other known risk factors for CHD, suggesting an important role of the paraoxonase B isoform in the pathogenesis of CHD.

Prevalence and clinical characterization of Japanese diabetes mellitus with an A-to-G mutation at nucleotide 3243 of the mitochondrial tRNA(Leu(UUR)) gene.

An A-to-G mutation at nucleotide position 3243 of the mitochondrial genome has been associated with insulin-dependent diabetes mellitus (IDDM) and with noninsulin-dependent diabetes mellitus (NIDDM) with deafness. We investigated the prevalence of this mutation in Japanese patients with IDDM, NIDDM, and impaired glucose tolerance (IGT) and in nondiabetic control individuals, and we identified it in 3 of 300 patients with NIDDM or IGT (1.0%). None of these individuals had significant sensorineural hearing loss. None of the 94 IDDM or the 115 nondiabetic control subjects was positive for this mutation. Oral glucose tolerance test revealed that a 57-yr-old male with this mutation was rather hyperinsulinemic in the fasting state. The insulin secretion in this patient decreased with age; he did not complain of any hearing disorder, although audiometry revealed a slight elevation of hearing threshold at high frequencies. In conclusion, we found that a mitochondrial gene mutation at nucleotide position 3243 was present in about 1% of NIDDM patients including those patients with IGT. The subtype of diabetes mellitus with this mutation may have a clinical profile similar to that found in patients with NIDDM commonly seen in outpatient clinics.

A 3-basepair in-frame deletion (delta Leu999) in exon 17 of the insulin receptor gene in a family with insulin resistance.

We studied a woman with acanthosis nigricans and insulin resistance. The patient's Epstein-Barr virus-transformed lymphocytes revealed slightly decreased insulin binding and markedly decreased insulin-stimulated autophosphorylation of the insulin receptor. The nucleotide sequence analysis of the patient's genomic DNA revealed a 3-basepair in-frame deletion in one allele, resulting in the loss of leucine at position 999 of the insulin receptor (delta Leu999). The messenger ribonucleic acid transcripts from the mutant allele in the patient's lymphocytes were not decreased. Insulin-stimulated autophosphorylation of the insulin receptor from cells expressing delta Leu999 mutant insulin receptor complementary DNA was markedly decreased. The proband, her mother, elder brother, and younger brother, who were heterozygous for this mutation, showed moderate or marked hyperinsulinemia during oral glucose tolerance tests. Although fasting glucose levels were normal and fasting insulin values were preserved in all subjects with the mutation for the 8-yr period of observation, a tendency of progressive increase in postload glucose levels was observed. These results suggest that the delta Leu999 mutation, which reduces tyrosine kinase activity, was responsible for insulin resistance and contributed to postload hyperglycemia.

Defect in tyrosine kinase activity of the insulin receptor from a patient with insulin resistance and acanthosis nigricans.

We report here a defect in tyrosine kinase activity of the insulin receptor from an insulin-resistant patient with acanthosis nigricans using cultured Ebstein-Barr virus (EBV)-transformed B-lymphocytes. As judged by affinity labeling and immunoblotting, the alpha- and beta-subunits of insulin receptors from the patient's lymphocytes exhibited the same mol wt as those from control subjects. Lectin-purified extracts from lymphocytes of the patient and the control subjects containing the same insulin-binding capacity were assayed for autophosphorylation and the ability to phosphorylate histone H2B. The degree of insulin-dependent autophosphorylation and the tyrosine kinase activity of the insulin receptor from the patient's lymphocytes were decreased to 15% and 13%, respectively, in a cell-free system. The insulin-dependent autophosphorylation of the insulin receptor was also impaired in intact EBV lymphocytes from the patient. Consistent with these results, we found that one of this patient's alleles had a mutation in which valine is substituted for Gly996, the third glycine in the conserved Gly-X-Gly-X-X-Gly motif in the kinase domain. Thus, it seems likely that the defect in tyrosine kinase activity of the insulin receptor cause the insulin resistance in this patient. The EBV lymphocyte can be a good system to detect genetically determined abnormalities in the insulin receptor.

Involvement of mitochondrial gene abnormalities in the pathogenesis of diabetes mellitus.

An A to G mutation at nucleotide position 3243 of the mitochondrial genome has been shown to be associated with insulin-dependent diabetes mellitus (IDDM) and with noninsulin-dependent diabetes mellitus (NIDDM) with deafness. We investigated the prevalence of this mutation in Japanese patients with IDDM, NIDDM, and impaired glucose tolerance (IGT) and in nondiabetic control individuals and identified it in three of 300 patients with NIDDM or IGT (1.0%). None of these individuals had significant sensorineural hearing loss. None of the 94 IDDM or the 115 nondiabetic control subjects was positive for this mutation. Oral glucose tolerance test revealed that a 57-year-old male with this mutation was rather hyperinsulinemic in the fasting state. The insulin secretion in this patient decreased with age; he did not complain of any hearing disorder, although audiometry revealed a slight elevation of hearing threshold at high frequencies. In conclusion, we found that a mitochondrial gene mutation at np 3243 was present in about 1% of NIDDM patients including IGT, and the subtype of diabetes mellitus with this mutation may have a similar clinical profile to that found in patients with NIDDM commonly seen in outpatient clinics. Screening of 116 patients with type 1 diabetes mellitus and 149 patients with autoimmune thyroid diseases revealed that this mutation rarely exists in patients with autoimmune diseases.

Blinking is controlled primarily by ocular surface conditions.

PURPOSE: To investigate the relation between blinking and ocular surface conditions and to introduce and examine a new index, the maximum blink interval. METHODS: In a prospective study, the blink rate of subjects under relaxed conditions was determined from a video recording taken by a hidden observer. The maximum blink interval was defined as the longest time subjects can avoid blinking without feeling uncomfortable. RESULTS: Significant changes in the blink rate and maximum blink interval were induced by factors that directly or indirectly affect the ocular surface: topical anesthesia, changing exposed ocular surface area, and wind. Moreover, the blink rate and maximum blink interval were significantly different in dry eye patients compared with healthy volunteers, with the values of the former approaching the values of the latter after use of artificial tears. The maximum blink interval was decreased by the same factors that increased the blink rate, and there was a significant inverse correlation between blink rate and maximum blink interval. Use of video display terminals was associated with decreased maximum blink interval and, hence, the development of dry eye symptoms. CONCLUSIONS: There was an important association among blink rate, maximum blink interval, and ocular surface conditions. The blink rate and our newly introduced measurement, the maximum blink interval, should prove useful in assessing factors that cause dry eye. This prospective study should contribute to the understanding and treatment of dry eyes.

Predicting long-term glycemic control of post-educational type II diabetic patients by evaluating serum 1,5-anhydroglucitol levels.

1,5-Anhydroglucitol (1.5-AG) is known to closely reflect diabetic control within several days. The possibility of predicting long-term glycemic control after an educational hospitalization of type II diabetic patients was investigated by examining the relationship between changes in serum 1,5-AG levels after a short-term trial home stay following an educational program and long-term changes in glycosylated hemoglobin A1c (HbA1c) levels after discharge. After 22 patients with type II diabetes had successfully completed the educational hospitalization program, they returned as outpatients for 5 nights in a row. Changes in serum 1,5-AG levels were determined during this period. The HbA1c levels were then determined over a period of 3 months after discharge, and the relationship between changes in 1,5-AG and HbA1c levels was examined. Changes in serum 1,5-AG levels during the 5-day trial home stay and the changes in HbA1c levels during the 3 months after discharge from the hospital were found to be significantly correlated (r = 0.70, P < 0.01). A comparison of the decreased group, which exhibited a decrease in 1.5-AG levels of 5.0 mumol/l or more during the trial home stay, and the unchanged group, revealed that increases in body mass index 3 months after discharge were significantly higher in the decreased group (1.2 +/- 0.4%) than in the unchanged group (0.2 +/- 0.5%) (P < 0.05). Determination of serum 1,5-AG levels of patients with type II diabetes before and after a trial home stay following educational hospitalization was found to be useful in identifying patients at high risk of recurrence of poor glycemic control in the future.

Syndrome of inappropriate secretion of antidiuretic hormone (SIADH) and Gerhardt syndrome associated with Shy-Drager syndrome.

This is the first report on a case of syndrome of inappropriate secretion of antidiuretic hormone (SIADH) associated with Gerhardt syndrome (paralysis of bilateral vocal cords). A 67-year-old Japanese man suffering from progressive autonomic failure was diagnosed as having Shy-Drager syndrome (SDS) with hyponatremia due to SIADH and severe sleep apnea caused by a bilateral recurrent nerve palsy. Water load test showed alteration in diuresis which was corrected by phenytoin. Arginine vasopressin secretion was not suppressed by plasma osmolality below 280 mOsm/kgH2O. Impairment of the afferent pathways of baroreceptors, or impairment of the osmoreceptors could be speculated as the etiological factor of the SIADH observed in this case.

[Glucokinase gene abnormalities in maturity-onset diabetes of the young (MODY) and late-onset NIDDM].

Glucokinase is a key enzyme of glucose metabolism that phosphorylates glucose to glucose-6-phosphate (G-6-P). This is the first step of glucose metabolism after the uptake of glucose by glucose transporter 2 (GLUT 2). Glucokinase is one of the hexo-kinases and is expressed only in pancreatic beta cells and hepatocytes. Recently it was reported that glucokinase gene is associated with some families with MODY (maturity-onset diabetes of the young). As MODY is a subtype of diabetes which is inherited autosomal dominantly, the correlation of diabetes with glucokinase gene was vigorously studied in many laboratories. The first mutation in exon 7 of the glucokinase gene was reported in 1992. Since the first report of the glucokinase gene mutation in exon 7, a number of mutations and a deletion were reported to be associated with MODY or late-onset NIDDM. But investigations by many groups revealed that glucokinase gene abnormalities are responsible for less than one per cent of NIDDM which is relatively small compared with diabetes with mitochondrial gene alterations.