Improved insulin sensitivity with sodium-glucose cotransporter 2 inhibitor treatment in a patient with slowly progressive type 1 diabetes mellitus with metabolic syndrome: a case report.

We herein report the clinical course of a 56-year-old Japanese patient with slowly progressive type 1 diabetes mellitus, metabolic syndrome, non-alcoholic fatty liver disease, and severe insulin resistance. The patient's intravenous glucose tolerance test indicated marked reductions in insulin sensitivity and endogenous insulin secretion. Accordingly, administration of ipragliflozin l-proline, a sodium-glucose cotransporter 2 inhibitor, promoted improvements in insulin sensitivity and blood glucose levels, as well as a decrease in visceral fat, improvement in dyslipidemia, and decrease in hepatic lipid content, suggesting the potential efficacy of sodium-glucose cotransporter 2 inhibitors for obese patients with type 1 diabetes mellitus exhibiting insulin resistance.

Predictors of glycemic control in Japanese subjects with type 2 diabetes mellitus.

The purpose of this study was to investigate which pathophysiological and demographic characteristics of Japanese subjects with type 2 diabetes mellitus were associated with poor glycemic control and to propose a statistical model for predicting their glycemic control. A total of 220 subjects with type 2 diabetes mellitus were enrolled in this study. Frequently sampled intravenous glucose tolerance test was performed to determine the first-phase C-peptide secretion rate (CS1) and insulin sensitivity index. Multiple regression analysis in a stepwise manner was carried out to identify independent regulators of glycemic control. Upon stepwise linear regression analysis with hemoglobin A1c as a dependent parameter, fasting plasma glucose concentration (FPG), CS1, and onset age remained as predictors, explaining 41.0% of glycemic control. The young-onset group (onset age < or =48 years) had significantly higher hemoglobin A1c than the old-onset group (onset age >48 years) (P = .0148), although the present age was significantly older in the old-onset group; and there were no significant differences in duration of diabetes, treatment, body mass index, FPG, fasting insulin level, homeostasis model assessment of insulin resistance, CS1, and log(insulin sensitivity index) between them. Worsening factors of glycemic control in Japanese subjects with type 2 diabetes mellitus were elevated FPG, impaired first-phase insulin secretion, and young age of onset of the disease. Because glycemic control in the subjects with young-onset diabetes tends to be worse, early and aggressive intervention should be required for those with young-onset diabetes to prevent long-term complications.

Continuous glucose monitoring reveals hypoglycemia risk in elderly patients with type 2 diabetes mellitus.

AIMS/INTRODUCTION: The incidence of type 2 diabetes is higher in elderly patients, in whom this disease is associated with dementia, falling, stroke and death. We utilized a continuous glucose monitoring device to analyze the relationship between hypoglycemia and diabetes treatments to identify risk factors for hypoglycemia (defined as a blood glucose level <70 mg/dL). MATERIALS AND METHODS: We classified 170 patients aged ≥65 years with type 2 diabetes who were receiving steady-state medication (29 of whom were inpatients) into hypoglycemic and non-hypoglycemic groups, and compared their glycosylated hemoglobin levels, treatment types, continuous glucose monitoring data and other parameters. We carried out univariate analyses to identify variables associated with hypoglycemia risk, followed by multivariate analyses of drug class and other factors. The accuracy of the continuous glucose monitoring data was confirmed by calibration. RESULTS: Hypoglycemia risk was higher in the patients using insulin (odds ratio [OR] 2.17, 95% confidence interval [CI] 1.16-4.08, P = 0.015), and lower in patients who were being treated with dipeptidyl peptidase-4 inhibitors (OR 0.47, 95% CI: 0.25-0.89, P = 0.019). Patients with lower variability in blood glucose had a significantly lower hypoglycemia risk (OR 0.87, 95% CI: 0.83-0.91, P < 0.0001), and those with a lower average blood glucose level had a significantly higher risk (OR 1.09, 95% CI: 1.06-1.12, P < 0.0001). CONCLUSIONS: In patients aged ≥65 years with type 2 diabetes, higher glucose variability and lower average glucose levels indicate a greater hypoglycemia risk. It is therefore necessary to ensure comprehensive blood glucose control in such patients to prevent hypoglycemia.

Serum resistin level is associated with insulin sensitivity in Japanese patients with type 2 diabetes mellitus.

Impaired insulin secretion and decreased insulin sensitivity are the main pathophysiologic features responsible for development of hyperglycemia in type 2 diabetes mellitus. Insulin resistance is often associated with increased adipose tissue mass. To examine which variables influence insulin sensitivity, we compared metabolic parameters, serum resistin, leptin, and adiponectin concentrations to the insulin sensitivity, obtained by frequently sampled intravenous glucose tolerance test using the minimal model analysis, in 113 Japanese patients with type 2 diabetes mellitus. Duration of diabetes, fasting plasma glucose, fasting insulin, homeostasis model assessment of insulin resistance index, and serum resistin concentration were significantly higher in the insulin-resistant subgroup compared with the insulin-sensitive subgroup and correlated with insulin sensitivity. Stepwise regression analysis also identified these parameters as independent regulators of insulin sensitivity. The present study reconfirmed that fasting insulin level or homeostasis model assessment of insulin resistance would be a surrogate measure of insulin resistance and demonstrated that insulin resistance increases progressively after the onset of overt diabetes and that the serum resistin level is associated with insulin sensitivity, suggesting that resistin plays an important role in the development of insulin resistance in Japanese patients with type 2 diabetes mellitus.

The Arg121Trp variant in PAX4 gene is associated with beta-cell dysfunction in Japanese subjects with type 2 diabetes mellitus.

Mutations in PAX4, a transcription factor involved in the beta-cell differentiation, could predispose to the development of type 2 diabetes mellitus. To clarify the role of PAX4 Arg121Trp mutation on the development of type 2 diabetes mellitus, we try to determine the clinical phenotype in diabetic subjects with this mutation. Study subjects consisted of 793 type 2 diabetic patients and 318 control subjects. Genotyping for Arg121Trp polymorphism was performed by Invader assay. Clinical phenotype was determined in diabetic subjects including 20 Trp121 carriers and 142 wild-type subjects using a combination of 2-compartment model of C-peptide kinetics and minimal model analysis during intravenous glucose tolerance test. We detected 3 Trp/Trp, 51 Arg/Trp, and 739 Arg/Arg in diabetic subjects, and 16 Arg/Trp and 302 Arg/Arg in control subjects. The frequency of Trp121 allele was 3.59% and 2.51% in diabetic and control groups, respectively (P = .19). Rate of insulin users was higher in Trp121 carriers compared with the wild-type group (42.5% vs 25.0%, P = .0046). First-phase C-peptide secretion was significantly decreased in the diabetic subjects with Trp121 allele compared with the patients with wild type (P = .0048), whereas there were no significant differences in insulin sensitivity and glucose effectiveness between the groups. Arg121Trp mutation in PAX4 gene could be associated with beta-cell dysfunction in Japanese subjects with type 2 diabetes mellitus.

Relationship between kidney function decline and initial risk factors for the progression of diabetic kidney disease: a retrospective analysis of 91 Japanese patients with type 2 diabetes.

BACKGROUND: Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease (ESRD) in Japan. The clinical course and factors related to the progression of DKD to ESRD are important issues when treating patients with DKD. METHODS: Ninety-one type 2 diabetic patients with DKD that had progressed from chronic kidney disease (CKD) stages G1-3 on their initial clinical visit to ESRD were enrolled. The decline in the estimated glomerular filtration rate (eGFR) was analyzed and the initial clinical factors that influenced the decline rate were explored. RESULTS: There was a linear decline in eGFR before progression to ESRD, with a median annual decline rate (∆eGFR) of 9.2 mL/min/1.73 m2. In all patients, a history of coronary artery disease and increased levels of initial eGFR and high-density lipoprotein cholesterol (HDL-C) were positive predictors of log ∆eGFR, whereas age, history of cerebral infarction (CI), and an increased level of serum albumin were negative predictors of log ∆eGFR. In patients with CKD stages G1-2 on their first visit, male sex and increased diastolic blood pressure were positive predictors. In patients with CKD stage G3 on their first visit, an increased level of LDL-C was a positive predictor, whereas a history of CI and an increased level of serum total bilirubin (TBil) were negative predictors. CONCLUSION: In addition to the common risk factors, initial eGFR, HDL-C, and TBil were identified as novel risk factors for ESRD. These risk factors may differ between patients with early and advanced stages of CKD.

Beta-cell dysfunction in late-onset diabetic subjects carrying homozygous mutation in transcription factors NeuroD1 and Pax4.

Polymorphisms in beta-cell transcription factor genes, Ala45Thr in the NeuroD1 gene and Arg121Trp in the Pax4 gene, have been reported. To clarify the role of these mutations in the pathogenesis of late-onset diabetes, we examined the insulin secretion and sensitivity in diabetic patients carrying the homozygous mutation in the NeuroD1 gene or Pax4 gene. We screened for the polymorphisms in NeuroD1 and Pax4 genes in 296 late-onset diabetic patients and 177 unrelated control subjects over 60 years of age. Genotyping was performed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) followed by direct sequencing. Acute insulin secretion was evaluated using a 2-compartment model analysis of C-peptide kinetics after intravenous glucose load (CS1). Insulin sensitivity was estimated by the insulin-modified minimal model analysis (Si). Four diabetic patients carried the homozygous mutation (Thr/Thr) in the NeuroD1 gene and 3 patients carried the homozygous mutation (Trp/Trp) in the Pax4 gene, while both homozygous mutations were not detected in the control subjects. In patients A, B, C, and D with homozygous mutations in NeuroD1, CS1 (normal range, 6.8 to 18.5 ng/mL/min) was 0.508, 1.481, 1.223, and 1.584 ng/mL/min, respectively, and Si (normal range, 2.6 to 7.6 x 10(-4)/min/[microU/mL]) was 0.727, 3.31, 3.79, and 0.00 x 10(-4)/min/(microU/mL), respectively. In patients X, Y, and Z with homozygous mutation in Pax4, CS was 0.418, 0.208, and 1.279 ng/mL/min, respectively, and Si was 1.11, 2.88, and 0.00 x 10(-4)/min/(microU/mL), respectively. Since acute insulin secretion in response to glucose was markedly impaired and insulin resistance was varied in the patients carrying the homozygous mutations in the NeuroD1 and Pax4 genes, the mutations are ones of the factors involved in the beta-cell dysfunction and do not relate to the insulin resistance. These homozygous mutations appear to play a part in the pathogenesis of beta-cell defect in about 2.5% of Japanese patients with late-onset diabetes.

Effects of weight loss in obese subjects with normal fasting plasma glucose or impaired glucose tolerance on insulin release and insulin resistance according to a minimal model analysis.

We investigated effects of weight loss from diet and exercise regimen in obese subjects with normal fasting plasma glucose or impaired glucose tolerance (IGT) on insulin release capacity and insulin sensitivity. Eight subjects were recruited among visceral obesity patients (4 men, 4 women; age range, 24 to 57 years; body mass index [BMI], 32.8 to 60.3 kg/m(2)). All were admitted to Chiba University Hospital for 2 weeks, were treated with a tapering 5,023 to 2,930 kJ diet, and were given exercise equivalent to 628 kJ/d. For assessments, we used a combination of C-peptide secretion rate determination and minimal model analysis as previously reported. BMI and visceral fat area (V) significantly decreased (BMI on initiation v after intervention, 43.0 +/- 3.2 v 40.3 +/- 3.1 kg/m(2), P <.05; V, 224 +/- 22 v 188 +/- 22 cm(2); P <.05). Fasting immunoreactive insulin (F-IRI) and leptin concentrations decreased significantly. Capacity for insulin release in response to glucose increased in all subjects (first-phase insulin secretion [CS1], 4.66 +/- 4.05 v 6.81 +/- 4.57 ng/mL/5 min, P <.05), but the insulin sensitivity index (S(i)) did not change significantly. These data suggest that weight reduction early in development of type 2 diabetes can oppose progression of diabetes by improving capacity for insulin release.

Five missense mutations in glucagon-like peptide 1 receptor gene in Japanese population.

To address the possibility that the partial disruption of Glucagon-like peptide-1 (GLP-1) signaling could cause diabetes, we tried to detect the mutation in GLP-1 receptor (GLP-1R) gene in the population with type 2 diabetes. Genomic DNA was extracted from 36 unrelated Japanese type 2 diabetic subjects and directly sequenced for the GLP-1R gene. For the detected polymorphisms, 791 patients with type 2 diabetes and 318 controls were screened by polymerase chain reaction-restricted fragment length polymorphism and association study was carried out. Five missense and four silent variants were detected in the GLP-1R gene. There were no significant differences in the frequencies of Pro7Leu, Arg44His and Leu260Pro polymorphism between the diabetic and control groups. And also there were no significant differences in body mass index (BMI), onset age and fasting IRI among the wild type, heterozygote and homozygote of these variants in diabetic patients. Thr149Met mutation was detected in one case among 791 type 2 diabetes patients, but not in control subjects. The patient with this mutation exhibited impairment of both insulin secretion, insulin sensitivity and glucose effectiveness, which may be partially explained by Thr149Met mutation in GLP-1R, though family linkage analysis and function analysis remain to be examined.

Evaluation of insulin secretion and sensitivity in a patient with slowly progressive type 1 diabetes mellitus.

We herein report the case of a patient with slowly progressive type 1 diabetes and insulin independence lasting for >10 years despite the detection of continuously elevated glutamic acid decarboxylase autoantibody titers. We monitored the patient's clinical course and analyzed his endogenous insulin secretion and sensitivity using an intravenous glucose tolerance test (IVGTT) and oral glucose tolerance test (OGTT). His body mass index remained at approximately 22, while his serum C-peptide immunoreactivity level gradually decreased. The level of insulin secretion was significantly higher on the OGTT than the IVGTT. The patient's insulin sensitivity was within the normal limits. These results suggest that maintaining a lifestyle sufficient to preserve insulin secretion and/or normal insulin sensitivity is important and that ß-cell responsiveness to incretins may, in part, contribute to insulin independence.

Frequency of the G/G genotype of resistin single nucleotide polymorphism at -420 appears to be increased in younger-onset type 2 diabetes.

OBJECTIVE: Resistin is an adipocyte-secreted cytokine associated with insulin resistance in mice. We previously reported that the G/G genotype of a resistin single nucleotide polymorphism (SNP) at -420 increases type 2 diabetes susceptibility by enhancing its promoter activity. The aim of the present study was to determine the relevance of SNP -120 in a large number of subjects. RESEARCH DESIGN AND METHODS: We examined 2,610 type 2 diabetic case and 2,502 control subjects. The relation between SNP -420 and the age of type 2 diabetes onset was further analyzed by adding 237 type 2 diabetic subjects with age of onset or=40 years (G/G vs. C/C, P = 0.003). In a total of 2,430 type 2 diabetic subjects with age of onset <60 years, the trend test showed that the G/G genotype had an increasing linear trend as the age grade of type 2 diabetes onset became younger (P = 0.0379). In control subjects, the frequency of C/G genotype showed an increasing linear trend with increasing age (P = 0.010). CONCLUSIONS: The G/G genotype frequency of resistin SNP -420 appears to be increased in younger-onset type 2 diabetic subjects.