Trends in glycemic control in patients with insulin therapy compared with non-insulin or no drugs in type 2 diabetes in Japan: a long-term view of real-world treatment between 2002 and 2018 (JDDM 66).

INTRODUCTION: We investigated trends in the proportion of diabetes treatment and glycemic control, which may be altered by recent advances in insulin and non-insulin drugs, in Japanese patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: A serial cross-sectional study was performed using a multicenter large-population database from the Japan Diabetes Clinical Data Management study group. Patients with type 2 diabetes who attended clinics belonging to the study group between 2002 and 2018 were included to examine trends in glycated hemoglobin A1c (HbA1c) by treatment group using multivariable non-linear regression model. RESULTS: The proportion of patients with insulin only decreased from 15.0% to 3.6%, patients with insulin+non-insulin drugs increased from 8.1% to 15.1%, patients with non-insulin drugs increased from 50.8% to 67.0%, and those with no drugs decreased from 26.1% to 14.4% from 2002 to 2018, respectively. The HbA1c levels of each group, except for no drugs, continued to decrease until 2014 (unadjusted mean HbA1c (%) from 2002 to 2014: from 7.89 to 7.45 for insulin only, from 8.09 to 7.63 for insulin+non-insulin, and from 7.51 to 6.98 for non-insulin) and remained unchanged thereafter. Among insulin-treated patients, use of human insulin decreased, use of long-acting analog insulin increased, and concomitant use of non-insulin drugs increased (from 35.1% in 2002 to 80.9% in 2018), which included increased use of dipeptidyl peptidase 4 inhibitors, sodium-glucose cotransporter 2 inhibitors, and glucagon-like peptide 1 receptor agonists, and the persistently high use of metformin. CONCLUSIONS: During the past two decades, combined use of insulin and non-insulin drugs increased and glycemic control improved and leveled off after 2014 in Japanese patients with type 2 diabetes. Further studies of the trend in association with age and factors related to metabolic syndrome are necessary to investigate strategies aiming at personalized medicine in diabetes care.

Patient characteristics associated with improvement in glycemic control following addition of an oral antidiabetic drug to DPP-4 inhibitor monotherapy in Japanese patients with type 2 diabetes mellitus (JDDM 60).

AIMS: The current study evaluated patient demographics and clinical characteristics that associated with HbA1c reduction following addition of one oral antidiabetic drug (OAD) to DPP4i monotherapy. METHODS: A retrospective study was conducted using CoDiC database. Adult T2DM patients treated with sitagliptin monotherapy for ≥ 6 months and adding one OAD were extracted. Association between patient characteristics at the time of add-on OAD and following HbA1c reduction was assessed. RESULTS: Of 444 included patients, mean age was 62 years and 33% were female. All add-on OAD classes demonstrated further HbA1c reduction (p < 0.05). The majority received biguanide (BG; 61%) or sulfonylurea (SU; 25%) add-on therapy. BG and SU groups showed a significant association between higher baseline HbA1c categories and greater HbA1c reductions (BG: - 0.24 to - 1.75%, p < 0.0001; SU: - 0.15 to - 2.11%, p < 0.0001). Lower HDL-cholesterol/higher non-HDL-cholesterol (BG), male gender (SU), and lower SBP (SU) were associated with larger HbA1c reductions. The results for baseline HbA1c (BG and SU) and gender (SU) were also confirmed by multivariate analysis. CONCLUSION: The majority of Japanese T2DM patients on sitagliptin monotherapy who require an add-on OAD utilized BG or SU. There were 2 determinants of glycemic response: baseline HbA1c with BG and SU and gender with SU during add-on OAD therapy. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13340-021-00514-5.

Association of a SNP in the IAPP gene and hyperglycemia on ß-cell dysfunction in type 2 diabetes: the Toon Genome Study.

OBJECTIVE: In type 2 diabetes, the significant pathological change in pancreatic islets is amyloid deposits. Its major component is islet amyloid polypeptide (IAPP). The objective of this study was to evaluate the possibility that the effect of the IAPP genotype on ß-cell dysfunction in type 2 diabetes is modified by variations in plasma glucose levels. METHODS: Participants from the Toon Genome Study underwent a 75 g OGTT for the diagnosis of glucose tolerance and the evaluation of insulin secretion. We examined the effect of a SNP, rs77397980, on ß-cell function by analyzing an interaction (statistics) between the IAPP genotype and AUC glucose. RESULTS: The ratio of the C-allele carriers was essentially the same among subjects with normal glucose tolerance, impaired glucose tolerance and diabetes. In subjects with diabetes, along with an increase in AUC glucose, fasting insulin remained constant in the T/T homozygotes and appeared to decrease in the C-allele carriers. A homeostasis model assessment (HOMA)-IR appeared to be increased in the former and decreased in the latter. In subjects with diabetes stratified into cases with higher AUC glucose than the median, fasting insulin and HOMA-IR were lower in the C-allele carriers than in the T/T homozygotes. An interaction between the IAPP genotype and AUC glucose was indicated in the effect on HOMA-IR. CONCLUSIONS: The possibility that the association between IAPP genotype and basal insulin level is modified by variation in plasma glucose, resulting in a decreased basal insulin in type 2 diabetes, cannot be excluded. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13340-021-00523-4.

Combination of disease duration-to-age at diagnosis and hemoglobin A1c-to-serum C-peptide reactivity ratios predicts patient response to glucose-lowering medication in type 2 diabetes: A retrospective cohort study across Japan (JDDM59).

AIMS/INTRODUCTION: Knowing the collective clinical factors that determine patient response to glucose-lowering medication would be beneficial in the treatment of type 2 diabetes. We carried out a retrospective cohort study to explore the combination of clinical factors involved in its therapeutic efficacy. MATERIALS AND METHODS: The results of cohort studies retrieved using the CoDiC® database across Japan from January 2005 to July 2018 were analyzed based on criterion that using insulin therapy indicates severe type 2 diabetes. RESULTS: A logistic regression analysis showed that age at diagnosis, disease duration, hemoglobin A1c (HbA1c) and serum C-peptide reactivity (CPR) at medication commencement were associated with the probability of insulin treatment. Receiver operating characteristic curve showed that these clinical factors predicted insulin treatment positivity with an area under the curve of >0.600. The area under the curve increased to 0.674 and 0.720 for the disease duration-to-age at diagnosis ratio and HbA1c-to-CPR ratio, respectively. Furthermore, area under the curve increased to 0.727 and 0.750 in the indices (duration-to-age ratio at diagnosis × 43 + HbA1c) and (duration-to-age ration at diagnosis × 21 + HbA1c-to-CPR ratio), respectively. After stratification to three groups according to the indices, monthly HbA1c levels during 6 months of treatment were higher in the upper one-third than in the lower one-third of patients, and many patients did not achieve the target HbA1c level (53 mmol/mol) in the upper one-third, although greater than fourfold more patients were administered insulin in the upper one-third. CONCLUSIONS: The combination of disease duration-to-age at diagnosis and HbA1c-to-CPR ratios is a collective risk factor that predicts response to the medications.

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.

Correction to: IAPP/amylin and ß­cell failure: implication of the risk factors of type 2 diabetes.

[This corrects the article DOI: 10.1007/s13340-018-0347-1.].

IAPP/amylin and ß-cell failure: implication of the risk factors of type 2 diabetes.

In type 2 diabetes (T2D), the most significant pathological change in pancreatic islets is amyloid deposits, of which a major component is islet amyloid polypeptide (IAPP), also called amylin. IAPP is expressed in ß-cells and co-secreted with insulin. Together with the inhibitory effects of synthetic human IAPP (hIAPP) on insulin secretion, our studies, using hIAPP transgenic mice, in which glucose-stimulated insulin secretion was moderately reduced without amyloid deposit, and hIAPP gene-transfected ß-cell lines, in which insulin secretion was markedly impaired without amyloid, predicted that soluble hIAPP-related molecules would exert cytotoxicity on ß-cells. Human IAPP is one of the most aggregation-prone peptides that interact with cell membranes. While it is widely reported that soluble hIAPP oligomers promote cytotoxicity, this is still a hypothesis since the mechanisms are not yet fully defined. Several hIAPP transgenic mouse models did not develop diabetes; however, in models with backgrounds characterized for diabetic phenotypes, ß-cell function and glucose tolerance did worsen, compared to those in non-transgenic models with similar backgrounds. Together with these findings, many studies on metabolic and molecular disorders induced by risk factors of T2D suggest that in T2D subjects, toxic IAPP oligomers accumulate in ß-cells, impair their function, and reduce mass through disruption of cell membranes, resulting in ß-cell failure. IAPP might be central to ß-cell failure in T2D. Anti-amyloid aggregation therapeutics will be developed to create treatments with more durable and beneficial effects on ß-cell function.

Relationship between the efficacy of oral antidiabetic drugs and clinical features in type 2 diabetic patients (JDDM38).

AIMS/INTRODUCTION: We carried out an observational cohort study to examine the relationship between the efficacy of oral antidiabetic drugs and clinical features in type 2 diabetics. MATERIALS AND METHODS: We analyzed the CoDiC(®) database of the Japan Diabetes Data Management Study Group across 67 institutions in Japan. In a total of 3,698 drug-naïve patients who were initiated with metformin, dipeptidyl peptidase-4 inhibitor (DPP-4i) or sulfonylurea (SU) from 2007 to 2012, we evaluated body mass index (BMI) and hemoglobin A1c (HbA1c). The patients were stratified according to their clinical features, and matched using a propensity score to adjust for baseline factors. RESULTS: HbA1c was reduced with all drugs, with the largest effect elicited by DPP-4i and the smallest by SU (P = 0.00). HbA1c increased with SU after 6 months in the patients stratified by an age-of-onset of <50 years (P = 0.00). BMI increased with SU in the patients stratified by a BMI of <25 (P = 0.00), and decreased with metformin in the patients with a BMI >25 (P = 0.00). The reduction in HbA1c was larger in patients with HbA1c of ≥8%, compared with that in patients with HbA1c of <8% (P = 0.00). HbA1c during the study period was higher in patients who were added to or swapped with other drug(s), than in patients continued on the original drug (P = 0.00). CONCLUSIONS: The effect on bodyweight and glycemic control differed among metformin, DPP-4i and SU, and the difference was associated with clinical features.

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.

Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin compared with alpha-glucosidase inhibitor in Japanese patients with type 2 diabetes inadequately controlled on metformin or pioglitazone alone (Study for an Ultimate Combination Therapy to Control Diabetes with Sitagliptin-1): A multicenter, randomized, open-label, non-inferiority trial.

AIMS/INTRODUCTION: To assess the efficacy and safety of sitagliptin compared with α-glucosidase inhibitors in Japanese patients with type 2 diabetes inadequately controlled by metformin or pioglitazone alone. MATERIALS AND METHODS: In the present multicenter, randomized, open-label, parallel-group, active-controlled, non-inferiority trial, 119 patients aged 20-79 years with type 2 diabetes who had glycated hemoglobin 6.9-8.8% on stable metformin (500-1,500 mg/day) or pioglitazone (15-30 mg/day) alone were randomly assigned (1:1) to receive the addition of sitagliptin (50 mg/day) or an α-glucosidase inhibitor (0.6 mg/day voglibose or 150 mg/day miglitol) for 24 weeks. The primary end-point was change in glycated hemoglobin from baseline to week 12. All data were analyzed according to the intention-to-treat principle. RESULTS: After 12 weeks, reductions in adjusted mean glycated hemoglobin from baseline were -0.70% in sitagliptin and -0.21% in the α-glucosidase inhibitor groups respectively; between-group difference was -0.49% (95% confidence interval -0.66 to -0.32, P < 0.0001), meeting the predefined non-inferiority criterion (0.25%) and showing statistical significance. This statistical significance also continued after 24 weeks. Although sitagliptin did not affect bodyweight, α-glucosidase inhibitors decreased bodyweight significantly from baseline (-0.39 kg; P = 0.0079). Gastrointestinal disorders were significantly lower with sitagliptin than with an α-glucosidase inhibitor (6 [10.3%] patients vs 23 [39.7%]; P = 0.0003). Minor hypoglycemia occurred in two patients (3.5%) in each group. CONCLUSIONS: Sitagliptin showed greater efficacy and better tolerability than an α-glucosidase inhibitor when added to stable doses of metformin or pioglitazone. These findings support the use of sitagliptin in Japanese patients with type 2 diabetes inadequately controlled by insulin-sensitizing agents. This trial was registered with UMIN (no. 000004675).

Evaluation of insulin regimens as an effective option for glycemic control in patients with type 2 diabetes: A propensity score-matched cohort study across Japan (JDDM31).

AIMS/INTRODUCTION: We evaluated the long-term efficacy of insulin regimens in patients with type 2 diabetes mellitus and poor glycemic control despite oral antidiabetic drugs (OAD). MATERIALS AND METHODS: We carried out a propensity score-matched cohort study using the CoDiC(®) database of the Japan Diabetes Data Management Study Group across 54 institutions in Japan from 2005 to 2010. A total of 10,854 patients on OAD in 2005 were studied, and 1,253 patients (11.5%) were treated with insulin until 2010. The changes in insulin regimens and glycated hemoglobin (HbA1c) levels were analyzed over this study period. RESULTS: Propensity score matching showed no differences in the baseline patient characteristics. A total of 96 patients transferred to insulin, and HbA1c gradually and significantly decreased in the patients on a twice-daily premixed preparation of rapid-acting human-insulin analogs (twice-daily MIX) and basal-bolus therapy with rapid-acting human-insulin analogs (RA) plus long-acting insulin analog (LA; P < 0.001). A total of 418 patients had insulin added to OAD treatment, and HbA1c decreased in the patients with a twice-daily MIX (P < 0.001), but HbA1c did not differ from the baseline values in the patients on basal LA (P = 0.497). The mean decline in HbA1c at the end of the study was therefore larger in the patients receiving twice-daily MIX than in the patients receiving basal LA (P < 0.05). CONCLUSION: The present study could suggest the potential loss of opportunity for many patients treated using basal LA to have received alternative insulin regimens and to achieve better glycemic control.

Changes in oral antidiabetic prescriptions and improved glycemic control during the years 2002-2011 in Japan (JDDM32).

AIMS/INTRODUCTION: Six kinds of oral antidiabetic drugs (OADs), including the new dipeptidyl peptidase 4 (DPP-4) inhibitors, are available. The present study aimed to define trends within the prescribing patterns of OADs, as well as changes in glycemic control in Japan over a 10-year period from 2002 to 2011. MATERIALS AND METHODS: We carried out a cross-sectional study using data of type 2 diabetes mellitus patients from 24 clinics for 2002, 2005, 2008 and 2011. OAD use was analyzed combined with clinical data. RESULTS: Sulfonylureas (SUs) were the most commonly used OAD, but their use for monotherapy markedly decreased over the study period. Biguanides (BGs) were the second most commonly used OAD, and their prescribing rate increased both for mono- and combination therapy. DPP-4 inhibitors (DPP-4I), released in 2009, were the third most commonly prescribed OAD in 2011 both for mono- and combination therapy. Among combination therapies, two OADs were mostly prescribed, but the use of three OADs and four OADs in 2011 was two- and 14.8-fold those in 2002. These trends were accompanied by an improvement in average glycated hemoglobin from 7.5 ± 1.2% in 2002 to 7.1 ± 0.9% in 2011. CONCLUSIONS: The OAD prescribing trend has moved away from monotherapy with SUs and toward combination therapies to achieve better glycemic control. Increased use of BGs and DPP-4I was predominant in 2011. These trends were accompanied by an improvement of the glycated hemoglobin level.

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.

Self-reported rate of eating is significantly associated with body mass index in Japanese patients with type 2 diabetes. Japan Diabetes Clinical Data Management Study Group (JDDM26).

We examined whether the rate of eating was associated with the body mass index and glycemic control status in Japanese patients with type 2 diabetes (50% women, mean±SD age 59.4±7.5 years). Rapid eating was significantly associated with body mass index (p=0.047). The body mass index of those who reported eating quickly was 0.8 kg/m² higher than in individuals who reported eating at medium speed even after adjustment for known confounders. No significant association was observed between the rate of eating and HbA(1c). Our findings suggest an association between self-reported rapid eating and an elevated body mass index in patients with type 2 diabetes.

Uniformity in clinical and HLA-DR status regardless of age and gender within fulminant type 1 diabetes.

To clarify the detailed clinical features and HLA subtype in the patients with fulminant type 1 diabetes, we investigated consecutive 250 case records registered to the committee of the Japan Diabetes Society between 2000/7/15 and 2006/6/30. After the classification with age at onset or gender, clinical data and HLA DR were evaluated. As a result, the prevalence of male patients, BMI, HbA(1c) and ALT levels at the onset increased significantly according to the elder quartile, but no other data showed any significant difference. Only age at onset and blood glucose level were significantly higher in male patients than in female patients without pregnancy by multivariate analysis. The distribution of HLA DR was not different in any subtype by gender or age at onset. Our present study revealed common feature in clinical and HLA-DR status regardless of age and gender within fulminant type 1 diabetes except pregnant women.

Nationwide survey to compare the prevalence of transient elevation of liver transaminase during treatment of diabetic ketosis or ketoacidosis in new-onset acute and fulminant type 1 diabetes mellitus.

BACKGROUND AIMS: A mild increase in liver enzyme levels is sometimes observed in patients with diabetic ketosis or ketoacidosis. The aim of the present study was to assess the cause and prevalence of the elevation of liver transaminase levels in fulminant and acute-onset type 1 diabetic patients experiencing diabetic ketosis or ketoacidosis. METHODS: We analyzed data on the liver transaminase levels of 108 patients over 18 years of age with newly diagnosed type 1 diabetes complicated by ketosis or ketoacidosis. The data were collated from a nationwide survey on fulminant type 1 diabetes and retrospective medical records. RESULTS: Thirty-two (60.4%) out of the 53 patients suffering from fulminant type 1 diabetes were detected with transient elevation of liver transaminase (TELT) levels during the first month after initiation of insulin therapy; in the case of acute-onset type 1 diabetes, such an observation was noted in 16 (29.1%) out of 55 patients. Fatty liver was diagnosed in 20% of the patients, and 65% of these patients exhibited TELT. The dosage of insulin injected in these patients was significantly high. CONCLUSIONS: High blood glucose and fatty liver may influence the elevation of liver transaminase levels during the treatment of new-onset type 1 diabetes.

Insulin intervention in slowly progressive insulin-dependent (type 1) diabetes mellitus.

OBJECTIVE: We tested the hypothesis that insulin therapy rather than sulfonylurea (SU) treatment is preferable to reverse or preserve beta-cell function among patients with slowly progressive insulin-dependent (type 1) diabetes (SPIDDM) or latent autoimmune diabetes in adults. METHODS: This multicenter, randomized, nonblinded clinical study screened 4089 non-insulin-dependent diabetic patients for glutamic acid decarboxylase autoantibodies (GADAb). Sixty GADAb-positive non-insulin-requiring diabetic patients with a 5-yr duration or shorter of diabetes were assigned to either the SU group (n = 30) or the insulin group (n = 30). Serum C-peptide responses to annual oral glucose tolerance tests were followed up for a mean of 57 months. The primary endpoint was an insulin-dependent state defined by the sum of serum C-peptide values during the oral glucose tolerance test (SigmaC-peptide) less than 4 ng/ml (1.32 nmol/liter). RESULTS: The progression rate to an insulin-dependent state in the insulin group (three of 30, 10%) was lower than that in the SU group (13 of 30, 43%; P = 0.003, log-rank). Longitudinal analysis demonstrated that SigmaC-peptide values were better preserved in the insulin group than in the SU group. Multiple regression analysis demonstrated that insulin treatment, a preserved C-peptide response, and a low GADAb titer at entry were independent factors in preventing progression to an insulin-dependent state. Subgroup analysis suggested that insulin intervention was highly effective for SPIDDM patients with high GADAb titers [> or =10 U/ml (180 World Health Organization U/ml)] and preserved beta-cell function [SigmaC-peptide > or = 10 ng/ml (3.31 nmol/liter)] at entry. No severe hypoglycemic episodes occurred during the study. CONCLUSIONS: Insulin intervention to preserve beta-cell function is effective and safe for patients with SPIDDM or latent autoimmune diabetes in adults.

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.

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.

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.