Different role of zinc transporter 8 between type 1 diabetes mellitus and type 2 diabetes mellitus

Diabetes can be simply classified into type 1 diabetes mellitus and type 2 diabetes mellitus. Zinc transporter 8 (ZnT8), a novel islet autoantigen, is specifically expressed in insulin‐containing secretory granules of β‐cells. Genetic studies show that the genotypes of SLC30A8 can determine either protective or diabetogenic response depending on environmental and lifestyle factors. The ZnT8 protein expression, as well as zinc content in β‐cells, was decreased in diabetic mice. Thus, ZnT8 might participate in insulin biosynthesis and release, and subsequently involved deteriorated β‐cell function through direct or indirect mechanisms in type 1 diabetes mellitus and type 2 diabetes mellitus. From a clinical feature standpoint, the prevalence of ZnT8A is gradiently increased in type 2 diabetes mellitus, latent autoimmune diabetes in adults and type 1 diabetes mellitus. The frequency and epitopes of ZnT8‐specific T cells and cytokine release by ZnT8‐specific T cells are also different in diabetic patients and healthy controls. Additionally, the response to ZnT8 administration is also different in type 1 diabetes mellitus and type 2 diabetes mellitus. In the present review, we summarize the literature about clinical aspects of ZnT8 in the pathogenesis of diabetes, and suggest that ZnT8 might play a different role between type 1 diabetes mellitus and type 2 diabetes mellitus.     

Impact of primary aldosteronism on renal function in patients with type 2 diabetes

Aims/IntroductionRenal dysfunction might quickly progress in patients with type 2 diabetes mellitus, when accompanied by hypertension. However, whether primary aldosteronism (PA), which autonomously over‐secretes aldosterone, causes additional renal damage in patients with type 2 diabetes mellitus is unclear. We evaluated the impact of PA on renal function in patients with type 2 diabetes mellitus.Materials and MethodsA retrospective review of all patients with type 2 diabetes mellitus who visited Yokohama Rosai Hospital’s (Yokohama Japan) outpatient department between April 2017 and March 2018 was carried out. Records of patients with PA who underwent PA treatment by adrenalectomy or mineralocorticoid receptor antagonists (PA group) and those without PA (non‐PA group) were extracted, and renal function was compared between the two groups. Untreated PA patients were excluded, as their renal function might be overestimated as a result of glomerular hyperfiltration.ResultsThere were 83 patients in the PA group and 1,580 patients in the non‐PA group. The PA group had significantly lower estimated glomerular filtration rates than the non‐PA group (66.3 [52.4–78.2] vs 70.5 [56.0–85.6] mL/min/1.73 m², P = 0.047). Multiple regression analysis showed that PA was a factor for decreased estimated glomerular filtration rate, independent of age, sex, glycated hemoglobin, diuretic use and hypertension (P = 0.025). PA induced a 3.7‐mL/min/1.73 m² (95% confidence interval 0.47–6.9) decrease in estimated glomerular filtration rate, equivalent to that induced by 4.4 years of aging.ConclusionsOur results show that in patients with type 2 diabetes mellitus, PA is an independent risk factor for renal dysfunction. To prevent the progression of renal failure, PA should not be overlooked.     

Fear of hypoglycemia and its determinants in insulin‐treated patients with type 2 diabetes mellitus

The aim of the present study was to investigate the prevalence of fear of hypoglycemia, in association with severe hypoglycemia and social factors, in insulin‐treated patients with type 2 diabetes mellitus. A questionnaire survey on hypoglycemia and patient–physician communication was carried out in 355 patients with insulin‐treated type 2 diabetes mellitus patients at 16 hospitals and clinics. A fear of hypoglycemia was reported by 27.7% of patients. A stepwise logistic regression analysis found that severe hypoglycemia during the past 1 year was a significant determinant of fear of hypoglycemia (odds ratio 2.16, 95% confidence interval 1.06–4.41; P = 0.034), and age (odds ratio 1.02, 95% confidence interval 1.00–1.05, P = 0.038) and living alone (odds ratio 1.93, 95% confidence interval 1.00–3.73, P < 0.05) were significantly higher in patients with fear of hypoglycemia than in those without it.     

Antiplatelet strategy in primary and secondary prevention of cardiovascular disease in patients with type 2 diabetes mellitus: A perspective from the guideline appraisal

Aims/IntroductionTo appraise guidelines on the antiplatelet strategy of prevention of cardiovascular disease (CVD) in patients with type 2 diabetes mellitus, and highlight the consensuses and controversies to aid clinician decision‐making.Materials and MethodsA systematic search was carried out for guidelines regarding CVD prevention or focusing on type 2 diabetes patients. Appraisal of Guidelines for Research and Evaluation II instrument was utilized to appraise the quality of included guidelines.ResultsOf the 15 guidelines with discrepant Appraisal of Guidelines for Research and Evaluation II scores (66%; interquartile range 51–71%), 10 were defined as “strongly recommended” guidelines. For secondary prevention, >60% of guidelines advocated that the dual antiplatelet therapy was used within 12 months when the type 2 diabetes patients experienced acute coronary syndrome and/or post‐percutaneous coronary intervention or coronary artery bypass grafting, with subsequent long‐term aspirin use. For primary prevention, 80% of guidelines supported that aspirin should not be routinely used by patients with type 2 diabetes. No consensus on whether to prolong dual antiplatelet therapy in secondary prevention, and whether to use aspirin in type 2 diabetes patients with high CVD risk exists in current guidelines.ConclusionsPhysicians should use the recommendations from “strongly recommended” guidelines to make informed decisions and know the consensuses of current guidelines. Dual antiplatelet therapy should be used within 12 months when type 2 diabetes patients experience acute coronary syndrome and/or percutaneous coronary intervention/coronary artery bypass grafting, with subsequent long‐term aspirin use. In primary prevention, aspirin should not be routinely used by individuals with type 2 diabetes, but might be considered for those with high CVD risk.     

Correlation analysis of microribonucleic acid-155 and microribonucleic acid-29 with type 2 diabetes mellitus,and the prediction and verification of target genes

Aims/IntroductionMicroribonucleic acid‐155 (microRNA155) and microRNA29 are reported to inhibit glucose metabolism in some cell and animal models, but no evidence from susceptible populations that examines the relationship between microRNA155 or microRNA29 and type 2 diabetes mellitus currently exists. Furthermore, target genes regulated by microRNA155 and microRNA29 that affect glucose and lipid metabolism remain unknown.Materials and MethodsHuman participants were divided into normal weight (n = 72), obesity (n = 120) and type 2 diabetes (n = 59) groups. The contents of microRNA155 and microRNA29 abundance in serum were measured, and candidate genes potentially related to glucose and lipid metabolism targeted by either microRNA155 or microRNA29 were screened. Overexpression of microRNA155 and microRNA29 in HepG2 cells was used to verify candidate gene expression, and measure the effects on glucose and lipid metabolism.ResultsSerum levels of microRNA155 and microRNA29 show a significant increase in individuals with obesity and type 2 diabetes compared with normal weight individuals. Identified target genes for microRNA155 were MAPK14, MAP3K10, DUSP14 and PRKAR2B. Identified target genes for microRNA29 were PEX11A and FADS1. Overexpression of microRNA155 or microRNA29 in HepG2 cells was found to downregulate the expression of identified target genes, and result in inhibition of triglyceride synthesis and glucose incorporation.ConclusionsMicroRNA155 and microRNA29 were significantly higher in type 2 diabetes patients compared with the control patients, their levels were also positively correlated with fasting plasma glucose levels, and over‐expression of microRNA155 or microRNA29 were found to downregulate glucose and lipid metabolism target genes, and reduce lipid synthesis and glucose incorporation in HepG2 cells.     

Potential biomarker in serum for predicting susceptibility to type 2 diabetes mellitus: Free fatty acid 22:6

Aims/IntroductionType 2 diabetes mellitus is closely linked to increased levels of free fatty acids (FFAs) in obese individuals, although which FFA is most associated with type 2 diabetes mellitus is unclear. This study aimed to identify the specific FFAs that best predict the occurrence of type 2 diabetes mellitus in obese individuals, and assess their potential application value.Materials and MethodsParticipants were divided into three groups: a normal weight group (n = 20), an obese group (n = 10) and a type 2 diabetes mellitus group (n = 10). FFAs in serum samples were determined by ultra‐high‐pressure liquid chromatography–mass spectrometry, and orthogonal partial least squares discriminant analysis models were used to study the FFA profile among the three groups.ResultsCompared with the normal weight group, 14 FFAs (C8:0/10:0/14:0/16:1/18:1/20:2/ 20:3 /20:4/ 20:5/ 22:6/7:0/9:0/11:0 and C13:0) were significantly increased in the obese group, and nine FFAs (C14:0, C18:1, C20:1, C 18:2, C20:2, C20:3, C18:3, C20:5 and C22:6) were significantly increased in the type 2 diabetes mellitus group. Subsequently, the Venn diagram results showed that six FFAs (C14:0, C18:1, C20:2, C20:3, C20:5 and C22:6) were significantly increased in both the obese and type 2 diabetes mellitus groups. Among these six, C22:6 was finally identified as an independent risk factor for type 2 diabetes mellitus, and had a great potential to predict the susceptibility to type 2 diabetes mellitus (area under the curve 0.803).ConclusionsC22:6 can be an independent risk factor for type 2 diabetes mellitus, and it has a great potential to predict the susceptibility to type 2 diabetes mellitus.     

Serum adiponectin levels predict the risk of coronary heart disease in Japanese patients with type 2 diabetes

Aims/Introduction

An inverse association between adiponectin and coronary heart disease (CHD) has been found in Caucasians, but it is uncertain whether this association can be extrapolated to the East Asian population. The present study aimed to investigate whether serum adiponectin levels can predict CHD in Japanese patients with type 2 diabetes as observed in Caucasians.

Materials and Methods

This longitudinal study included 504 patients with type 2 diabetes (342 men and 162 women) who were admitted to Sumitomo Hospital between July 2005 and December 2006. We used Cox proportional hazard analysis to estimate the hazard ratio (HR) of CHD associated with serum adiponectin levels at baseline.

Results

During a median follow up of 5.7 years (2177 person‐years), 40 participants had new CHD and 10 had recurrent CHD. After multivariate adjustment, the highest compared with the lowest quartile of serum adiponectin levels had a significantly reduced risk of CHD (hazard ratio [HR] 0.35; 95% confidence interval [CI] 0.13–0.94; P = 0.017). The multivariate adjusted HR for the risk of CHD according to a doubling of adiponectin at baseline was 0.61 (95% CI 0.39–0.97; P = 0.037).

Conclusions

High serum adiponectin levels are significantly associated with a lower risk of CHD in Japanese patients with type 2 diabetes. This association is independent of other well‐known CHD risk factors.     

Safety and effectiveness of tofogliflozin in Japanese patients with type 2 diabetes mellitus treated in real-world clinical practice: Results of a 36-month post-marketing surveillance study (J-STEP/LT)

Aims/IntroductionTofogliflozin is a sodium–glucose cotransporter 2 (SGLT2) inhibitor that lowers plasma glucose levels by enhancing urinary glucose excretion. After its approval in Japan in 2014 for the treatment of type 2 diabetes mellitus, we carried out a 3‐year prospective observational post‐marketing surveillance study in Japanese patients (Japanese Study of Tofogliflozin with Type 2 Diabetes Mellitus Patients/Long Term [J‐STEP/LT]).Materials and MethodsThis surveillance was carried out between September 2014 and February 2019, and recorded safety in terms of adverse drug reactions (ADRs) and ADRs of special interest, and effectiveness in terms of changes in glycated hemoglobin and bodyweight from baseline to last observation carried forward.ResultsOf 6,897 patients with type 2 diabetes mellitus registered, 6,711 and 6,451 were analyzed for safety and effectiveness, respectively. ADRs were reported in 846 patients (12.61%), with serious ADRs in 101 patients (1.5%). ADRs of special interest included hypoglycemia (62 patients [0.9%]), polyuria/pollakiuria (90 [1.3%]), volume depletion‐related disorders (135 [2.0%]), urinary tract infections (91 [1.4%]), genital infections (117 [1.7%]) and skin diseases (53 [0.8%]). One case of diabetic ketoacidosis was reported. The mean ± standard deviation changes from baseline to last observation carried forward in glycated hemoglobin and bodyweight were −0.68 ± 1.34% (n = 6,158, P < 0.0001) and −3.13 ± 4.67 kg (n = 5,213, P < 0.0001), respectively.ConclusionsJ‐STEP/LT, a 3‐year, prospective, observational, post‐marketing study in Japan, found no unprecedented ADRs, and consistent reductions from baseline in glycated hemoglobin and bodyweight over the observation period. The present results provide further evidence regarding the safety and tolerability of tofogliflozin in Japanese patients with type 2 diabetes mellitus.