Important role of 5‐hydroxytryptamine in glucocorticoid‐induced insulin resistance in liver and intra‐abdominal adipose tissue of rats

Aim/Introduction

Both glucocorticoids and 5‐hydroxytryptamine (5‐HT) have been shown to induce insulin resistance (IR) in hepatocytes and adipocytes. Here, we explore whether there is a correlation between them.

Materials and Methods

Except for the control group, male rats were exposed to dexamethasone treated with or without para‐chlorophenylalanine (pCPA), or carbidopa for 20 days. Except for the control group, buffalo rat liver 3A (BRL‐3A) cells were exposed to dexamethasone for 24 h, treated with or without pCPA, carbidopa, or clorgiline for 48 h, or exposed to 5‐HT treated with or without fluoxetine for 48 h. Whole‐body IR was determined by both glucose tolerance test and measurement of fasting blood glucose and insulin, whereas hepatocytes or adipocytes IR was determined by examining either hepatic gluconeogenesis, steatosis and glucose transporter 2 expression or lipolysis.

Results

Dexamethasone‐induced whole‐body IR, liver and intraabdominal adipose IR were accompanied by upregulated expressions of tryptophan hydroxylase‐1 and aromatic amino acid decarboxylase with increased 5‐HT level in both tissues, which were attenuated significantly by pCPA, inhibiting tryptophan hydroxylase‐1, or carbidopa, inhibiting aromatic amino acid decarboxylase. [Correction added on 22 September 2015, after first online publication: ‘inhibiting aromatic amino acid decarboxylase’ was duplicated and has been replaced by ‘tryptophan hydroxylase‐1’.] In the BRL‐3A cells, dexamethasone‐induced IR was also accompanied by upregulated 5‐HT synthesis in dose‐ and time‐dependent manners, and was attenuated by pCPA or carbidopa, but exacerbated by clorgiline, inhibiting monoamine oxidase‐A to further increase 5‐HT level. Dexamethasone also enhanced 5‐HT 2A and 2B receptor expressions in both tissues and BRL‐3A cells. Additionally, blocking 5‐HT transporter with fluoxetine significantly suppressed 5‐HT‐induced IR in BRL‐3A cells.

Conclusion

Enhancement of 5‐HT synthesis in liver and intra‐abdominal adipose is an important reason for glucocorticoids‐induced IR.     

Difference between old and young adults in contribution of β‐cell function and sarcopenia in developing diabetes mellitus

Aims/Introduction

To investigate the difference in contributing factors in developing diabetes between old and young adults.

Materials and Methods

Subjects with recent‐onset diabetes were selected from a nationwide survey data and classified according to age: elderly (age ≥75 years), middle‐age (age 45–64 years) and young (age 25–39 years). The homeostasis model assessment of insulin resistance and β‐cell function were calculated. Sarcopenia was assessed using dual‐energy X‐ray absorptiometry.

Results

The prevalence of recent‐onset diabetes was 13.5%, 8.0%, and 1.4% in patients aged ≥75 years (unweighted n = 1,082), 45–64 years (unweighted n = 6,532), and 25–39 years (unweighted n = 5,178), respectively. Homeostasis model assessment of β‐cell function along with homeostasis model assessment of insulin resistance showed increasing trends as onset age increased in recent‐onset diabetes (P for trend < 0.001 in both). Elderly‐onset diabetic patients had significantly higher homeostasis model assessment of β‐cell function and homeostasis model assessment of insulin resistance compared with the middle‐age‐onset group (P < 0.001 and 0.014, respectively). Multivariate analysis showed that sarcopenia was significantly associated with recent‐onset diabetes only in patients aged ≥75 years (odds ratio [OR] 2.478, 95% confidence interval [CI] 1.379–4.452) but not in patients aged 45–64 years. In the middle‐age group, abdominal obesity (OR 2.933, 95% CI 2.086–4.122), hypertriglyceridemia (OR 1.529, 95% CI 1.078–2.169]) and low high‐density lipoprotein cholesterolemia (OR 1.930, 95% CI 1.383–2.695) were associated with recent‐onset diabetes.

Conclusions

Elderly‐onset diabetic patients had higher insulin resistance and relatively preserved β‐cell function compared with middle‐age‐onset patients. Sarcopenia might play a more important role in developing diabetes in the elderly population.     

Higher intake of fruits,vegetables or their fiber reduces the risk of type 2 diabetes: A meta‐analysis

Aims/Introduction

Some previous studies reported no significant association of consuming fruit or vegetables, or fruit and vegetables combined, with type 2 diabetes. Others reported that only a greater intake of green leafy vegetables reduced the risk of type 2 diabetes. To further investigate the relationship between them, we carried out a meta‐analysis to estimate the independent effects of the intake of fruit, vegetables and fiber on the risk of type 2 diabetes.

Materials and Methods

Searches of MEDLINE and EMBASE for reports of prospective cohort studies published from 1 January 1966 to 21 July 2014 were carried out, checking reference lists, hand‐searching journals and contacting experts.

Results

The primary analysis included a total of 23 (11 + 12) articles. The pooled maximum‐adjusted relative risk of type 2 diabetes for the highest intake vs the lowest intake were 0.91 (95% confidence interval [CI] 0.87–0.96) for total fruits, 0.75 (95% CI 0.66–0.84) for blueberries, 0.87 (95% CI 0.81–0.93) for green leafy vegetables, 0.72 (95% CI 0.57–0.90) for yellow vegetables, 0.82 (95% CI 0.67–0.99) for cruciferous vegetables and 0.93 (95% CI 0.88–0.99) for fruit fiber in these high‐quality studies in which scores were seven or greater, and 0.87 (95% CI 0.80–0.94) for vegetable fiber in studies with a follow‐up period of 10 years or more.

Conclusions

A higher intake of fruit, especially berries, and green leafy vegetables, yellow vegetables, cruciferous vegetables or their fiber is associated with a lower risk of type 2 diabetes.     

Impact of cigarette smoking on impaired insulin secretion and insulin resistance in Japanese men: The Saku Study

Aims/Introduction

To assess the impact of smoking on impaired insulin secretion and insulin resistance in Japanese men.

Materials and Methods

This study included 1,199 men aged 30–79 years without diabetes, impaired insulin secretion and insulin resistance at baseline who underwent a comprehensive medical check‐up between April 2006 and March 2007 at Saku Central Hospital. Smoking status was categorized as current, ex‐smoker and never‐smoker. Insulinogenic index and homeostasis model assessment‐insulin resistance were determined using a standard 75‐g oral glucose tolerance test. The Japan Diabetes Society criteria were used to define impaired insulin secretion and insulin resistance. Participants were followed up until March 2011.

Results

A total of 449 and 99 men developed impaired insulin secretion and insulin resistance during 3,403 and 4,092 person‐years follow up, respectively. The multivariable‐adjusted hazard ratios (HRs) for impaired insulin secretion were 1.06 (95% confidence interval [CI] 0.84–1.33) in ex‐smokers and 1.95 (95% CI 1.44–2.63) in current smokers compared with never‐smokers after adjustment for age, familial history of diabetes, alcohol consumption, exercise, systolic blood pressure, triglyceride, γ‐glutamyltransferase, waist circumference, leukocyte count, changes in smoking status and changes in waist circumference. The number of pack‐years was positively associated with the risk for impaired insulin secretion in a dose‐dependent manner (P‐values for trend <0.001). The multivariable‐adjusted HRs for insulin resistance were 0.95 (95% CI 0.56–1.61) in ex‐smokers and 1.11 (95% CI 0.67–1.79) in current smokers compared with never‐smokers.

Conclusions

Cigarette smoking is a modifiable risk factor for impaired insulin secretion. The findings might also be important for other Asian populations, which have low insulin secreting ability.     

Replication study for the association of rs391300 in SRR and rs17584499 in PTPRD with susceptibility to type 2 diabetes in a Japanese population

Aims/Introduction

Genetic risk variants for type 2 diabetes; rs391300‐G in SRR and rs17584499‐T in PTPRD, have been identified by a genome‐wide association study using Han Chinese individuals living in Taiwan. In an attempt to know the effects of these two variants in conferring susceptibility to type 2 diabetes in the Japanese, we carried out a replication study for the association of the two single nucleotide polymorphisms (SNPs) with type 2 diabetes in a Japanese population.

Materials and Methods

We genotyped 11,530 Japanese individuals (8,552 type 2 diabetes patients and 2,978 controls) for rs391300 and rs17584499, and analyzed the association of these two SNPs with type 2 diabetes by logistic regression analysis.

Results

Neither of the variants was associated with susceptibility to type 2 diabetes in the Japanese population (rs391300‐G: odds ratio [OR] = 0.97; 95% confidence interval [CI] 0.91–1.04; P = 0.44; rs17584499‐T: OR = 1.04; 95% CI 0.96–1.14; P = 0.34). Adjustment or stratified analysis for age, sex and body mass index (BMI) did not affect the association of these variants with the disease. We did not observe a significant association of the SNPs with any metabolic traits, BMI, fasting plasma glucose, homeostasis model assessment of β‐cell function (HOMA‐β) and HOMA of insulin resistance (HOMA‐IR) (P > 0.05).

Conclusions

Neither rs391300 nor rs17584499 had a significant effect on conferring susceptibility to type 2 diabetes in the Japanese population.     

Risk of hospitalization for diabetic macrovascular complications and in‐hospital mortality with irregular physician visits using propensity score matching

Aims/Introduction

The objective of the present study was to evaluate the risk of diabetic macrovascular complications and in‐hospital mortality among diabetic patients with irregular physician visits.

Materials and Methods

We carried out a health insurance‐based retrospective cohort study using claims data from diabetic patients who were newly hospitalized between April 2010 and September 2010 among beneficiaries of the Fukuoka National Health Insurance Organization. Regular visits were defined as physician visits for diabetes mellitus at least every 3 months between April 2009 and March 2010, whereas other visits or no visits were defined as irregular visits. We assigned 5,940 patients to the regular visit or the irregular visit groups using propensity score matching. We compared in‐hospital mortality and hospitalization for diabetic macrovascular complications between the two groups by multiple logistic regression models.

Results

The irregular visit group had a significantly higher risk of hospitalization for acute myocardial infarction (AMI), ischemic heart diseases (IHDs) except AMI, all IHDs, all strokes and diabetic macrovascular complications than did the regular visit group. Adjusted odds ratios for AMI, IHDs except AMI, all IHDs, all strokes, and diabetic macrovascular complications were 3.52 (95% confidence interval [CI] 1.79–6.96), 1.25 (95% CI 1.02–1.54), 1.37 (95% CI 1.12–1.66), 1.29 (95% CI 1.04–1.60), and 1.28 (95% CI 1.10–1.48), respectively.

Conclusions

The present study shows that the irregular visit group had significantly higher risks of hospitalization for IHD and stroke among diabetic patients. Insurers need to motivate diabetic beneficiaries to make regular visits to physicians.     

Insulin degludec compared with insulin glargine in insulin‐naïve patients with type 2 diabetes: A 26‐week,randomized, controlled,Pan‐Asian,treat‐to‐target trial

Introduction

Insulin degludec (IDeg) is an ultra‐long‐acting basal insulin with a consistent action profile of >42 h. This trial compared the efficacy and safety of IDeg with insulin glargine (IGlar) in insulin‐naïve Asian patients with type 2 diabetes.

Materials and Methods

In this multinational, 26‐week, open‐label, treat‐to‐target trial, 435 participants (202 females, 233 males; mean age 58.6 years; mean body mass index 25 kg/m²; mean glycated hemoglobin [HbA_1c] 8.5%) were randomized (2:1) to IDeg or IGlar, each administered once daily with ≥1 oral antidiabetic drug(s) (OAD).

Results

After 26 weeks, HbA_1c had decreased by 1.24 and 1.35% in the IDeg and IGlar groups, respectively (treatment difference [IDeg – IGlar] 0.11%, 95% confidence interval [CI] −0.03 to 0.24), confirming non‐inferiority. Rates of overall confirmed hypoglycemia were similar for IDeg and IGlar during the full trial period (3.0 vs 3.7 episodes/patient‐year of exposure [PYE]; rate ratio [RR] 0.82, 95% CI 0.60 to 1.11, P = 0.20), but significantly lower (by 37%) for IDeg during the maintenance period (from week 16 onward; RR 0.63, 95% CI 0.42 to 0.94, P = 0.02). No significant difference in the rate of nocturnal confirmed hypoglycemia was found between IDeg and IGlar in the full trial period (0.8 vs 1.2 episodes/PYE; RR 0.62, 95% CI 0.38 to 1.04, P = 0.07) or maintenance period (RR 0.52, 95% CI 0.27 to 1.00, P = 0.05). Adverse event rates were similar between treatments.

Conclusions

Initiating insulin therapy with IDeg in Asian patients with type 2 diabetes, inadequately controlled with OADs, provides similar improvements in long‐term glycemic control to IGlar, but at a significantly lower rate of overall confirmed hypoglycemia once stable glycemic control and insulin dosing are achieved. This trial was registered with www.clinicaltrials.gov (no. NCT01059799).     

Self‐perception of glycemic control among Japanese type 2 diabetic patients: accuracy of patient perception and characteristics of patients with misperception

Aims

Some diabetic patients, despite reporting a good perception of their glycemic control, actually show poor control and this misperception might well hinder successful diabetes management. This study aimed to assess patients'' self‐perception of glycemic control and to clarify factors associated with misperception of glycemic control status.

Methods

Baseline data from a hospital‐based prospective cohort of 519 type 2 diabetic patients were analyzed. Self‐perception of glycemic control and other items, including sociodemographic factors and blood test data, were determined from a self‐administered questionnaire and medical records. Factors associated with misperception were examined by age group (elderly [aged ≥ 65 years] vs non‐elderly [aged < 65 years]) using multiple logistic regression analysis.

Results

Among poorly controlled patients, misperception was higher in the elderly (glycated hemoglobin [HbA_1c] 7.4–8.3, 55.1%; HbA_1c >8.4, 44.8%) than in the non‐elderly (HbA_1c 7.4–8.3, 20.0%; HbA_1c >8.4, 18.9%). The factors significantly associated with misperception were as follows: high lifestyle regimen adherence in both age groups (non‐elderly group odds ratio [OR] 5.23; elderly group OR 5.15, respectively); high family support (OR = 7.32), failure to achieve blood pressure control (OR = 6.94) and having diabetic complications (OR = 0.06) among the non‐elderly; and long duration of diabetes (OR = 4.06) among the elderly.

Conclusions

For better management of diabetes, physicians should pay attention to the patient characteristics associated with misperception among uncontrolled diabetic patients, particularly among those who are elderly.     

Predicting type 2 diabetes using Sasang constitutional medicine

Aims/Introduction

Sasang constitutional medicine (SCM) has existed in traditional Korean medicine for more than 100 years. SCM consists of four different types: So‐Eum (SE), So‐Yang (SY), Tae‐Eum (TE) and Tae‐Yang (TY). It is of great importance that the Sasang constitution type (SCT) be evaluated accurately and recognized by medical communities.

Materials and Methods

From the Ansung–Ansan prospective cohort study, 10,038 participants were recruited from the years 2001–2002. Of 10,038 original participants, 2,460 participants underwent SCT evaluation. The Cox proportional hazard model was used to predict diabetes during the 10‐year follow‐up period.

Results

During 10 years of follow up (22,007 person‐years), 472 incidence cases (215/10,000 Incidence Density) of type 2 diabetes mellitus were documented. We identified that the TE group was significantly older, more obese, and had higher blood pressure, glucose metabolic values and lipid profiles levels. Relative risk (RR) and 95% confident intervals (CI) for type 2 diabetes were 1.696 (95% CI 1.204–2.39, P = 0.003) for TE when compared with the SE type. After controlling all potential confounders, the Cox proportional hazard model showed that RR was 1.635 (95% CI 1.111–2.406) in non‐obese (body mass index <25) TE, and RR was 1.725 (95% CI 1.213–2.452) in obese (body mass index ≥25) TE when compared with the SE type. We did not find any differences when comparing SE and SY types. The findings shows that TE is a higher risk factor for type 2 Diabetes, independent of obesity level.

Conclusions

The present study suggests that the TE type, independent of obesity level, is a strong risk factor of type 2 diabetes.     

Low high‐density lipoprotein cholesterol level is a significant risk factor for development of type 2 diabetes: Data from the Hawaii–Los Angeles–Hiroshima study

Aims/Introduction

A low level of high‐density lipoprotein cholesterol (HDLC) is a common feature of metabolic syndrome. We have reported that Japanese–Americans who share a virtually identical genetic makeup with native Japanese, but who have lived Westernized lifestyles for decades, have lower HDLC levels and a high prevalence of type 2 diabetes compared with native Japanese. However, the impact of low HDLC level on type 2 diabetes is unclear. The aims of the present study were to evaluate whether serum HDLC level was associated with development of type 2 diabetes and if the effect might be modified by lifestyle.

Materials and Methods

We examined 1,133 non‐diabetic Japanese–Americans and 1,072 non‐diabetic Japanese, who underwent the 75‐g oral glucose tolerance test (OGTT) and were followed for an average of 8.8 and 7.0 years, respectively. We analyzed whether serum HDLC level is a risk factor for development of type 2 diabetes based on the Cox proportional hazards model.

Results

After adjustment for age and sex, hazard ratios for development of type 2 diabetes per unit of serum HDLC level (mmol/L) were 0.292 (95% confidence interval [CI] 0.186–0.458, P < 0.0001) among Japanese–Americans and 0.551 (95% CI 0.375–0.88, P = 0.0023) among native Japanese. Comparable hazard ratios after further adjustment for category of OGTT and body mass index were 0.981 (95% CI 0.970–0.993, P = 0.0018) and 0.991 (95% CI 0.980–1.002, P = 0.112), respectively.

Conclusions

HDLC level was associated with development of type 2 diabetes in both Japanese–Americans and native Japanese. However, these results suggest that the impact of high‐density lipoprotein on glucose metabolism might be affected by lifestyle.     

Combination therapy with an angiotensin‐converting‐enzyme inhibitor and an angiotensin II receptor antagonist ameliorates microinflammation and oxidative stress in patients with diabetic nephropathy

Aims/Introduction

Recent studies have pointed to the effectiveness of combination therapy with an angiotensin‐converting‐enzyme inhibitor (ACEI) and an angiotensin receptor blocker (ARB) for diabetic nephropathy. However, some controversy over this combination treatment remains and the mechanisms underlying its renoprotective effects have not been fully clarified. Therefore, we compared the renoprotective effects of imidapril (ACEI) and losartan (ARB) combination therapy with losartan monotherapy in patients with diabetic nephropathy. We also compared the anti‐inflammatory and anti‐oxidative stress effects of these two treatments.

Materials and Methods

A total of 32 Japanese patients with type 2 diabetes and nephropathy were enrolled. Patients were randomized to either 100 mg/day losartan (n = 16) or 50 mg/day losartan plus 5 mg/day imidapril (n = 16). We evaluated clinical parameters, serum concentrations of high‐sensitivity C‐reactive protein (hs‐CRP), soluble intercellular adhesion molecule‐1 (sICAM‐1), interleukin‐18 (IL‐18) and monocyte chemotactic protein‐1 (MCP‐1), and the urinary concentrations of IL‐18, MCP‐1 and 8‐hydroxy‐2′‐deoxyguanosine (8‐OHdG) at 24 and 48 weeks after starting treatment.

Results

Blood pressure was not significantly different between the two groups. The serum levels of hs‐CRP, sICAM‐1 and IL‐18, as well as urinary excretion of albumin, IL‐18 and 8‐OHdG decreased significantly in the combination therapy group at 48 weeks. The percent decreases in serum IL‐18 concentrations and urinary IL‐18 and 8‐OHdG were significantly greater in the combination therapy group than in the monotherapy group.

Conclusions

Combination therapy with an ACEI and an ARB could be beneficial for treating diabetic nephropathy through its anti‐inflammatory and anti‐oxidative stress effects.     

Fasting serum insulin levels and insulin resistance are associated with colorectal adenoma in Koreans

Aims/Introduction

Insulin has been associated with the risk of colorectal cancer (CRC). However, few studies have evaluated the association between insulin and colorectal adenoma. We investigated the relationship between fasting serum insulin levels or homeostasis model assessment of insulin resistance (HOMA‐IR) and colorectal adenoma.

Materials and Methods

We retrospectively enrolled 15,427 participants who underwent both fasting serum insulin measurement and colonoscopy for a routine health examination at Asan Medical Center from January 2007 to December 2008. Participants with a history of any cancer, previous colectomy or polypectomy, those taking antidiabetic medications, and inflammatory bowel disease, non‐specific colitis, non‐adenomatous polyps only or CRC on colonoscopic findings were excluded. Finally, 3,606 participants with histologically confirmed colorectal adenoma and 6,019 controls with no abnormal findings on colonoscopy were included. Participants were categorized into quartiles (Q) based on fasting serum insulin levels and HOMA‐IR.

Results

Fasting serum insulin and HOMA‐IR were significantly higher in participants with colorectal adenomas compared with controls. Multivariate regression analysis adjusting for age, sex, smoking habits, drinking habits and family history of CRC showed that participants with higher quartiles of fasting serum insulin levels (odd ratio [OR] 1.17 for 2nd Q, 1.19 for 3rd Q, and 1.42 for 4th Q, P < 0.05) or HOMA‐IR (OR 1.18 for 2nd Q and 1.45 for 4th Q, P < 0.05) showed significantly increased ORs of colorectal adenoma compared with the lowest quartiles.

Conclusions

These findings showed that increased serum insulin levels and insulin resistance were significantly associated with the presence of colorectal adenoma.     

Association between diabetes or antidiabetic therapy and lung cancer: A meta‐analysis

Aims/Introduction

Diabetes can increase the risk of cancers at several sites, but the association between diabetes and lung cancer remains unclear. We aimed to provide the quantitative estimates for the association between diabetes or antidiabetic treatment and lung cancer risk in the present meta‐analysis.

Materials and Methods

Cohort studies were identified by searching the PubMed database (January 1960 through October 2012) and manually assessing the cited references in the retrieved articles. Study‐specific relative risks (RRs) and 95% confidence intervals (CIs) were estimated using a random‐effects model. Study quality was assessed using the Newcastle–Ottawa scale.

Results

A total of 19 cohort studies were included in the present meta‐analysis. Of these, 14 studies focused on the association between diabetes and lung cancer incidence, and seven studies focused on the association between antidiabetic treatment and lung cancer incidence. Compared with non‐diabetic individuals, diabetic patients do not have an increased risk of lung cancer (RR = 1.04, 95% CI 0.87–1.24). The association between diabetes and lung cancer remained not statistically significant in subgroup analysis stratified by study characteristics, study quality, diabetes ascertainment or important confounders. A null association between insulin or biguanides therapy and lung cancer risk was found. However, the diabetic patients receiving thiazolidinedione (TZD) treatment had a 20% reduced risk of lung cancer than those without TZD treatment.

Conclusions

No association between diabetes and lung cancer risk was found. However, TZD treatment might reduce lung cancer risk in diabetic patients.     

Age‐associated changes of islet endocrine cells and the effects of body mass index in Japanese

Aims/Introduction

Impaired growth and premature death of β‐cells are implicated in the progression of islet pathology in type 2 diabetes. It remains unclear, however, how aging affects islet cells, or whether the islet change in diabetes is an augmented process of aging. We studied age‐related changes of the islet structure in Japanese non‐diabetic subjects and explored the underlying mechanism of the changes.

Materials and Methods

A total of 115 non‐diabetic autopsy cases were subjected to morphometric analysis for volume densities of islets, β‐ and non‐β‐cells, as well as their masses. Proliferation activity identified by Ki67, and expressions of pancreatic and duodenal homeobox (PDX)‐1, cell cycle inhibitor P16, and oxidative stress marker γH2AX were also examined.

Results

There was a gradual and marginal decline of volume densities of islets, β‐ and non‐β‐cells with aging, while masses of these components were increased during maturation and slowly decreased after the 40s. Islet density was high in the young, but reduced after maturation. There was only a minimal influence of increased body mass index (BMI) on the increase in β‐cell mass, but not on the other variables. Ki67 positivity and PDX‐1 expressions were high in the young, but low after maturation, whereas expressions of P16 and γH2AX were elevated in the aged.

Conclusions

Age‐associated decline of β‐cell mass is marginal after maturation, and the reduction of β‐cell mass could be a specific process in diabetes. The impact of BMI on the islet structure is limited in Japanese with normal glucose tolerance.     

Dipeptidyl peptidase‐4 inhibitors are effective in Japanese type 2 diabetic patients with sustained endogenous insulin‐secreting capacity,a higher body mass index and insulin resistance

Aims/Introduction

Recently, dipeptidyl peptidase‐4 (DPP‐4) inhibitors have become available in Japan. It has not yet been clarified what clinical parameters could discriminate DPP‐4 inhibitor‐effective patients from DPP‐4 inhibitor‐ineffective patients.

Materials and Methods

We reviewed 33 consecutive patients with type 2 diabetes admitted to Osaka University Hospital for glycemic control. All of the patients were treated with medical nutrition therapy plus insulin therapy to improve fasting plasma glucose (FPG) and postprandial glucose below 150 and 200 mg/dL, respectively. After insulin secretion and insulin resistance were evaluated, insulin was replaced by DPP‐4 inhibitors. The efficacy of DPP‐4 inhibitors was determined according to whether glycemic control was maintained at the target levels.

Results

Dipeptidyl peptidase‐4 inhibitors were effective in 16 of 33 patients. DPP‐4 inhibitor‐effective patients were younger than DPP‐4 inhibitor‐ineffective patients. Body mass index (BMI) was significantly higher in DPP‐4 inhibitor‐effective patients. Endogeneous insulin‐secreting capacity, including insulinogenic index (II), fasting plasma C‐peptide (F‐CPR) and C‐peptide index (CPI), was more sustained in DPP‐4 inhibitor‐effective patients than DPP‐4 inhibitor‐ineffective patients. Insulin resistance evaluated by homeostasis model assessment of insulin resistance (HOMA‐IR) was significantly higher in DPP‐4 inhibitor‐effective patients than DPP‐4 inhibitor‐ineffective patients. In receiver operating characteristic analyses, the cut‐off values for predicting the efficacy of DPP‐4 inhibitors were 0.07 for II, 1.5 ng/mL for F‐CPR, 1.0 for CPI, 23.0 kg/m² for BMI, 1.3 for HOMA‐IR and 67.5 years for age.

Conclusions

Dipeptidyl peptidase‐4 inhibitors were effective in Japanese type 2 diabetic patients with sustained endogenous insulin‐secreting capacity, a higher BMI and insulin resistance.     

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.     

Effect of endurance training on retinol‐binding protein 4 gene expression and its protein level in adipose tissue and the liver in diabetic rats induced by a high‐fat diet and streptozotocin

Aims/Introduction

The present study was designed to investigate from which tissues the decrease in retinol‐binding protein 4 (RBP4) expression could contribute to the improvement of serum RBP4 and insulin resistance (IR) after endurance training.

Materials and Methods

Male 7‐week‐old Wistar rats were randomly assigned into four groups including control (C), trained (T), diabetic control (DC) and trained diabetic (TD). At 8 weeks‐of‐age, diabetes was induced by a high‐fat diet and intraperitoneal injection of low‐dose streptozotocin (STZ; 35 mg/kg). Rats in the T and TD groups carried out a 7‐week exercise program on a motorized treadmill (15–20 m/min for 20 min/day for 5 weeks), whereas the C and DC remained sedentary in their cages. Tissues gene expression and protein levels of RBP4 were assessed by using real‐time polymerase chain reaction and western blot, respectively, while serum RBP4 was measured using an enzyme‐linked immunosorbent assay kit.

Results

Exercise significantly improved IR and reduced serum concentration of RBP4 in the TD group. This reduction of serum RBP4 was accompanied by decreased RBP4 protein expression in visceral fat tissue. In contrast, exercise had no significant effect on RBP4 expression in liver and subcutaneous fat tissue in the TD group. Exercise also significantly decreased RBP4 gene expression in visceral fat tissue and muscle, whereas the effect of exercise on liver RBP4 messenger ribonucleic acid expression was not significant.

Conclusions

The present study showed that the mechanism for RBP4 reducing the effect of endurance training could involve decreased RBP4 messenger ribonucleic acid expression and its protein level in adipose tissue in STZ‐induced diabetic rats.     

Palmitate induces reactive oxygen species production and β‐cell dysfunction by activating nicotinamide adenine dinucleotide phosphate oxidase through Src signaling

Aims/Introduction

Chronic hyperlipidemia impairs pancreatic β‐cell function, referred to as lipotoxicity. We have reported an important role of endogenous reactive oxygen species (ROS) overproduction by activation of Src, a non‐receptor tyrosine kinase, in impaired glucose‐induced insulin secretion (GIIS) from diabetic rat islets. In the present study, we investigated the role of ROS production by Src signaling in palmitate‐induced dysfunction of β‐cells.

Materials and Methods

After rat insulinoma INS‐1D cells were exposed to 0.6 mmol/L palmitate for 24 h (palmitate exposure); GIIS, ROS production and nicotinamide adenine dinucleotide phosphate oxidase (NOX) activity were examined with or without exposure to10 μmol/L 4‐amino‐5‐(4‐chlorophenyl)‐7‐(t‐butyl)pyrazolo[3,4‐d]pyrimidine (PP2), a Src inhibitior, for 30 or 60 min.

Results

Exposure to PP2 recovered impaired GIIS and decreased ROS overproduction as a result of palmitate exposure. Palmitate exposure increased activity of NOX and protein levels of NOX2, a pathological ROS source in β‐cells. Palmitate exposure increased the protein level of p47^phox, a regulatory protein of NOX2, in membrane fraction compared with control, which was reduced by PP2. Transfection of small interfering ribonucleic acid of p47^phox suppressed the augmented p47^phox protein level in membrane fraction, decreased augmented ROS production and increased impaired GΙIS by palmitate exposure. In addition, exposure to PP2 ameliorated impaired GIIS and decreased ROS production in isolated islets of KK‐A^y mice, an obese diabetic model with hyperlipidemia.

Conclusions

Activation of NOX through Src signaling plays an important role in ROS overproduction and impaired GΙIS caused by chronic exposure to palmitate, suggesting a lipotoxic mechanism of β‐cell dysfunction of obese mice.     

Secretory units of islets in transplantation index is a useful predictor of insulin requirement in Japanese type 2 diabetic patients

Aims/Introduction

The objective of the present study was to clarify the validity of β‐cell function‐related parameters for predicting the insulin requirement of Japanese type 2 diabetic patients.

Materials and Methods

In 188 patients with type 2 diabetes who had been admitted to the University of Toyama Hospital (Toyama, Japan) without receiving insulin therapy, we carried out a cross‐sectional study examining the relationship between the homeostasis model assessment of β‐cell function (HOMA‐β) and C‐peptide‐based indices, and also carried out a retrospective study to examine the utility for predicting insulin requirement of several β ‐cell function‐related indices using a receiver operating characteristic (ROC) curve analysis.

Results

The secretory units of islets in transplantation index (SUIT) had the strongest correlation with HOMA‐β, followed by the fasting serum C‐peptide immunoreactivity index (CPI); the fasting serum C‐peptide immunoreactivity itself (F‐CPR) had the least correlation. The CPI, HOMA‐β and SUIT were significantly lower in the insulin‐requiring group than in the non‐insulin‐requiring group, even after adjustments for confounding factors (P < 0.01). The areas under the ROC curve for insulin requirement were 0.622, 0.774, 0.808, and 0.759 for F‐CPR, CPI, SUIT, and HOMA‐β, respectively. The cut‐off values of SUIT, CPI, and HOMA‐β for an over 80% specificity for the prediction of insulin therapy were 23.5, 1.00, and 14.9, respectively.

Conclusions

The present study shows that SUIT is the best predictor of insulin requirement among these β‐cell function‐related markers.     

Postprandial C‐peptide to glucose ratio as a predictor of β‐cell function and its usefulness for staged management of type 2 diabetes

Aims/Introduction

Type 2 diabetes is characterized by progressive deterioration of β‐cell function. Recently, it was suggested that the C‐peptide‐to‐glucose ratio after oral glucose ingestion is a better predictor of β‐cell mass than that during fasting. We investigated whether postprandial C‐peptide‐to‐glucose ratio (PCGR) reflects β‐cell function, and its clinical application for management of type 2 diabetes.

Materials and Methods

We carried out a two‐step retrospective study of 919 Korean participants with type 2 diabetes. In the first step, we evaluated the correlation of PCGR level with various markers for β‐cell function in newly diagnosed and drug‐naïve patients after a mixed meal test. In the second step, participants with well‐controlled diabetes (glycated hemoglobin <7%) were divided into four groups according to treatment modality (group I: insulin, group II: sulfonylurea and/or dipeptityl peptidase IV inhibitor, group III: metformin and/or thiazolidinedione and group IV: diet and exercise group).

Results

In the first step, PCGR was significantly correlated with various insulin secretory indices. Furthermore, PCGR showed better correlation with glycemic indices than homeostatic model assessment of β‐cell function (HOMA‐β). In the second step, the PCGR value significantly increased according to the following order: group I, II, III, and IV after adjusting for age, sex, body mass index and duration of diabetes. The cut‐off values of PCGR for separating each group were 1.457, 2.870 and 3.790, respectively (P < 0.001).

Conclusions

We suggest that PCGR might be a useful marker for β‐cell function and an ancillary parameter in the choice of antidiabetic medication in type 2 diabetes.