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.     

Effect of serum 25‐hydroxyvitamin D3 on insulin resistance and β‐cell function in newly diagnosed type 2 diabetes patients

Aims/Introduction

To evaluate serum 25‐hydroxyvitamin D₃ (25(OH)D₃) in newly diagnosed type 2 diabetes patients and to explore the associations of 25(OH)D₃ with insulin resistance and β‐cell function.

Materials and Methods

A total of 97 newly diagnosed type 2 diabetes patients and 69 healthy controls were recruited. Serum 25(OH)D₃ was determined using high‐pressure liquid chromatography. Insulin resistance was measured using a homeostasis model assessment of insulin resistance (HOMA‐IR). β‐Cell function was determined using the HOMA β‐cell function index (HOMA‐β), early‐phase insulin secretion index (ΔI30/ΔG30) and area under the insulin curve (AUCins). Correlation analysis was carried out using Pearson''s correlation and multiple stepwise regression analysis.

Results

Serum 25(OH)D₃ was much lower in patients with newly diagnosed type 2 diabetes (t = −13.00, P < 0.01), and the prevalence of hypovitaminosis 25(OH)D₃ was 62.9% (61/97) in diabetic patients. Among the diabetic patients, patients with hypovitaminosis 25(OH)D₃ showed higher glycosylated hemoglobin and AUCglu (P < 0.01) as well as lower HOMA‐β, ΔI30/ΔG30 and AUCins. Serum 25(OH)D₃ was independently positively correlated with ΔI30/ΔG30 and AUCins (P < 0.05), but was not significantly correlated with either HOMA‐IR or HOMA‐β. Only triglycerides, glycosylated hemoglobin and ΔI30/ΔG30 emerged as independent factors associated with serum 25(OH)D₃ in both diabetes patients and the health control group.

Conclusions

The present results further showed a low serum 25(OH)D₃ concentration in patients with newly diagnosed type 2 diabetes. 25(OH)D₃ deficiency is associated with disturbances in glucose metabolism and lipid metabolism. Serum 25(OH)D₃ is not correlated with basal insulin resistance or β‐cell function, but is significantly positively correlated with glucose‐stimulated insulin secretion and β‐cell function.     

Expression profiling analysis: Uncoupling protein 2 deficiency improves hepatic glucose,lipid profiles and insulin sensitivity in high‐fat diet‐fed mice by modulating expression of genes in peroxisome proliferator‐activated receptor signaling pathway

Aims/Introduction

Uncoupling protein 2 (UCP2), which was an important mitochondrial inner membrane protein associated with glucose and lipid metabolism, widely expresses in all kinds of tissues including hepatocytes. The present study aimed to explore the impact of UCP2 deficiency on glucose and lipid metabolism, insulin sensitivity and its effect on the liver‐associated signaling pathway by expression profiling analysis.

Materials and Methods

Four‐week‐old male UCP2−/− mice and UCP2+/+ mice were randomly assigned to four groups: UCP2−/− on a high‐fat diet, UCP2−/− on a normal chow diet, UCP2+/+ on a high‐fat diet and UCP2+/+ on a normal chow diet. The differentially expressed genes in the four groups on the 16th week were identified by Affymetrix gene array.

Results

The results of intraperitoneal glucose tolerance test and insulin tolerance showed that blood glucose and β‐cell function were improved in the UCP2−/− group on high‐fat diet. Enhanced insulin sensitivity was observed in the UCP2−/− group. The differentially expressed genes were mapped to 23 pathways (P < 0.05). We concentrated on the ‘peroxisome proliferator‐activated receptor (PPAR) signaling pathway’ (P = 3.19 × 10⁻¹¹), because it is closely associated with the regulation of glucose and lipid profiles. In the PPAR signaling pathway, seven genes (PPARγ, Dbi, Acsl3, Lpl, Me1, Scd1, Fads2) in the UCP2−/− mice were significantly upregulated.

Conclusions

The present study used gene arrays to show that activity of the PPAR signaling pathway involved in the improvement of glucose and lipid metabolism in the liver of UCP2‐deficient mice on a long‐term high‐fat diet. The upregulation of genes in the PPAR signaling pathway could explain our finding that UCP2 deficiency ameliorated insulin sensitivity. The manipulation of UCP2 protein expression could represent a new strategy for the prevention and treatment of diabetes.     

Comparison of three α‐glucosidase inhibitors for glycemic control and bodyweight reduction in Japanese patients with obese type 2 diabetes

Aims/Introduction

α‐Glucosidase inhibitors (αGIs) are widely used for the primary treatment of type 2 diabetes. We compared the clinical effects of three αGIs (miglitol, acarbose and voglibose) in patients with obese type 2 diabetes.

Materials and Methods

Japanese patients (n = 81) with obese type 2 diabetes (body mass index [BMI] ≥25 kg/m²) were enrolled in this multicenter, open‐label study. The participants were randomized into the miglitol (n = 18), acarbose (n = 22), voglibose (n = 19) or control (n = 22) groups. Glycemic control (fasting blood glucose and glycated hemoglobin [HbA1c]), bodyweight, BMI, serum insulin, serum lipids (low‐density lipoprotein and high‐density lipoprotein cholesterol, and triacylglycerols) and adipocytokines (leptin and adiponectin) were evaluated every 4 weeks for 12 weeks.

Results

In the miglitol group, HbA1c was improved significantly from the baseline at all points. The changes in HbA1c at 8 and 12 weeks from baseline were greater in the miglitol group than the control group. The voglibose group showed significant improvements in HbA1c at 12 weeks. Bodyweight and BMI were decreased significantly in the miglitol group. In addition, significant correlations were observed between the decrements in HbA1c and bodyweights over 12 weeks in the miglitol (r = 0.759, P < 0.001) and voglibose groups (r = 0.667, P = 0.002). Serum lipid and adipocytokine levels were not altered in any groups.

Conclusions

αGIs, especially miglitol, can effectively control blood glucose and bodyweight in obese type 2 diabetes. This study was registered with UMIN (no. UMIN000006465).     

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.     

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).     

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.     

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.     

Efficacy and safety of 40 mg or 60 mg duloxetine in Japanese adults with diabetic neuropathic pain: Results from a randomized, 52‐week,open‐label study

Introduction

To examine the long‐term efficacy and safety of duloxetine in the treatment of Japanese patients with diabetic neuropathic pain, we carried out a 52‐week, randomized, open‐label extension of a 12‐week, double‐blind, placebo‐controlled study.

Materials and Methods

Japanese adults with diabetic neuropathic pain who completed the double‐blind study were eligible for this long‐term study, carried out at 71 sites in Japan (March 2008 to March 2010). Participants (n = 258) were re‐randomized (1:1) to 40 mg/day or 60 mg/day duloxetine. Pain (Brief Pain Inventory severity and interference), quality of life (Patient''s Global Impression of Improvement), and safety (primary outcome; adverse events, vital signs, metabolic measures) were measured.

Results

Significant (P < 0.0001) and sustained improvements (change ± standard deviation; n = 257) were observed in Brief Pain Inventory severity (average pain score −2.1 ± 1.7). Improvements were also seen in Brief Pain Inventory interference (mean of subscores −0.96 ± 1.52) and Patient''s Global Impression of Improvement (−0.9 ± 1.1) scores; these scores decreased significantly (P < 0.0001) during the long‐term study. Frequently reported adverse events included somnolence (13.6%), constipation (13.2%) and nausea (10.5%). Increases were observed in plasma glucose, glycosylated hemoglobin and total cholesterol levels, and in bodyweight and heart rate; however, none of these were clinically meaningful. Overall, there were no clinically significant safety concerns.

Conclusions

This is the first publication of a long‐term study carried out in Asia with an entirely Japanese patient population to suggest that long‐term duloxetine therapy for diabetic neuropathic pain is effective and has an acceptable safety profile.     

Diabetes mellitus,but not small dense low‐density lipoprotein,is predictive of cardiovascular disease: A Korean community‐based prospective cohort study

Aims/Introduction

Small dense low‐density lipoprotein (sdLDL) has been suggested to be a potential risk factor for cardiovascular diseases (CVD).

Materials and Methods

We carried out a prospective nested case–control study in the Korean Health and Genome Study. Participants were men and women aged 40–69 years who developed CVD (n = 313), and were matched by age and sex to controls who remained free of CVD (n = 313) during the 8‐years follow‐up period (from 2001 to 2009). LDL subfractions were analyzed in frozen samples collected from the 626 participants using polyacrylamide tube gel electrophoresis.

Results

Patients with CVD had a significantly higher glycated hemoglobin level compared with the controls (5.72 vs 5.56). The proportion of patients with diabetes mellitus (DM) was higher in those who developed CVD during follow up (8.0% vs 1.9%). The frequency of CVD according to each tertile of LDL particle size and the number of metabolic syndrome components did not differ significantly. In the multivariate analysis, DM (odds ratio 4.244, 95% confidence interval 1.693–10.640, P = 0.002) was the only independent predictive factor of CVD. LDL particle size was not associated with the risk for future CVD.

Conclusions

Small dense LDL might not be a significant predictor of CVD in this Korean community‐based prospective cohort study.     

Influence of atherosclerosis‐related risk factors on serum high‐sensitivity C‐reactive protein levels in patients with type 2 diabetes: Comparison of their influence in obese and non‐obese patients

Aims/Introduction

Increased levels of high‐sensitivity C‐reactive protein (hs‐CRP) likely leads to the development of atherosclerosis. Therefore, it is very important to know which factors largely influence hs‐CRP levels. In the present study, we examined the influence of various atherosclerosis‐related factors on hs‐CRP levels in patients with type 2 diabetes.

Materials and Methods

A total of 275 patients (176 men, 99 women) were enrolled in this study. We tested the relationship between the number of risk factors reaching a desired value and hs‐CRP levels. The Mann–Whitney U‐test was used to compare two groups. The Kruskal–Wallis test was used to carry out overall group comparisons, and the Steel–Dwass test was used to carry out between‐group comparisons. Spearman''s rank correlation was carried out to study the correlation between hs‐CRP levels and clinical parameters. Multivariate regression method was used to analyze the factors independently contributing to hs‐CRP levels.

Results

Hs‐CRP levels were lower in patients with a larger number of risk factors reaching a desired value. In particular, triglyceride and body mass index (BMI) were independent risk factors determining hs‐CRP levels in a multivariate regression analysis. Furthermore, we compared the influence of various factors on hs‐CRP levels in both obese (BMI ≥25 kg/m²) and non‐obese patients with type 2 diabetes (BMI <25 kg/m²). In obese groups, BMI and urinary albumin were independent risk factors determining hs‐CRP levels, whereas triglyceride and statin were independent risk factors in non‐obese patients.

Conclusions

There is some difference in the factors responsible for hs‐CRP levels in obese and non‐obese patients with type 2 diabetes.     

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.     

Liraglutide is effective and well tolerated in combination with an oral antidiabetic drug in Japanese patients with type 2 diabetes: A randomized, 52‐week,open‐label,parallel‐group trial

Introduction

The safety and efficacy of liraglutide in combination with an oral antidiabetic drug (OAD) compared with combination of two OADs were assessed in Japanese patients with type 2 diabetes.

Materials and Methods

This was a 52‐week, open‐label, parallel‐group trial in which patients whose type 2 diabetes was inadequately controlled with a single OAD (glinide, metformin, α‐glucosidase inhibitor or thiazolidinedione) were randomized 2:1 to either pretrial OAD in combination with liraglutide 0.9 mg/day (liraglutide group; n = 240) or pretrial OAD in combination with an additional OAD (additional OAD group; n = 120). The primary outcome measure was the incidence of adverse events (AEs).

Results

Overall, 86.3% of patients in the liraglutide group and 85.0% of patients in the additional OAD group experienced AEs; these were similar in nature and severity. Adverse event rates were 361 and 331 per 100 patient‐years of exposure, respectively. Confirmed hypoglycemia was rare (seven episodes in two patients on liraglutide, and two in two patients on additional OAD). There were no reported pancreatitis events, and no unexpected safety signals were identified. Mean reductions in glycosylated hemoglobin were significantly greater in the liraglutide group than the additional OAD group [estimated mean treatment difference −0.27% (95% confidence interval (CI) −0.44, −0.09; P = 0.0026)]; reductions in mean fasting plasma glucose levels were also greater with liraglutide [estimated mean difference −5.47 mg/dL (−0.30 mmol/L; 95% CI: −10.83, −0.10; P = 0.0458)].

Conclusions

Liraglutide was well tolerated and effective as combination therapy with an OAD in Japanese patients with type 2 diabetes.     

Number of circulating pro‐angiogenic cells,growth factor and anti‐oxidative gene profiles might be altered in type 2 diabetes with and without diabetic foot syndrome

Aims/Introduction

Type 2 diabetes is often complicated by diabetic foot syndrome (DFS). We analyzed the circulating stem cells, growth factor and anti‐oxidant gene expression profiles in type 2 diabetes patients without or with different forms of DFS.

Materials and Methods

Healthy volunteers (n = 13) and type 2 diabetes patients: (i) without DFS (n = 10); or with (ii) Charcot osteoneuropathy (n = 10); (iii) non‐infected (n = 17); (iv) infected (n = 11); and (v) healed ulceration were examined (n = 12). Peripheral blood endothelial progenitor cells (EPC), mesenchymal stem cells (MSC), hematopoietic stem cells (HSC) and very small embryonic‐like (VSEL) cells were phenotyped using flow cytometry. Plasma cytokine concentrations and gene expressions in blood cells were measured by Luminex and quantitative real‐time polymerase chain reaction assays, respectively.

Results

Patients with non‐complicated type 2 diabetes showed reduced HMOX1 expression, accompanied by HMOX2 upregulation, and had less circulating EPC, MSC or HSC than healthy subjects. In contrast, VSEL cells were elevated in the type 2 diabetes group. However, subjects with DFS, even with healed ulceration, had fewer VSEL cells, more CD45‐CD29⁺CD90⁺MSC, and upregulated HMOX1 when compared with the type 2 diabetes group. Patients with Charcot osteopathy had lowered plasma fibroblast growth factor‐2. Elevated plasma tumor necrosis factor‐α and decreased catalase expression was found in all diabetic patients.

Conclusions

Patients with type 2 diabetes and different forms of DFS have an altered number of circulating stem cells. Type 2 diabetes might also be associated with a changed plasma growth factor and anti‐oxidant gene expression profile. Altogether, these factors could contribute to the pathogenesis of different forms of DFS.     

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.     

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.     

Interactive effects of an isocaloric high‐protein diet and resistance exercise on body composition,ghrelin, and metabolic and hormonal parameters in untrained young men: A randomized clinical trial

Aims/Introduction

The interactive effects of resistance training and dietary protein on hormonal responses in adults are not clear and remain controversial. We tested the effect of an isocaloric high‐protein diet on body composition, ghrelin, and metabolic and hormonal parameters during a 12‐week resistance training program in untrained healthy young men.

Material and Methods

We randomized 18 healthy young men to a standard diet (ST group) or an isocaloric high protein diet (HP group). Both groups participated in a 12‐week resistance exercise program. We measured body composition, lipid profile, homeostatic model assessment of insulin resistance (HOMA‐IR) indices, total ghrelin, and exercise‐related hormones at baseline and 12 weeks.

Results

In the HP group, lean body mass (LBM), total ghrelin, growth hormone, testosterone and cortisol levels showed an increase, whereas body fat percentage and HOMA‐IR showed a decrease at 12 weeks, compared with baseline (P ≤ 0.05). In the ST group, no changes in these parameters were observed during the 12‐week period. During the 12‐week period, significant differences in the pattern of change of LBM (P = 0.032), total ghrelin (P = 0.037), HOMA‐IR (P = 0.040) and high‐density lipoprotein cholesterol (P = 0.011) over time were observed between the groups.

Conclusions

The findings of the present study suggest that an isocaloric high‐protein diet can ameliorate body composition, metabolic profiles and energy metabolism during a 12‐week scheduled resistance training program in untrained healthy young men. This trial was registered with ClinicalTrials.gov (no. NCT01714700).     

Postprandial serum C‐peptide value is the optimal index to identify patients with non‐obese type 2 diabetes who require multiple daily insulin injection: Analysis of C‐peptide values before and after short‐term intensive insulin therapy

Aims/Introduction

Type 2 diabetes is a progressive disease characterized by a yearly decline in insulin secretion; however, no definitive evidence exists showing the relationship between decreased insulin secretion and the need for insulin treatment. To determine the optimal insulin secretory index for identifying patients with non‐obese type 2 diabetes who require multiple daily insulin injection (MDI), we evaluated various serum C‐peptide immunoreactivity (CPR) values.

Materials and Methods

We near‐normalized blood glucose with intensive insulin therapy (IIT) over a 2‐week period in 291 patients with non‐obese type 2 diabetes, based on our treatment protocol. After improving hyperglycemia, we challenged with oral hypoglycemic agent (OHA), and according to the responsiveness to OHA, patients were classified into three therapy groups: OHA alone (n = 103), basal insulin plus OHA (basal insulin‐supported oral therapy [BOT]; n = 56) and MDI (n = 132). Glucagon‐loading CPR increment (ΔCPR), fasting CPR (FCPR), CPR 2 h after breakfast (CPR2h), the ratio of FCPR to FPG (CPI), CPI 2 h after breakfast (CPI2h) and secretory unit of islets in transplantation (SUIT) were submitted for the analyses. Receiver operating characteristic (ROC) and multiple logistic analyses for these CPR indices were carried out.

Results

Many CPR values were significantly lower in the MDI group compared with the OHA alone or BOT groups. ROC and multiple logistic analyses disclosed that post‐prandial CPR indices (CPR2h and CPI2h) were the most reliable CPR markers to identify patients requiring MDI.

Conclusions

Postprandial CPR level after breakfast is the most useful index for identifying patients with non‐obese type 2 diabetes who require MDI therapy.