Usefulness of the insulin tolerance test in patients with type 2 diabetes receiving insulin therapy

Aims/Introduction

To establish the validity of the plasma glucose disappearance rate (KITT), derived from an insulin‐tolerance test (ITT), for evaluating the insulin sensitivity of patients with type 2 diabetes after insulin therapy.

Materials and Methods

In the first arm of the study, 19 patients with poorly controlled diabetes were treated with insulin and underwent an ITT and a euglycemic clamp test (clamp‐IR). The relationship between the insulin resistance index, as assessed by both the clamp‐IR and KITT tests, was examined. In the second arm of the study, the relationships between KITT values and various clinical parameters were investigated in 135 patients with poorly controlled diabetes, after achieving glycemic control with insulin.

Results

In study 1, a close correlation between KITT and the average glucose infusion rate during the last 30 min of the standard clamp‐IR test (M‐value) was noted (P < 0.001). In study 2, body mass index (P = 0.0011), waist circumference (P = 0.0004), visceral fat area (P = 0.0011) and the log‐transformed homeostasis model assessment of insulin resistance value (P = 0.0003) were negatively correlated with the log‐transformed KITT. High‐density lipoprotein cholesterol (P = 0.0183), low‐density lipoprotein cholesterol (P = 0.0121) and adiponectin (P = 0.0384) levels were positively correlated with the log‐transformed KITT.

Conclusions

The ITT is a valid and useful test for evaluating the insulin sensitivity of patients with diabetes, even after treatment with insulin.     

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.     

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.     

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.     

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.     

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.     

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).     

Accurate method to estimate insulin resistance from multiple regression models using data of metabolic syndrome and oral glucose tolerance test

Aims/Introduction

How to measure insulin resistance (IR) accurately and conveniently is a critical issue for both clinical practice and research. In the present study, we tried to modify the β‐cell function, insulin sensitivity, and glucose tolerance test (BIGTT) in patients with normal glucose tolerance (NGT) and abnormal glucose tolerance (AGT) by oral glucose tolerance test (OGTT) and metabolic syndrome (MetS) components.

Materials and Methods

There were 327 participants enrolled and divided into NGT or AGT. Data from 75% of the participants were used to build the models, and the remaining 25% were used for external validation. Steady‐state plasma glucose (SSPG) concentration derived from the insulin suppression test was regarded as the standard measurement for IR. Five models were built from multiple regression: model 1 (MetS model with sex, age and MetS components); model 2 (simple OGTT model with sex, age, plasma glucose, and insulin concentrations at 0 and 120 min during OGTT); model 3 (full OGTT model with sex, age, and plasma glucose and insulin concentrations at 0, 30, 60, 90, 120, and 180 min during OGTT); model 4 (simple combined model): model 1 and model 2; and model 5 (full model): model 1 and 3.

Results

In general, our models had higher r² compared with surrogates derived from OGTT, such as homeostasis model assessment‐insulin resistance and quantitative insulin sensitivity check index. Among them, model 5 had the highest r² (0.505 in NGT, 0.556 in AGT, respectively).

Conclusions

Our modified BIGTT models proved to be accurate and easy methods for estimating IR, and can be used in clinical practice and research.     

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.     

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.     

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.     

Transgenic zebrafish model of the C43G human insulin gene mutation

Aims/Introduction

The human insulin gene/preproinsulin protein mutation C43G disrupts disulfide bond formation and causes diabetes in humans. Previous in vitro studies showed that these mutant proteins are retained in the endoplasmic reticulum (ER), are not secreted and are associated with decreased secretion of wild‐type insulin. The current study extends this work to an in vivo zebrafish model. We hypothesized that C43G‐green fluorescent protein (GFP) would be retained in the ER, disrupt β‐cell function and lead to impaired glucose homeostasis.

Materials and Methods

Islets from adult transgenic zebrafish expressing GFP‐tagged human proinsulin mutant C43G (C43G‐GFP) or wild‐type human proinsulin (Cpep‐GFP) were analyzed histologically across a range of ages. Blood glucose concentration was determined under fasting conditions and in response to glucose injection. Insulin secretion was assessed by measuring circulating GFP and endogenous C‐peptide levels after glucose injection.

Results

The majority of β‐cells expressing C43G proinsulin showed excessive accumulation of C43G‐GFP in the ER. Western blotting showed that C43G‐GFP was present only as proinsulin, indicating defective processing. GFP was poorly secreted in C43G mutants compared with controls. Despite these defects, blood glucose homeostasis was normal. Mutant fish maintained β‐cell mass well into maturity and secreted endogenous C‐peptide.

Conclusions

In this model, the C43G proinsulin mutation does not impair glucose homeostasis or cause significant loss of β‐cell mass. This model might be useful for identifying potential therapeutic targets for proper trafficking of intracellular insulin or for maintenance of β‐cell mass in early‐stage diabetic patients.     

Pharmacokinetic and pharmacodynamic properties of insulin degludec in Japanese patients with type 1 diabetes mellitus reflect similarities with Caucasian patients

Introduction

The present study aimed to evaluate the pharmacokinetic and pharmacodynamic properties of insulin degludec (IDeg) in Japanese patients with type 1 diabetes.

Materials and Methods

This was a randomized, single‐center, double‐blind, two‐period, crossover, multiple‐dose trial. Patients were randomized into two treatment sequences, and received IDeg or insulin detemir for 6 days and a washout period (7–21 days) before switching treatment. Blood samples for pharmacokinetic measurements were obtained before each dose and up to 120 h after the last dose of each treatment period. Pharmacodynamic measurements were obtained using a 26‐h euglycemic clamp procedure after the last dose of each treatment period.

Results

A total of 22 patients were randomized (14 men, 8 women; mean glycosylated hemoglobin at baseline of 7.5% [based on Japanese Diabetes Society value]). At steady state, total glucose‐lowering effect (area under the glucose infusion rate [GIR] curve during one dosing interval [τ, 0–24 h] at steady state [AUC_{GIR ,τ, SS}]) was 1,446 mg/kg and total exposure (geometric mean) of IDeg (AUC_{ID eg,τ, SS}) was 81,270 pmol h/L. Both the glucose‐lowering effect and the exposure of IDeg were evenly distributed over the dosing interval, with AUC for the first 12‐h intervals being approximately 50% of the total (geometric mean; AUC_{GIR ,0–12h, SS}/AUC_{GIR ,τ, SS} = 48%; AUC_{ID eg,0–12h, SS}/AUC_{ID eg,τ, SS} = 53%).

Conclusions

IDeg has a flat, consistent and ultra‐long glucose‐lowering effect that is evenly distributed across a 24‐h interval and an ultra‐long duration of action in Japanese patients with type 1 diabetes. These data support once‐daily dosing of IDeg in all patients. Overall, the pharmacodynamic and pharmacokinetic end‐points and safety observations are consistent with those previously reported in Caucasian patients.     

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.     

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).     

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.     

Effects of insulin changes on quality of life and glycemic control in Japanese patients with type 2 diabetes mellitus: The insulin‐changing study intending to gain patients' insights into insulin treatment with patient‐reported health outcomes in actual clinical treatments (INSIGHTs) study

Aims/Introduction

Our primary objective was to assess changes in quality of life (QOL) associated with changes in insulin regimen in patients with type 2 diabetes mellitus. Secondary objectives were to assess the reasons for and patterns of changes in insulin regimen, and the effects on glycemic control.

Materials and Methods

This 12‐week, observational study included patients with type 2 diabetes mellitus (n = 625) who planned to change insulin regimen (type of insulin, injection device and/or number of injections). The primary outcome measure was a change from baseline in QOL assessed by the Insulin Therapy‐Related (ITR) QOL questionnaire. The secondary outcome measures included change from baseline in plasma glycated hemoglobin (HbA_1c) level, the reasons for and pattern of insulin regimen change, and change from baseline in QOL assessed by Diabetes Treatment Satisfaction Questionnaire (DTSQ).

Results

QOL did not worsen during the study. Improvements were seen in the ITR‐QOL ‘daily activities’ subscale score (baseline: 12.7 ± 2.3; week 12: 12.9 ± 2.3; P = 0.038, n = 568) and the DTSQ ‘perceived frequency of hyperglycemia’ subscale score (baseline: 3.4 ± 1.6; week 12: 3.0 ± 1.7; P < 0.001, n = 573). Glycemic control improved, as evidenced by decreased plasma HbA_1c levels (baseline: 8.21 ± 1.47%; week 12: 7.85 ± 1.31%; P < 0.001, n = 606).

Conclusions

It was suggested that insulin regimen changes might improve glycemic control in Japanese patients with type 2 diabetes mellitus without worsening QOL. This trial was registered with ClinicalTrials.gov (no. NCT01055808).     

Glucagon and insulin have opposite effects on tissue chromium distribution in an obese mouse model

Aims/Introduction

Previous studies have suggested that chromium (Cr) is an essential cofactor for normal carbohydrate metabolism and affects insulin sensitivity, especially in rodent models. Several factors, such as insulin challenge, high carbohydrate intake, and response to stress (e.g., in obesity), alter Cr excretion or distribution. Glucagon is known to regulate carbohydrate metabolism and hyperglucagonemia plays a role in the development of hyperglycemia in diabetic subjects.

Materials and Methods

In the present study we investigated possible modulation of Cr levels by glucagon using an obese mouse model. Mice were kept on a high‐fat diet and then used as an obesity model. These obese mice were injected with one dose of glucagon or insulin and Cr levels in their tissues were determined.

Results

In obese mice, glucagon challenge significantly increased Cr levels in bone but decreased them in the fat and liver. In contrast, insulin challenge significantly decreased Cr levels in bone but increased them in the fat, liver and muscle.

Conclusions

The results show that glucagon and insulin have opposite effects on Cr levels in bone, fat, liver, and muscle.     

Correlations of serum visfatin and metabolisms of glucose and lipid in women with gestational diabetes mellitus

Aims/Introduction

Visfatin is a newly discovered adipocytokine hormone, which exerts an insulin‐like effect by binding to the insulin receptor‐1. However, the role of visfatin in human gestational diabetes mellitus (GDM) remains controversial. The purpose of the present study was to investigate the correlation between serum visfatin and metabolism of glucose and lipid in GDM.

Materials and Methods

This was a prospective study. A total of 38 GDM patients and 35 age‐ and body mass index‐matched controls were studied between January 2012 and October 2013. Fasting serum levels of visfatin, fasting plasma glucose, hemoglobin A1c and lipid profile were measured. Two‐tailed t‐tests and Pearson''s correlation coefficient were used to analyze the data.

Results

Perinatal visfatin levels were negatively correlated with fasting plasma glucose, insulin resistance index and triglycerides in controls (r = −0.47, −0.51, −0.57, respectively; P < 0.05), and positively correlated with high‐density lipoprotein cholesterol (r = 0.32, P < 0.05). A positive correlation with visfatin level only appeared in weight gain and body mass index in women with GDM (r = 0.36, 0.45, respectively; P < 0.05).

Conclusions

Visfatin appears to be involved in glucose and lipid metabolism regulation and insulin resistance, suggesting a role in GDM pathogenesis.     

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.