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).     

The once‐daily human glucagon‐like peptide‐1 analog,liraglutide, improves β‐cell function in Japanese patients with type 2 diabetes

Aims/Introduction: β‐cell function was evaluated by homeostasis model assessment of β‐cell function (HOMA‐B) index, proinsulin:insulin and proinsulin:C‐peptide ratios in adult, Japanese type 2 diabetes patients receiving liraglutide. Materials and Methods: Data from two randomized, controlled clinical trials (A and B) including 664 Japanese type 2 diabetes patients (mean values: glycated hemoglobin [HbA_1c] 8.61–9.32%; body mass index [BMI] 24.4–25.3 kg/m²) were analyzed. In two 24‐week trials, patients received liraglutide 0.9 mg (n = 268) or glibenclamide 2.5 mg (n = 132; trial A), or liraglutide 0.6, 0.9 mg (n = 176) or placebo (n = 88) added to previous sulfonylurea therapy (trial B). Results: Liraglutide was associated with improved glycemic control vs sulfonylurea monotherapy or placebo. In liraglutide‐treated groups in trials A and B, area under the curve (AUC) _{insulin 0–3 h} was improved (P < 0.001 for all) and the AUC_{insulin 0–3 h}:AUC_{glucose 0–3 h} ratio was increased (estimated treatment difference [liraglutide–comparator] 0.058 [0.036, 0.079]). HOMA‐B significantly increased with liraglutide relative to comparator in trial B (P < 0.05), but not in trial A. The reduction in fasting proinsulin:insulin ratio was 50% greater than in comparator groups. Conclusions: In Japanese type 2 diabetes patients, liraglutide was associated with effective glycemic control, restoration of prandial insulin response and indications of improved β‐cell function. This trial was registered with Clinicaltrials.gov (trial A: no. NCT00393718/JapicCTI‐060328 and trial B: no. NCT00395746/JapicCTI‐060324). (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2012.00193.x, 2012)     

Role of insulin receptor substrate‐1 for diethylnitrosamine plus high‐fat diet‐induced hepatic tumorigenesis in mice

We investigated the role of insulin receptor substrate (Irs)‐1 for diethylnitrosamine (DEN) plus high‐fat (HF) diet‐induced hepatic tumorigenesis in mice. We gave DEN by intraperitoneal injection at the dose of 80 mg/kg to 18‐week‐old wild‐type (WT) and Irs1‐knockout (Irs1^−/−) mice, which were fed a HF diet from 8 weeks‐of‐age until they were killed (52 weeks). The Irs1^−/− mice showed significantly lower plasma alanine aminotransferase levels, triglyceride contents in the liver and also lower expression levels of the genes encoding inflammatory cytokines than the WT mice. The incidence of DEN plus HF diet‐induced hepatic tumors was 71.4% in the WT mice, whereas it was just 14.3% in the Irs1^−/− mice. The present study showed that Irs1 played an important role in DEN plus HF diet‐induced hepatic tumorigenesis.     

β‐Cell failure in type 2 diabetes

Type 2 diabetic patients are insulin resistant as a result of obesity and a sedentary lifestyle. Nevertheless, it has been known for the past five decades that insulin response to nutrients is markedly diminished in type 2 diabetes. There is now a consensus that impaired glucose regulation cannot develop without insulin deficiency. First‐phase insulin response to glucose is lost very early in the development of type 2 diabetes. Several prospective studies have shown that impaired insulin response to glucose is a predictor of future impaired glucose tolerance (IGT) and type 2 diabetes. Recently discovered type 2 diabetes‐risk gene variants influence β‐cell function, and might represent the molecular basis for the low insulin secretion that predicts future type 2 diabetes. We believe type 2 diabetes develops on the basis of normal but ‘weak’β‐cells unable to cope with excessive functional demands imposed by overnutrition and insulin resistance. Several laboratories have shown a reduction in β‐cell mass in type 2 diabetes and IGT, whereas others have found modest reductions and most importantly, a large overlap between β‐cell masses of diabetic and normoglycemic subjects. Therefore, at least initially, the β‐cell dysfunction of type 2 diabetes seems more functional than structural. However, type 2 diabetes is a progressive disorder, and animal models of diabetes show β‐cell apoptosis with prolonged hyperglycemia/hyperlipemia (glucolipotoxicity). β‐Cells exposed in vitro to glucolipotoxic conditions show endoplasmic reticulum (ER) and oxidative stress. ER stress mechanisms might participate in the adaptation of β‐cells to hyperglycemia, unless excessive. β‐Cells are not deficient in anti‐oxidant defense, thioredoxin playing a major role. Its inhibitor, thioredoxin‐interacting protein (TXNIP), might be important in leading to β‐cell apoptosis and type 2 diabetes. These topics are intensively investigated and might lead to novel therapeutic approaches. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2010.00094.x, 2011)     

One‐minute mental status examination for category fluency is more useful than mini‐mental state examination to evaluate the reliability of insulin self‐injection in elderly diabetic patients

Aims/Introduction

We investigated the factors associated with the reliability of insulin self‐injection in elderly diabetic patients receiving insulin therapy.

Materials and Methods

We enrolled diabetic patients aged ≥65 years and receiving insulin therapy, and assessed their cognitive function by the mini‐mental state examination and 1‐min mental status examination for category fluency. We also observed their technique of insulin self‐injection, and evaluated whether or not patients were able to inject insulin by themselves according to nine defined details in terms of insulin self‐injection. The predictive factors for the reliability of insulin self‐injection were determined by univariate and multivariate logistic regression analysis. There were 278 participants (135 males, 143 females) enrolled in the present study.

Results

According to multivariate logistic regression analysis, only the 1‐min mental status examination score was found to be a significant independent predictor of the reliability of insulin self‐injection (odds ratio 0.75; 95% confidence interval 0.62–0.90; P = 0.002).

Conclusions

The 1‐min mental status examination for category fluency can be considered more useful than mini‐mental state examination to evaluate the reliability of insulin self‐injection in elderly diabetic patients receiving insulin therapy.     

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.     

Biphasic insulin aspart‐30 reduces glycemic variability to a greater degree than insulin detemir: A randomized controlled trial of once‐daily insulin regimens using continuous glucose monitoring

Introduction

We compared the efficacy of insulin detemir and biphasic insulin aspart‐30 given in the morning as an add‐on to oral hypoglycemic agents in type 2 diabetes patients.

Materials and Methods

The present study enrolled 30 patients with poorly controlled type 2 diabetes (8% ≤ glycated hemoglobin < 11%) being treated with oral hypoglycemic agent mono‐ or combination therapy with biguanides, sulfonylureas or thiazolidinediones. The patients were randomly assigned to insulin detemir (group D) or insulin aspart‐30 (group A) given in the morning as add‐on to oral hypoglycemic agents. After adjusting their insulin doses, the patients that underwent continuous glucose monitoring during a 3‐day hospitalization and with day 2 continuous glucose monitoring data were subjected to analysis.

Results

There was no significant difference in patient background, baseline glycated hemoglobin levels and insulin doses during continuous glucose monitoring between the two groups. The percent coefficient of variation of 24‐h glucose levels was significantly lower in group A (20.4 ± 7.6) than in group D (27.1 ± 6.5; P = 0.015). Similarly, mean amplitude of glycemic excursions was significantly smaller in group A (80 ± 32) than in group D (102 ± 14; P = 0.021). Postprandial glucose excursions were significantly smaller after breakfast in group A (65 ± 31 mg/dL) than in group D (106 ± 32 mg/dL; P = 0.002).

Conclusions

As once‐daily insulin injection therapy given before breakfast in type 2 diabetes patients, the biphasic insulin analog might represent a better insulin option in significantly lowering the percent coefficient of variation and mean amplitude of glycemic excursions than the long‐acting insulin preparation.     

Current status of regeneration of pancreatic β‐cells

Newly generated insulin‐secreting cells for use in cell therapy for insulin‐deficient diabetes mellitus require properties similar to those of native pancreatic β‐cells. Pancreatic β‐cells are highly specialized cells that produce a large amount of insulin, and secrete insulin in a regulated manner in response to glucose and other stimuli. It is not yet explained how the β‐cells acquire this complex function during normal differentiation. So far, in vitro generation of insulin‐secreting cells from embryonic stem cells, induced‐pluripotent stem cells and adult stem/progenitor‐like cells has been reported. However, most of these cells are functionally immature and show poor glucose‐responsive insulin secretion compared to that of native pancreatic β‐cells (or islets). Strategies to generate functional β‐cells or a whole organ in vivo have also recently been proposed. Establishing a protocol to generate fully functional insulin‐secreting cells that closely resemble native β‐cells is a critical matter in regenerative medicine for diabetes. Understanding the physiological processes of differentiation, proliferation and regeneration of pancreatic β‐cells might open the path to cell therapy to cure patients with absolute insulin deficiency.     

Regular insulin,rather than rapid‐acting insulin,is a suitable choice for premeal bolus insulin in lean patients with type 2 diabetes mellitus

The aim of the present study was to compare the usefulness of premeal rapid‐acting and regular insulin in type 2 diabetes patients. A total of 56 type 2 diabetic patients were investigated during hospitalization. Premeal rapid‐acting insulin was applied instead of other medications. Premeal insulin was titrated to adjust premeal and bedtime blood glucose levels to 81–120 mg/dL. Premeal rapid‐acting insulin was changed to regular insulin just before a meal at the same dosage if the postmeal blood glucose level was lower than the premeal blood glucose level. A total of 15 patients changed to regular insulin, and 41 patients continued rapid‐acting insulin. The blood glucose level was comparable between these two groups. Body mass index was significantly lower in the patients using regular insulin. According to the multivariate logistic regression analysis, low body mass index was an independent variable accounting for the usefulness of regular insulin. Regular insulin, rather than rapid‐acting insulin, is a suitable choice for premeal insulin in lean type 2 diabetic patients.