Impact of insulin glargine and lixisenatide on β‐cell function in patients with type 2 diabetes mellitus: A randomized open‐label study

It is known that β‐cell function can be enhanced by direct stimulation of insulin secretion or by induction of β‐cell rest, but whether both strategies can complement each other has not yet been examined. A total of 28 people with type 2 diabetes (glycated haemoglobin 7.8% ± 0.5%) were treated with either lixisenatide or titrated insulin glargine, followed by their combined administration, each over 4 weeks. First‐ and second‐phase insulin secretion during an intravenous glucose challenge were calculated. First‐ and second‐phase insulin secretion were not increased with glargine alone, but increased after addition of lixisenatide ( P < .001). Lixisenatide alone increased first‐ and second‐phase insulin secretion ( P < .01). Addition of insulin glargine tended to further increase first‐phase insulin secretion (P = .054), as well as insulin and C‐peptide concentrations ( P < .05). Second‐phase insulin secretion was not affected by the addition of glargine. The sequence of initiating lixisenatide or glargine had no effect on the final measures of glycaemia or insulin secretion. Thus, lixisenatide and, to a lesser extent, insulin glargine, increase glucose‐stimulated insulin secretion in an additive manner.     

LY2189265, a long‐acting glucagon‐like peptide‐1 analogue,showed a dose‐dependent effect on insulin secretion in healthy subjects

Aim: To assess the safety, tolerability, pharmacokinetics, pharmacodynamics and potential immunogenicity of single, escalating subcutaneous injections of a once‐weekly glucagon‐like peptide‐1 analogue in healthy subjects. Methods: This phase 1, three‐period, crossover, double‐blind, placebo‐controlled study investigated single, escalating subcutaneous doses of LY2189265 (LY) ranging from 0.1 to 12 mg; approximately six subjects were randomized to each dose. Parameters of safety, including adverse events, were assessed. The pharmacokinetic profile was assessed over 14 days. Pharmacodynamic parameters (glucose and insulin concentrations) were measured following a step‐glucose infusion (day 3) and as part of an oral glucose tolerance test (OGTT) (day 5). Results: LY was generally well tolerated with some increase in gastrointestinal symptoms with escalating doses. There were small dose‐dependent increases in pulse rate with doses ≥1.0 mg and diastolic blood pressure with doses ≥3.0 mg. The half‐life of LY was approximately 90 h, with C_max occurring between 24 and 48 h in most subjects. Evidence of increase in glucose‐dependent insulin secretion and suppression of serum glucose excursions were observed during an OGTT at all doses compared to placebo; no episodes of hypoglycaemia occurred. No subjects developed antibodies to LY2189265. Conclusions: LY showed an acceptable safety profile and exhibited the expected glucagon‐like peptide‐1 pharmacological effects on glucose suppression and insulin secretion with a half‐life that supports once‐weekly dosing.     

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)     

Reactive hypoglycaemia following GLP‐1 infusion in pancreas transplant recipients

The aim of the study was to determine whether reactive hypoglycaemia in pancreas transplant recipients that followed administration of glucagon‐like peptide‐1 (GLP‐1) was associated with excessive insulin, insufficient glucagon, or both. Methodology involved six portally drained pancreas recipients who received GLP‐1 (1.5 pmol/kg/min) or placebo infusion on randomized occasions during glucose‐potentiated arginine testing. The second subject developed symptomatic hypoglycaemia [plasma glucose (PG) 42 mg/dl] 1 h after GLP‐1 administration; subsequent subjects received intravenous glucose following GLP‐1, but not placebo, infusion for PG levels <65 mg/dl. Following GLP‐1 vs. placebo infusion, PG was lower (58 ± 4 vs. 76 ± 5 mg/dl; p < 0.05) despite administration of intravenous glucose. During hypoglycaemia, insulin levels and the insulin‐to‐glucagon ratio were greater after GLP‐1 vs. placebo infusion (p < 0.05), while glucagon did not vary. It can be concluded from the study that GLP‐1 can induce reactive hypoglycaemia in pancreas transplant recipients through excessive insulin secretion associated with an increased insulin‐to‐glucagon ratio.     

Postprandial glucose‐lowering effect of premeal consumption of protein‐enriched,dietary fiber‐fortified bar in individuals with type 2 diabetes mellitus or normal glucose tolerance

Aims/Introduction

Protein preload improves postprandial glycemia by stimulating secretion of insulin and incretin hormones. However, it requires a large dose of protein to produce a significant effect. The present study was carried out to investigate the postprandial glucose‐lowering effect of a premeal protein‐enriched, dietary fiber‐fortified bar (PFB), which contains moderate amounts of protein, in individuals with type 2 diabetes mellitus or normal glucose tolerance (NGT).

Materials and Methods

The participants (15 type 2 diabetes mellitus and 15 NGT) were randomly assigned to either a premeal or postmeal PFB group and underwent two mixed meal tolerance tests, 1 week apart in reverse order. Plasma levels of glucose, insulin, glucagon‐like peptide‐1 and glucose‐dependent insulinotropic polypeptide were measured.

Results

During the mixed meal tolerance tests, the incremental area under the curve from 0 to 180 min of plasma glucose levels was lower with premeal PFB than with postmeal PFB in the type 2 diabetes mellitus (14,723 ± 1,310 mg min/dL vs 19,642 ± 1,367 mg min/dL; P = 0.0002) and NGT participants (3,943 ± 416 mg min/dL vs 4,827 ± 520 mg min/dL, P = 0.0296). In the type 2 diabetes mellitus participants, insulinogenic index and the incremental area under the curve from 0 to 180 min of plasma total glucagon‐like peptide‐1 levels were higher with premeal PFB than with postmeal PFB, but not in the NGT participants. There was no difference in postprandial glucose‐dependent insulinotropic polypeptide levels between premeal and postmeal PFB in both groups.

Conclusions

Acute administration of premeal PFB decreased postprandial glucose excursion in both type 2 diabetes mellitus and NGT participants. In the type 2 diabetes mellitus participants, premeal PFB augmented the early‐phase insulin secretion, possibly through enhancing glucagon‐like peptide‐1 secretion.     

Improved glycaemic control with minimal hypoglycaemia and no weight change with the once‐daily human glucagon‐like peptide‐1 analogue liraglutide as add‐on to sulphonylurea in Japanese patients with type 2 diabetes

Aim: Sulphonylureas (SUs) are often used as first‐line treatments for type 2 diabetes in Japan, hence it is important to study new antidiabetic drugs in combination with SUs in Japanese patients. Methods: The efficacy and safety of the once‐daily human glucagon‐like peptide‐1 (GLP‐1) analogue liraglutide were compared in 264 Japanese subjects [mean body mass index (BMI) 24.9 kg/m²; mean glycated haemoglobin (HBA1c) 8.4%] randomized and exposed to receive liraglutide 0.6 mg/day (n = 88), 0.9 mg/day (n = 88) or placebo (n = 88) each added to SU monotherapy (glibenclamide, glicazide or glimeprimide) in a 24‐week, double‐blind, parallel‐group trial. Results: The mean change in HBA1c from baseline to week 24 (LOCF) was ?1.56 (s.d. 0.84) and ?1.46 (s.d. 0.95) with liraglutide 0.9 and 0.6 mg respectively, and ?0.40 (s.d. 0.93) with placebo. HBA1c decreased in the placebo group from 8.45 to 8.06%, while liraglutide reduced HBA1c from 8.60 to 7.14%, and from 8.23 to 6.67% at the 0.6 and 0.9 mg doses respectively. Mean HBA1c at week 24 of the two liraglutide groups were significantly lower than the placebo group (p < 0.0001 for both). More subjects reached HBA1c < 7.0% with liraglutide (0.6 mg: 46.5%; 0.9 mg: 71.3%) vs. placebo (14.8%). Fasting plasma glucose (FPG) levels were significantly improved with liraglutide (difference ?1.47 mmol/l and ?1.80 mmol/l with 0.6 and 0.9 mg vs. placebo; p < 0.0001). Overall safety was similar between treatments: no major hypoglycaemic episodes were reported, while 84/77/38 minor hypoglycaemic episodes occurred in the 0.6 mg/0.9 mg and placebo treatment groups (all in combination with SU), reflecting lower ambient glucose levels. No relevant change in mean body weight occurred in subjects receiving liraglutide (0.6 mg: 0.06 kg; 0.9 mg: ?0.37 kg), while mean body weight decreased in subjects receiving placebo (?1.12 kg). Conclusions: The addition of liraglutide to SU treatment for 24 weeks dose‐dependently improved glycaemic control vs. SU monotherapy, without causing major hypoglycaemia or weight gain or loss.     

Liraglutide is effective in type 2 diabetic patients with sustained endogenous insulin‐secreting capacity

Aims/Introduction: Recently, glucagon‐like peptide‐1 (GLP‐1) receptor agonists of liraglutide have become available in Japan. It has not yet been clarified what clinical parameters could discriminate liraglutide‐effective patients from liraglutide‐ineffective patients. Materials and Methods: We reviewed 23 consecutive patients with type 2 diabetes admitted to Osaka University Hospital for glycemic control. All of the patients were treated with diet plus insulin (or plus oral antidiabetic drugs) 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 liraglutide. The efficacy of liraglutide was determined according to whether glycemic control was maintained at the target levels. Results: Liraglutide was effective in 13 of 23 patients. There were significant differences in the parameters of insulin secretion, including fasting C‐peptide (F‐CPR), C‐peptide index (CPI), insulinogenic index (I.I.) and urine C‐peptide (U‐CPR), between liraglutide‐effective and ‐ineffective patients. The duration of diabetes was significantly shorter in liraglutide‐effective patients than in liraglutide‐ineffective patients. In receiver operating characteristic analyses, the cut‐off value for predicting the efficacy of liraglutide was 0.14 for I.I., 1.1 for CPI, 1.5 ng/mL for F‐CPR, 33.3 μg/day for U‐CPR and 19.5 years for duration of type 2 diabetes. Conclusions: Insulin secretion evaluated by F‐CPR, CPI, I.I., U‐CPR and the duration of type 2 diabetes were useful parameters for predicting the efficacy of liraglutide in patients with type 2 diabetes. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2011.00168.x, 2011)     

Effect of initial combination therapy with sitagliptin and metformin on β-cell function in patients with type 2 diabetes

Aim: To examine the effect of sitagliptin and metformin, alone and in combination, on modelled parameters of β‐cell function in patients with type 2 diabetes. Methods: The data used in the present analyses are from a 104‐week study, which included a 24‐week, placebo‐ and active controlled phase followed by a 30‐week, active controlled, continuation phase and an additional 50‐week, active controlled extension phase. Patients were randomised to one of six blinded treatments: sitagliptin 50 mg + metformin 1000 mg b.i.d., sitagliptin 50 mg + metformin 500 mg b.i.d., metformin 1000 mg b.i.d., metformin 500 mg b.i.d., sitagliptin 100 mg q.d. or placebo. Patients on placebo were switched in a blinded manner to metformin 1000 mg b.i.d. at week 24. Subsets of patients volunteered to undergo frequently sampled meal tolerance tests at baseline and at weeks 24, 54 and 104. β‐cell responsivity was assessed with the C‐peptide minimal model. The static component (Φ_s) estimates the rate of insulin secretion related to above‐basal glucose concentration. The dynamic component (Φ_d) is related to the rate of change in glucose. The total index (Φ_total) represents the overall response to a glycaemic stimulus and is calculated as a function of Φ_s and Φ_d. Insulin sensitivity was estimated with the Matsuda index (ISI). The disposition index, which assesses insulin secretion relative to the prevailing insulin sensitivity, was calculated based on the Φ_total and ISI. Results: At week 24, substantial reductions in postmeal glucose were observed with all active treatment groups relative to the placebo group. Φ_s, Φ_total and the disposition index were significantly improved from baseline at week 24 with all active treatments relative to placebo. Generally larger effects were observed with the initial combination of sitagliptin and metformin relative to the monotherapy groups. When expressed as median percent change from baseline, Φ_s increased from baseline by 137 and 177% in the low‐ and high‐dose combination groups and by 85, 54, 73 and ?9% in the high‐dose metformin, low‐dose metformin, sitagliptin monotherapy and placebo groups, respectively. At weeks 54 and 104, the combination treatment groups continued to demonstrate greater improvements in β‐cell function relative to their respective monotherapy groups. Conclusions: After 24 weeks of therapy, relative to placebo, initial treatment with sitagliptin or metformin monotherapy improved β‐cell function; moreover, initial combination therapy demonstrated larger improvements than the individual monotherapies. Improvements in β‐cell function were found with treatments for up to 2 years.     

A double‐blind,randomized, placebo‐controlled trial of the short‐term effect of vitamin D3 supplementation on insulin sensitivity in apparently healthy,middle‐aged,centrally obese men

Aim To determine the short‐term effect of vitamin D₃ supplementation on insulin sensitivity in apparently healthy, middle‐aged, centrally obese men. Subjects and methods A double‐blind randomized controlled trial was conducted at a tertiary care facility in which 100 male volunteers aged ≥ 35 years received three doses of vitamin D₃ (120 000 IU each; supplemented group) fortnightly or placebo (control group). Hepatic fasting insulin sensitivity [homeostasis model assessment (HOMA), quantitative insulin‐sensitivity check index, HOMA‐2], postprandial insulin sensitivity [oral glucose insulin sensitivity (OGIS)], insulin secretion (HOMA%B, HOMA2‐%B), lipid profile and blood pressure were measured at baseline and at 6 weeks’ follow‐up. Results Seventy‐one of the recruited subjects completed the study (35 in supplemented group, 36 in control group). There was an increase in OGIS with supplementation by per protocol analysis (P = 0.038; intention‐to‐treat analysis P = 0.055). The age‐ and baseline 25‐hydroxyvitamin D level‐adjusted difference in change in OGIS was highly significant (mean difference 41.1 ± 15.5; P = 0.01). No changes in secondary outcome measures (insulin secretion, basal indices of insulin sensitivity, blood pressure or lipid profile) were found with supplementation. Conclusion The trial indicates that vitamin D₃ supplementation improves postprandial insulin sensitivity (OGIS) in apparently healthy men likely to have insulin resistance (centrally obese but non‐diabetic).     

Chronic liraglutide therapy induces an enhanced endogenous glucagon‐like peptide‐1 secretory response in early type 2 diabetes

Sustained exogenous stimulation of a hormone‐specific receptor can affect endogenous hormonal regulation. In this context, little is known about the impact of chronic treatment with glucagon‐like peptide‐1 (GLP‐1) agonists on the endogenous GLP‐1 response. We therefore evaluated the impact of chronic liraglutide therapy on endogenous GLP‐1 and glucose‐dependent insulinotropic polypeptide (GIP) response to an oral glucose challenge. A total of 51 people with type 2 diabetes of 2.6 ± 1.9 years’ duration were randomized to daily subcutaneous liraglutide or placebo injection and followed for 48 weeks, with an oral glucose tolerance test (OGTT) every 12 weeks. GLP‐1 and GIP responses were assessed according to their respective area under the curve (AUC) from measurements taken at 0, 30, 60, 90 and 120 minutes during each OGTT. There were no differences in AUC_GIP between the groups. By contrast, although fasting GLP‐1 was unaffected, the liraglutide arm had ~2‐fold higher AUC_{GLP ‐1} at 12 weeks ( P < .001), 24 weeks ( P < .001), 36 weeks ( P = .03) and 48 weeks ( P = .03), as compared with placebo. Thus, chronic liraglutide therapy induces a previously unrecognized, robust and durable enhancement of the endogenous GLP‐1 response, highlighting the need for further study of the long‐term effects of incretin mimetics on L‐cell physiology.     

Effect of liraglutide on ectopic fat in polycystic ovary syndrome: A randomized clinical trial

Women with polycystic ovary syndrome (PCOS) were treated with the GLP‐1 receptor agonist liraglutide to investigate the effect on liver fat content, visceral adipose tissue (VAT) and the prevalence of nonalcoholic fatty liver disease (NAFLD). In a double‐blind, placebo‐controlled, randomized clinical trial 72 women with PCOS, with a BMI > 25 kg/m² and/or insulin resistance, were treated with liraglutide or received placebo 1.8 mg/d (2:1) for 26 weeks. Liver fat content was assessed by ¹ HMR spectroscopy, VAT by MRI, body composition by DXA, and glucose metabolism by oral glucose tolerance test. Compared with placebo, liraglutide treatment reduced body weight by 5.2 kg (5.6%), liver fat content by 44%, VAT by 18%, and the prevalence of NAFLD by two‐thirds (all P < .01). Sex‐hormone‐binding‐globulin (SHBG) levels increased by 19% (P = .03), and free testosterone decreased by 19% (P = .054). HbA1c, fasting glucose and leptin were reduced (all: P < .05), whereas measures of insulin resistance, adiponectin and glucagon did not change. In conclusion, 26 weeks of liraglutide treatment in PCOS resulted in significant reductions in liver fat content, VAT and the prevalence of NAFLD.     

Relationship between serum adipsin and the first phase of glucose‐stimulated insulin secretion in individuals with different glucose tolerance

Aims/Introduction

To detect serum adipsin levels in individuals with different glucose tolerance, and investigate the relationship between adipsisn and the first phase of insulin secretion.

Materials and Methods

A total of 56 patients with newly diagnosed type 2 diabetes mellitus, 36 patients with impaired glucose tolerance (IGT) and 45 individuals with normal glucose tolerance were enrolled. Intravenous glucose tolerance tests were carried out to evaluate pancreatic β‐cell function. The serum levels of adipsin, interleukin‐1β and high‐sensitivity C‐reactive protein were assayed.

Results

Serum adipsin levels were significantly lower in the type 2 diabetes mellitus and the IGT patients than those in the normal glucose tolerance group (P < 0.05). The acute insulin response and area under the curve showed a progressive decrease in the normal glucose tolerance and IGT groups, and decreased to the lowest levels in the type 2 diabetes mellitus group (P < 0.05). Adipsin was found to be negatively correlated with waist‐to‐hip ratio, free fatty acid, fasting plasma glucose, 2‐h postprandial plasma glucose, glycated hemoglobin, homeostasis model assessment of insulin resistance, interleukin‐1β and high‐sensitivity C‐reactive protein (P < 0.05 or P < 0.001), and positively correlated with homeostasis model assessment of β‐cell function, high‐density lipoprotein cholesterol, the area under the curve of the first phase insulin secretion and acute insulin response (P < 0.05 or P < 0.001). Stepwise multiple regression analysis showed that homeostasis model assessment for β‐cell function and acute insulin response were independently related to adipsin (P < 0.05).

Conclusions

Serum adipsin levels were lower in type 2 diabetes mellitus and IGT patients, and correlated with the first phase of insulin secretion. Adipsin might be involved in the pathology of type 2 diabetes mellitus.     

Liraglutide,a once‐daily human GLP‐1 analogue,added to a sulphonylurea over 26 weeks produces greater improvements in glycaemic and weight control compared with adding rosiglitazone or placebo in subjects with Type 2 diabetes (LEAD‐1 SU)

Aim To compare the effects of combining liraglutide (0.6, 1.2 or 1.8 mg/day) or rosiglitazone 4 mg/day (all n ≥ 228) or placebo (n = 114) with glimepiride (2–4 mg/day) on glycaemic control, body weight and safety in Type 2 diabetes. Methods In total, 1041 adults (mean ± sd ), age 56 ± 10 years, weight 82 ± 17 kg and glycated haemoglobin (HbA_1c) 8.4 ± 1.0% at 116 sites in 21 countries were stratified based on previous oral glucose‐lowering mono : combination therapies (30 : 70%) to participate in a five‐arm, 26‐week, double‐dummy, randomized study. Results Liraglutide (1.2 or 1.8 mg) produced greater reductions in HbA_1c from baseline, (?1.1%, baseline 8.5%) compared with placebo (+0.2%, P < 0.0001, baseline 8.4%) or rosiglitazone (?0.4%, P < 0.0001, baseline 8.4%) when added to glimepiride. Liraglutide 0.6 mg was less effective (?0.6%, baseline 8.4%). Fasting plasma glucose decreased by week 2, with a 1.6 mmol/l decrease from baseline at week 26 with liraglutide 1.2 mg (baseline 9.8 mmol/l) or 1.8 mg (baseline 9.7 mmol/l) compared with a 0.9 mmol/l increase (placebo, P < 0.0001, baseline 9.5 mmol/l) or 1.0 mmol/l decrease (rosiglitazone, P < 0.006, baseline 9.9 mmol/l). Decreases in postprandial plasma glucose from baseline were greater with liraglutide 1.2 or 1.8 mg [?2.5 to ?2.7 mmol/l (baseline 12.9 mmol/l for both)] compared with placebo (?0.4 mmol/l, P < 0.0001, baseline 12.7 mmol/l) or rosiglitazone (?1.8 mmol/l, P < 0.05, baseline 13.0 mmol/l). Changes in body weight with liraglutide 1.8 mg (?0.2 kg, baseline 83.0 kg), 1.2 mg (+0.3 kg, baseline 80.0 kg) or placebo (?0.1 kg, baseline 81.9 kg) were less than with rosiglitazone (+2.1 kg, P < 0.0001, baseline 80.6 kg). Main adverse events for all treatments were minor hypoglycaemia (< 10%), nausea (< 11%), vomiting (< 5%) and diarrhoea (< 8%). Conclusions Liraglutide added to glimepiride was well tolerated and provided improved glycaemic control and favourable weight profile.     

Effects of liraglutide on cardiovascular risk biomarkers in patients with type 2 diabetes and albuminuria: A sub‐analysis of a randomized,placebo‐controlled,double‐blind,crossover trial

We assessed the effects of liraglutide treatment on five cardiovascular risk biomarkers, reflecting different pathophysiology: tumour necrosis factor (TNF)‐α; soluble urokinase plasminogen activator receptor (suPAR); mid‐regional pro‐adrenomedullin (MR‐proADM); mid‐regional pro‐atrial natriuretic peptide (MR‐proANP); and copeptin, in people with type 2 diabetes with albuminuria. In a randomized, double‐blind, placebo‐controlled, crossover trial we enrolled people with type 2 diabetes and persistent albuminuria (urinary albumin‐to‐creatinine ratio [UACR] >30 mg/g) and estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m². Participants received liraglutide (1.8 mg/d) and matched placebo for 12 weeks, in random order. The primary endpoint was change in albuminuria; this was a prespecified sub‐study. A total of 32 participants were randomized, of whom 27 completed the study. TNF‐α level was 12% (95% confidence interval [CI] 3; 20) lower after liraglutide treatment compared with placebo (P = .012); MR‐proADM level was 4% (95% CI 0; 8) lower after liraglutide treatment compared with placebo (P = .038), and MR‐proANP level was 13% (95% CI 4; 21) lower after liraglutide treatment compared with placebo (P = .006). In the present study, we showed anti‐inflammatory effects of liraglutide treatment, reflected in reductions in levels of TNF‐α and MR‐proADM, while the reduction in MR‐proANP levels may represent a clinically relevant benefit with regard to heart failure.     

2‐Methoxyestradiol ameliorates glucose tolerance with the increase in β‐cell mass in db/db mice

Aims/Introduction: 2‐Methoxyestradiol (2ME) is an estradiol metabolite with little estrogenic activity. Previous data identified its anti‐carcinogenic properties and possible cardiovascular benefits. However, its effect on diabetes mellitus has not been fully elucidated. The aim of the present study was to determine the effects of 2ME on glucose metabolism in the diabetic state. Materials and Methods: To evaluate the effects of 2ME, pellets of two different doses of the drug were implanted into female db/db mice at the age of 5 weeks. Intraperitoneal glucose tolerance test and insulin tolerance test were carried out at the age of 8 weeks. The pancreas was harvested for morphological analysis and β‐cell function at the age of 9 weeks. Results: 2ME improved random blood glucose levels and glucose tolerance with increases in insulin levels during an intraperitoneal glucose tolerance test. Insulin sensitivity judged by an insulin tolerance test was comparable in the low‐ and high‐dose 2ME groups and the control group. Although glucose‐stimulated insulin secretion in isolated islets was comparable among the three groups, β‐cell mass in 2ME‐treated groups was higher than the control group. In the 2ME‐treated groups, the number of Ki67‐positive cells in islets was higher, whereas the number of cleaved caspase‐3‐positive cells was comparable with the control. Conclusions: 2ME ameliorates glucose tolerance by promoting the proliferation of β‐cell mass in db/db mice. Our data suggests its potential clinical usefulness as a disease‐modifying drug for type 2 diabetes mellitus. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2010.00087.x, 2011)     

Strong association between insulin resistance in liver and skeletal muscle in non‐diabetic subjects

Objective To examine the association between insulin resistance in skeletal muscle and liver in non‐diabetic subjects. Research design and methods A total of 182 Mexican American subjects without Type 2 diabetes underwent an oral glucose tolerance test and euglycaemic–hyperinsulinaemic clamp performed with ³[H]glucose. Insulin sensitivity in skeletal muscle was measured as the insulin‐stimulated rate of total glucose disposal during the insulin clamp divided by steady‐state plasma insulin concentration (TGD/SSPI). Hepatic insulin resistance was measured as the product of basal hepatic glucose production and fasting plasma insulin concentration (HGP × FPI). Results Hepatic insulin resistance was strongly correlated (r = 0.68, P < 0.0001) with skeletal muscle insulin resistance. Thirty‐eight per cent of subjects had increased insulin resistance in both liver and skeletal muscle, while 39% were insulin sensitive in both skeletal muscle and liver. Twenty‐three per cent of subjects were discordant for muscle and hepatic insulin resistance (P < 0.0001). Subjects with increased skeletal muscle insulin resistance had a higher 2‐h plasma glucose concentration, greater incremental area under the plasma glucose concentration curve, lower fasting plasma insulin concentration and lower rate of basal hepatic glucose production compared with subjects with increased insulin resistance in liver. Conclusion In non‐diabetic subjects, insulin resistance in skeletal muscle is an important determinant of the fasting and 2‐h plasma glucose concentrations and strongly correlates with hepatic insulin resistance.     

Insulin‐secretion capacity in normal glucose tolerance,impaired glucose tolerance,and diabetes in obese and non‐obese Japanese patients

Aims/Introduction: Pronounced reduction of insulin secretion in response to a rise in glucose level has been reported in Japanese patients compared with Caucasian patients, but the mean body mass index (BMI) is also lower in Japanese patients. As BMI is a determinant of insulin secretion, we examined insulin‐secretion capacity in obese and non‐obese Japanese patients. Materials and Methods: Using the oral glucose tolerance test (OGTT), we estimated the insulin‐secreting capacity in obese (BMI ≥ 25) and non‐obese (BMI < 25) Japanese patients, including 1848 patients with normal glucose tolerance (NGT), 321 patients with impaired glucose tolerance (IGT) and 69 diabetes (DM) patients. Results: The insulinogenic index (I.I.), calculated by dividing the increment in serum insulin by the increment in plasma glucose from 0 to 30 min during OGTT, decreased from NGT to IGT and to DM in patients with and without obesity. In patients with NGT, IGT and DM, the I.I. values of obese patients were higher than those of the non‐obese patients. The peak of insulin concentration in OGTT appeared at 60 min in NGT and at 120 min in IGT in both obese and non‐obese patients, but in DM it was observed at 120 min in obese patients and at 60 min in non‐obese patients. Conclusions: These results show that early‐phase insulin secretion in obese Japanese patients is higher than in non‐obese patients in all stages of glucose tolerance, and delayed insulin‐secretion capacity is also conserved in obese Japanese patients, even in IGT and DM, which is similar to Caucasian patients. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2011.00180.x , 2011)     

Plasma gastric inhibitory polypeptide and glucagon‐like peptide‐1 levels after glucose loading are associated with different factors in Japanese subjects

Aims/Introduction: Gastric inhibitory polypeptide (GIP) and glucagon‐like peptide‐1 (GLP‐1) are major incretins that potentiate insulin secretion from pancreatic β‐cells. The factors responsible for incretin secretion have been reported in Caucasian subjects, but have not been thoroughly evaluated in Japanese subjects. We evaluated the factors associated with incretin secretion during oral glucose tolerance test (OGTT) in Japanese subjects with normal glucose tolerance (NGT). Materials and Methods: We measured plasma GIP and GLP‐1 levels during OGTT in 17 Japanese NGT subjects and evaluated the factors associated with GIP and GLP‐1 secretion using simple and multiple regression analyses. Results: GIP secretion (AUC‐GIP) was positively associated with body mass index (P < 0.05), and area under the curve (AUC) of C‐peptide (P < 0.05) and glucagon (P < 0.01), whereas GLP‐1 secretion (AUC‐GLP‐1) was negatively associated with AUC of plasma glucose (P < 0.05). The insulinogenic index was most strongly associated with GIP secretion (P < 0.05); homeostasis model assessment β‐cell was the most the strongly associated factor in GLP‐1 secretion (P < 0.05) among the four indices of insulin secretion and insulin sensitivity. Conclusions: Several distinct factors might be associated with GIP and GLP‐1 secretion during OGTT in Japanese subjects. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2010.00078.x, 2011)     

Effects of dapagliflozin on insulin‐requirement,glucose excretion and ß‐hydroxybutyrate levels are not related to baseline HbA1c in youth with type 1 diabetes

Youth with type 1 diabetes (T1D) infrequently achieve HbA1c targets. Therefore, this placebo‐controlled, randomized, crossover study was set up to assess the safety, effect and pharmacokinetics of a single dose of 10 mg dapagliflozin (DAPA) as add‐on to insulin in relationship to HbA1c in youth. A total of 33 youths (14 males, median age 16 years, diabetes duration 8 years) were included and stratified into 3 baseline HbA1c categories (<7.5%, 7.5%‐9.0% or >9.0; n = 11 each). During the study period of 24 hours, intravenous insulin administration and glucose‐infusion kept blood glucose levels at 160 to 220 mg/dL. DAPA reduced mean insulin dose by 13.6% ( P < .0001 by ANOVA) and increased urinary glucose excretion by 610% (143.4 vs 22.4 g/24 h; P < .0001), both irrespective of baseline HbA1c. Six independent episodes in 6 patients with plasma ß‐hydroxybutyrate levels between ≥0.6 and <1.0 mmol/L were observed after liquid meal challenges, 5 episodes in the DAPA group and 1 in the placebo group. This study provides a proof‐of‐concept, irrespective of preexisting HbA1c levels, for adjunct SGLT2‐inhibitor therapy in the paediatric age group by lowering insulin dose and increasing glucose excretion.