Progressive loss of beta cell function is the main determinant of progression from normal glucose tolerance (NGT) to impaired glucose tolerance (IGT), a US study has found.

Glucose intolerance is a continuum and declines progressively throughout the entire range of NGT and IGT, say R DeFronzo, from the University of Texas Health Science Center in San Antonio, USA.

They note that there has been a lack of large studies characterizing the pathophysiological disturbances responsible for IGT and employing sophisticated measures of beta cell function and insulin sensitivity.

For their study, the researchers examined the determinants of oral glucose tolerance in 602 people with IGT who participated in the Actos Now for Prevention of Diabetes (ACT NOW) study, along with 115 people with NGT and 50 with impaired fasting glucose (IFG) who were identified during screening. Insulin secretion and insulin sensitivity indices were derived from plasma glucose and insulin during an oral glucose tolerance test (OGTT).

At baseline, fasting plasma glucose, 2-hour postprandial glucose (OGTT) and hemoglobin A_1c were, on average, 5.8 mmol/l, 10.5 mmol/l and 5.5%, respectively, in participants with IGT.

IGT was associated with defects in early and total insulin secretion and in insulin sensitivity. IGT patients who had a 2-hour plasma glucose level of 7.8 “8.3 mmol/l, had a 63% decrease in scores on the insulin sensitivity/insulin resistance index compared with NGT participants. Moreover, this defect worsened progressively as 2-hour plasma glucose levels rose, with a 73% decrease in those with levels of 8.9 “9.94 mmol/l and an 80% decrease in those with levels of 10.0 “11.05 mmol/l.

The Matsuda insulin sensitivity index was significantly reduced by 40% in IGT compared with NGT participants. In multivariate analysis, beta cell function was the primary determinant of glucose area under the curve during OGTT, explaining 62% of the variance.

Writing in the journal Diabetologia, the researchers conclude: “The two major pathophysiological disturbances ” insulin resistance and beta cell dysfunction ” declined progressively over the range of NGT and IGT. Participants in the upper tertile of IGT lost approximately 80% of their beta cell function compared with participants with NGT.”

They comment: “The establishment of defined glucose cut-off points for the diagnosis of IGT and Type 2 diabetes is somewhat arbitrary and needs to be re-evaluated.”

MedWire (www.medwire-news.md) is an independent clinical news service provided by Current Medicine Group, a trading division of Springer Healthcare Limited. © Springer Healthcare Ltd; 2009

Free abstract

Add-on treatment with liraglutide improves glycemic control without causing major hypoglycemia or weight gain, a trial in patients with Type 2 diabetes has found.

The study suggests that liraglutide, a new once-daily human analogue of glucagon-like peptide-1 (GLP-1), may be a useful new treatment in patients who are suboptimally controlled on sulfonylurea monotherapy.

Liraglutide mimics the glucoregulatory actions of endogenous GLP-1 by targeting the incretin system, and has been shown to bring about sustained improvements in glycemic control, beta-cell function, and weight, with a low risk for hypoglycemia.

The present study evaluated the safety and efficacy of liraglutide in 264 Japanese patients with a mean body mass index of 24.9 kg/m² and mean glycated hemoglobin (HbA1c) level of 8.4%. They were randomly assigned to take liraglutide 0.6 mg/day, liraglutide 0.9 mg/day, or placebo, each added to sulfonylurea monotherapy, for 24 weeks.

At the end of the study period, HbA1c had fallen by 1.56%, 1.46%, and 0.40% in the liraglutide 0.9 mg/day, 0.6 mg/day, and placebo groups, respectively. The differences between active treatment and placebo were statistically significant.

Furthermore, a significantly greater proportion of patients in the liraglutide treatment groups had achieved target HbA1c levels of less than 7.0% (46.5% with lower-dose and 71.3% with higher-dose liraglutide versus 14.8% with placebo).

Liraglutide treatment was also associated with significant reductions in fasting plasma glucose and postprandial plasma glucose.

Finally, overall safety was comparable among the three groups. There were no major hypoglycemic episodes in any group and body weight was unchanged in both liraglutide groups, whereas mean weight fell by 1.12 kg in the placebo group.

Writing in the journal Diabetes, Obesity, and Metabolism, Kohei Kaku (Kawasaki Medical School, Okayama, Japan) and fellow investigators say that liraglutide provides “superior glycemic control” compared with placebo, offering sustained and significant reductions in HbA1c in a dose-dependent manner.

They conclude: “In Japanese subjects with Type 2 diabetes, once-daily liraglutide administered at 0.9 mg/day is both effective and well-tolerated in combination with sulfonylurea agents, demonstrating significantly greater glycemic control than sulfonylurea monotherapy, without causing adverse weight gain or loss.”

A 28-week follow-up study of the study participants is ongoing and will provide long-term safety and efficacy data.

MedWire (www.medwire-news.md) is an independent clinical news service provided by Current Medicine Group, a trading division of Springer Healthcare Limited. © Springer Healthcare Ltd; 2010

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