Results from a proof-of-concept study show that ghrelin reduces glucose-stimulated insulin secretion and subsequently lowers plasma glucose in healthy nondiabetic individuals.

“Our findings raise the possibility that endogenous ghrelin has a role in physiologic insulin secretion, and that ghrelin antagonists could improve ?-cell function,” say Jenny Tong (University of Cincinnati, Ohio, USA) and colleagues.

For their study, the researchers recruited 12 healthy, nondiabetic volunteers (eight men, four women) aged 18-55 years and with a body mass index (BMI) between 18 and 29 kg/m².

The participants were given an infusion of saline, or ghrelin 0.3, 0.9, or 1.5 nmol/kg/hour for more than 65 minutes on four separate occasions separated by at least 5 days. The team then measured fasting insulin and glucose, and intravenous glucose tolerance (glucose disappearance constant; Kg) and the acute insulin response to intravenous glucose (AIRg).

Tong and co-workers found that, compared with saline, the three ghrelin infusions did not significantly change fasting plasma insulin or glucose levels.

However, AIRg was significantly decreased by the three concentrations of ghrelin to 1478, 1419, and 1120 pmol/l after the ghrelin 0.3, 0.9, and 1.5 nmol/kg/hour infusions, respectively, compared with 2152 pmol/l with saline.

C-peptide concentration was also suppressed in the three ghrelin groups versus saline, at a respective 4.1, 4.2, and 3.6 nmol/l versus 5.8 nmol/l. Kg was significantly reduced after ghrelin 0.3 and 1.5 nmol/kg/hour infusions to 1.00 and 1.05 %change/min, respectively, compared with 1.40 %change/min with saline.

“Preclinical studies support a role for ghrelin to regulate glucose metabolism as well as energy balance and growth hormone secretion,” write the authors in the journal Diabetes.

“However, the effect of ghrelin on insulin secretion and glucose tolerance in humans has not been clearly established in the limited number of studies reported previously.”

Tong et al conclude: “Our study demonstrates that exogenous ghrelin markedly reduces the first-phase insulin and C-peptide responses to intravenous glucose in healthy humans.”

They add that ghrelin antagonists have the potential to improve ?-cell function and say they could provide a novel drug target for the treatment of Type 2 diabetes.

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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Intravenous (iv) insulin does not prevent rises in inflammatory or oxidative stress markers after percutaneous coronary intervention (PCI) in patients with diabetes compared with standard insulin treatment, study findings suggest.

Diabetic patients who have undergone PCI are usually managed with insulin administered subcutaneously, which generally fails to attain plasma glucose targets, note the researchers from Hospital de Clínicas de Porto Alegre in Brazil.

They examined the value of iv insulin in an open-label, randomized trial in 70 patients with diabetes and stable coronary artery disease who had a mean age of 60.5 years and had undergone angioplasty with bare metal stent implantation.

Participants were randomly assigned to a standard approach, where hyperglycemia was managed with subcutaneous regular insulin as needed with a target of 250 mg/dl or less, or to 24 hours of continuous iv insulin infusion, targeting glucose levels of 80 to 100 mg/dl in premeal periods and lower than 140 mg/dl in random glucose measurements.

Blood samples were collected immediately after PCI and again 24 hours later.

At 24 hours after PCI, mean glycemia was significantly lower and insulinemia higher among patients receiving iv versus subcutaneous insulin, report Beatriz D’Agord Schaan and co-workers in the Journal of Clinical Endocrinology and Metabolism.

Levels of the inflammatory marker C-reactive protein doubled in the 24 hours after PCI in both groups, and interleukin-6 levels doubled with iv-insulin and tripled with standard treatment, but differences between the groups were not statistically significant.

Endothelin 1 levels were approximately 30% higher 24 hours after PCI compared with immediately after the procedure in both groups, with no significantly between-group differences.

The treatment groups also did not significantly differ in protein oxidation, with the plasma carbonyl content not significantly changing in either group in the 24 hours after PCI and total serum antioxidant status rising in both.

The authors conclude that despite the fact that “continuous iv insulin effectively increased insulin levels and prevented hyperglycemia, a clear rise in inflammatory markers was observed after PCI.”

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

Free abstract

The prevalence of Type 2 diabetes in Iranian children with childhood obesity is low, but around one in 20 show evidence of impaired fasting glucose (IFG), results of a cross-sectional study show.

Iran is experiencing a period of rapid urbanization and modernization, a process that is often associated with a move toward a less physically active population, and one that is less likely to have a healthy diet. The country is consequently facing a rapid growth in the prevalence of non-communicable diseases such as Type 2 diabetes.

Obesity is a major risk factor for developing Type 2 diabetes but, until now, few data were available on the prevalence of IFG and Type 2 diabetes in the high-risk group of obese Iranian children.

Roya Kelishadi (Isfahan University of Medical Sciences, Iran) and co-workers identified 1109 overweight and obese children from a population of 7554 students in one Iranian city. Of these, 672 were randomly selected for screening.

Fasting plasma glucose was used as the screening test, with IFG diagnosed if levels were between 100 and 125 mg/dl and Type 2 diabetes diagnosed if levels were greater than 125 mg/dl. In children with IFG, an oral glucose tolerance test was performed and insulin levels measured.

Among the 672 overweight and obese children screened, there was only one documented case of Type 2 diabetes, whereas 31 were diagnosed with IFG. The overall prevalence of IFG was 4.61%, affecting 2% of children aged 6 to 10 years and 5% of those aged 10.1 to 19 years. Insulin resistance was detected in six participants with IFG.

The body mass index of obese students was significantly higher in those with IFG (29.9 kg/m²) than in those with normal fasting plasma glucose (27.4 kg/m²), but there was no significant difference in the lipid profile between individuals with and without IFG.

As obesity is an emerging and escalating problem in Middle Eastern countries, the authors suggest that prevention and control of childhood obesity should be considered as a national health priority, and preventive measures should be implemented early in life.

“Dietary change and encouraging physical activity, and regular screening of fasting plasma glucose should be considered in obese children who are prone to Type 2 diabetes and other chronic diseases,” they conclude in the journal Pediatric Diabetes.

MedWire (www.medwire-news.md) is an independent clinical news service provided by Current Medicine Group, a part of Springer Science+Business Media. © Current Medicine Group Ltd; 2009

Free abstract

Vildagliptin is an effective and well-tolerated add-on therapy to glimepiride for the treatment of patients with Type 2 diabetes, report Japanese researchers.

The dipeptidyl peptidase-4 inhibitor vildagliptin has previously been shown to significantly improve glycemic control in Type 2 diabetics when added to metformin therapy, as reported by MedWire News.

In the current study, Matthew Goodman (Novartis Pharmaceuticals, Horsham, UK) and colleagues assessed the efficacy of adding vildagliptin (100 mg/day) to the sulfonylurea glimepiride (1 mg/day or more) in Japanese patients with Type 2 diabetes and inadequate glycemic control.

The study took place over 12 weeks, during which time 102 patients were randomly assigned to take vildagliptin and 100 were randomly assigned to take placebo in addition to their existing dose of glimepiride. A total of 99 and 96 patients in the respective groups completed the study.

At baseline, the mean glycated hemoglobin (HbA1c) was 7.9% and average fasting plasma glucose (FPG) was 163.8 mg/dl.

At study completion, HbA1c had decreased by 1.0% in the vildagliptin group compared with just 0.1% in the placebo group, a significant difference.

In addition, 45.0% of patients treated with vildagliptin achieved an HbA1c of 6.5% or below compared with only 3.0% of patients in the placebo group.

The adjusted mean change in FPG at study completion was a 20.9 mg/dl decrease in vildagliptin-treated patients versus a 6.3 mg/dl increase in the placebo group.

Adverse events occurred at a similar frequency in the vildagliptin and placebo groups, at 59.8% and 57.0%, respectively. The corresponding rates of serious adverse events, suspected drug-related adverse events, and discontinuation due to adverse events, were 0.0% versus 2.0%, 21.6% versus 23.0%, and 1.0% versus 3.0%. Two vildagliptin- and one placebo-treated patient experienced hypoglycemia during the study.

Goodman and co-authors conclude that vildagliptin 100 mg/day is “an efficacious and well tolerated addition to pharmacotherapy in the management of diabetes in Japanese patients with Type 2 diabetes mellitus.”

The results of this study are published in the journal Diabetes Research and Clinical Practice.

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

Free abstract

MedWire Links
Vildagliptin ‘promising’ adjunct to metformin
Vildagliptin effective as thiazolidinediones as metformin add-on

Study findings presented at the American
Diabetes Association (ADA) 2010 Scientific Sessions demonstrate
that Technosphere (MannKind, Valencia, California, USA) inhaled
prandial insulin combined with bedtime insulin glargine is
noninferior to conventional twice daily biaspart insulin (BIAsp30)
in patients with Type 2 diabetes and poor glycemic control.

Previous attempts to develop an effective inhaled insulin
treatment have been only moderately successful and the first
version to be approved by the US Food and Drug Administration was
discontinued in 2007.

From baseline, the technosphere group achieved a mean reduction
in fasting plasma glucose of 2.0 mmol/l compared with 1.0 mmol/l in
the biaspart insulin group, a statistically significant between
group difference.

In addition, change in glycated hemoglobin (HbA1c) with inhaled
insulin plus insulin glargine over the study period was
non-inferior to that of conventional insulin treatment, at -0.68%
versus -0.76%.

The 211 patients who were assigned to the inhaled insulin group
and completed the 52-week study also had significantly lower weight
gain than the 237 who were taking biaspart insulin, at 0.9 versus
2.5 kg, and experienced less hypoglycemia, at 31% versus 49%.

Apart from transient cough, which occurred in 33% of those
treated with inhaled insulin compared with only 6% of the insulin
biaspart group, the adverse event profile for technosphere was
similar to that of conventional insulin therapy. Serious adverse
events were reported by 11% and 9% of the inhaled insulin and
insulin biaspart groups, respectively.

The results were presented at the ADA meeting in Orlando,
Florida, by co-investigator Daniel Lorber (Diabetes Care and
Information Center, Flushing, New York, USA).

He concluded: “Our findings demonstrate that technosphere
insulin plus glargine alone, or used in combination with an oral
agent such as metformin, is an effective alternative to
conventional insulin therapy using 70/30 biaspart insulin in
uncontrolled Type 2 diabetes.

“We believe that the use of technosphere insulin in combination
with basal insulin provides comparable HbA1c control [to
conventional insulin therapy] with less weight gain and lower rates
of hypoglycemia in patients with Type 2 diabetes.”

The study was published in The Lancet to coincide with
the conference. In an accompanying commentary article, Clifford
Bailey (Aston University, Birmingham, UK) and Anthony Barnett
(University of Birmingham, UK) cautioned: “Potential safety
concerns must await more extensive and longer evaluation, including
further details about the manner in which the inhaled insulin
traverses the alveoli.”

They concluded: “The opportunity for convenient inhaled bolus
insulin, to facilitate complex insulin-delivery regimens, will be
welcomed by some patients. For now, we say: proceed with
caution.”

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

Free abstract

Oxidized low-density lipoprotein (LDL) is associated with both Type 2 diabetes- and obesity-related traits in Black and White individuals, results from a large prospective study show.

Oxidative stress is thought to play an important role in the development of many pathological conditions.

Wen-Chi Hsueh (University of California, San Francisco, USA) and co-workers examined data from the Health, Aging, and Body Composition (Health ABC) Study to determine whether plasma oxidized LDL, a commonly used marker for oxidative stress, is involved in the development of Type 2 diabetes- and obesity-related traits.

Health ABC recruited 3075 men and women aged 70??”79 years; 41.6% of the study population was Black and 51.6% were female. Baseline examinations occurred during 1997??”1998 and participants were examined annually for 7 years.

In the present analysis, 2985 participants with baseline measurement of oxidized LDL were examined for six Type 2 diabetes-related traits (Type 2 diabetes status, glycated hemoglobin [HbA1c], fasting plasma glucose, insulin, adiponectin, and homeostasis model assessment of insulin resistance [HOMA-IR]), and six obesity-related traits (obesity status, body mass index [BMI], leptin, percent body fat, visceral, and subcutaneous fat mass) using logistic and linear regression models.

At baseline, oxidized LDL was positively associated with all Type 2 diabetes-related traits except adiponectin, with which it was negatively associated. It was also associated with obesity and its related traits BMI, percent body fat, and visceral fat.

After 7 years of follow-up, the investigators found no significant association between oxidized LDL at baseline and incident Type 2 diabetes in either Blacks or Whites.

For obesity-related traits, baseline oxidized LDL levels remained significantly associated with risk for obesity, higher BMI and percent total body fat in both races at 7 years. The authors found that the level of the association with obesity-related traits at baseline and follow-up was much greater in Blacks than Whites.

Furthermore, oxidized LDL was significantly associated with percent change in Type 2 diabetes- and obesity-related traits in White but not Black people. “Why this association was significant in Whites but not in Blacks is difficult to interpret and warrants further investigation,” note the authors.

“Our findings suggest the need for more investigations of oxidative stress in the etiology of Type 2 diabetes and its implication in Type 2 diabetes prevention and treatments,” they conclude in the journal Diabetes/Metabolism Research and Reviews.

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

A high-mix biphasic insulin aspart (BIAsp) insulin three-times-daily regimen achieves lower blood glucose levels during the day for Type 2 diabetics than a twice-daily premix human insulin regimen, researchers report.

Meal-related glucose excursions can be a problem with both twice-daily injections of premixed (biphasic) human insulin and premixed insulin analogues.

To investigate approaches to improving postmeal blood glucose that do not involve moving to a four injection (mealtime plus basal) regimen, Umesh Dashora and colleagues (Newcastle University, Newcastle, UK) compared BIAsp three times a day (using 70/30 rapid acting: protamine complexed, high-mix) with biphasic human insulin (30/70) twice daily in adults with Type 2 diabetes already treated with insulin.

In the 60-day crossover study, BIAsp three times daily was administered as BIAsp 70/30 before breakfast and lunch, and BIAsp 30 before dinner to ensure sufficient basal insulin overnight. The human premix insulin was given before breakfast and dinner.

The total daily insulin dose of the BIAsp regimen was 110% of the human premix regimen and the doses were not changed during the study.

Blood glucose levels and insulin doses were reviewed every 15 days. In between, participants performed daily self-monitoring of blood glucose before meals. A 24-hour in-patient plasma glucose assessment was performed at the end of each 30-day treatment period.

The results, reported in the journal Diabetes, Obesity and Metabolism, show that the average 24-hour plasma glucose did not differ statistically between BIAsp and human premix regimens (7.3 mmol/l vs 7.7 mmol/l, respectively), but daytime average glucose concentration was 0.9 mmol/l lower with BIAsp (8.3 mmol/l vs 9.2 mmol/l, respectively).

BIAsp was also associated with lower mealtime serum glucose excursions than human premix and significantly less glucose excursions above 7.0 mmol/l.

The authors suggest that these observations might be clinically relevant, particularly as they relate to a reduction in the peaks of glucose after meals, which are the highest and most harmful glucose levels of the day.

The proportion of participants experiencing confirmed hypoglycemic episodes was similar between regimens (42% vs 43%), but the authors note that the study lacks power to provide reliable estimates of hypoglycemia.

“This study suggests that a thrice-daily analogue-based BIAsp regimen using high ratio free: protamine-complexed insulin with about 10% daytime insulin dose increase can trim postlunch glucose excursions when compared with a conventional human premix regimen,” conclude the authors.

“However, the utility of and safety of the regimen would need longer study to define which groups of people with Type 2 diabetes might benefit,” they add.

MedWire (www.medwire-news.md) is an independent clinical news service provided by Current Medicine Group, a part of Springer Science+Business Media. © Current Medicine Group Ltd; 2009

Free abstract

Results from a randomized trial of the bile acid sequestrant colestilan show that it is effective for improving glycated hemoglobin (HbA1c) and reducing low-density lipoprotein (LDL) cholesterol in Type 2 diabetics.

“Diabetes and frequently complicating hypercholesterolemia are known independent risk factors for onset and progression of cardiovascular and cerebrovascular events,” say Kazuoki Kondo (Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan) and co-workers.

In this study, the team recruited 183 patients with Type 2 diabetes with a fasting plasma glucose of 7.2??”11.1 mmol/l and an HbA1c of 7.0% or more. They were randomly assigned to receive either colestilan 4.5 g/day or placebo for 12 weeks.

Writing in the journal Diabetes, Obesity and Metabolism, the team report that at 12 weeks, colestilan had significantly reduced both HbA1c and fasting plasma glucose by 0.9% and 1.2 mmol/l, respectively, but no significant reductions in fasting insulin were observed.

A significant 22.5% reduction in LDL cholesterol was also achieved by the treatment group versus placebo at 12 weeks.

The most frequently observed adverse events were constipation, nasopharyngitis, and eczema, which occurred in 13.0%, 19.6%, and 5.4% of the colestilan-treated patients, respectively, versus a corresponding 4.4%, 13.2%, and 0.0% of the placebo-treated group. No cases of hypoglycemia or death occurred during the study.

“Colestilan when given alone alleviates markers of hyperglycemia and dyslipidemia in patients with Type 2 diabetes,” summarize the authors.

“This drug might therefore be expected to exert diverse beneficial effects in a wide range of patients with multiple cardiovascular risk factors,” they add.

MedWire (www.medwire-news.md) is an independent clinical news service provided by Current Medicine Group, a part of Springer Science+Business Media. © Current Medicine Group Ltd; 2009

Free abstract

Intensifying a dual oral agent regimen of metformin plus insulin secretagogue by adding pioglitazone significantly improves glycemic control in comparison with adding placebo in patients with baseline glycated hemoglobin (HbA1c) levels of less than 8.5%, albeit with increased weight gain, French researchers report.

“Early combination therapy, including the use of metformin plus a thiazolidinedione and a sulfonylurea, is gaining increasing acceptance and may offer some advantages over the earlier introduction of insulin,” explain Guillaume Charpentier (Centre Hospitalier Sud Francilien, Corbeil Essonnes) and co-workers.

But they add that “the question remains as to when the optimal time is to introduce a third oral agent versus insulin in failing dual therapy.“

To investigate the glycemic effects of triple oral therapy that includes pioglitazone versus dual oral therapy plus placebo, the researchers randomly assigned 299 patients with Type 2 diabetes inadequately controlled with metformin and an insulin secretagogue to add-on pioglitazone 30 mg/day or placebo for 7 months.

For the last 4 months of the study the dose of pioglitazone was dependent on HbA1c levels: 30 mg pioglitazone if HbA1c levels were less than or equal to 6.5%, and up to 45 mg if HbA1c levels were greater than 6.5%.

Presenting the findings in the journal Diabetes, Obesity and Metabolism, the authors report that after 7 months the addition of pioglitazone to existing metformin and a sulfonylurea or glinide resulted in a between-group difference in HbA1c levels of 1.18% in favor of pioglitazone. The thiazolidinedione reduced mean HbA1c level from a baseline of 8.2% to a level of 7.3%, whereas in the placebo group there was a slight increase to 8.4%. Decreases in fasting plasma glucose were also significantly greater in the pioglitazone group.

“Almost half (44.4%) of the patients in the pioglitazone group who had a baseline HbA1c level of less than 8.5% achieved the HbA1c target of less than 7.0% by final visit compared with 4.9% in the placebo group,” note the authors.

When baseline HbA1c levels were greater than 8.5%, 13% of patients achieved the HbA1c target of less than 7.0% in the pioglitazone group compared with none in the placebo group. This suggests that the addition of a thiazolidinedione to failing dual oral therapy is most effective when baseline HbA1c is less than 8.5% and that insulin should be considered in patients with higher levels, say the authors.

In agreement with other studies, pioglitazone was associated with improvements in indices of beta-cell function including homeostasis model assessment of beta-cell function (HOMA-B).

Mean body weight increased by 3.9 kg in the pioglitazone group compared with no change in the placebo group, but overall tolerability was good apart from an increased incidence of edema with pioglitazone.

“Future studies should address the potential benefits of early triple therapy with a thiazolidinedione in terms of weight gain, compliance, and overall tolerability compared with early insulin therapy,” the authors conclude.

MedWire (www.medwire-news.md) is an independent clinical news service provided by Current Medicine Group, a part of Springer Science+Business Media. © Current Medicine Group Ltd; 2009

Free abstract