Does des-acyl ghrelin improve glycemic control in obese diabetic subjects by decreasing acylated ghrelin levels?

Abstract

Objective: The objective of this study was to assess the effects of a continuous overnight infusion of des-acyl ghrelin (DAG) on acylated ghrelin (AG) levels and glucose and insulin responses to a standard breakfast meal (SBM) in eight overweight patients with type 2 diabetes. Furthermore, in the same patients and two additional subjects, the effects of DAG infusion on AG concentrations and insulin sensitivity during a hyperinsulinemic-euglycemic clamp (HEC) were assessed. Research design and methods: A double-blind, placebo-controlled cross-over study design was implemented, using overnight continuous infusions of 3 and 10 mg DAG/kg per h and placebo to study the effects on a SBM. During a HEC, we studied the insulin sensitivity. Results: We observed that, compared with placebo, overnight DAG administration significantly decreased postprandial glucose levels, both during continuous glucose monitoring and at peak serum glucose levels. The degree of improvement in glycemia was correlated with baseline plasma AG concentrations. Concurrently, DAG infusion significantly decreased fasting and postprandial AG levels. During the HEC, 2.5 h of DAG infusion markedly decreased AG levels, and the M-index, a measure of insulin sensitivity, was significantly improved in the six subjects in whom we were able to attain steady-state euglycemia. DAG administration was not accompanied by many side effects when compared with placebo. Conclusions: DAG administration improves glycemic control in obese subjects with type 2 diabetes through the suppression of AG levels. DAG is a good candidate for the development of compounds in the treatment of metabolic disorders or other conditions with a disturbed AG:DAG ratio, such as type 2 diabetes mellitus or Prader-Willi syndrome.

Response to inquiry by Gaylinn et al. on ‘Administration of UAG improves glycemic control in obese subjects with diabetes’

“…In a recent Letter to the Editor Gaylinn et al (1) discuss the outcomes of a study that we published in the European Journal of Endocrinology in which we reported that the administration of unacylated ghrelin (UAG) improves glycemic control in obese subjects with diabetes and (2) that this effect might be mediated by a decrease in acylated ghrelin (AG) levels in response to UAG administration (2). They comment that, while we clearly demonstrated the anti-diabetogenic potential of UAG, our observation that AG levels are suppressed may be an assay artefact.…”

“…Additionally, the blood samples in those two studies were stabilized in a slightly different way. In the study by Ozcan et al (2), whole blood was equilibrated in an acidic isotonic solution containing high concentration of AEBSF and NaF, whereas in Tong et al AEBSF was dissolved in the blood samples and only after preparation of plasma was the sample acidified. 4.…”

“…Consequently, we used a cautious title to the study: does des-acyl ghrelin improve glycemic control in obese diabetic subjects by decreasing AG levels? (2). …”

Ghrelin and Insulin Secretion in Humans: Not a Tale of Two Hormones?

“…Experimental AG administration commonly causes weight gain and hyperglycemia by enhancing food intake, fat deposition, and hepatic gluconeogenesis (3)(4)(5). A more comprehensive understanding of the metabolic impact of ghrelin has been recently allowed by the increasing appreciation of the independent, and generally more favorable, effects of its unacylated form (UAG), which does not increase food intake or circulating glucose in vivo (3,4,6). Although no specific UAG receptor has been yet identified, UAG coadministration may counteract the glucogenic effects of AG as well as AG-induced hyperglycemia (3,4,7), and positive or negative associations have been respectively reported in humans between AG or UAG and markers of whole-body insulin resistance (8).…”

“…Moreover, AG-UAG interactions should be systematically investigated in clinical conditions characterized by insulin resistance, when a decline in circulating UAG and higher AG-UAG ratios have been reported (3,4,8). Under these conditions, potential differential modulation by AG and UAG of additional regulators of insulin secretion should be also considered, including autonomic nervous signaling (13), circulating hormones such as growth hormone and cortisol (1,6,19), and dietary carbohydrate intake as shown by Tong et al (19). Finally, the well-demonstrated positive impact of both AG and UAG on b-cell survival and proliferation, leading to enhanced b-cell mass and higher circulating insulin in streptozotocin-induced type 1 diabetes models (10,20), poses important questions; longer-term interactions between altered insulin release and beneficial changes in b-cell mass should be directly investigated during longterm modification of ghrelin profile.…”