Original ArticleWeight gain and changes in plasma adiponectin and leptin concentrations after 12-month insulin intensive therapy for Chinese male patients with newly diagnosed type 2 diabetes
Introduction
In patients with type 2 diabetes, tight glycaemic control with intensive insulin therapy (IIT) including subcutaneous injection of insulin 3 or 4 times daily, has been associated with weight gain, especially during the first year following initiation of treatment [1], [2], [3]. Several explanations for the mechanism(s) by which IIT causes weight gain have been discussed, including hyperphagia following hypoglycaemic stimuli, alteration of physical activity level, the anabolic and/or lipogenic actions of insulin, and/or decreased glycosuria [1], [4], [5], [6]. However, it has been proven difficult to establish the mechanisms underlying weight gain in human studies due to the complex nature of potential mechanisms [7]. Recently, Balkau et al. [8] found that a high baseline A1 C and insulin dose requirements were independently associated with greater weight gain in people with type 2 diabetes starting on insulin. The overall conclusion has been that the cause(s) of weight gain associated with IIT remain unclear.
Adiponectin is exclusively expressed from adipocytes, and circulates in human blood as multiple isoforms, trimeric low molecular weight (LMW), hexameric middle molecular weight (MMW), and high molecular weight (HMW) forms. All these forms have shown distinct biological effects through differential activation of downstream signalling cascades [9]. Studies in humans have revealed that circulating adiponectin levels decreased in patients with type 2 diabetes and in most obese human subjects, and significantly increased in patients with type 2 diabetes following treatment with glimepiride, peroxisome proliferator-activated receptor-γ agonists and various hypoglycaemic therapy and antihypertensive agents and in patients with obesity with loss of weight [10], [11], [12], [13]. Also, IIT for improving glycaemic control in type 2 diabetes patients resulted in a modest, but statistically significant, increment in adiponectin in the short-time [14]. However, few studies have examined whether long-term IIT would affect circulating adiponectin levels [15]. Particularly, little information was given in regard to the isoform(s) of adiponectin measured in the study. In addition, adiponectin is known to cause directly weight reduction by regulating lipid and glucose metabolism in mice [16]. Furthermore, both central and peripheral adiponectin administration have been associated with reduced body weight via either food intake suppression or increased energy expenditure [17], but very little attention has been directed toward possible weight-regulating functions in human. Recently, Hivert et al. [18] reported that adiponectin (total and HMW) levels are associated with subsequent weight gain in healthy women participating in the Nurses’ Health Study over 4 years of prospective follow-up.
In humans, leptin, another adipokine, is produced predominantly by adipose tissue and plays a pivotal role in the regulation of appetite and body weight. In leptin-deficient obese mice and humans, administration of leptin reduces food intake and raises energy expenditure resulting in weight loss [19], [20]. However, plasma leptin concentrations were shown to be elevated in obese individuals, implying the presence of leptin resistance, which is characterised by deficient regulation of energy balance of leptin [21] and can lead to aggravated weight gain in the condition of exposure to a high-fat diet [22]. Many studies have revealed that elevated leptin levels and body weight may occur after insulin-induced improved glycaemic control in subjects with type 2 diabetes, and the increments in leptin levels were correlated with the increments in weight and body mass index (BMI) in patients on insulin monotherapy [23], [24], [25], [26], [27]. Aas et al. suggested that the increase in serum leptin-levels (so called hyperleptinemia) observed during insulin treatment in type 2 diabetes may induce leptin resistance, contributing to weight gain [23].
Based on the background above, we hypothesised the changes in plasma adiponectin and leptin levels under the same condition are associated with subsequent weight change in patients with type 2 diabetes with long-term IIT. To test this hypothesis, we examined the effects of IIT in Chinese male patients who are newly diagnosed with type 2 diabetes in 12 months, on circulating adiponectin and leptin levels and body weight including subcutaneous and visceral fat mass. We also assessed the relationship between changes in plasma adiponectin as well leptin concentrations and subsequent weight gain of these patients.
Section snippets
Materials and methods
From May 2009 to December 2011, totally 84 male patients with newly diagnosed type 2 diabetes were admitted to our hospital and wanted to be treated on an inpatient for education about their disease started IIT. All the patients met the following inclusion criteria: (A) fasting plasma glucose (FPG) concentration ≥11.1 mmol/L, and 2 h postprandial plasma glucose (2hPG) concentration ≥13.9 mmol/L (determined in the absence of hypoglycaemic agents); (B) age between 35 and 65 years; (C) urinary
Results
Overall 84 type 2 diabetes patients completed this study. Among these, twenty subjects experienced adverse events during the study period including 14 patients with hypoglycaemia, none of the patients developed severe hypoglycaemia, 4 patients with blurred vision, 2 patients with skin pruritus. All the adverse events were considered to be treatment-related.
Fig. 1(A), (B), (C) and (D) shows the profiles of FPG, 2hPG, HbA1c and the daily dose of insulin over 12 months after IIT, respectively. FPG
Discussion
The main finding in the present study was the significant correlation between the increases in plasma total, HMW adiponectin and leptin levels and the weight gain that accompanied IIT in male patients with newly diagnosed type 2 diabetes for 12 months, meanwhile satisfactory glycaemic control could be maintained (as reflected by a mean HbA1c of approximately 6.5%). After 12 months of IIT, the higher increments of total and HMW adiponectin levels from inclusion to the end of study were all
Disclosure
The authors declare that they have no competing interests.
Acknowledgments
This study was supported by the National TCM Clinical Research Base of Special Foundation (No. JDZX2012005) and the Chinese Society of Endocrinology (13061050490). We thank the participants of this study including the doctors, nurses, and researchers from the Department of Endocrinology in The First Affiliated Hospital of Anhui Medical University and Anhui Provincial key Laboratory of Endocrinology & Metabolism.
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These authors contributed equally.