OBJECTIVE -Glucagon-like peptide-1 (GLP-1) has been proposed as a new treatment modality for type 2 diabetes. To circumvent the drawback of the short half-life of GLP-1, inhibitors of the GLP-1-degrading enzyme dipeptidyl peptidase IV (DPP IV) have been examined. Such inhibitors improve glucose tolerance in insulin-resistant rats and mice. In this study, we examined the 4-week effect of 1- [[[2-[(5-cyanopyridin-2-yl)amino]ethyl]amino]acetyl]-2-cyano-(S)-pyrrolidine (NVP DPP728), a selective, orally active inhibitor of DPP IV, in subjects with diet-controlled type 2 diabetes in a placebo-controlled double-blind multicenter study. -A total of 93 patients (61 men and 32 women), aged 64 Ϯ 9 years (means Ϯ SD) and with BMI 27.3 Ϯ 2.7 kg/m 2 , entered the study. Fasting blood glucose was 8.5 Ϯ 1.5 mmol/l, and HbA 1c was 7.4 Ϯ 0.7%. Before and after treatment with NVP DPP728 at 100 mg ϫ 3 (n ϭ 31) or 150 mg ϫ 5 (n ϭ 32) or placebo (n ϭ 30), subjects underwent a 24-h study with standardized meals (total 2,000 kcal). RESEARCH DESIGN AND METHODSRESULTS -Compared with placebo, NVP DPP728 at 100 mg t.i.d. reduced fasting glucose by 1.0 mmol/l (mean), prandial glucose excursions by 1.2 mmol/l, and mean 24-h glucose levels by 1.0 mmol/l (all P Ͻ 0.001). Similar reductions were seen in the 150-mg b.i.d. treatment group. Mean 24-h insulin was reduced by 26 pmol/l in both groups (P ϭ 0.017 and P ϭ 0.023).Although not an efficacy parameter foreseen in the study protocol, HbA 1c was reduced to 6.9 Ϯ 0.7% in the combined active treatment groups (P Ͻ 0.001). Laboratory safety and tolerability was good in all groups.CONCLUSIONS -We conclude that inhibition of DPP IV is a feasible approach to the treatment of type 2 diabetes in the early stage of the disease. Diabetes Care 25:869 -875, 2002T he gut hormones glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP) are both incretin hormones that are released postprandially and markedly augment glucose-stimulated insulin secretion through sensitizing the ␤-cell action of glucose (1-3). GLP-1 also exhibits other effects of importance for glucose homeostasis, viz., inhibiting glucagon secretion, delaying gastric emptying, and stimulating insulin biosynthesis (2,3). These effects, along with a potential increase in peripheral insulin action (4), will together be antidiabetogenic. GLP-1 has also been shown to reduce postprandial and fasting glycemia in subjects with type 1 and type 2 diabetes (3,4 -9) and may, therefore, be a potentially useful new therapeutic agent in the treatment of diabetes. However, GLP-1 is rapidly degraded in plasma by the enzyme dipeptidyl peptidase IV (DPP IV), resulting in the short circulating half-life of intact GLP-1 being Ͻ1 min (3,10,11). Therefore, GLP-1 is unattractive as chronic therapy because multiple daily injections are required to maintain glycemic control.The short half-life of GLP-1 has prompted development of alternate strategies to harness the potent antidiabetic activity of GLP-1. One approach is to inhibit DPP IV activity, thereb...

Objective: To examine the possibility that interleukin-6 (IL-6) can act as a paracrine regulator in adipose tissue by examining effects on adipogenic genes and measuring interstitial IL-6 concentrations in situ. Research Methods and Procedures:Circulating and interstitial IL-6 concentrations in abdominal and femoral adipose tissue were measured using the calibrated microdialysis technique in 20 healthy male subjects. The effects of adipose cell enlargement on gene expression and IL-6 secretion were examined, as well as the effect of IL-6 in vitro on gene expression of adiponectin and other markers of adipocyte differentiation.

The epidemic increase in type 2 diabetes can be prevented only if markers of risk can be identified and used for early intervention. We examined the clinical phenotype of individuals characterized by normal or low IRS-1 protein expression in fat cells as well as the potential molecular mechanisms related to the adipose tissue. Twenty-five non-obese individuals with low or normal IRS-1 expression in subcutaneous abdominal fat cells were extensively characterized and the results compared with 71 carefully matched subjects with or without a known genetic predisposition for type 2 diabetes. In contrast to the commonly used risk marker, known heredity for diabetes, low cellular IRS-1 identified individuals who were markedly insulin resistant, had high proinsulin and insulin levels, and exhibited evidence of early atherosclerosis measured as increased intima media thickness in the carotid artery bulb. Circulating levels of adiponectin were also significantly reduced. Gene analyses of fat cells in a parallel study showed attenuated expression of several genes related to fat cell differentiation (adiponectin, aP2, PPARgamma, and lipoprotein lipase) in the group of individuals characterized by a low IRS-1 expression and insulin resistance. A low IRS-1 expression in fat cells is a marker of insulin resistance and risk for type 2 diabetes and is associated with evidence of early vascular complications. Impaired adipocyte differentiation, including low gene expression and circulating levels of adiponectin, can provide a link between the cellular marker and the in vivo phenotype.

Context:The chemokine monocyte chemoattractant protein-1 (MCP-1) is implicated in obesity-associated chronic inflammation, insulin resistance, and atherosclerosis. Objectives:The objectives of this study were to: 1) characterize the interstitial levels and the gene expression of MCP-1 in the sc abdominal adipose tissue (SCAAT), 2) elucidate the response of MCP-1 to acute hyperinsulinemia, and 3) determine the relationship between MCP-1 and arterial stiffness.Design: Nine lean (L) and nine uncomplicated obese (OB) males were studied in the fasting state and during a euglycemic-hyperinsulinemic clamp combined with the microdialysis technique. Interstitial and serum MCP-1 (iMCP-1 and sMCP-1, respectively) levels, pulse wave analysis, and SCAAT biopsies were characterized at baseline and after hyperinsulinemia.Results: OB showed elevated sMCP-1 (P Ͻ 0.01) but similar iMCP-1 levels as compared with L. Basal iMCP-1 concentrations were considerably higher than sMCP-1 (P Ͻ 0.0001), and a gradient between iMCP-1 and sMCP-1 levels was maintained throughout the hyperinsulinemia. At baseline, SCAAT gene expression profile revealed a "co-upregulation" of MCP-1, MCP-2, macrophage inflammatory protein-1␣, and CD68 in OB, and whole-body glucose disposal inversely correlated with the MCP-1 gene expression. After hyperinsulinemia, MCP-1 and MCP-2 mRNA levels significantly increased in L, but not in OB. Finally, sMCP-1 excess in the OB positively correlated with the stiffer vasculature.Conclusions: These observations demonstrate similar interstitial concentrations and a differential gene response to hyperinsulinemia of MCP-1 in the SCAAT from L and OB individuals. In human obesity, we suggest the SCAAT MCP-1 gene overexpression as a biomarker of an "inflamed" adipose organ and impaired glucose metabolism.

Obese subjects with postprandial hyperglycemia need higher circulating insulin levels than lean controls to attain similar interstitial insulin levels in adipose tissue and skeletal muscle, indicating an impaired transfer of insulin across the endothelium.

The aim of this study was to examine subcutaneous lactate production in the relatives of individuals with type 2 diabetes. Therefore, we recruited seven healthy first-degree relatives of type 2 diabetic patients and seven pairwise, matched, healthy control subjects without any heredity for diabetes. All subjects were studied with a euglycemic insulin clamp at ϳ600 pmol/l, abdominal subcutaneous microdialysis, and 133 Xe clearance. Furthermore, a subcutaneous needle biopsy was performed to determine fat cell size. In the fasting state, interstitial lactate was 40% higher in relatives than in control subjects (P ‫؍‬ 0.043), but net lactate production was similar in both groups. However, during the insulin clamp, interstitial lactate (2.50 ؎ 0.29 vs. 1.98 ؎ 0.26 mmol/l, P ‫؍‬ 0.018), interstitial-arterial lactate concentration difference (1.08 ؎ 0.30 vs. 0.53 ؎ 0.24 mmol/l, P ‫؍‬ 0.028), and net lactate release per fat cell (10.9 ؎ 3.7 vs. 2.8 ؎ 1.3 fmol ⅐ cell -1 ⅐ min -1 , P ‫؍‬ 0.018) were increased in the relatives. We conclude that first-degree relatives of type 2 diabetic patients may have an enhanced net lactate release per fat cell in abdominal subcutaneous tissue. This could suggest a pathological regulation in adipose tissue that is of importance for the metabolic defects known in type 2 diabetic relatives.

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The liver is an important target for interleukin-6 (IL-6) action leading to an increased inflammatory response with impaired insulin signaling and action. The aims of this study are to address if insulin is anti-inflammatory and attenuates IL-6-induced inflammation in the human hepatoma cell line HepG2 and if this involves signal transducer and activator of transcription 3 (STAT3) signal transduction. It was found that insulin significantly reduced IL-6-induced gene transcription of serum amyloid 1 (SAA1), serum amyloid 2 (SAA2), haptoglobin, orosomucoid, and plasmin activator inhibitor-1 (PAI-1). However, the authors did not find any evidence that insulin inhibited IL-6 signal transduction, i.e., no effect of insulin was detected on STAT3 phosphorylation or its translocation to cell nucleus. The potential role of PKCδ was also analyzed but no evidence of its involvement was found. Taken together, these results suggest that the anti-inflammatory effect of insulin on IL-6 action is exerted at the level of the transcriptional activation of the genes. Further analysis revealed that insulin regulates nuclear localization of FOXO1, which is an important co-activator for STAT3 mediated transcription. Insulin induced nuclear exit and Thr24 phosphorylation of FOXO1, thus, inhibiting STAT3-mediated transcription.