Increased Skeletal Muscle Tumor Necrosis Factor- and Impaired Insulin Signaling Persist in Obese Women With Gestational Diabetes Mellitus 1 Year Postpartum

Department of Pediatrics, University of Colorado Denver, P.O. Box 6511, MS-8106, Aurora, CO 80045, USA.
Diabetes (Impact Factor: 8.1). 03/2008; 57(3):606-13. DOI: 10.2337/db07-1356
Source: PubMed


Women with gestational diabetes mellitus (GDM) demonstrate chronic and progressive insulin resistance and a markedly increased risk of converting to type 2 diabetes after pregnancy. However, the cellular mechanisms underlying this insulin resistance are unknown.
We investigated the progression of insulin resistance in nine obese women with GDM during late pregnancy (30-36 weeks) and 1 year postpartum. Skeletal muscle biopsies were obtained at each visit, and insulin resistance was determined by the hyperinsulinemic-euglycemic clamp technique.
Insulin resistance was not significantly improved in GDM women (4.1 +/- 0.4 vs. 5.8 +/- 1.1 10(-2) mg x kg FFM x min(-1)/microU x ml(-1)). Subjects did not experience significant weight loss postpartum. Body weight, fat mass, fasting glucose, and plasma tumor necrosis factor (TNF)-alpha remained higher 1 year postpartum than seen in previously studied normal glucose-tolerant women. Skeletal muscle TNF-alpha mRNA was elevated five- to sixfold in GDM women and remained higher 1 year postpartum. While levels of insulin receptor (IR), IR substrate (IRS)-1, and p85 alpha improved postpartum, insulin-stimulated IR tyrosine phosphorylation and receptor tyrosine kinase activity did not significantly improve postpartum in GDM. The levels of (312)Ser-IRS-1 also did not improve postpartum and correlated with TNF-alpha mRNA (r(2) = 0.19, P < 0.03), consistent with a state of subclinical inflammation and chronic skeletal muscle insulin resistance.
These results suggest the mechanisms underlying chronic insulin resistance in GDM women may be driven by increased inflammation that impinges on the IR and IRS-1 signaling cascade in skeletal muscle. These findings have important implications for the health of GDM women during subsequent pregnancies and their risk for progression to type 2 diabetes.

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Available from: John P Kirwan, Oct 03, 2015
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    • "Gestational diabetes mellitus (GDM) can be defined as an impaired carbohydrate metabolism observed for the first time in pregnant woman irrespective of insulin or diet modification required.[1] Globally, the prevalence of GDM has been increasing rapidly at a rate proportionate to type-2 diabetes. "
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    ABSTRACT: Aim: To assess the safety and efficacy of insulin lispro in improving glycemic control in patients with gestational diabetes. Materials and Methods: A retrospective observational study was conducted at a single center on 201 gestational women with diabetes. Subjects who received insulin lispro performed blood glucose self-monitoring and recorded the readings in the fasting state and 1 h after each meal. At each contact (in person or telephonic contact), the insulin dose was adjusted based on the readings measured. A total of 53 subjects also recorded glucose levels post-partum. Pregnancy and post-delivery glucose level and insulin requirements of these 53 patients were compared. Results: Analysis of glucose levels both fasting and post-prandial glucose levels revealed that after using insulin lispro, the number of episodes of post-prandial hyperglycemia (1 h plasma glucose >120 mg/dL) was minimal and so was the incidence of hypoglycemia. Hypoglycemia was defined as a blood sugar value of. There was neither any congenital abnormality except for a poorly formed pinna in the right ear of one baby nor any post-partum complications of note. Conclusion: Insulin lispro is an effective and safe treatment option in gestational diabetes.
    07/2014; 18(4):491-5. DOI:10.4103/2230-8210.137492
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    • "It is especially important to introduce healthy lifestyle changes, as well as a proper diet based on individualized caloric needs and weight gain [22]. It should be pointed out, that limiting excessive growth of fatty tissue may also decrease the adverse effect of adipokines on the insulin secretion [23] and reduce the intensity of insulin resistance of skeletal muscles [6]. "
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    ABSTRACT: Chronic insulin resistance, exacerbated in the course of pregnancy, is an important pathophysiologic mechanism of gestational diabetes mellitus(GDM). We hypothesise that the degree of insulin resistance, assessed at diagnosis of GDM, is a parameter of its pathophysiologic heterogeneity and/or severity. Thus, it offers potential to open new avenues for the personalization of therapy in affected women. 1254 Polish Caucasian women with GDM were recruited into the study. The following parameters were assessed in the course of the study: body mass index(BMI), parity, weight gain during pregnancy, glycated haemoglobin, glucose level during an oral glucose tolerance test(OGTT), insulin, insulin resistance and insulin secretion. The severity of GDM was assessed based on insulin use and daily insulin dose during gestation. In order to evaluate insulin secretion and insulin resistance the homeostatic method was used (HOMA-B and HOMA-IR, respectively). We compared all the metabolic parameters and methods of treatment of GDM in women subdivided by quartiles of insulin resistance. The HOMA-IR in the whole population ranged from 0.34 to 20.39. The BMI, fasting insulin, fasting glucose and insulin dose per day increased along with increasing quartiles (HOMA-IR > 1.29). We observed a decrease of HOMA-B in the third quartile(1.92-2.89) compared with the first quartile(0.34-1.29). Insulin treatment was associated with HOMA-IR(<1.29 vs. >2.89), OR: 3.37, fasting glucose(<=6.11 vs. >6.11 mmol/dl), OR: 2.61, age (<=30 vs. >30 y. o.), OR: 1.54, and BMI(<25 vs. >=25 kg/m2), OR: 1.45. Maximum insulin dose was associated with HOMA-IR, OR: 2.00, after adjustment for family history of diabetes, and 2-h OGTT glucose. Insulin resistance assessed by the HOMA index at diagnosis is associated with the severity and pathophysiological heterogeneity of GDM. A HOMA-IR >1.29 points to the major role of insulin resistance, indicating the need for a treatment aimed at improving tissue sensitivity to insulin. A HOMA-IR 1.29-2.89 suggests reduced insulin secretion, which is an indication for the introduction of insulin therapy. A HOMA-IR >2.89 indicates insufficient compensation for insulin resistance, which suggests the need for a treatment aimed at improving susceptibility of tissues to insulin combined with insulin therapy.
    BMC Endocrine Disorders 07/2013; 13(1):21. DOI:10.1186/1472-6823-13-21 · 1.71 Impact Factor
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    • "Human leukocyte antigen (HLA) class I, HLA class II and secretion of inflammatory cytokine increase when a proinflammatory stimulus is given to normal muscle tissues [15]. TNF-α mRNA expression after delivery was higher in gestational diabetes patients than in patients with normal glucose tolerance, and this was also related to insulin resistance [16]. The inflammatory process was observed in the skeletal muscle of diabetes patients, in whom chronic systemic inflammation is known to be present. "
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    ABSTRACT: Inflammation plays a role in the response to metabolic stress in type 2 diabetes. However, the effects of rosiglitazone on inflammation of skeletal muscle have not been fully examined in type 2 diabetes. We investigated the effects of the insulin-sensitizing anti-diabetic agent, rosiglitazone, on the progression of skeletal muscle inflammation in Otsuka Long-Evans Tokushima Fatty (OLETF) type 2 diabetic rats. We examined the expression of serologic markers (serum glucose, insulin and free fatty acid) and inflammatory cytokines (tumor-necrosis factor-alpha, interleukin [IL]-1beta and IL-6) in OLETF rats from early to advanced diabetic stage (from 28 to 40 weeks of age). Serum glucose and insulin concentrations were significantly decreased in rosiglitazone-treated OLETF rats compared to untreated OLETF rats. Rosiglitazone treatment significantly decreased the concentrations of serum inflammatory cytokines from 28 to 40 weeks of age. The mRNA expression of various cytokines in skeletal muscle was reduced in rosiglitazone-treated OLETF rats compared with untreated OLETF rats. Furthermore, rosiglitazone treatment resulted in the downregulation of ERK1/2 phosphorylation and NF-kappaB expression in the skeletal muscle of OLETF rats. These results suggest that rosiglitazone may improve insulin sensitivity with its anti-inflammatory effects on skeletal muscle.
    Korean Diabetes Journal 06/2010; 34(3):191-9. DOI:10.4093/kdj.2010.34.3.191
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