Insulin resistance in obese subjects and newly diagnosed NIDDM patients and derangements of pyruvate dehydrogenase in their circulating lymphocytes

Pyruvate dehydrogenase (PDH) has low activity in the circulating lymphocytes (CL) of obese adolescents and adults. In vitro, it is unresponsive to insulin at 5μ-units/ml and is activated at 50μ-units/ml, in contrast with activation and inhibition respectively at these concentrations in CL from controls. These changes are seen as being indicative of a molecular disorder underlying insulin resistance. The aims of the present study were to determine whether a substantial enhancement of blood insulin levels restores the PDH activity in CL from obese adolescents and abolishes the in vitro alterations, and whether PDH activity and indices of insulin resistance are correlated. Six obese adolescents and six normal-weight controls underwent a 4h frequently sampled intravenous glucose test with minimal model analysis, to bring about a sharp rise in blood insulin and provide a reliable index of insulin sensitivity (SI). PDH activity was evaluated in CL obtained from blood samples at set times before and after their exposure to insulin in vitro. Insulin levels rose in all subjects in the first 10min, although to a much greater extent in the obese group, and then decreased until the end of the test (240min; t240). PDH activity in CL paralleled the insulin pattern in the control subjects, whereas in the obese subjects it was below normal 3min before the start of the test (t-3), but rose significantly throughout the test. PDH responses in vitro to insulin in CL taken from the control subjects at t-3 and t240 and in CL taken from the obese subjects at t-3 were as reported above, but were normal (i.e. the same as in control CL) in CL taken from the obese subjects at t240. Baseline PDH activity was inversely correlated with body mass index and with fasting insulin, and directly correlated with SI. These results show that a brief and sharp enhancement of blood insulin overcomes derangements in PDH that reflect systemic insulin resistance in obese adolescents.

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Down-regulation of Pyruvate Dehydrogenase Phosphatase in Obese Subjects is a Defect that Signals Insulin Resistance

Obesity Research ◽

10.1038/oby.2005.76 ◽

2005 ◽

Vol 13 (4) ◽

pp. 678-686 ◽

Cited By ~ 10

Author(s):

Marco Piccinini ◽

Michael Mostert ◽

Gianfrancesco Alberto ◽

Cristina Ramondetti ◽

Rosa F. Novi ◽

...

Keyword(s):

Insulin Resistance ◽

Pyruvate Dehydrogenase ◽

Down Regulation ◽

Obese Subjects ◽

Pyruvate Dehydrogenase Phosphatase

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Association between 25 hydroxyvitamin D levels and insulin resistance in a cohort of obese subjects

Endocrine Abstracts ◽

10.1530/endoabs.63.p509 ◽

2019 ◽

Author(s):

Ponce Maria Hayon ◽

Carmen Serrano Laguna Maria del ◽

Utrero Sara Leon ◽

Torres Enrique Redondo ◽

Martin Socorro Leyva ◽

...

Keyword(s):

Insulin Resistance ◽

Hydroxyvitamin D ◽

25 Hydroxyvitamin D ◽

Obese Subjects

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268-OR: Insulin Resistance in the Liver, but Not Muscle or Adipose, Is Essential for Remission from Newly Diagnosed Type 2 Diabetes by Short-Term Insulin Intensive Therapy

Diabetes ◽

10.2337/db19-268-or ◽

2019 ◽

Vol 68 (Supplement 1) ◽

pp. 268-OR

Author(s):

XUESI WAN ◽

ZHIMIN HUANG ◽

YANBING LI

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Intensive Therapy ◽

Newly Diagnosed ◽

Short Term

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Defects in insulin-receptor internalization and processing in monocytes of obese subjects and obese NIDDM patients

Diabetes ◽

10.2337/diabetes.38.12.1579 ◽

1989 ◽

Vol 38 (12) ◽

pp. 1579-1584 ◽

Cited By ~ 9

Author(s):

V. Trischitta ◽

A. Brunetti ◽

A. Chiavetta ◽

L. Benzi ◽

V. Papa ◽

...

Keyword(s):

Insulin Receptor ◽

Receptor Internalization ◽

Obese Subjects ◽

Niddm Patients

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Plasma resistin, adiponectin and leptin levels in lean and obese subjects: correlations with insulin resistance

Acta Endocrinologica ◽

10.1530/eje.0.1490331 ◽

2003 ◽

Vol 149 (4) ◽

pp. 331-335 ◽

Cited By ~ 350

Author(s):

JV Silha ◽

M Krsek ◽

JV Skrha ◽

P Sucharda ◽

BL Nyomba ◽

...

Keyword(s):

Insulin Resistance ◽

Body Mass Index ◽

Adipose Tissue ◽

Statistical Significance ◽

Model Assessment ◽

Fasting Insulin ◽

Homeostasis Model Assessment ◽

Glucose Levels ◽

Obese Subjects ◽

The Relationship

OBJECTIVE: Adipose tIssue regulates insulin sensitivity via the circulating adipocytokines, leptin, resistin and adiponectin. The objective of this study was to compare the levels of resistin, adiponectin and leptin in lean and obese subjects and determine the relationship between circulating adipocytokines and insulin resistance. METHODS: We examined plasma levels of resistin, adiponectin and leptin in 17 lean subjects with a mean body mass index (BMI) of approximately 23 and 34 non-diabetic obese individuals with a mean BMI approximately 33. Insulin resistance was assessed using the homeostasis model assessment ratio (HOMA-R) formula derived from fasting insulin and glucose levels. RESULTS: Resistin levels were not significantly different between the two groups but were significantly higher in women compared with men, 35.4+/-6.5 (s.e.) vs 15.4+/-2.9 microg/L, P<0.01. Resistin did not correlate with BMI but did significantly correlate with HOMA-R, P<0.01, and this correlation remained significant after adjustment for gender and BMI. Adiponectin levels were significantly lower in obese compared with lean subjects, P<0.005, and higher in women, P<0.001, but showed no significant correlation with HOMA-R. Leptin levels were significantly higher in obese subjects and women and correlated with HOMA-R and resistin. DISCUSSION: In this small group of patients we demonstrated that insulin resistance correlated most strongly with leptin levels. A significant correlation between resistin levels and insulin resistance was also observed. Although a similar trend was apparent for adiponectin, the correlation with insulin resistance did not achieve statistical significance.

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NF-κB-Inducing Kinase (NIK) Mediates Skeletal Muscle Insulin Resistance: Blockade by Adiponectin

Endocrinology ◽

10.1210/en.2011-1343 ◽

2011 ◽

Vol 152 (10) ◽

pp. 3622-3627 ◽

Cited By ~ 26

Author(s):

Sanjeev Choudhary ◽

Sandeep Sinha ◽

Yanhua Zhao ◽

Srijita Banerjee ◽

Padma Sathyanarayana ◽

...

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Glucose Uptake ◽

Kinase Activity ◽

Pi3 Kinase ◽

Dominant Negative ◽

Muscle Insulin Resistance ◽

Akt Phosphorylation ◽

Skeletal Muscle Insulin Resistance ◽

Obese Subjects

Enhanced levels of nuclear factor (NF)-κB-inducing kinase (NIK), an upstream kinase in the NF-κB pathway, have been implicated in the pathogenesis of chronic inflammation in diabetes. We investigated whether increased levels of NIK could induce skeletal muscle insulin resistance. Six obese subjects with metabolic syndrome underwent skeletal muscle biopsies before and six months after gastric bypass surgery to quantitate NIK protein levels. L6 skeletal myotubes, transfected with NIK wild-type or NIK kinase-dead dominant negative plasmids, were treated with insulin alone or with adiponectin and insulin. Effects of NIK overexpression on insulin-stimulated glucose uptake were estimated using tritiated 2-deoxyglucose uptake. NF-κB activation (EMSA), phosphatidylinositol 3 (PI3) kinase activity, and phosphorylation of inhibitor κB kinase β and serine-threonine kinase (Akt) were measured. After weight loss, skeletal muscle NIK protein was significantly reduced in association with increased plasma adiponectin and enhanced AMP kinase phosphorylation and insulin sensitivity in obese subjects. Enhanced NIK expression in cultured L6 myotubes induced a dose-dependent decrease in insulin-stimulated glucose uptake. The decrease in insulin-stimulated glucose uptake was associated with a significant decrease in PI3 kinase activity and protein kinase B/Akt phosphorylation. Overexpression of NIK kinase-dead dominant negative did not affect insulin-stimulated glucose uptake. Adiponectin treatment inhibited NIK-induced NF-κB activation and restored insulin sensitivity by restoring PI3 kinase activation and subsequent Akt phosphorylation. These results indicate that NIK induces insulin resistance and further indicate that adiponectin exerts its insulin-sensitizing effect by suppressing NIK-induced skeletal muscle inflammation. These observations suggest that NIK could be an important therapeutic target for the treatment of insulin resistance associated with inflammation in obesity and type 2 diabetes.

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Improvement in Glucose Tolerance and Insulin Resistance in Obese Subjects Treated with Troglitazone

New England Journal of Medicine ◽

10.1056/nejm199411033311803 ◽

1994 ◽

Vol 331 (18) ◽

pp. 1188-1193 ◽

Cited By ~ 615

Author(s):

John J. Nolan ◽

Bernhard Ludvik ◽

Patricia Beerdsen ◽

Mary Joyce ◽

Jerrold Olefsky

Keyword(s):

Insulin Resistance ◽

Glucose Tolerance ◽

Obese Subjects

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The activity of the pyruvate dehydrogenase complex in heart and liver from mice during the development of obesity and insulin resistance

Biochemical Journal ◽

10.1042/bj2430549 ◽

1987 ◽

Vol 243 (2) ◽

pp. 549-553 ◽

Cited By ~ 7

Author(s):

I D Caterson ◽

L D Astbury ◽

P F Williams ◽

M A Vanner ◽

G J Cooney ◽

...

Keyword(s):

Insulin Resistance ◽

Pyruvate Dehydrogenase ◽

Serum Insulin ◽

Pyruvate Dehydrogenase Complex ◽

Active Form ◽

Whole Body ◽

Acid Oxidation ◽

Mitochondrial Fatty Acid Oxidation ◽

Gold Thioglucose ◽

Mitochondrial Fatty Acid

The amount of pyruvate dehydrogenase in the active form (PDHa) was increased 1.7-fold compared with controls in heart muscle of mice 1 week after induction of obesity with a single injection of gold-thioglucose. At 4 weeks post injection, the amount of PDHa was decreased to 32% of control, a value which was observed in later stages of the obesity syndrome. In contrast, liver PDHa was increased and remained at an increased activity during the development of obesity. Despite normal post-prandial serum insulin contents, liver membrane insulin-receptor numbers were decreased 1 week after gold-thioglucose injection, and there was no change in receptor affinity. The decrease in heart PDHa in the obese animals was reversed by a single dose of 2-tetradecylglycidic acid, but this inhibitor of mitochondrial fatty acid oxidation did not affect liver PDHa in these animals. These early and diverse changes in PDHa argue for a multifactorial aetiology in the development of the whole-body insulin resistance seen in older gold-thioglucose-treated obese animals.

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