Start of insulin therapy in patients with type 2 diabetes mellitus promotes the influx of macrophages into subcutaneous adipose tissue

Jansen, Henry; Stienstra, Rinke; Diepen, Janna A. van; Hijmans, Anneke; Laak, J.A.W.M. van der; Vervoort, G.M.M.; Tack, Cees J.

doi:10.1007/s00125-013-3018-6

Cited by 25 publications

(20 citation statements)

References 24 publications

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“…These include reports of increased pro-inflammatory cytokine expression and macrophage infiltration into AT during a hyperinsulinemic-euglycemic clamp [38–43] . Furthermore, increased pro-inflammatory activity has also been reported in human AT from subjects following insulin therapy [44] . However, whether obesity-associated hyperinsulinemia promotes AT inflammation and the mechanism by which this occurs remains to be fully elucidated.…”

Section: Introductionmentioning

confidence: 94%

A major role of insulin in promoting obesity-associated adipose tissue inflammation

Pedersen

Guilherme

Danai

et al. 2015

Molecular Metabolism

126

106

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ObjectiveAdipose tissue (AT) inflammation is associated with systemic insulin resistance and hyperinsulinemia in obese rodents and humans. A longstanding concept is that hyperinsulinemia may promote systemic insulin resistance through downregulation of its receptor on target tissues. Here we tested the novel hypothesis that insulin also impairs systemic insulin sensitivity by specifically enhancing adipose inflammation.MethodsCirculating insulin levels were reduced by about 50% in diet-induced and genetically obese mice by treatments with diazoxide or streptozotocin, respectively. We then examined AT crown-like structures, macrophage markers and pro-inflammatory cytokine expression in AT. AT lipogenesis and systemic insulin sensitivity was also monitored. Conversely, insulin was infused into lean mice to determine its affects on the above parameters.ResultsLowering circulating insulin levels in obese mice by streptozotocin treatment decreased macrophage content in AT, enhancing insulin stimulated Akt phosphorylation and de novo lipogenesis (DNL). Moreover, responsiveness of blood glucose levels to injected insulin was improved by streptozotocin and diazoxide treatments of obese mice without changes in body weight. Remarkably, even in lean mice, infusion of insulin under constant euglycemic conditions stimulated expression of cytokines in AT. Consistent with these findings, insulin treatment of 3T3-L1 adipocytes caused a 10-fold increase in CCL2 mRNA levels within 6 h, which was blocked by the ERK inhibitor PD98059.ConclusionTaken together, these results indicate that obesity-associated hyperinsulinemia unexpectedly drives AT inflammation in obese mice, which in turn contributes to factors that suppress insulin-stimulated adipocyte DNL and systemic insulin sensitivity.

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Section: Introductionmentioning

confidence: 94%

A major role of insulin in promoting obesity-associated adipose tissue inflammation

Pedersen

Guilherme

Danai

et al. 2015

Molecular Metabolism

126

106

View full text Add to dashboard Cite

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“…Bariatric surgery in such obese human subjects markedly reduces circulating lactate in conjunction with bringing insulin levels to within the normal range through decreased lactate-driven gluconeogenesis 8 . Additionally, hyperinsulinemia in both rats 44 and humans 45–51 enhances activation of inflammatory pathways, which in turn can impair insulin responsiveness in target tissues 52 . Even relatively acute infusions of insulin in human subjects causes elevated circulating cytokines 53 .…”

Section: Hyperinsulinemia and Insulin Resistancementioning

confidence: 99%

Insulin action and resistance in obesity and type 2 diabetes

Czech

2017

Nat Med

982

692

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Nutritional excess is a major forerunner of type 2 diabetes and enhances the secretion of insulin but attenuates its metabolic actions in the liver, skeletal muscle and adipose tissue. However, conflicting evidence indicates a lack of knowledge of the timing of these events during the development of obesity and diabetes and is a key gap in our understanding of metabolic disease. This Perspective reviews alternate viewpoints and recent results on the temporal and mechanistic connections between hyperinsulinemia, obesity and insulin resistance. Although much attention has addressed early steps in the insulin signaling cascade, insulin resistance in obesity appears to be largely elicited downstream of these steps. New findings also connect insulin resistance to extensive metabolic crosstalk between liver, adipose, pancreas and skeletal muscle. These and other advances over the last 5 years offer both exciting opportunities and daunting challenges in developing new therapeutic strategies for the treatment of type 2 diabetes.

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“…Insulin-naïve patients with T2D developed an influx of macrophages into adipose tissue independent of weight gain 6 months after initiation of insulin therapy 218 . Lowering insulin levels in obese mice with streptozotocin or diazoxide decreased macrophage content in adipose tissue 219 .…”

Section: Therapeutic Implications Of Macrophage Biologymentioning

confidence: 99%

Macrophage functions in lean and obese adipose tissue

2017

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Summary Interactions between macrophages and adipocytes influence both metabolism and inflammation. Obesity-induced changes to macrophages and adipocytes lead to chronic inflammation and insulin resistance. This paper reviews the various functions of macrophages in lean and obese adipose tissue and how obesity alters adipose tissue macrophage phenotypes. Metabolic disease and insulin resistance shift the balance between numerous pro- and anti-inflammatory regulators of macrophages and create a feed-forward loop of increasing inflammatory macrophage activation and worsening adipocyte dysfunction. This ultimately leads to adipose tissue fibrosis and diabetes. The molecular mechanisms underlying these processes have therapeutic implications for obesity, metabolic syndrome, and diabetes.

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Start of insulin therapy in patients with type 2 diabetes mellitus promotes the influx of macrophages into subcutaneous adipose tissue

Cited by 25 publications

References 24 publications

A major role of insulin in promoting obesity-associated adipose tissue inflammation

A major role of insulin in promoting obesity-associated adipose tissue inflammation

Insulin action and resistance in obesity and type 2 diabetes

Macrophage functions in lean and obese adipose tissue

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