Insulin Receptors and Insulin Resistance

Flier, Jeffrey S.

doi:10.1146/annurev.me.34.020183.001045

Cited by 73 publications

(44 citation statements)

References 49 publications

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“…We investigated the mechanisms underlying an adiponectin effect on insulin signaling. Previous studies have reported that hyperinsulinemia-induced downregulation of IR is considered an important mechanism promoting insulin resistance (46,47). Consistent with these studies, we show that insulin overexposure markedly reduces IR expression in SH-SY5Y cells.…”

Section: Discussionsupporting

confidence: 91%

Central Resistin/TLR4 Impairs Adiponectin Signaling, Contributing to Insulin and FGF21 Resistance

et al. 2016

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Adiponectin, an insulin-sensitizing hormone, and resistin, known to promote insulin resistance, constitute a potential link between obesity and type 2 diabetes. In addition, fibroblast growth factor (FGF)21 has effects similar to those of adiponectin in regulating glucose and lipid metabolism and insulin sensitivity. However, the interplay between adiponectin, FGF21, and resistin signaling pathways during the onset of insulin resistance is unknown. Here, we investigated whether central resistin promotes insulin resistance through the impairment of adiponectin and FGF21 signaling. We show that chronic intracerebroventricular resistin infusion downregulated both hypothalamic and hepatic APPL1, a key protein in adiponectin signaling, associated with decreased Akt-APPL1 interaction and an increased Akt association with its endogenous inhibitor tribbles homolog 3. Resistin treatment also decreased plasma adiponectin levels and reduced both hypothalamic and peripheral expression of adiponectin receptors. Additionally, we report that intracerebroventricular resistin increased plasma FGF21 levels and downregulated its receptor components in the hypothalamus and peripheral tissues, promoting FGF21 resistance. Interestingly, we also show that resistin effects were abolished in TLR4 knockout mice and in neuronal cells expressing TLR4 siRNAs. Our study reveals a novel mechanism of insulin resistance onset orchestrated by a central resistin-TLR4 pathway that impairs adiponectin signaling and promotes FGF21 resistance.

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Section: Discussionsupporting

confidence: 91%

Central Resistin/TLR4 Impairs Adiponectin Signaling, Contributing to Insulin and FGF21 Resistance

et al. 2016

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“…22 Downregulation of the level of IR protein itself, with insulin resistance, has been demonstrated in various insulin-target tissues central to energy metabolism (e.g., liver, skeletal muscle, adipose tissue) [11][12][13] but not specifically in kidney. Here we demonstrate that kidneys of insulin-resistant rat models (obese Zucker rats and rats fed a high-fat diet for several weeks) have a reduction in IR protein.…”

Section: Discussionmentioning

confidence: 99%

Reduced Expression of Insulin Receptors in the Kidneys of Insulin-Resistant Rats

Tiwari¹,

Halagappa²,

Riazi³

et al. 2007

Journal of the American Society of Nephrology

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Insulin resistance is accompanied by hyperinsulinemia and activation of the renin-angiotensin system, both of which are associated with hypertension. Because the kidney plays a major role in the regulation of blood pressure, we studied the regulation of insulin receptor expression in the kidney during states of insulin resistance. Using two rat models of insulin resistance, Western blot analysis demonstrated a significant reduction in the expression of insulin receptor subunits in the kidney compared to lean control rats. Treatment of insulin resistance in Zucker rats with the insulin-sensitizing drug rosiglitazone partially restored renal insulin receptor levels. Conversely, treatment with the angiotensin II type 1 receptor (AT1) antagonist candesartan increased renal insulin receptor expression compared to untreated rats. Streptozotocin-induced hyperglycemia, which results from hypoinsulinemia, reduced expression of renal insulin receptors. Hyperinsulinemia induced by insulin infusion, however, did not produce a similar effect. In conclusion, insulin receptors are downregulated in the kidneys of insulin resistant rats, possibly mediated by hyperglycemia and angiotensin II.

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“…To reconcile the strong association of obesity, hypertension, and glucose intolerance on the one hand and their separate occurrence on the other, one must assume that each of the three conditions is mediated by different facets of the insulinresistant state (14,66). However, since insulin and its receptors constitute a mutually regulating loop, it is believed that regardless of the original abnormality, once initiated, insulin resistance is self-compounding (13,14).…”

Section: Discussionmentioning

confidence: 99%

“…However, since insulin and its receptors constitute a mutually regulating loop, it is believed that regardless of the original abnormality, once initiated, insulin resistance is self-compounding (13,14). Accordingly, the development of any one of the conditions could lead to the others.…”

Section: Discussionmentioning

confidence: 99%

“…Impaired glucose tolerance and obesity are characterized by hyperinsulinemia, which reflects peripheral insulin resistance. Noninsulin-dependent diabetes is also an insulinresistant state, although insulin response may be in the normal range or lower (10)(11)(12)(13)(14). Although there are not many direct studies of insulin response in hypertension (2), hyperinsulinemia has been ascribed a pathogenetic role in obese hypertension via increased renal sodium retention (15).…”

Section: Introductionmentioning

confidence: 99%

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Hyperinsulinemia. A link between hypertension obesity and glucose intolerance.

Modan¹,

Halkin²,

Almog³

et al. 1985

J. Clin. Invest.

1,391

547

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Hypertension and glucose intolerance, determined in a random population sample (n = 2,475), showed a highly significant (P < 0.001) association from the mildest levels of both conditions, independent of the confounding effects of age, sex, obesity, and antihypertensive medications. Summary rate ratios for hypertension were 1.48 (1.18-1.87) in abnormal tolerance and 2.26 (1.69-2.84) in diabetes compared with normal tolerance. Altogether, 83.4% of the hypertensives were either glucoseintolerant or obese-both established insulin-resistant conditions. Fasting and post-load insulin levels in a representative subgroup (a = 1,241) were significantly elevated in hypertension independent of obesity, glucose intolerance, age, and antihypertensive medications. The mean increment in summed 1-and 2-h insulin levels (milliunits per liter) compared with nonobese normotensives with normal tolerance was 12 for hypertension alone, 47 for obesity alone, 52 for abnormal tolerance alone, and 124 when all three conditions were present. The prevalence of concentrations (milliequivalents per liter) of erythrocyte Na' 2 7.0, K+ < 92.5, and plasma K+ 2 4.5 in a subsample of 59 individuals with all combinations of abnormal tolerance obesity and hypertension was compared with those in 30 individuals free of these conditions. Altogether, 88.1% of the former vs. 40.0% of the latter group presented at least one of these three markers of internal cation imbalance (P < 0.001). We conclude that insulin resistance and/or hyperinsulinemia (a) are present in the majority of hypertensives, (b) constitute a common pathophysiologic feature of obesity, glucose intolerance, and hypertension, possibly explaining their ubiquitous association, and (c) may be linked to the increased peripheral vascular resistance of hypertension, which is putatively related to elevated intracellular sodium concentration.

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Insulin Receptors and Insulin Resistance

Cited by 73 publications

References 49 publications

Central Resistin/TLR4 Impairs Adiponectin Signaling, Contributing to Insulin and FGF21 Resistance

Central Resistin/TLR4 Impairs Adiponectin Signaling, Contributing to Insulin and FGF21 Resistance

Reduced Expression of Insulin Receptors in the Kidneys of Insulin-Resistant Rats

Hyperinsulinemia. A link between hypertension obesity and glucose intolerance.

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