Several lines of evidence suggest a pathogenic role of insulin resistance on kidney dysfunction. Potential mechanisms are mostly due to the effect of single abnormalities related to insulin resistance and clustering into the metabolic syndrome. Hyperinsulinemia, which is inevitably associated to insulin resistance in non diabetic states, also appears to play a role on kidney function by inducing glomerular hyperfiltration and increased vascular permeability. More recently, adipocytokine which are linked to insulin resistance, low grade inflammation, endothelial dysfunction and vascular damage have been proposed as additional molecules able to modulate kidney function. In addition, recent evidences point also to a role of insulin resistance at the level of the podocyte, an important player in early phases of diabetic kidney damage, thus suggesting a new mechanism through which a reduction of insulin action can affect kidney function. In fact, mouse models not expressing the podocyte insulin receptor develop podocytes apoptosis, effacement of its foot processes along with thickening of the glomerular basement membrane, increased glomerulosclerosis and albuminuria. A great number of epidemiological studies have repeatedly reported the association between insulin resistance and kidney dysfunction in both non diabetic and diabetic subjects. Among these, studies addressing the impact of insulin resistance genes on kidney dysfunction have played the important role to help establish a cause-effect relationship between these two traits. Finally, numerous independent intervention studies have shown that a favourable modulation of insulin resistance has a positive effect also on urinary albumin and total protein excretion. In conclusion, several data of different nature consistently support the role of insulin resistance and related abnormalities on kidney dysfunction. Intervention trials designed to investigate whether treating insulin resistance ameliorates also hard renal end-points are both timely and needed.

Role of insulin resistance in kidney dysfunction: insights into the mechanism and epidemiological evidence

Diabetes mellitus is a highly heterogeneous disorder encompassing several distinct forms with different clinical manifestations including a wide spectrum of age at onset. Despite many advances, the causal genetic defect remains unknown for many subtypes of the disease, including some of those forms with an apparent Mendelian mode of inheritance. Here we report two loss-of-function mutations (c.1655T>A [p.Leu552∗] and c.280G>A [p.Asp94Asn]) in the gene for the Adaptor Protein, Phosphotyrosine Interaction, PH domain, and leucine zipper containing 1 (APPL1) that were identified by means of whole-exome sequencing in two large families with a high prevalence of diabetes not due to mutations in known genes involved in maturity onset diabetes of the young (MODY). APPL1 binds to AKT2, a key molecule in the insulin signaling pathway, thereby enhancing insulin-induced AKT2 activation and downstream signaling leading to insulin action and secretion. Both mutations cause APPL1 loss of function. The p.Leu552∗ alteration totally abolishes APPL1 protein expression in HepG2 transfected cells and the p.Asp94Asn alteration causes significant reduction in the enhancement of the insulin-stimulated AKT2 and GSK3β phosphorylation that is observed after wild-type APPL1 transfection. These findings—linking APPL1 mutations to familial forms of diabetes—reaffirm the critical role of APPL1 in glucose homeostasis.

Loss-of-Function Mutations in APPL1 in Familial Diabetes Mellitus

The existence of breast cancer stem cells (BCSCs) is a major reason underlying cancer metastasis and recurrence after chemotherapy and radiotherapy. Targeting BCSCs may ameliorate breast cancer relapse and therapy resistance. Here we report that expression of the pseudokinase Tribble 3 (TRIB3) positively associates with breast cancer stemness and progression. Elevated TRIB3 expression supports BCSCs by interacting with AKT to interfere with the FOXO1-AKT interaction and suppress FOXO1 phosphorylation, ubiquitination, and degradation by E3 ligases SKP2 and NEDD4L. The accumulated FOXO1 promotes transcriptional expression of SOX2, a transcriptional factor for cancer stemness, which in turn, activates FOXO1 transcription and forms a positive regulatory loop. Disturbing the TRIB3-AKT interaction suppresses BCSCs by accelerating FOXO1 degradation and reducing SOX2 expression in mouse models of breast cancer. Our study provides insights into breast cancer development and confers a potential therapeutic strategy against TRIB3-overexpressed breast cancer.

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TRIB3 supports breast cancer stemness by suppressing FOXO1 degradation and enhancing SOX2 transcription

High insulin/IGF is a biologic link between diabetes and cancers, but the underlying molecular mechanism remains unclear. Here we report a previously unrecognized tumour-promoting mechanism for stress protein TRB3, which mediates a reciprocal antagonism between autophagic and proteasomal degradation systems and connects insulin/IGF to malignant promotion. We find that several human cancers express higher TRB3 and phosphorylated insulin receptor substrate 1, which correlates negatively with patient's prognosis. TRB3 depletion protects against tumour-promoting actions of insulin/IGF and attenuates tumour initiation, growth and metastasis in mice. TRB3 interacts with autophagic receptor p62 and hinders p62 binding to LC3 and ubiquitinated substrates, which causes p62 deposition and suppresses autophagic/proteasomal degradation. Several tumour-promoting factors accumulate in cancer cells to support tumour metabolism, proliferation, invasion and metastasis. Interrupting TRB3/p62 interaction produces potent antitumour efficacies against tumour growth and metastasis. Our study opens possibility of targeting this interaction as a potential novel strategy against cancers with diabetes.

TRB3 links insulin/IGF to tumour promotion by interacting with p62 and impeding autophagic/proteasomal degradations.

Mitochondrial unfolded protein response is a form of retrograde signaling that contributes to ensuring the maintenance of quality control of mitochondria, allowing functional integrity of the mitochondrial proteome. When misfolded proteins or unassembled complexes accumulate beyond the folding capacity, it leads to alteration of proteostasis, damages, and organelle/cell dysfunction. Extensively studied for the ER, it was recently reported that this kind of signaling for mitochondrion would also be able to communicate with the nucleus in response to impaired proteostasis. The mitochondrial unfolded protein response (UPRmt) is activated in response to different types and levels of stress, especially in conditions where unfolded or misfolded mitochondrial proteins accumulate and aggregate. A specific UPRmt could thus be initiated to boost folding and degradation capacity in response to unfolded and aggregated protein accumulation. Although first described in mammals, the UPRmt was mainly studied in Caenorhabditis elegans, and accumulating evidence suggests that mechanisms triggered in response to a UPRmt might be different in C. elegans and mammals. In this review, we discuss and integrate recent data from the literature to address whether the UPRmt is relevant to mitochondrial homeostasis in mammals and to analyze the putative role of integrated stress response (ISR) activation in response to the inhibition of mtDNA expression and/or accumulation of mitochondrial mis/unfolded proteins.

https://www.mdpi.com/1422-0067/16/8/18224/pdf

Mitochondria Retrograde Signaling and the UPRmt: Where Are We in Mammals?

Insulin signaling plays a physiological role in traditional insulin target tissues controlling glucose homeostasis as well as in pancreatic β-cells and in the endothelium. Insulin signaling abnormalities may, therefore, be pathogenic for insulin resistance, impaired insulin secretion, endothelial dysfunction, and eventually, type 2 diabetes mellitus (T2DM) and cardiovascular disease. Tribbles homolog 3 (TRIB3) is a 45-kDa pseudokinase binding to and inhibiting Akt, a key mediator of insulin signaling. Akt-mediated effects of TRIB3 in the liver, pancreatic β-cells, and skeletal muscle result in impaired glucose homeostasis. TRIB3 effects are also modulated by its direct interaction with other signaling molecules. In humans, TRIB3 overactivity, due to TRIB3 overexpression or to Q84R genetic polymorphism, with R84 being a gain-of-function variant, may be involved in shaping the risk of insulin resistance, T2DM, and cardiovascular disease. TRIB3 overexpression has been observed in the liver, adipose tissue, skeletal muscle, and pancreatic β-cells of individuals with insulin resistance and/or T2DM. The R84 variant has also proved to be associated with insulin resistance, T2DM, and cardiovascular disease. TRIB3 direct effects on the endothelium might also play a role in increasing the risk of atherosclerosis, as indicated by studies on human endothelial cells carrying the R84 variant that are dysfunctional in terms of Akt activation, NO production, and other proatherogenic changes. In conclusion, studies on TRIB3 have unraveled new molecular mechanisms underlying metabolic and cardiovascular abnormalities. Additional investigations are needed to verify whether such acquired knowledge will be relevant for improving care delivery to patients with metabolic and cardiovascular alterations.

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The Mammalian Tribbles Homolog TRIB3, Glucose Homeostasis, and Cardiovascular Diseases

Objective—Insulin resistance induces increased pulse pressure (PP), endothelial dysfunction (ED), and reduced bioavailability of endothelium-derived nitric oxide (NO). The genetic background of these 3 cardiovascular risk factors might be partly common. The ENPP1 K121Q polymorphism is associated with insulin resistance and cardiovascular risk. Methods and Results—We investigated whether the K121Q polymorphism is associated with increased PP in white Caucasians and with ED in vitro. In 985 individuals, (390 unrelated and 595 from 248 families), the K121Q polymorphism was associated with PP (P8.010 4 ). In the families, the Q121 variant accounted for 0.08 of PP heritability (P9.410 4 ). This association was formally replicated in a second sample of 475 individuals (P2.610 2 ) but not in 2 smaller samples of 289 and 236 individuals (P0.49 and 0.21, respectively). In the individual patients’ data meta-analysis, comprising 1985 individuals, PP was associated with the Q121 variant (P1.210 3 ). Human endothelial cells carrying the KQ genotype showed, as compared to KK cells, reduced insulin-mediated insulin receptor autophosphorylation (P0.03), Ser 473 -Akt phosphorylation (P0.03), and NO synthase activity (P0.003). Conclusions—Our data suggest that the ENPP1 Q121 variant is associated with increased PP in vivo and reduced insulin signaling and ED in vitro, thus indicating a possible pathogenic mechanism for the increased cardiovascular risk observed in ENPP1 Q121 carriers. (Arterioscler Thromb Vasc Biol. 2009;29:1678-1683.)

National Cholesterol Awareness Month ENPP1 Q121 Variant, Increased Pulse Pressure and Reduced Insulin Signaling, and Nitric Oxide Synthase Activity in Endothelial Cells

Agostino Consoli

Papers

The Mammalian Tribbles Homolog TRIB3, Glucose Homeostasis, and Cardiovascular Diseases

National Cholesterol Awareness Month ENPP1 Q121 Variant, Increased Pulse Pressure and Reduced Insulin Signaling, and Nitric Oxide Synthase Activity in Endothelial Cells