In the wake of the worldwide increase in type-2 diabetes, a major focus of research is understanding the signaling pathways impacting this disease. Insulin signaling regulates glucose, lipid, and energy homeostasis, predominantly via action on liver, skeletal muscle, and adipose tissue. Precise modulation of this pathway is vital for adaption as the individual moves from the fed to the fasted state. The positive and negative modulators acting on different steps of the signaling pathway, as well as the diversity of protein isoform interaction, ensure a proper and coordinated biological response to insulin in different tissues. Whereas genetic mutations are causes of rare and severe insulin resistance, obesity can lead to insulin resistance through a variety of mechanisms. Understanding these pathways is essential for development of new drugs to treat diabetes, metabolic syndrome, and their complications.

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Insulin Receptor Signaling in Normal and Insulin-Resistant States

Type 2 diabetes mellitus (T2DM) is one of the leading causes of morbidity and mortality. While all ethnic groups are affected, the prevalence of T2DM in South Asians, both in their home countries and abroad, is extremely high and is continuing to rise rapidly. Innate biological susceptibilities coupled with rapid changes in physical activity, diet, and other lifestyle behaviors are contributing factors propelling the increased burden of disease in this population. The large scope of this problem calls for investigations into the cause of increased susceptibility and preventative efforts at both the individual and population level that are aggressive, culturally sensitive, and start early. In this review, we outline the biological and environmental factors that place South Asians at elevated risk for T2DM, compared with Caucasian and other ethnic groups.

Type 2 diabetes in South Asians: similarities and differences with white Caucasian and other populations

Insufficient insulin secretion and reduced pancreatic beta cell mass are hallmarks of type 2 diabetes (T2DM). Here, we confirm that a previously identified polymorphism (rs2295490/Q84R) in exon 2 of the pseudokinase-encoding gene tribbles 3 (TRB3) is associated with an increased risk for T2DM in 2 populations of people of mixed European descent. Carriers of the 84R allele had substantially reduced plasma levels of C-peptide, the product of proinsulin processing to insulin, suggesting a role for TRB3 in beta cell function. Overexpression of TRB3 84R in mouse beta cells, human islet cells, and the murine beta cell line MIN6 revealed reduced insulin exocytosis, associated with a marked reduction in docked insulin granules visualized by electron microscopy. Conversely, knockdown of TRB3 in MIN6 cells restored insulin secretion and expression of exocytosis genes. Further analysis in MIN6 cells demonstrated that TRB3 interacted with the transcription factor ATF4 and that this complex acted as a competitive inhibitor of cAMP response element-binding (CREB) transcription factor in the regulation of key exocytosis genes. In addition, the 84R TRB3 variant exhibited greater protein stability than wild-type TRB3 and increased binding affinity to Akt. Mice overexpressing TRB3 84R in beta cells displayed decreased beta cell mass, associated with reduced proliferation and enhanced apoptosis rates. These data link a missense polymorphism in human TRB3 to impaired insulin exocytosis and thus increased risk for T2DM.

https://dm5migu4zj3pb.cloudfront.net/manuscripts/36000/36849/JCI36849.v2.pdf

The pseudokinase tribbles homolog 3 interacts with ATF4 to negatively regulate insulin exocytosis in human and mouse β cells

https://genepi.qimr.edu.au/contents/p/staff/Luciano_BioPsychEPUB.pdf

Whole genome association scan for genetic polymorphisms influencing information processing speed

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

Context: The prevalence of type 2 diabetes (T2D), particularly among young adults, has been rising steadily during the past 2 decades. T2D, especially in its early-onset subtype, is under genetic control. TRIB3 inhibits insulin-stimulated Akt phosphorylation and subsequent insulin action. A TRIB3 gain-of-function polymorphism, Q84R (rs2295490), impairs insulin signaling.

Objective: The objective of the study was to verify the association of TRIB3 Q84R with: 1) T2D, either subtyped or not according to age at diagnosis (early-onset, <45 yr, or ≥ 45 yr); 2) insulin secretion and sensitivity in nondiabetic individuals; or 3) in vitro insulin secretion from isolated human islets.

Design: Four different case-control samples comprising a total of 5469 whites were examined. Insulinogenic and insulin sensitivity indexes and their interplay (disposition index) were assessed in 645 nondiabetic individuals at oral glucose tolerance test, glucose (16.7 mmol/liter)-induced in vitro insulin secretion was assessed in islets isolated from 54 nondiabetic donors.

Results: In the whole sample, the R84 variant was nominally associated with T2D (odds ratio 1.17, 95% confidence interval 1.00–1.36, P = 0.04). When stratifying according to age of diabetes onset, R84 carriers had an increased risk of early-onset T2D (odds ratio 1.32, 95% confidence interval 1.10–1.58, P = 0.002). Among 645 nondiabetic subjects, R84 carriers had higher glucose levels (P = 0.005) and lower insulinogenic (P = 0.03) and disposition index (P = 0.02) during the oral glucose tolerance test. R84 islets were more likely to display relatively low glucose-stimulated insulin release (P = 0.04).

Conclusions: The TRIB3 R84 variant is associated with early-onset T2D in whites. Alteration in the insulin secretion/insulin sensitivity interplay appears to underlie this association.

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The TRIB3 Q84R polymorphism and risk of early-onset type 2 diabetes

Although Asian Indian (people of Indian subcontinent descent) men are shown to have higher total and truncal body fat as well as greater insulin resistance compared to white men matched for total body fat and age, data in women are not conclusive. The objective of this study was to compare total and regional fat distribution and insulin sensitivity between healthy young premenopausal Asian Indian and white women of similar body mass index (BMI). Twenty Asian Indian women (65% immigrants and 35% first generation living in Dallas) and 31 white women of similar age and BMI [age 24±3 vs. 25±4; BMI 22±4 vs. 23±5; mean±standard deviation (SD) in Asian Indian and white, respectively] without diabetes were evaluated with anthropometric measurements, underwater weighing for percentage of total body fat mass, magnetic resonance imaging of whole abdomen for measurement of abdominal subcutaneous and intraperitoneal fat mass, and euglycemic–hyperinsulinemic clamp study for measurement of insulin sensitivity. ...

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Rong Li

Papers

The TRIB3 Q84R polymorphism and risk of early-onset type 2 diabetes

Fat distribution and insulin resistance in young adult nonobese Asian Indian women.