Renal insulin resistance in type 2 diabetes mellitus and progression of chronic kidney disease: potential pathogenic mechanisms

ABSTRACT

Introduction

A bidirectional association exists between insulin resistance (IR) and chronic kidney disease (CKD) in Type 2 Diabetes Mellitus (T2DM). Baseline measures of IR are predictive of CKD progression, and uremia in progressive CKD is itself, in turn, associated with a worsening of IR. Pre-clinical research reveals that intrinsic IR in glomerular podocytes and the renal tubule may serve as a pathogenic driver of CKD in T2DM.

Areas covered

The present manuscript takes as its point of departure, the recently identified prognostic utility of severe insulin resistance as a predictor of CKD in T2DM. Findings from a series of studies describing the association of IR with pathological alterations in both established, and less commonly assessed dynamic measures of renal impairment are discussed. Drawing upon the pre-clinical mechanistic evidence base, the cellular and molecular basis of intrinsic renal IR as a promoter of CKD is considered.

Expert opinion

Measurement of insulin sensitivity may add value to profiling of renal risk in T2DM. Rational selection of therapeutic strategies targeting the enhancement of insulin sensitivity merits special attention regarding the personalized management of CKD in insulin resistance predominant T2DM.

KEYWORDS:

• Insulin
• kidney
• CKD
• podocyte
• tubular epithelium
• diabetes
• obesity

Article highlights

• Severe IR as a phenotypic measure of T2DM is highly predictive of incident CKD and CKD progression at medium-long term follow-up.

• The kidney is a major target of the actions of insulin in the context of glucose homeostasis and volume and electrolyte balance.

• Intrinsic renal IR is an important component of the pathogenic IR-CKD association through the cumulative effects of dysregulation of renal glucose and sodium handling on glomerular haemodynamics and barrier function (Figure 2).

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

Work in the laboratory of NG Docherty is currently funded by an award from the Wellcome Trust Institutional Strategic Support Fund. P Swan was funded as a Pre-doctoral Fellow by the Irish Health Research Board (ILP-HSR-2017-007).