Muscle-specific knockout of PKC-lambda impairs glucose transport and induces metabolic and diabetic syndromes

Area of Science:

• Biochemistry
• Metabolic Diseases
• Molecular Biology

Background:

• Obesity, metabolic syndrome, and type 2 diabetes mellitus (T2DM) are significant global health issues.
• Insulin resistance is a common feature of these disorders, but its underlying causes and consequences remain unclear.

Purpose of the Study:

• To investigate the role of muscle-specific atypical protein kinase C lambda (aPKC) in insulin-stimulated glucose transport and its contribution to metabolic dysfunction.
• To determine if impaired aPKC function in muscle can induce features of the metabolic syndrome and T2DM.

Main Methods:

• Generated muscle-specific knockout mice for PKC-lambda, a key mediator of insulin signaling.
• Assessed glucose transport, glucose transporter 4 (GLUT4) translocation, and systemic metabolic parameters in knockout and wild-type mice.

Main Results:

• Reduced glucose transport and GLUT4 translocation in muscles of PKC-lambda knockout mice (homozygous and heterozygous).
• Knockout mice exhibited systemic insulin resistance, impaired glucose tolerance, diabetes, islet beta cell hyperplasia, abdominal obesity, hepatosteatosis, and dyslipidemia (elevated triglycerides, FFAs, LDL-C; diminished HDL-C).
• Insulin signaling and actions were unaffected in muscle, liver, and adipocytes, despite defective muscle aPKC activation.

Conclusions:

• Muscle aPKC is crucial for insulin-stimulated glucose transport in vivo.
• Muscle-specific insulin resistance caused by aPKC deficiency is sufficient to induce obesity and metabolic syndrome hallmarks.
• Defective muscle aPKC activation/levels in humans with obesity, impaired glucose tolerance, and T2DM support these findings.