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Chronic Insulin Infusion Down-Regulates Circulating and Urinary Nitric Oxide (NO) Levels Despite Molecular Changes in

Maurice B Fluitt1, Sophia Rizvi2, Lijun Li3

  • 1Division of Endocrinology and Metabolism, Department of Medicine, Georgetown University, Washington, DC 20057, USA. mbf79@georgetown.edu.

International Journal of Molecular Sciences
|September 26, 2018
PubMed

Insights

Insulin infusion in insulin-resistant mice caused metabolic acidosis and worsened insulin resistance, despite initial increases in kidney nitric oxide production. This suggests potential long-term risks of insulin therapy in type 2 diabetes.

Area of Science:

  • Endocrinology
  • Nephrology
  • Cardiovascular Physiology

Background:

  • Type 2 diabetes often requires insulin therapy to manage insulin receptor resistance.
  • The effects of exogenous insulin on hyperinsulinemic, insulin-resistant states are not fully understood.

Purpose of the Study:

  • To investigate the physiological impact of sustained insulin infusion in insulin-resistant mice.
  • To assess the consequences of insulin therapy on metabolic acidosis, blood pressure, and renal function.

Main Methods:

  • Male TALLYHO/Jng mice (insulin resistant) received continuous insulin or vehicle infusion for 14 days.
  • A subset of insulin-infused mice was fed a high-sodium diet (HSD) during the second week.
  • Evaluated blood chemistry, blood pressure, heart rate, and renal nitric oxide synthase (NOS) activity and expression.

Main Results:

  • Insulin infusion led to higher anion gap and blood sodium, indicating metabolic acidosis.
  • Elevated systolic blood pressure and heart rate were observed with insulin infusion.
  • Despite increased endothelial nitric oxide synthase (eNOS) activity in kidneys, plasma and urine nitrates/nitrites (NOx) decreased, suggesting worsening insulin resistance.

Conclusions:

  • Insulin infusion in insulin-resistant mice induces metabolic acidosis and transiently increases blood pressure.
  • While kidney nitric oxide pathways are upregulated, overall NOx levels decline, indicating impaired nitric oxide bioavailability.
  • Long-term insulin therapy may exacerbate insulin receptor resistance, despite attempts to enhance vasodilatory and natriuretic mechanisms.
Keywords:
blood pressureheart ratehypertensionmetabolic syndromeoxidative stress

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