Human Kallistatin Ameliorates Insulin Resistance in Diet Induced Obese Mice

Kallistatin (KST), or SERPIN A4, is a circulating plasma protein with anti-angiogenic and anti-inflammatory properties. Clinical studies in humans revealed increased levels of KST in poor glycemic control and microvessel disease. Whether KST has a direct effect on glucose homeostasis in the setting of insulin resistance and T2D is currently unknown.

To address this question, the expression of human KST in subcutaneous white adipose tissue (sWAT) of obese patients (n=47) before and after 6 months of dietary intervention (B-SMART study) was measured. There was a more than 1.5-fold increase in KST expression in subjects with a body weight loss of more than 6% after intervention.

For in depth understanding of this association, we studied transgenic mice overexpressing human KST systemically (hKST-TG) and wildtype mice (WT) under chow (ND) and high fat diet (HFD) conditions. Body weights were similar between hKST-TG and WT mice up to an age of 24 weeks on both diets. Intraperitoneal glucose tolerance tests (IPGTT) yielded similar glucose and insulin excursion curves in ND animals. In the weight matched HFD cohort, IPGTT revealed an improvement in glucose tolerance in hKST-TG mice. Additionally, HOMA-IR was significantly lower in hKST-TG on HFD. In hyperinsulinemic euglycemic clamp studies with tracer labelled glucose, glucose infusion rates were higher in hKST-TG mice. Specifically, hKST overexpression protected against HFD induced hepatic insulin resistance.

We conclude that human KST protects from diet induced insulin resistance in mice and that increased KST levels in the setting of poor glycemic control might be of compensatory nature.

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Artikel online veröffentlicht:
26. Mai 2022