NK cell activation initiates type II diabetes

Type II diabetes is a complex syndrome involving endocrine, immune and metabolic abnormalities. It is well known that obesity can lead to type II diabetes. But how?

New study in Nature Immunology suggests that obesity-induced adipocyte stress activates NK cells  via NCR1 receptor driving IFN-γ mediated insulin insensitivity characteristic to type II diabetes.

The authors observed that NK cell depletion in mice fed high fat diet (HFD) ameliorated insulin insensitivity and glucose intolerance.

Ex vivo examination of visceral adipose tissue (VAT), a target tissue of type II diabetes, revealed that HFD induced expression of NK cell ligand in VAT detected by NCR1 (NKp46 in humans).

Interestingly, VAT but not subcutaneous (Sc fat) adipose tissue from HFD fed mice could stimulate NK cells.

In vivo experiments confirmed that NCR1 deficiency improved insulin sensitivity.

Finally, the authors showed that IFN-γ derived from NCR1 activated NK cells promotes inflammatory macrophages in VAT leading to glucose intolerance, that can be ameliorated with NCR1 blockade.

In summary, these results showed that HFD induces visceral adipose tissue stress that activates local NK cells via NCR1 ligand leading to inflammatory macrophage polarization and reduced insulin sensitivity. Targeting NK cell activation may interrupt this disease cycle and improve type II diabetes management.

I was always wondered why diet-induced obesity leading to VAT stress should activate inflammatory, M1 type macrophages? What is an evolutionary advantage for such response, in general? No idea.  

David Usharauli

Stress-release with IL-22

Type II Diabetes (T2D) is part of a complex metabolic syndrome. Typically, conditional insulin deficiency as observed during T2D is a result of an imbalance between production and demand for insulin. I always wondered why would nature develop such a system where packaging of excess glucose would be controlled by a single molecule (insulin), while glucose unpacking, it's release into bloodstream are controlled by so many molecules, including corticosteroids.

Prevalence of T2D is increasing in modern population. Speculation varies as to the cause of such increase in T2D (availability of excess food, poor physical activity, widespread use of broad-spectrum antibiotics causing changes in gut microflora, etc).

Frequently the metabolic syndrome is associated with the changes in immune cytokines. Occasionally, immune cytokines are directly implicated in disease, for example IL-17 and TNF-alpha in psoriasis or rheumatoid arthritis.

On other hand, the list of immune cytokines are constantly expanding and maybe some of them would show a beneficial effect.

This new paper in Nature Medicine is one such research. This study, led by Michael McGuckin from the University of Queensland (Australia), has uncovered the protective role for cytokine IL-22 in T2D. 

IL-22 is a member of IL-10 cytokine super-family that includes IL-10, IL-22, IL-24, IL-26, so far.

Using in vitro assay to measure beta cell ER stress, the authors showed that IL-23, IL-24, IL-33 were the potent inducers of ER stress.

Parallel experiments with beta cell exposure to the pairwise combination of cytokines revealed that IL-22 (and IL-10) could reverse ER stress caused by any other cytokines examined, including IL-23, IL-24, IL-33. Two exceptions were IL-17A for IL-22 and IL-17F for IL-10 for which the effectiveness of such inhibition were less prominent.

As a consequence of reduced ER stress, IL-22 was able to improve secretion of insulin from primary mouse beta islets.

Importantly, using high-fat diet induced obesity mouse model (HF-DIO mouse), the authors showed that in vivo treatment with IL-22 could reduce beta cell ER stress and reverse decline in insulin secretion in response to HF diet.

In addition, IL-22 treatment could reverse high-fat diet effect on body weight and glucose tolerance.  

Mechanistically, this beneficial effect of IL-22 was associated with decrease in ER-stressor inflammatory cytokines and in increase for enzymes responsible for neutralization of free radicals.

Finally, the authors showed that this beneficial effect of IL-22 could be reproduced in an in vitro experiments with human beta islets as well.

In summary, this figure-packed research showed that IL-22 can have a protective characteristics beneficial for management of beta cell functions.

It is not immediately clear why immune cytokines play such important roles in non-immune functions. For example, why would IL-23 induce beta cell stress and reduce insulin secretion? Similarly, it is not clear why IL-22 would develop protective function for beta cells. Previous studies showed that IL-22 has a protective role in gut epithelial cell function (probably through it's effects on cell surface fucosylation). On the other hand, IL-22 has been implicated in promoting skin epithelial hyper-proliferation characteristic to psoriasis. So, the field is quite confusing, to say the least.

David Usharauli