The centenary of insulin’s isolation, and its seismic impact on the treatment of diabetes mellitus, have received worldwide commemoration. Such has the impact of insulin been in diabetes, however, and so potent is it at lowering blood glucose, that its complex additional metabolic growth-promoting effects are commonly under-appreciated. This glucocentric perspective on insulin action can lead us to overlook important aspects of the disorder we call ‘insulin resistance’ (IR).¹

UNDERSTANDING IR

IR is defined by a decreased ability of insulin to lower blood glucose. Providing the pancreatic β-cells are fully functional, the response to IR is to make more insulin, until blood concentrations are high enough to return blood glucose to normal. If this simply compensated for reduced insulin responsiveness, and if all insulin’s actions were blunted to a similar degree, then an affected person would be restored to normal, albeit with elevated blood insulin levels. However this is not what is seen.

IR is closely associated with non-alcoholic fatty liver disease, polycystic ovary syndrome, a velvety thickening of flexural skin called acanthosis nigricans, soft tissue overgrowth resembling acromegaly in severe cases, and increased risk of some cancers.² These are all likely consequences of high insulin levels, which appear capable of exerting growth and other effects, despite IR. In other words, the clinical syndrome of IR is actually a mixture of reduced insulin action, and likely secondary increased insulin action due to compensatory hyperinsulinaemia.³

The mechanisms which attenuate insulin’s actions in some target tissues but not others are challenging to dissect in humans with common IR of unknown cause. Many common and important components of the IR syndrome are not seen in mice. A fruitful line of enquiry has thus been to evaluate people with rare syndromes of severe IR caused by single gene defects.

SEVERE IR SYNDROMES

Severe IR syndromes include primary disorders of the cellular insulin signalling pathway, for example genetic or acquired dysfunction of the insulin receptor itself, or of downstream signalling components, and lipodystrophy syndromes, defined by partial or complete absence of adipose (fat) tissue, with numerous causative genes.² Both groups exhibit reduced glucose lowering by insulin, polycystic ovaries and hyperandrogenism, acanthosis nigricans, and other soft tissue overgrowth depending on IR severity. These can be regarded as core features of the IR syndrome.

More surprisingly, while lipodystrophy is associated with severe dyslipidaemia and fatty liver – effectively a severe form of the obesity-associated metabolic syndrome – these are not seen in primary IR.⁴ This underscores the critical role of adipose tissue as a buffer and regulator of inter-organ energy and substrate fluxes. Overloading adipose tissue – whether in lipodystrophy or unhealthy obesity – produces ‘lipotoxicity’ in distant organs such as the liver. This causes local and systemic inflammation, and fatty liver, among other problems, as well as causing IR. The converse is not true, however, and the absence of lipotoxicity in primary IR indicates that lipotoxicity is likely a consequence of ‘adipose failure’ itself.⁵

COMMON ‘IR SYNDROME’

So, it appears that the common ‘IR syndrome’ may actually be explained by a combination of adipose failure and IR, combining to produce lipotoxic IR. But this still fails to explain how IR produces features of increased insulin-like action, especially on soft tissues.

It is theorised, with some supporting evidence, that certain tissues are more insulin-resistant than others, due to different local configurations of their insulin signalling pathways.⁶ This means that they may ‘see’ compensatory hyperinsulinaemia differently. In some tissues, IR will be perfectly balanced by increased insulin concentrations, while other, less insulin-resistant tissues will show increased insulin action: a ‘bystander’ effect of correcting blood glucose levels. It is also plausible that highly increased insulin concentrations activate signalling via the insulin-like growth factor-1 (IGF-1) receptor in some tissues, a possibility supported by the soft tissue overgrowth seen in infants with extreme IR and no functional insulin receptor. This concept of partial or selective IR has been articulated since at least the 1980s, and may yet yield novel strategies to mitigate some IR-related diseases.⁷ Much work remains to be done, probably in humans, to understand it fully.

DISEASE MANAGEMENT

In keeping with much rare disease, the evidence base for targeted treatment in monogenic IR is relatively thin, with no randomised clinical trials, but key principles and strategies have emerged.⁸ 

Management of lipodystrophy recognises it as a state of ‘adipose failure’, and prioritises adipose ‘offloading’, just as we would diurese to offload a failing heart. This means caloric restriction to reduce the burden of lipotoxicity, assisted in severe cases by recombinant human leptin, which lowers pathologically increased appetite. Bariatric surgery has shown promise in partial lipodystrophy, even where body mass index is below normal thresholds for surgery. In a complementary approach, pioglitazone can expand residual adipose depots and raise the threshold for lipotoxicity, though often at the expense of aesthetic distress. 

Treatment for primary IR focuses on insulin-sensitising agents and suppressing hyperandrogenism in women. Recombinant human IGF-1 has been reported as helpful in extreme cases, whilst use of gonadotrophin-releasing hormone analogues can reduce even the most extreme levels of IR-associated hyperandrogenaemia.⁹

As endocrinologists, we face the consequences of IR every day, albeit in different guises. Thanks to our patients with severe IR, we can move towards a more nuanced understanding of insulin’s pleiotropic actions, in which the tissue-specific consequences of both under- and over-insulinisation are appreciated. Not only do these insights guide current management strategies in our patients with monogenic IR, but they provide an important framework for developing new approaches to tackling common IR and its consequences.

ISABEL HUANG-DORAN
Wellcome Trust–MRC Institute of Metabolic Science, University of Cambridge

ROBERT K SEMPLE
Centre for Cardiovascular Science, University of Edinburgh

REFERENCES

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