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Multiple Metabolic Abnormalities Seen in Lupus

— Targeting insulin resistance alone won't be enough

MedpageToday

Lupus patients had a bi-hormone metabolic abnormality characterized by increased insulin resistance and glucagon levels, despite normal glucose tolerance, according to a Brazilian study.

When compared with a control group, patients with systemic lupus erythematosus (SLE) had higher insulin resistance and hyperglucagonemia, even when their fasting glucose, glucose response, and skeletal muscle GLUT4 translocation appeared normal, reported Fabiana Benatti, PhD, of the University of Sao Paulo School of Medicine, and colleagues.

Action Points

  • Note that this meal-tolerance study suggested that patients with mild or inactive lupus had greater indices of insulin resistance than healthy controls.
  • Be aware that the small sample size precluded final adjustment for potential confounders.

Specifically, SLE patients who underwent meal tolerance tests (MTT) showed higher:

  • Fasting insulin levels: effect size 1.2 (P=0.01)
  • Homeostatic model assessment of insulin resistance (HOMA IR): effect size 1.1 (P=0.03)
  • Insulin-to-glucose ratio response to MTT: effect size 1.2 (P=0.02)
  • Fasting glucagon levels: effect size 2.7 (P=0.002)
  • Glucagon response to MTT: effect size 2.6 (P=0.0001)

They also showed a tendency toward lower Matsuda index of whole-body insulin sensitivity (effect size 0.5, P=0.06), the authors wrote in .

"Strategies capable of ameliorating insulin sensitivity to reduce the risk of type 2 diabetes and cardiovascular disease in SLE may require more than targeting insulin resistance alone," the authors stated.

This is the first study to use MTT to evaluate insulin sensitivity in lupus patients and the potential molecular mechanisms involved in insulin signaling in SLE, according to the authors, as previous studies did not control for confounding factors that significantly affect insulin sensitivity -- physical activity, body composition, food intake -- or provided static estimates that may have reflected primarily hepatic insulin sensitivity.

Benatti's group studied adult female patients with mild or inactive SLE (n=33) and healthy female controls (n=16), matched by age and BMI. All participants underwent a MTT and were evaluated for insulin sensitivity and beta-cell function.

They assessed skeletal protein expressions of total and membrane GLUT4 (SLE n=10; control group n=5) by performing muscle biopsies after MTT. They also measured inflammatory cytokines, adipocytokines, physical activity levels, body composition, and food intake.

They observed that despite similar glucose tolerance, SLE patients had higher insulin resistance than the control group. This increase occurred despite similar levels of physical activity, body composition (especially total and trunk fat), and food intake between the two groups.

The authors noted that one of the most striking findings of the study was that the higher insulin levels in SLE patients were not able to control glucagon production. Although glucose and insulin effectively suppressed glucagon secretion during MTT, the SLE group's glucagon levels remained higher than the control group's levels at all times.

Because patients, and has been independently , the researchers speculated that the pancreatic alpha cell of SLE patients may be less responsive to the inhibitory action of insulin in the presence of insulin resistance, potentially playing a role in the development of type 2 diabetes.

The investigators also noted that insulin sensitivity was correlated with inflammation markers C-reactive protein and leptin, which could point to inflammation having a role in insulin resistance in SLE.

They added that drugs -- notably, prednisone and hydroxychloroquine -- could have influenced their results.

"Corticosteroids have been shown to decrease glucose tolerance by increasing hepatic glucose production and decreasing peripheral glucose uptake via a decrease in skeletal muscle and adipose tissue insulin sensitivity," they stated. "Because 30% of our SLE patients were using prednisone, this could have contributed to the higher insulin resistance observed in this group."

In contrast, patients has been linked to lower levels of fasting glucose and HOMA IR, and reduced risk of type 2 diabetes. The researchers did not observe any association between hydroxychloroquine use and insulin sensitivity. "However, because 70% of our patients were using this medication, it is possible that hydroxychloroquine may have attenuated potential deleterious effects of prednisone on insulin sensitivity," they wrote.

has been suggested as a major cause of insulin resistance and type 2 diabetes and also could partially explain their results, they said.

Study limitations included those inherent in MTT and sample selection. Although MTT allows whole-body insulin sensitivity calculations, it does not differentiate between hepatic and peripheral insulin resistance, the authors noted.

They also cautioned that their results might apply only to lupus patients who are in remission and cannot be extrapolated to other SLE populations.

"Larger studies including patients with active disease may also be needed to further explore the role of inflammation and drug intake (alone or combined) on insulin sensitivity and glucagon levels and their impact on long-term cardiovascular disease risk," they stated.

Disclosures

The study was supported by Fubdacao de Amparo a Pesquisa do Estado de Sao Paulo and Conselho Nacional de Desenvolvimento Cientifico de Tecnologico.

Benatti and co-authors disclosed no relevant relationships with industry.

Primary Source

Arthritis Care & Research

Miyake N, et al "Increased insulin resistance and glucagon levels in mild/inactive systemic lupus patients despite normal glucose tolerance" Arthritis Care Res 2017; DOI:10.1002/acr.23237.