Insulin Resistance: New Insights into Development, Diagnosis, and Treatment

As we celebrate the centennial of insulin’s discovery, recent research from Endocrine Society journals sheds new light on the often-confounding condition of insulin resistance, its comorbidities, and treatment. 

This month marks the centennial of what can only be called one of the 20th century’s greatest medical breakthroughs: successfully lowering dangerously high blood glucose levels with therapeutic insulin injections. The interdisciplinary medical–research team that included physiologist J. J. R Macleod, surgeon Frederick C. Banting and Banting’s student Charles Best, and biochemist J. B. Collip had thwarted what was until 1922 an automatic death sentence from diabetes-induced hyperglycemia by extracting insulin from cattle.

Although therapy was not discovered until the 20th century, diabetes has been known to physicians for millennia. By the fifth century, ancient doctors in Asia were able to differentiate between types 1 and 2 diabetes, noting that the latter was more common in wealthy individuals (who back then likely ate more and exercised less). This distinction was gradually refined over the next thousand years until Sir Harold Percival Himsworth published research in 1936 describing the phenomenon of insulin resistance. We now classically define it as attenuated sensitivity to insulin-mediated glucose disposal causing such consequences as hyperlipidemia, hypertension, and cardiovascular disease.

While the field of therapeutic insulin development has pushed way past extraction from animal pancreata since the 1980s (with Humulin, a recombinant human insulin formulated in 1978), insulin resistance remains a deeply challenging and complex condition for the hundreds of millions of people globally dealing with it. On the centennial anniversary of the discovery of therapeutic insulin, three recent studies in Endocrine Society journals address this phenomenon in a variety of patients.

Vaping and Insulin Resistance

In “Association Between Smoking Behavior and Insulin Resistance Using Triglyceride-Glucose Index Among South Korean Adults,” published in The Journal of Clinical Endocrinology & Metabolism (JCEM) in June, Eun-Cheol Park, MD, PhD, of the Department of Preventive Medicine and Institute of Health Services Research, Yonsei University College of Medicine, in Seoul, Korea, and team take a look at the association between insulin resistance and smoking behavior, including dual smoking of e-cigarettes and traditional cigarettes, a facet so far understudied.

A total of 11,653 participants ages 19 years and older and excluding patients with known high blood glucose levels from the 2016 – 2018 Korea National Health and Nutrition Examination Survey were divided into four groups: dual-smokers (245), single smokers (1,931), previous smokers (2,312), and never smokers (7,408) and tested for insulin resistance using the triglyceride-glucose (TyG) index, a simple blood test that is less expensive than insulin testing and validated by previous studies as a reliable indicator of insulin resistance.

While the field of therapeutic insulin development has pushed way past extraction from animal pancreata since the 1980s (with Humulin, a recombinant human insulin formulated in 1978), insulin resistance remains a deeply challenging and complex condition for the hundreds of millions of people globally dealing with it.

In general, smoking is believed to contribute to insulin resistance by various proposed pathways. So, not surprisingly, the dual- and single-smoker groups had higher incidences of insulin resistance. When combined with such co-factors as existing abdominal obesity and unhealthy lifestyle behaviors (e.g., frequent alcohol use, reduced exercise), this association more than doubled when compared to the never-smoker group.

Other surprises did emerge, however. Primary among them is that dual-smoking had the highest association of all (although a direct link was not found), despite that e-cigarettes were introduced as a healthy alternative to traditional cigarettes. Another surprise is that studies using the homeostasis model assessment of insulin resistance (HOMA-IR) to assess insulin resistance found no association between insulin resistance and smoking behavior, although this is an indirect method, whereas the TyG index is a direct method. The researchers attribute these conflicting results to the difference in measurement tools.

Future studies should be done to consider specifics such as type of e-cigarette and e-cigarette use only to further determine whether an association between vaping and insulin resistance exists.

Diagnosing Severe Insulin Resistance with Limited Resources

From July’s JCEM, “Approach to Diagnosing a Pediatric Patient With Severe Insulin Resistance in Low- or Middle-Income Countries,” a team of researchers including Abhimanyu Garg MD, of the UT Southwestern Medical Center, Dallas, Texas, and Daniëlle C. M. van der Kaay, MD, PhD, of the Erasmus Medical Center-Sophia Children’s Hospital, in Rotterdam, The Netherlands, propose a clinical method to close a gap in diagnosing extreme insulin resistance in children in developing countries, noting that timely diagnosis and treatment are essential in preventing dangerous complications. While comprehensive diagnostic approaches that can address even the rarest underlying disorders are available in developed countries, such resources are commonly unavailable in low- or middle-income countries.

Based on the case of a 15-year-old Surinamese girl presenting with signs of severe insulin resistance such as excessive insulin requirements to lower blood glucose levels, increased muscularity and marked paucity of body fat, and acanthosis nigricans, Garg, van der Kaay, and team developed a systematic approach to a diagnostic work-up that allows investigation of a broad set of differential diagnoses (e.g., insulin resistance syndromes, endocrinopathies, neuroendocrine tumors, anti-insulin autoantibodies, subcutaneous insulin resistance, medications, lipodystrophy syndromes, other genetic syndromes) through a thorough history and physical examination instead of expensive and possibly hard-to-come-by tests.

Smoking is believed to contribute to insulin resistance by various proposed pathways. So, not surprisingly, the dual- and single-smoker groups had higher incidences of insulin resistance. When combined with such co-factors as existing abdominal obesity and unhealthy lifestyle behaviors (e.g., frequent alcohol use, reduced exercise), this association more than doubled when compared to the never-smoker group.

Any family history of consanguinity, for example, in a child with diabetes should prompt suspicion for underlying genetic causes of insulin resistance. Likewise, from evaluation of body fat distribution in the physical exam alongside any available lab investigations of liver and kidney function, hormone levels, and so on, other clues can emerge. The researchers have created helpful tables that clinicians can consult to match up assessment data with possible interpretations.

Meanwhile, their Surinamese patient’s hyperglycemia persisted four months after admission to the hospital despite several treatment approaches. Ultimately, genetic testing revealed her as having congenital generalized lipodystrophy type 1, also known as Berardinelli–Seip syndrome, that occurs particularly in children with consanguineous parents. The researchers believe, however, that such lipodystrophies can be diagnosed based on the overall clinical picture. At the time of study publication, their patient was stable, and without disabling visual or renal complications of diabetes.

“We provide a systematic approach to the differential diagnosis and work-up to clinically diagnose a child with insulin-resistant diabetes mellitus,” says van der Kaay.

Gut Dysbiosis and Insulin Resistance

Finally, from the October issue of Endocrinology, “Intestinal Flora is a Key Factor in Insulin Resistance and Contributes to the Development of Polycystic Ovary Syndrome,” by Hong-Wei Zhou, PhD, of the Microbiome Medicine Center, Division of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, in Guangzhou, China, and team examined how dysbiosis might contribute to disordered glucose metabolism in patients with polycystic ovary syndrome (PCOS).

With evidence accumulating that the gut microbiota is involved in the etiology of insulin resistance, they compared the gut microbiome of healthy study participants with that of patients with PCOS. Prior studies demonstrated inconsistent results regarding type of bacterial species in the microbiota of these patients.

Participants included 56 patients with PCOS (according to the Rotterdam criteria) and 31 healthy controls recruited from the Gynecology and Obstetrics outpatient clinic at the Zhujiang Hospital of Southern Medical University. They provided stool samples, which were then transplanted into mice. Notably, the stool samples from patients with PCOS had high levels of Bacteroidetes, a potentially characteristic finding of PCOS intestinal flora that bears further investigation. Compared with mice transplanted with stool from healthy controls, mice transplanted with stool from individuals with PCOS displayed insulin resistance but not disordered glucose metabolism.

From evaluation of body fat distribution in the physical exam alongside any available lab investigations of liver and kidney function, hormone levels, and so on, other clues can emerge. The researchers have created helpful tables that clinicians can consult to match up assessment data with possible interpretations.

PCOS mice given a 35-day antibiotic cocktail treatment improved in terms of both phenotype and insulin resistance, suggesting that the presence of Bacteroidetes in the gut microbiome may indeed be a factor in insulin resistance and may promote the pathogenesis of PCOS. These mice also demonstrated decreased serum testosterone and increased cecal farnesoid X receptor levels, which activates the bile acid chenodeoxycholic acid ([CDCA] found in reduced levels in PCOS from Bacteroidetes hydrolysis). When the PCOS mice were treated with CDCA, glucose levels improved.

Thus, the intestinal flora might be a target for therapy in patients with PCOS, ameliorating the insulin resistance that led to the development of PCOS in these patients.

As these three studies show, the complexities of insulin resistance continue to emerge, but researchers are discovering new ways to diagnose it and ultimately to treat it.

Horvath is a freelance writer based in Baltimore, Md. In the August issue, she wrote the cover story on the usefulness of a prediabetes designation in older adults.

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