When to Suspect Metabolic Syndrome

Given the widespread and increasing prevalence of metabolic dysfunction,1 being able to assess patient risk during a physical exam has become increasingly important. For many, obesity may be seen as the first indicator of this dysfunction, but research suggests that not all obese patients are metabolically unhealthy.2 The converse is also true; approximately 20% of normal-weight individuals are estimated to have metabolic disturbances.3 Moreover, certain conditions may predispose a patient to metabolic dysfunction, as can prescribed medications. How can clinicians move beyond BMI and use advanced physical exam skills and a comprehensive patient history to provide clues to insulin resistance in individuals of all body types?

IFM educator Kristi Hughes, ND, discusses ways to gain deeper insight into patients’ unique metabolic states:

Kristi Hughes, ND, is IFM’s director of medical education. At her clinic in Minnesota, she manages an integrated team of healthcare providers: naturopathic physicians, nurses, acupuncturists, massage therapists, and lifestyle coaches.
Beyond BMI

The first head-to-head comparison of a large number of cardiometabolic risk phenotypes revealed that normal-weight people (as defined by a BMI of <25 kg/m2) may experience insulin secretion failure, insulin resistance, and increased carotid intima-media thickness (cIMT).3 According to the study, insulin secretion failure may be of major relevance for cardiometabolic risk in normal-weight patients, as it promotes hyperglycemia. Furthermore, compared to people who are of normal weight and metabolically healthy, subjects who are of normal weight but metabolically unhealthy (~20% of the normal-weight adult population) have a greater than three-fold higher risk of all-cause mortality and/or cardiovascular events.3

A variety of factors may increase the likelihood of metabolic syndrome, including:

  • Celiac disease: A 2015 study of patients with celiac disease showed a high risk of metabolic syndrome one year after starting a gluten-free diet; the authors suggested potential causes such as an improvement in intestinal absorption and the subjects eating foods that were higher in sugar, fat, and calories after going gluten-free.4 A 2018 study found that in celiac disease patients, following a gluten-free diet may contribute to the development of metabolic syndrome.5
  • Polycystic ovary syndrome (PCOS): In women with polycystic ovary syndrome, the risk of developing gestational diabetes is approximately three times greater than in non-PCOS women;6 insulin resistance occurs in 30% of lean women with PCOS.7
  • Schizophrenia: A genetics study in 2014 found that a large percentage (45%) of patients with schizophrenia using clozapine as the primary treatment modality suffered metabolic adverse effects.8
  • Stress: Stress has also been seen as a precursor to metabolic syndrome. A five-year longitudinal study in a rapid response police unit supports the hypothesis that work-related stress induces metabolic syndrome, particularly through its effects on blood lipids.9
Diagnosing Metabolic Syndrome

With the results of these studies in mind, how can clinicians identify metabolic disease in patients with all body types and conditions?

One study suggests that manifestations of insulin resistance on the skin may be more reliable than other forms of diagnosis.10 Skin manifestations may also indicate severity of metabolic syndrome.11 Even in children and adolescents, acanthosis nigricans offers a reliable physical exam clue for metabolic syndrome.12 Other physical signs of metabolic syndrome can be hirsutism,13 peripheral neuropathy,14 and xanthelasma palpebrarum.15 Inflammation also appears to play a key role in the development of insulin resistance and future atherogenesis in patients with metabolic syndrome.16 Another major physiological change in cardiometabolic syndrome and its associated diseases is excess cellular oxidative stress and oxidative damage to mitochondrial components.17

Researchers suggest that when a patient with normal weight has two or more parameters of the metabolic syndrome, it is important to determine whether impaired glucose tolerance, fatty liver, or early atherosclerosis is present.3 The physical exam offers numerous ways to zero in on nutritional and metabolic concerns to help the clinician precisely understand the pathophysiology of cardiometabolic disease and develop targeted lifestyle and pharmacological interventions.3 With early diagnosis and intervention, the disease course of metabolic syndrome may be controlled or even reversed.

Learn more about lifestyle modifications to modify cardiometabolic disease risk

Gain some clinical pearls on cardiometabolic treatment

Read about the effects of the microbiome on cardiovascular health


  1. Kelli HM, Kassas I, Lattouf OM. Cardio metabolic syndrome: a global epidemic. J Diabetes Metab. 2015;6(3):513. doi:10.4172/2155-6156.1000513.
  2. Jung CH, Lee WJ, Song KH. Metabolically healthy obesity: a friend or foe? Korean J Intern Med. 2017;32(4):611-621. doi:10.3904/kjim.2016.259.
  3. Stefan N, Schick F, Häring HU. Causes, characteristics, and consequences of metabolically unhealthy normal weight in humans. Cell Metab. 2017;26(2):292-300. doi:10.1016/j.cmet.2017.07.008.
  4. Tortora R, Capone P, De Stefano G, et al. Metabolic syndrome in patients with coeliac disease on a gluten-free diet. Aliment Pharmacol Ther. 2015;41(4):352-359. doi:10.1111/apt.13062.
  5. Ciccone A, Gabrieli D, Cardinale R, et al. Metabolic alterations in celiac disease occurring after following a gluten-free diet. Digestion. 2018;14:1-7. doi:10.1159/000495749.
  6. Yao K, Bian C, Zhao X. Association of polycystic ovary syndrome with metabolic syndrome and gestational diabetes: aggravated complication of pregnancy. Exp Ther Med. 2017;14(2):1271-1276. doi:10.3892/etm.2017.4642.
  7. Baldani DP, Skrgatic L, Ougouag R. Polycystic ovary syndrome: important underrecognised cardiometabolic risk factor in reproductive-age women. Int J Endocrinol. 2015;2015:786362. doi:10.1155/2015/786362.
  8. Faasen N, Niehaus DJH, Koen L, Jordaan E. Undiagnosed metabolic syndrome and other adverse effects among clozapine users of Xhosa descent. S Afr J Psyc. 2014;20(2):a528. doi:10.4102/sajpsychiatry.v20i2.528.
  9. Garbarino S, Magnavita N. Work stress and metabolic syndrome in police officers. A prospective study. PLoS One. 2015;10(12):e0144318. doi:10.1371/journal.pone.0144318.
  10. González-Saldivar G, Rodríguez-Gutiérrez R, Ocampo-Candiani J, González-González JG, Gómez-Flores M. Skin manifestations of insulin resistance: from a biochemical stance to a clinical diagnosis and management. Dermatol Ther. 2017;7(1):37-51. doi:10.1007/s13555-016-0160-3.
  11. Huang Y, Chen J, Wang X, Li Y, Yang S, Qu S. The clinical characteristics of obese patients with acanthosis nigricans and its independent risk factors. Exp Clin Endocrinol Diabetes. 2017;125(3):191-195. doi:10.1055/s-0042-123035.
  12. Velazquez-Bautista M, López-Sandoval JJ, González-Hita M, Vázquez-Valls E, Cabrera-Valencia IZ, Torres-Mendoza BM. Association of metabolic syndrome with low birth weight, intake of high-calorie diets and acanthosis nigricans in children and adolescents with overweight and obesity. Endocrinol Diabetes Nutr. 2017;64(1):11-17. doi:10.1016/j.endinu.2016.09.004.
  13. Talaei A, Adgi Z, Mohamadi Kelishadi M. Idiopathic hirsutism and insulin resistance. Int J Endocrinol. 2013;2013:593197. doi:10.1155/2013/593197.
  14. Stino AM, Smith AG. Peripheral neuropathy in prediabetes and the metabolic syndrome. J Diabetes Investig. 2017;8(5):646-655. doi:10.1111/jdi.12650.
  15. Nair PA, Singhal R. Xanthelasma palpebrarum – a brief review. Clin Cosmet Investig Dermatol. 2018;11:1-5. doi:10.2147/CCID.S130116.
  16. Devaraj S, Jialal I. The skinny on metabolic syndrome in adolescents. Transl Pediatr. 2016;5(2):97-99. doi:10.21037/tp.2016.03.06.
  17. Anupama N, Sindhu G, Raghu KG. Significance of mitochondria on cardiometabolic syndromes. Fundam Clin Pharmacol. 2018;32(4):346-356. doi:10.1111/fcp.12359.

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