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Diabetes Watch

Understanding The Relationship Of Metabolic Syndrome And Pre-Diabetes

First describing metabolic syndrome in 1988, Reaven discussed several metabolic findings with this syndrome and proposed that the central characteristic is insulin resistance with an increased risk for diabetes and cardiovascular disease.1

The World Health Organization established a more formal description of metabolic syndrome, stressing the requirement of insulin resistance as a major factor for diagnosis.1 Due to multiple organizations having their own definition of the syndrome, a joint scientific statement in 2009 established a criteria for diagnosis of metabolic syndrome (see the table “A Closer Look At The Criteria For The Diagnosis Of Metabolic Syndrome” at left).1 The presence of three of five risk factors constitutes a diagnosis of metabolic syndrome. The key to understanding metabolic syndrome is remembering that it is not a disease but a clustering of individual risk factors for disease.

Often confused with metabolic syndrome, pre-diabetes is an intermediate condition between true diabetes mellitus and normoglycemia. The American Diabetes Association (ADA) defines pre-diabetes as a hemoglobin A1C ranging from 5.7% to 6.4%, a fasting plasma glucose ranging from 100 mg/dL to 125 mg/dL and an oral glucose tolerance ranging from 140 mg/dL to 199 mg/dL.2 As our obese, hypertensive, inactive, unhealthy patients slowly develop insulin resistance, they also often begin to develop pre-diabetes. In 2010, an estimated 79 million people over the age of 20 in the United States had pre-diabetes with only 11 percent of those people aware of their condition.3 This is where screening and proactive steps by physicians of varying specialties can assist in identifying patients at risk, and setting them on paths of treatment.

Although not all patients with pre-diabetes progress to type 2 diabetes, the literature cites a 70 percent progression/conversion rate.4 Nathan and colleagues showed that within a three- to five-year time period, 25 percent of patients with pre-diabetes progress to type 2 diabetes, 25 percent revert to regular glucose tolerance and 50 percent stay in the pre-diabetes class.4 The timeline of progression for those who convert from pre-diabetes to diabetes varies greatly but averages 29 months.5 It is important that we screen anyone older than 45 (especially those who are overweight/obese) and counsel our patients on prevention methods including diet, exercise, and medical management with their primary care physician.4 The ADA reports that lifestyle changes can have a more profound impact on disease progression than early treatment with medication.6–9

What You Should Know About The Risk Factors

With a more clear definition of metabolic syndrome, one can appreciate the accumulation of these risk factors as a potential for metabolic issues, specifically related to cardiovascular disease and diabetes.1 It is important to understand, however, that these conditions may or may not occur together, and it is possible for a patient with metabolic syndrome not to have pre-diabetes or diabetes, or vice versa. Many of the comorbidities of the two conditions often coincide but the actual criteria to make a diagnosis are not the same.

That being said, metabolic syndrome and pre-diabetes often do coexist, and both play a significant role in various pathologies such as cardiovascular disease, peripheral neuropathy, fatty liver, cancer, and the progression from normoglycemia through pre-diabetes to full type 2 diabetes.1

Obesity, a risk factor for metabolic syndrome, is strongly associated with all cardiovascular disease risk factors while researchers have cited a link between obese adipose tissue releases of several pathogenic molecules (i.e., fatty acids, cytokines) that may induce insulin resistance.10

While having pre-diabetes alone minimally increases the risk of vascular disease, the comorbidities that often lead to pre-diabetes and metabolic syndrome are themselves risk factors.11 Metabolic syndrome and pre-diabetes both include hypertension and endothelial dysfunction as well as a pro-inflammatory, pro-oxidant and prothrombotic environment. These lend themselves to both peripheral vascular and cardiovascular disease.11 An unhealthy endothelium leads to stiffening of the vessels and decreased vasodilation, which in turn contributes to hypertension and peripheral edema.

To compound this, insulin resistance has a strong link to atherogenic dyslipidemia, pro-inflammatory states and is a risk factor for cardiovascular disease.12 Sixty-one percent of newly diagnosed patients with type 2 diabetes also fit the criteria for metabolic syndrome and are at a significantly higher risk of stroke or myocardial infarction in a 10-year period while patients with metabolic syndrome have a five- to sevenfold increased risk of developing type 2 diabetes.1

The same chronic metabolic inflammation and oxidative stress that leads to vascular disease are also driving factors of peripheral neuropathy. A study examining patients with metabolic syndrome and peripheral neuropathy found that while glucose control had a strong positive effect on those with type 1 diabetes, it only had a marginal effect on those with type 2 diabetes, suggesting that factors other than glucose alone were driving nerve injury in patients with type 2 diabetes.13 This begs the question: are patients with type 2 diabetes or those with pre-diabetes likely to already have nerve damage secondary to their many comorbidities? Other studies suggest that having a greater number of components of metabolic syndrome (independent of glycemic status) may play a role in nerve injury, not just in patients with type 2 diabetes but in those with idiopathic peripheral neuropathy as well.14,15

The patient populations that we must recognize as being at higher risk of complications from metabolic syndrome or pre-diabetes include those with known atherosclerosis and vascular disease, a positive family history and genetic background, and phenotypes of insulin resistance (i.e., obesity, polycystic ovary syndrome, women with gestational diabetes, men with androgen deficiency).16 The gender of your patient could play a role not only in his or her risk factors, but also in how you counsel the patient. A recent study noted that physical activity was more important in the outcome of pre-diabetes in men while waist circumference reduction was more important in women.17

Key Insights On Treatment Options

We must recognize the patients who are most likely to follow the progression of the disease as this could very well affect how we choose to treat them with regard to conservative versus surgical treatments, adjunctive therapies, preventative care, multi-specialty care (i.e., cardiologist, vascular surgeon, endocrinologist and dietician), etc.

Treatment recommendations are twofold. The first is management of underlying risk factors.12 This includes targeting overweight/obesity, physical inactivity and dietary modifications through an emphasis on modifying the lifestyles of these patients. Second is the management of metabolic risk factors. This first starts with a risk assessment and any necessary lab work to identify the presence and severity of these factors. Treatments target atherogenic dyslipidemia, hypertension, insulin resistance/hyperglycemia, prothrombotic states and proinflammatory states.12 Grundy and colleagues offered specific treatment recommendations (see the table “Treatment Recommendations For Metabolic Syndrome Development” at left).9,12,18

Appreciating these risk factors is important in our daily treatment of these patients and our perioperative considerations. While a diagnosis of pre-diabetes or metabolic syndrome carries some additional surgical risk, these diagnoses alone are not a relative contraindication to elective surgical treatment. These patients may carry a higher risk of prolonged postoperative edema or slower healing secondary to their gradually progressing vascular disease, neuropathy, and pro-inflammatory cytokines. Those with hypertension may need extra attention when one is using a tourniquet. Additionally, metabolic syndrome is linked with similar pathways as osteoporosis, which can play a role in your expectations of bone healing or your choice in surgical fixation options.7 As always, evaluating whether someone is a good surgical candidate is a much larger picture than just one diagnosis.

Final Words

In the end, it is vital that we not only understand the disease but understand how to screen and guide our patients accordingly. A great advantage of the recommended intervention for lifestyle modification in treating pre-diabetes and metabolic syndrome is that it presents few to no drawbacks while addressing multiple risk factors such as hyperglycemia, hypertension, hyper/dyslipidemia, and obesity, all without the potential of adding medications to treat each factor. By determining if a patient has pre-diabetes or metabolic syndrome, and encouraging the aforementioned recommendations, the physician and colleagues through a multidisciplinary approach can provide the starting point to adopt a healthier lifestyle and decrease the conversion rate from carrying risk factors to having actual disease.

Dr. Hood is a fellowship-trained foot and ankle surgeon associate at Premier Orthopaedics and Sports Medicine in Malvern, PA. He is on the faculty of the Phoenixville Hospital Podiatric Medicine and Surgery Residency Program in Phoenixville, PA, and the Suburban Community Hospital Podiatry Residency Program in East Norriton, PA. Follow Dr. Hood on Twitter at @crhoodjrdpm.

Dr. Kragt is a second-year resident within the Phoenixville Hospital Podiatric Medicine and Surgery Residency in Phoenixville, PA.

Dr. Badaczewski is a second-year resident within the Suburban Community Hospital Podiatry Residency Program in East Norriton, PA.

References

  1. Samson SL, Garber AJ. Metabolic syndrome. Endocrinol Metab Clin North Am. 2014;43(1):1-23.
  2. Papanas N, Ziegler D. Prediabetic neuropathy: does it exist? Curr Diab Rep. 2012;12(4):376-383.
  3. Centers for Disease Control and Prevention. Morbidity and mortality weekly report: awareness of prediabetes - united states, 2005-2010. MMWR Morb Mortal Wkly Rep. 2012;61(11):181-196.
  4. Nathan DM, Davidson MB, DeFronzo RA, et al. Impaired fasting glucose and impaired glucose tolerance: Implications for care. Diabetes Care. 2007;30(3):753-759.
  5. Fonseca VA. Defining and characterizing the progression of type 2 diabetes. Diabetes Care. 2009;32 Suppl 2(November):S151-S156.
  6. Islam MR, Attia J, Ali L, et al. Zinc supplementation for improving glucose handling in pre-diabetes: a double blind randomized placebo controlled pilot study. Diabetes Res Clin Pract. 2016;115:39-46.
  7. Kawahara T, Suzuki G, Inazu T, et al. Rationale and design of diabetes prevention with active vitamin d (dpvd): a randomised, double-blind, placebo-controlled study. BMJ Open. 2016;6(7):1-8.
  8. Taltavull N, Ras R, Mariné S, et al. Protective effects of fish oil on pre-diabetes: a lipidomic analysis of liver ceramides in rats. Food Funct. 2016;7(9):3981-3988.
  9. Vendrame S, Del Bo’ C, Ciappellano S, Riso P, Klimis-Zacas D. Berry fruit consumption and metabolic syndrome. Antioxidants. 2016;5(34):1-21.
  10. Han TS, Lean ME. A clinical perspective of obesity, metabolic syndrome and cardiovascular disease. JRSM Cardiovasc Dis. 2016;5(10):1-13.
  11. McCain J. Prediabetes: pre- does not mean preordained. Manag Care. 2016;25(5):35-41.
  12. Grundy SM, Hansen B, Smith SC, Cleeman JI, Kahn RA. Clinical management of metabolic syndrome: report of the American Heart Association/National Heart, Lung, and Blood Institute/American Diabetes Association Conference on Scientific Issues Related to Management. Circulation. 2004;109(4):551-556.
  13. Callaghan BC, Xia R, Reynolds E, et al. Association between metabolic syndrome components and polyneuropathy in an obese population. JAMA Neurol. 2016;73(12):1468-1476.
  14. Callaghan BC, Xia R, Banerjee M, et al. Metabolic syndrome components are associated with symptomatic polyneuropathy independent of glycemic status. Diabetes Care. 2016;39(5):801-807.
  15. Lee CC, Perkins BA, Kayaniyil S, et al. Peripheral neuropathy and nerve dysfunction in individuals at high risk for type 2 diabetes: The promise cohort. Diabetes Care. 2015;38(5):793-800.
  16. Kong APS, Luk AOY, Chan JCN. Detecting people at high risk of type 2 diabetes- how do we find them and who should be treated? Best Pract Res Clin Endocrinol Metab. 2016;30(3):345-355.
  17. Song X, Qiu M, Zhang X, et al. Gender-related affecting factors of prediabetes on its 10-year outcome. BMJ Open Diabetes Res Care. 2016;4(1):1-6.
  18. Rodriguez-Monforte M, Sanchez E, Barrio F, Costa B, Flores-Mateo G. Metabolic syndrome and dietary patterns: a systematic review and meta-analysis of observational studies. Eur J Nutr. 2016:1-23.
Diabetes Watch
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Christopher R. Hood, Jr., DPM, AACFAS, Lindsy L. Kragt, DPM, and Adam J. Badaczewski, DPM
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