Hyperinsulinemic syndrome: The metabolic syndrome is broader than you think Christopher T. Kelly, BA,a Janet Mansoor, BS,a G. Lynis Dohm, PhD,b William H. H. Chapman III, MD, FACS,c John R. Pender IV, MD, FACS,c and Walter J. Pories, MD, FACS,c Greenville, NC
Background. Type 2 diabetes mellitus (T2DM) is characterized by hyperinsulinemia. In 2011 we showed that gastric bypass (RYGB) corrects these high levels even though insulin resistance remains high, ie, the operation ‘‘dissociates’’ hyperinsulinemia from insulin resistance. RYGB produces reversal of T2DM along with other diseases associated with the metabolic syndrome. This observation led us to examine whether these illnesses also were characterized by hyperinsulinemia. Methods. A systematic review was performed to determine whether hyperinsulinemia was present in disorders associated with the metabolic syndrome. We reviewed 423 publications. 58 were selected because of appropriate documentation of insulin measurements. Comparisons were based on whether the studies reported patients as having increased versus normal insulin levels for each metabolic disorder. Results. The presence (+) or absence ( ) of hyperinsulinemia was documented in these articles as follows: central obesity (4+ vs 0 ), diabetes (5+ vs 0 ), hypertension (9+ vs 1 ), dyslipidemia (2+ vs 0 ), renal failure (4+ vs 0 ), nonalcoholic fatty liver disease (5+ vs 0 ), polycystic ovary syndrome (7+ vs 1 ), sleep apnea (7+ vs 0 ), certain cancers (4+ vs 1 ), atherosclerosis (4+ vs 0 ), and cardiovascular disease (8+ vs 0 ). Four articles examined insulin levels in the metabolic syndrome as a whole (4+ vs 0 ). Conclusion. These data document that disorders linked to the metabolic syndrome are associated with high levels of insulin, suggesting that these diseases share a common etiology that is expressed by high levels of insulin. This leads us to propose the concept of a ‘‘hyperinsulinemic syndrome’’ and question the safety of insulin as a chronic therapy for patients with T2DM. (Surgery 2014;156:405-11.) From the MD Program,a Department of Physiology,b and Department of Surgery,c Brody School of Medicine, East Carolina University, Greenville, NC
IN 1988, REAVEN INITIALLY DESCRIBED THE METABOLIC SYN(Syndrome X) as a clustering of diseases that was related through insulin resistance, which he equated with high serum levels of fasting insulin (hyperinsulinemia).1 In type 2 diabetes mellitus (T2DM), patients have markedly increased insulin levels (Fig 1),2 and this hyperinsulinemia traditionally has been considered a response to insulin
DROME
Dr Walter Pories receives grant funding from the National Institute of Health, GlaxoSmithKline, and Ethicon Endosurgery, and Johnson & Johnson. Presented at the 9th Annual Academic Surgical Congress in San Diego, CA, February 4–6, 2014. Accepted for publication April 15, 2014. Reprint requests: Walter J. Pories, MD, FACS, Professor of Surgery, Biochemistry, Sport and Exercise Science, Brody School of Medicine, East Carolina University, 600 Moye Boulevard, Greenville, NC 27834. E-mail: [email protected]. 0039-6060/$ - see front matter Ó 2014 Mosby, Inc. All rights reserved. http://dx.doi.org/10.1016/j.surg.2014.04.028
resistance. Recently, however, our group showed that gastric bypass corrects these high levels even though insulin resistance remains high, ie, the operation ‘‘dissociates’’ hyperinsulinemia from insulin resistance (Fig 2).3,4 High insulin levels also have been documented in the severely obese with and without T2DM. This observation makes it difficult to differentiate the observed hyperinsulinemia in T2DM from obesityrelated hyperinsulinemia because the coexistence of obesity and T2DM is common. It is of interest, however, that Lakdawala reported hyperinsulinemia in lean, type 2 diabetic patients, which was corrected after duodenojejunal bypass surgery (Lakdawala, personal communication). Bariatric surgery not only corrects hyperinsulinemia, it has also been shown to ‘‘cure’’ illnesses associated with the metabolic syndrome.2 In addition to control of severe obesity, it is now well established that the majority of patients who undergo bariatric surgery also experience some element of remission of T2DM (83%), hypertension (63%), SURGERY 405
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‘‘metabolic syndrome,’’ but suggest that this disorder may encompass a far broader collection of diseases with a shared etiogenesis. The purpose of this work was to evaluate our hypothesis that hyperinsulinemia is a common factor in the multiple disorders related to the metabolic syndrome. Such an examination may prove essential in our understanding of the interconnectedness between common pathologies affecting various biologic systems in the human body.
Fig 1. Previously published data (Pories et al2) showing insulin levels in normal, obese, impaired, early and late T2DM. Note that T2DM patients have insulin levels that are 9 times the normal level.
Fig 2. A new figure of previously published data (Reed et al3) showing that Roux-en-Y gastric bypass corrects hyperinsulinemia immediately after surgery. This normalization of insulin levels coincides with the remission of T2DM within 1 week of surgery. However, insulin sensitivity (SI), which is indicative of insulin resistance, is not normalized even 3 months after surgery, suggesting that hyperinsulinemia is not dependent on insulin resistance.
and dyslipidemias (61%), a group of diseases that are lumped into what is called ‘‘metabolic syndrome.’’5-9 In addition, multiple operative series also have reported the improvement of polycystic ovary syndrome, sleep apnea, nonalcoholic fatty liver disease, pseudotumor cerebri, gastroesophageal reflux disease, arthropathy of weight-bearing joints, and even a 70% decrease in the risk of developing various cancers within 5 years.10-17 These observations not only support the concept of a
METHODS A systematic review was performed to determine whether hyperinsulinemia was present in disorders associated with the metabolic syndrome. The metabolic disorders chosen for this analysis included central obesity, diabetes, hypertension, dyslipidemia, renal failure, nonalcoholic fatty liver disease, polycystic ovary syndrome, sleep apnea, certain cancers, vascular atherosclerosis, and cardiovascular disease. Manuscripts were identified through MEDLINE via PubMed and Google Scholar and by searching the reference lists of relevant papers and reviews. Search terms incorporated the disorders listed previously in addition to key words such as ‘‘insulin,’’ ‘‘hyperinsulinemia,’’ ‘‘insulin resistance,’’ and ‘‘metabolic syndrome.’’ Peer-reviewed manuscripts were selected on the basis of predetermined criteria that included the examination of patients with associated disorders of the metabolic syndrome and documentation of serum insulin levels along with weight and body mass index (BMI) in human subjects. In studies that included patients who had multiple metabolic components, investigators independently examined insulin levels in a specific disorder by controlling for factors such as age, weight, BMI, and serum glucose. The publications included in this analysis consisted of primarily three study designs: (1) prospective studies that documented insulin levels along with all other relevant risk factors in a large subject population; (2) retrospective studies with documented insulin levels and follow up data; and (3) cross-sectional, clinical epidemiologic studies with data that compared insulin levels in patients with associated metabolic syndrome illnesses with the insulin levels in normal control subjects. Analyses were made based on the objective data of documented insulin levels, and not necessarily on each paper’s final conclusion or main point of focus. Admittedly, as a systemic review, our methodology had limitations that did not allow for distinguishing association versus etiology between high insulin levels and expressions of the metabolic syndrome. Each paper was judged on an individual
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basis as supporting or not supporting the observations of hyperinsulinemia being associated with each of the given disorders. Unified controlled corrections with statistical calculations between the studies were not performed for factors such as BMI and glucose. It may be useful to perform such a meta-analysis in the future. RESULTS In this analysis, 423 publications were reviewed. Fifty-eight of these articles were selected because of appropriate documentation of insulin measurements. Six of these papers included independent evaluations of insulin levels with respect to multiple disorders and were, therefore, included as data points in more than one category. Comparisons were made on the basis of whether the studies reported patients as having increased insulin levels (+) versus normal insulin levels ( ) for each metabolic disorder. For example, if 5 papers were found that documented high insulin in ‘‘disease Y,’’ and 2 papers were found that documented normal insulin levels in that disease, this would be represented as: disease Y (5+ vs 2 ). The results of this analysis (Table I) and all pertinent citations are as follows: central obesity (4+18-21 vs 0 ), diabetes (5+4,22-25 vs 0 ), hypertension (9+19,24,26-32 vs 1 33), dyslipidemia (2+29,34 vs 0 ), renal failure (4+35-38 vs 0 ), nonalcoholic fatty liver disease (5+39-43 vs 0 ), polycystic ovary syndrome (7+33,44-49 vs 1 50), sleep apnea (7+51-57 vs 0 ), certain cancers (4+58-61 vs 1 62), atherosclerosis (4+ 25,63-65 vs 0 ), and cardiovascular disease (8+24,66-72 vs 0 ). Four articles were selected that examined insulin levels in the metabolic syndrome as a whole (4+45,73-75 vs 0 ). DISCUSSION Hyperinsulinemia is a common but still poorly defined factor found in the multiple medical disorders associated with the metabolic syndrome. Table II depicts a summary of the conflicting diagnostic criteria for the metabolic syndrome as defined by five organizations.76-81 Hyperinsulinemia was not only documented in the diseases included in the definition (ie, T2DM, dyslipidemia, hypertension, and obesity), but also in other disorders associated with the metabolic syndrome (ie, polycystic ovary syndrome, sleep apnea, nonalcoholic fatty liver disease, certain cancers, renal failure, atherosclerosis, and cardiovascular disease). These findings suggest the possibility of common etiopathogenesis that is expressed with high levels of insulin.
Table I. The hyperinsulinemic syndrome extends beyond the metabolic syndrome
Central obesity Diabetes Hypertension Dyslipidemia Renal failure NAFD Polycystic ovary syndrome Certain cancers Sleep apnea Atherosclerosis Cardiovascular disease Metabolic syndrome Combined total
No. studies documenting hyperinsulinemia
No. studies documenting normal insulin levels
4 5 9 2 4 5 7
0 0 1 0 0 0 1
4 7 4 8 4 63
1 0 0 0 0 3
Results of a widespread meta-analysis that included studies examining serum insulin levels in human subjects as an independent variable in multiple disorders commonly associated with the metabolic syndrome. NAFD, Nonalcoholic fatty liver disease.
At first glance, it appears unreasonable that high insulin levels could play a role in such a variety of diseases; however, hormones are well known to produce a broad range of symptoms involving many organ systems and tissues. For example, increased levels of thyroid hormone in patients with hyperthyroidism produces fatigue, weight loss, tremors, hypertension, tachycardia, excessive sweating, diarrhea, loss of hair, hunger, changes in menses, and bone loss. Similarly, increased levels of insulin in the bloodstream may have pathologic effects on various tissues, especially when considering the hormone’s widespread role and complex signal cascade. In addition to the involvement of insulin in glucose uptake via translocation of GLUT4 to the plasma membrane in skeletal muscle, heart and adipose tissue and glycogen synthesis via glycogen synthase kinase (GSK3b) phosphorylation and inhibition of glycogen synthase kinas, insulin signaling also activates other pathways involved in growth/mitogenesis (mitogen-activated protein kinase/extracellular signal-regulated kinases 1/2, mammalian target of rapamycin complex 1/S6 kinase), production of nitric oxide (endothelial nitric oxide synthase), the cell cycle (overcome G1/G2 arrest), survival (Bcl2, nuclear factor-kB), autophagy (autophagy-related gene, UNC-like-51-kinase), and remodeling of the actin cytoskeleton (S6 kinase 1).82 Insulin stimulates the sympathetic nervous system
At least three of the following: $150 150 $150 $150 $150 YHDL, mg/dL 30 >30 Microalbuminuria, mg/min, Urinary albumin excretion ratio mg/g $20 or Albumin/creatinine ratio $30 Required for diagnosis
US National Cholesterol Education Program Adult Treatment Panel III European Group for the Study of Insulin Resistance International Diabetes Federation
Table II. Summarized diagnostic criteria for the metabolic syndrome as defined by five different organizations
American Heart Association
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by triggering the carotid bodies and hypothalamus.83,84 Excessive insulin has been shown to inappropriately activate the renin-angiotensinaldosterone system in addition to promoting sodium and water reabsorption from the renal tubules, leading to blood volume expansion.82 Insulin helps control the sex hormones estrogen, progesterone, and testosterone, and sustained hyperinsulinemia has been shown to potentiate gonadotropin-stimulated ovarian androgen steroidogenesis.85,86 It also was demonstrated recently that insulin at the transcriptional level promotes gene expression of acyl-coenzyme A:cholesterol acyltransferase, an intracellular enzyme involved in cellular cholesterol homeostasis and atherosclerotic foam cell formation.87,88 These findings suggest the potential for pathologic mechanisms involving hyperinsulinemia, and this analysis exposes the presence of increased insulin levels in disorders related to the metabolic syndrome. During the early progression of many metabolic diseases, the b cells of the pancreas secrete increasing amounts of insulin, which has been explained conventionally as a desperate attempt to adequately control blood glucose levels. This increase in the secretion of insulin transpires until a point at which further hypersecretion of insulin is no longer possible, and hyperglycemia soon occurs. In T2DM, for example, patients experience increased insulin levels long before they develop the hyperglycemia (fasting blood sugar >125 mg/dL) that defines diabetes.89 In fact, increased fasting insulin levels (>9.0 mIU/mL) have been shown to accurately identify patients in a prediabetic state.90 Hence, patients with hyperglycemia inevitably have preexisting hyperinsulinemia assuming their pancreas remains functional. The phenomenon of insulin resistance is a similar concept in that insulin resistance is also tethered to hyperinsulinemia. Traditionally, hyperinsulinemia has been considered a response to insulin resistance. However, our previous findings suggest that hyperinsulinemia is primary in T2DM, and insulin resistance is most likely a secondary response by cells exposed to excess fuel.2,3 Thus, basal hyperinsulinemia generates and sustains insulin resistance.91 Nevertheless, the primary lesion initially responsible for causing hyperinsulinemia still needs to be defined. The initial hyperinsulinemia may be due to signals from the microbiome, the neuroendocrine cells of the gut, inflammatory cytokines, absorbed nutrients such as triglycerides, and/or other unknown factors. Hyperinsulinemia is an indicator of metabolic disorders, and increased fasting insulin may
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contribute to some of these diseases. The results of this analysis suggest that the concept of a metabolic syndrome encompasses a far broader collection of diseases than the disorder currently defines. We therefore propose the term ‘‘hyperinsulinemic syndrome’’ to describe patients with clinically relevant increased serum insulin levels who are at risk for diseases that extend beyond the metabolic syndrome. Further investigation into the development of hyperinsulinemia and insulin’s action in metabolic disorders will help answer four essential questions that may drastically change the way we care for countless patients throughout the world: (1) Can increased serum insulin or C-peptide be used as clinical markers in a primary care setting for early diagnosis and preventative care, and would these markers be more effective than glucose levels? (2) Would pharmacologic intervention that normalizes serum insulin levels before the emergence of glucose intolerance and hyperglycemia be a beneficial approach to hinder the progression of metabolic disorders? (3) Is the morbidity of T2DM caused by hyperinsulinemia in the presence of coexisting excess glucose, rather than simply by hyperglycemia alone? (4) Finally, is the current medical therapy for T2DM that includes insulin secretagogues and the administration of exogenous insulin an appropriate therapeutic approach, or is it causing increased risk of developing other metabolic disorders? After all, we do not treat hyperthyroidism with additional thyroxine. Why are we treating a disease associated with hyperinsulinemia with additional insulin? REFERENCES 1. Reaven GM. Banting lecture 1988. Role of insulin resistance in human disease. Diabetes 1988;37:1595-607. 2. Pories WJ, MacDonald KG Jr, Morgan EJ, et al. Surgical treatment of obesity and its effect on diabetes: 10-y followup. Am J Clin Nutr 1992;55(2 Suppl):582S-5S. 3. Reed MA, Pories WJ, Chapman W, et al. Roux-en-Y gastric bypass corrects hyperinsulinemia implications for the remission of type 2 diabetes. J Clin Endocrinol Metab 2011;96: 2525-31. 4. Pories WJ, Dohm GL. Diabetes: have we got it all wrong? Hyperinsulinism as the culprit: surgery provides the evidence. Diabetes Care 2012;35:2438-42. 5. Jimenez A, Perea V, Corcelles R, Moize V, Lacy A, Vidal J. Metabolic effects of bariatric surgery in insulin-sensitive morbidly obese subjects. Obes Surg 2013;23:494-500. 6. Lee WJ, Huang MT, Wang W, Lin CM, Chen TC, Lai IR. Effects of obesity surgery on the metabolic syndrome. Arch Surg 2004;139:1088-92. 7. Blackstone R, Bunt JC, Cortes MC, Sugerman HJ. Type 2 diabetes after gastric bypass: remission in five models using HbA1c, fasting blood glucose, and medication status. Surg Obes Relat Dis 2012;8:548-55.
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77. Alberti KG, Zimmet PZ. Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabet Med 1998;15:539-53. 78. Balkau B, Charles MA. Comment on the provisional report from the WHO consultation. european group for the study of insulin resistance (EGIR). Diabet Med 1999;16:442-3. 79. Grundy SM, Brewer HB Jr, Cleeman JI, et al. Definition of metabolic syndrome: Report of the national heart, lung, and blood institute/american heart association conference on scientific issues related to definition. Circulation 2004; 109:433-8. 80. Lorenzo C, Williams K, Hunt KJ, Haffner SM. The National Cholesterol Education Program - Adult Treatment Panel III, International Diabetes Federation, and World Health Organization definitions of the metabolic syndrome as predictors of incident cardiovascular disease and diabetes. Diabetes Care 2007;30:8-13. 81. Kassi E, Pervanidou P, Kaltsas G, Chrousos G. Metabolic syndrome: Definitions and controversies. BMC Med 2011;9:48. 82. Nistala R, Whaley-Connell A. Resistance to insulin and kidney disease in the cardiorenal metabolic syndrome; role for angiotensin II. Mol Cell Endocrinol 2013;378:53-8. 83. Ribeiro MJ, Sacramento JF, Gonzalez C, Guarino MP, Monteiro EC, Conde SV. Carotid body denervation prevents the development of insulin resistance and hypertension induced by hypercaloric diets. Diabetes 2013;62:2905-16. 84. Harlan SM, Guo DF, Morgan DA, Fernandes-Santos C, Rahmouni K. Hypothalamic mTORC1 signaling controls sympathetic nerve activity and arterial pressure and mediates leptin effects. Cell Metab 2013;17:599-606. 85. Tosi F, Negri C, Perrone F, et al. Hyperinsulinemia amplifies GnRH agonist stimulated ovarian steroid secretion in women with polycystic ovary syndrome. J Clin Endocrinol Metab 2012;97:1712-9. 86. Dunaif A. Insulin resistance and the polycystic ovary syndrome: mechanism and implications for pathogenesis. Endocr Rev 1997;18:774-800. 87. Ge J, Zhai W, Cheng B, et al. Insulin induces human acylcoenzyme A: cholesterol acyltransferase1 gene expression via MAP kinases and CCAAT/enhancer-binding protein alpha. J Cell Biochem 2013;114:2188-98. 88. Park YM, R Kashyap S, A Major J, Silverstein RL. Insulin promotes macrophage foam cell formation: potential implications in diabetes-related atherosclerosis. Lab Invest 2012; 92:1171-80. 89. Dankner R, Chetrit A, Shanik MH, Raz I, Roth J. Basal state hyperinsulinemia in healthy normoglycemic adults heralds dysglycemia after more than two decades of follow up. Diabetes Metab Res Rev 2012;28:618-24. 90. Johnson JL, Duick DS, Chui MA, Aldasouqi SA. Identifying prediabetes using fasting insulin levels. Endocr Pract 2010; 16:47-52. 91. Shanik MH, Xu Y, Skrha J, Dankner R, Zick Y, Roth J. Insulin resistance and hyperinsulinemia: Is hyperinsulinemia the cart or the horse? Diabetes Care 2008;31(Suppl 2):S262-8.
Background. Type 2 diabetes mellitus (T2DM) is characterized by hyperinsulinemia. In 2011 we showed that gastric bypass (RYGB) corrects these high levels even though insulin resistance remains high, ie, the operation ‘‘dissociates’’ hyperinsulinemia from insulin resistance. RYGB produces reversal of T2DM along with other diseases associated with the metabolic syndrome. This observation led us to examine whether these illnesses also were characterized by hyperinsulinemia. Methods. A systematic review was performed to determine whether hyperinsulinemia was present in disorders associated with the metabolic syndrome. We reviewed 423 publications. 58 were selected because of appropriate documentation of insulin measurements. Comparisons were based on whether the studies reported patients as having increased versus normal insulin levels for each metabolic disorder. Results. The presence (+) or absence ( ) of hyperinsulinemia was documented in these articles as follows: central obesity (4+ vs 0 ), diabetes (5+ vs 0 ), hypertension (9+ vs 1 ), dyslipidemia (2+ vs 0 ), renal failure (4+ vs 0 ), nonalcoholic fatty liver disease (5+ vs 0 ), polycystic ovary syndrome (7+ vs 1 ), sleep apnea (7+ vs 0 ), certain cancers (4+ vs 1 ), atherosclerosis (4+ vs 0 ), and cardiovascular disease (8+ vs 0 ). Four articles examined insulin levels in the metabolic syndrome as a whole (4+ vs 0 ). Conclusion. These data document that disorders linked to the metabolic syndrome are associated with high levels of insulin, suggesting that these diseases share a common etiology that is expressed by high levels of insulin. This leads us to propose the concept of a ‘‘hyperinsulinemic syndrome’’ and question the safety of insulin as a chronic therapy for patients with T2DM. (Surgery 2014;156:405-11.) From the MD Program,a Department of Physiology,b and Department of Surgery,c Brody School of Medicine, East Carolina University, Greenville, NC
IN 1988, REAVEN INITIALLY DESCRIBED THE METABOLIC SYN(Syndrome X) as a clustering of diseases that was related through insulin resistance, which he equated with high serum levels of fasting insulin (hyperinsulinemia).1 In type 2 diabetes mellitus (T2DM), patients have markedly increased insulin levels (Fig 1),2 and this hyperinsulinemia traditionally has been considered a response to insulin
DROME
Dr Walter Pories receives grant funding from the National Institute of Health, GlaxoSmithKline, and Ethicon Endosurgery, and Johnson & Johnson. Presented at the 9th Annual Academic Surgical Congress in San Diego, CA, February 4–6, 2014. Accepted for publication April 15, 2014. Reprint requests: Walter J. Pories, MD, FACS, Professor of Surgery, Biochemistry, Sport and Exercise Science, Brody School of Medicine, East Carolina University, 600 Moye Boulevard, Greenville, NC 27834. E-mail: [email protected]. 0039-6060/$ - see front matter Ó 2014 Mosby, Inc. All rights reserved. http://dx.doi.org/10.1016/j.surg.2014.04.028
resistance. Recently, however, our group showed that gastric bypass corrects these high levels even though insulin resistance remains high, ie, the operation ‘‘dissociates’’ hyperinsulinemia from insulin resistance (Fig 2).3,4 High insulin levels also have been documented in the severely obese with and without T2DM. This observation makes it difficult to differentiate the observed hyperinsulinemia in T2DM from obesityrelated hyperinsulinemia because the coexistence of obesity and T2DM is common. It is of interest, however, that Lakdawala reported hyperinsulinemia in lean, type 2 diabetic patients, which was corrected after duodenojejunal bypass surgery (Lakdawala, personal communication). Bariatric surgery not only corrects hyperinsulinemia, it has also been shown to ‘‘cure’’ illnesses associated with the metabolic syndrome.2 In addition to control of severe obesity, it is now well established that the majority of patients who undergo bariatric surgery also experience some element of remission of T2DM (83%), hypertension (63%), SURGERY 405
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‘‘metabolic syndrome,’’ but suggest that this disorder may encompass a far broader collection of diseases with a shared etiogenesis. The purpose of this work was to evaluate our hypothesis that hyperinsulinemia is a common factor in the multiple disorders related to the metabolic syndrome. Such an examination may prove essential in our understanding of the interconnectedness between common pathologies affecting various biologic systems in the human body.
Fig 1. Previously published data (Pories et al2) showing insulin levels in normal, obese, impaired, early and late T2DM. Note that T2DM patients have insulin levels that are 9 times the normal level.
Fig 2. A new figure of previously published data (Reed et al3) showing that Roux-en-Y gastric bypass corrects hyperinsulinemia immediately after surgery. This normalization of insulin levels coincides with the remission of T2DM within 1 week of surgery. However, insulin sensitivity (SI), which is indicative of insulin resistance, is not normalized even 3 months after surgery, suggesting that hyperinsulinemia is not dependent on insulin resistance.
and dyslipidemias (61%), a group of diseases that are lumped into what is called ‘‘metabolic syndrome.’’5-9 In addition, multiple operative series also have reported the improvement of polycystic ovary syndrome, sleep apnea, nonalcoholic fatty liver disease, pseudotumor cerebri, gastroesophageal reflux disease, arthropathy of weight-bearing joints, and even a 70% decrease in the risk of developing various cancers within 5 years.10-17 These observations not only support the concept of a
METHODS A systematic review was performed to determine whether hyperinsulinemia was present in disorders associated with the metabolic syndrome. The metabolic disorders chosen for this analysis included central obesity, diabetes, hypertension, dyslipidemia, renal failure, nonalcoholic fatty liver disease, polycystic ovary syndrome, sleep apnea, certain cancers, vascular atherosclerosis, and cardiovascular disease. Manuscripts were identified through MEDLINE via PubMed and Google Scholar and by searching the reference lists of relevant papers and reviews. Search terms incorporated the disorders listed previously in addition to key words such as ‘‘insulin,’’ ‘‘hyperinsulinemia,’’ ‘‘insulin resistance,’’ and ‘‘metabolic syndrome.’’ Peer-reviewed manuscripts were selected on the basis of predetermined criteria that included the examination of patients with associated disorders of the metabolic syndrome and documentation of serum insulin levels along with weight and body mass index (BMI) in human subjects. In studies that included patients who had multiple metabolic components, investigators independently examined insulin levels in a specific disorder by controlling for factors such as age, weight, BMI, and serum glucose. The publications included in this analysis consisted of primarily three study designs: (1) prospective studies that documented insulin levels along with all other relevant risk factors in a large subject population; (2) retrospective studies with documented insulin levels and follow up data; and (3) cross-sectional, clinical epidemiologic studies with data that compared insulin levels in patients with associated metabolic syndrome illnesses with the insulin levels in normal control subjects. Analyses were made based on the objective data of documented insulin levels, and not necessarily on each paper’s final conclusion or main point of focus. Admittedly, as a systemic review, our methodology had limitations that did not allow for distinguishing association versus etiology between high insulin levels and expressions of the metabolic syndrome. Each paper was judged on an individual
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basis as supporting or not supporting the observations of hyperinsulinemia being associated with each of the given disorders. Unified controlled corrections with statistical calculations between the studies were not performed for factors such as BMI and glucose. It may be useful to perform such a meta-analysis in the future. RESULTS In this analysis, 423 publications were reviewed. Fifty-eight of these articles were selected because of appropriate documentation of insulin measurements. Six of these papers included independent evaluations of insulin levels with respect to multiple disorders and were, therefore, included as data points in more than one category. Comparisons were made on the basis of whether the studies reported patients as having increased insulin levels (+) versus normal insulin levels ( ) for each metabolic disorder. For example, if 5 papers were found that documented high insulin in ‘‘disease Y,’’ and 2 papers were found that documented normal insulin levels in that disease, this would be represented as: disease Y (5+ vs 2 ). The results of this analysis (Table I) and all pertinent citations are as follows: central obesity (4+18-21 vs 0 ), diabetes (5+4,22-25 vs 0 ), hypertension (9+19,24,26-32 vs 1 33), dyslipidemia (2+29,34 vs 0 ), renal failure (4+35-38 vs 0 ), nonalcoholic fatty liver disease (5+39-43 vs 0 ), polycystic ovary syndrome (7+33,44-49 vs 1 50), sleep apnea (7+51-57 vs 0 ), certain cancers (4+58-61 vs 1 62), atherosclerosis (4+ 25,63-65 vs 0 ), and cardiovascular disease (8+24,66-72 vs 0 ). Four articles were selected that examined insulin levels in the metabolic syndrome as a whole (4+45,73-75 vs 0 ). DISCUSSION Hyperinsulinemia is a common but still poorly defined factor found in the multiple medical disorders associated with the metabolic syndrome. Table II depicts a summary of the conflicting diagnostic criteria for the metabolic syndrome as defined by five organizations.76-81 Hyperinsulinemia was not only documented in the diseases included in the definition (ie, T2DM, dyslipidemia, hypertension, and obesity), but also in other disorders associated with the metabolic syndrome (ie, polycystic ovary syndrome, sleep apnea, nonalcoholic fatty liver disease, certain cancers, renal failure, atherosclerosis, and cardiovascular disease). These findings suggest the possibility of common etiopathogenesis that is expressed with high levels of insulin.
Table I. The hyperinsulinemic syndrome extends beyond the metabolic syndrome
Central obesity Diabetes Hypertension Dyslipidemia Renal failure NAFD Polycystic ovary syndrome Certain cancers Sleep apnea Atherosclerosis Cardiovascular disease Metabolic syndrome Combined total
No. studies documenting hyperinsulinemia
No. studies documenting normal insulin levels
4 5 9 2 4 5 7
0 0 1 0 0 0 1
4 7 4 8 4 63
1 0 0 0 0 3
Results of a widespread meta-analysis that included studies examining serum insulin levels in human subjects as an independent variable in multiple disorders commonly associated with the metabolic syndrome. NAFD, Nonalcoholic fatty liver disease.
At first glance, it appears unreasonable that high insulin levels could play a role in such a variety of diseases; however, hormones are well known to produce a broad range of symptoms involving many organ systems and tissues. For example, increased levels of thyroid hormone in patients with hyperthyroidism produces fatigue, weight loss, tremors, hypertension, tachycardia, excessive sweating, diarrhea, loss of hair, hunger, changes in menses, and bone loss. Similarly, increased levels of insulin in the bloodstream may have pathologic effects on various tissues, especially when considering the hormone’s widespread role and complex signal cascade. In addition to the involvement of insulin in glucose uptake via translocation of GLUT4 to the plasma membrane in skeletal muscle, heart and adipose tissue and glycogen synthesis via glycogen synthase kinase (GSK3b) phosphorylation and inhibition of glycogen synthase kinas, insulin signaling also activates other pathways involved in growth/mitogenesis (mitogen-activated protein kinase/extracellular signal-regulated kinases 1/2, mammalian target of rapamycin complex 1/S6 kinase), production of nitric oxide (endothelial nitric oxide synthase), the cell cycle (overcome G1/G2 arrest), survival (Bcl2, nuclear factor-kB), autophagy (autophagy-related gene, UNC-like-51-kinase), and remodeling of the actin cytoskeleton (S6 kinase 1).82 Insulin stimulates the sympathetic nervous system
At least three of the following: $150 150 $150 $150 $150 YHDL, mg/dL 30 >30 Microalbuminuria, mg/min, Urinary albumin excretion ratio mg/g $20 or Albumin/creatinine ratio $30 Required for diagnosis
US National Cholesterol Education Program Adult Treatment Panel III European Group for the Study of Insulin Resistance International Diabetes Federation
Table II. Summarized diagnostic criteria for the metabolic syndrome as defined by five different organizations
American Heart Association
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by triggering the carotid bodies and hypothalamus.83,84 Excessive insulin has been shown to inappropriately activate the renin-angiotensinaldosterone system in addition to promoting sodium and water reabsorption from the renal tubules, leading to blood volume expansion.82 Insulin helps control the sex hormones estrogen, progesterone, and testosterone, and sustained hyperinsulinemia has been shown to potentiate gonadotropin-stimulated ovarian androgen steroidogenesis.85,86 It also was demonstrated recently that insulin at the transcriptional level promotes gene expression of acyl-coenzyme A:cholesterol acyltransferase, an intracellular enzyme involved in cellular cholesterol homeostasis and atherosclerotic foam cell formation.87,88 These findings suggest the potential for pathologic mechanisms involving hyperinsulinemia, and this analysis exposes the presence of increased insulin levels in disorders related to the metabolic syndrome. During the early progression of many metabolic diseases, the b cells of the pancreas secrete increasing amounts of insulin, which has been explained conventionally as a desperate attempt to adequately control blood glucose levels. This increase in the secretion of insulin transpires until a point at which further hypersecretion of insulin is no longer possible, and hyperglycemia soon occurs. In T2DM, for example, patients experience increased insulin levels long before they develop the hyperglycemia (fasting blood sugar >125 mg/dL) that defines diabetes.89 In fact, increased fasting insulin levels (>9.0 mIU/mL) have been shown to accurately identify patients in a prediabetic state.90 Hence, patients with hyperglycemia inevitably have preexisting hyperinsulinemia assuming their pancreas remains functional. The phenomenon of insulin resistance is a similar concept in that insulin resistance is also tethered to hyperinsulinemia. Traditionally, hyperinsulinemia has been considered a response to insulin resistance. However, our previous findings suggest that hyperinsulinemia is primary in T2DM, and insulin resistance is most likely a secondary response by cells exposed to excess fuel.2,3 Thus, basal hyperinsulinemia generates and sustains insulin resistance.91 Nevertheless, the primary lesion initially responsible for causing hyperinsulinemia still needs to be defined. The initial hyperinsulinemia may be due to signals from the microbiome, the neuroendocrine cells of the gut, inflammatory cytokines, absorbed nutrients such as triglycerides, and/or other unknown factors. Hyperinsulinemia is an indicator of metabolic disorders, and increased fasting insulin may
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contribute to some of these diseases. The results of this analysis suggest that the concept of a metabolic syndrome encompasses a far broader collection of diseases than the disorder currently defines. We therefore propose the term ‘‘hyperinsulinemic syndrome’’ to describe patients with clinically relevant increased serum insulin levels who are at risk for diseases that extend beyond the metabolic syndrome. Further investigation into the development of hyperinsulinemia and insulin’s action in metabolic disorders will help answer four essential questions that may drastically change the way we care for countless patients throughout the world: (1) Can increased serum insulin or C-peptide be used as clinical markers in a primary care setting for early diagnosis and preventative care, and would these markers be more effective than glucose levels? (2) Would pharmacologic intervention that normalizes serum insulin levels before the emergence of glucose intolerance and hyperglycemia be a beneficial approach to hinder the progression of metabolic disorders? (3) Is the morbidity of T2DM caused by hyperinsulinemia in the presence of coexisting excess glucose, rather than simply by hyperglycemia alone? (4) Finally, is the current medical therapy for T2DM that includes insulin secretagogues and the administration of exogenous insulin an appropriate therapeutic approach, or is it causing increased risk of developing other metabolic disorders? After all, we do not treat hyperthyroidism with additional thyroxine. Why are we treating a disease associated with hyperinsulinemia with additional insulin? REFERENCES 1. Reaven GM. Banting lecture 1988. Role of insulin resistance in human disease. Diabetes 1988;37:1595-607. 2. Pories WJ, MacDonald KG Jr, Morgan EJ, et al. Surgical treatment of obesity and its effect on diabetes: 10-y followup. Am J Clin Nutr 1992;55(2 Suppl):582S-5S. 3. Reed MA, Pories WJ, Chapman W, et al. Roux-en-Y gastric bypass corrects hyperinsulinemia implications for the remission of type 2 diabetes. J Clin Endocrinol Metab 2011;96: 2525-31. 4. Pories WJ, Dohm GL. Diabetes: have we got it all wrong? Hyperinsulinism as the culprit: surgery provides the evidence. Diabetes Care 2012;35:2438-42. 5. Jimenez A, Perea V, Corcelles R, Moize V, Lacy A, Vidal J. Metabolic effects of bariatric surgery in insulin-sensitive morbidly obese subjects. Obes Surg 2013;23:494-500. 6. Lee WJ, Huang MT, Wang W, Lin CM, Chen TC, Lai IR. Effects of obesity surgery on the metabolic syndrome. Arch Surg 2004;139:1088-92. 7. Blackstone R, Bunt JC, Cortes MC, Sugerman HJ. Type 2 diabetes after gastric bypass: remission in five models using HbA1c, fasting blood glucose, and medication status. Surg Obes Relat Dis 2012;8:548-55.
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