Insulin: The wrong therapy for type 2 diabetes Lessons learned from a half century of metabolic surgery

The biggest gift of metabolic surgery has been its role in sparking a revolutionary sea change in our understanding of type 2 diabetes mellitus (T2DM). Health care professionals have come to recognize that the traditional view of the disease is wrong—T2DM is no longer an unrelenting progressive disease, destined to end in blindness, kidney failure, amputations, and early deaths from heart disease or stroke. Furthermore, the dogma that strict control of glucose levels with insulin will prevent these unfortunate outcomes is also wrong. Instead, durable and full remission of T2DM, with a reduction in other comorbidities and lower mortality, can now be achieved with a metabolic operation that may take only an hour’s duration and a one- or two-day hospital stay.

This article elaborates on these remarkable claims, assesses the current and emerging evidence on these topics, considers potential mechanisms underlying T2DM progression and remission, and reassesses our traditional approaches to the care of patients who suffer from this epidemic disease.

A long history

Diabetes has long been identified as a disease related to sugar. In 1552 BC, Hindu writers noted that flies gathering on urine were an ominous sign. Circa 600 BC, Sushruta found it had a sweet taste. The Greeks named it “diabetes” (Greek for syphon) for the polyuria secondary to hyperglycemia. Since then, the basis of our treatment has been glucocentric. We measure our patients’ health and response to therapy with fasting and postprandial blood glucose levels, HbA1C, oral glucose tolerance tests, homeostasis model assessment (HOMA), and euglycemic clamps.

Because T2DM was more common in obese and physically inactive patients, diets and exercise have continued to be the initial approach to treatment. Our most effective drug, metformin, dates back to the Middle Ages, when physicians administered “goat’s rue” (galega officinalis), a perennial herb, in which guanidine was the active agent.1 The introduction of insulin for T2DM was and is based on a historic error. When Banting and Best discovered in 1921 that insulin could save the lives of children dying of diabetes by lowering their blood sugar levels, physicians soon learned that the hormone could achieve the same results in adults. The new approach to control glucose levels in older patients was rapidly adopted with the belief, still true today, that the hormone would prevent the feared complications of the disease. The warning by Sir Harold Percival Himsworth, MD, in 1936 that diabetes in adults was a different disease was ignored.2

Since the last century, when diet, exercise, and metformin fail to control glucose levels, as they do in most patients, treatment of T2DM has been insulin-centric. The current standard of care is to prescribe drugs that increase insulin sensitivity, stimulate insulin secretion and, when these fail, to administer various preparations of insulin. However, in spite of U.S. diabetes drug expenditures of approximately $51.5 billion in 2016,3 there is still little evidence that insulin and insulin-related drugs are effective. T2DM remains the primary cause of amputations, blindness, and renal failure, as well as a major cause of heart attacks and strokes.

Surprising effects of metabolic surgery

The first hint that surgery might have an influence on T2DM was reported by Friedman and colleagues in a 1955 article describing the improvement in glucose levels in three patients following subtotal gastrectomy.4 In 1980, after the dean of the new medical school at East Carolina University (ECU), Greenville, NC, decided to focus the institution’s research on obesity, surgeons were reluctant to participate, given the poor outcomes of the intestinal bypass. However, later that year, after reading studies by Edward E. Mason, MD, documenting weight loss following a “gastric bypass” in 1969,5 the ECU group developed and pursued a standardized “Greenville gastric bypass” (gastric pouch of 30 ml, gastrojejunostomy 10 mm in diameter with a jejunal Roux-en-Y loop of 60 cm), similar to the operations done today except with a jejunal limb shorter than the 100–150 cm commonly used today. These procedures were performed with open rather than laparoscopic approaches.

In 1980, to their surprise, in addition to producing profound weight loss, the operations led to corrections of glucose levels in severely obese patients who had T2DM.6 Initially, the team concluded that the remission of T2DM was due to weight loss, but after reviewing the course of their fifth patient, E.L. (see Table 1), it became apparent that the T2DM resolved by the sixth postoperative day before any significant change occurred in adiposity. The patient suffered from advanced T2DM. In spite of 90 units of insulin administered before the operation, the patient’s blood glucose was 495 mg/dL at the time of intubation. Within a day, her glucose level fell to 281 mg/dL. At that time, when patients were still titrated with sliding values, she dropped quickly to 8 units and required no further insulin after the sixth postoperative day. During the follow-up extending over 15 years, she required no further medication for her T2DM. This observation, that the operation produced rapid correction of hyperglycemia before a significant loss in body fat, suggested that T2DM might be produced, at least in part, by an intestinal signal and that decreasing contact between the gut and the food interfered with the production of this signal.

Table 1. Rapid resolution of type 2 diabetes mellitus following gastric bypass

Table 1. Rapid resolution of type 2 diabetes mellitus following gastric bypass

Further study of 837 consecutive patients undergoing the standardized procedure from 1980 to 1996 with a 95 percent follow-up rate confirmed that remission of T2DM was common and durable.7 At 9.2 years, 83 percent of the patients were still euglycemic, similar to the later report by Schauer and colleagues of 83 percent remission at five years.8 Since then, reported remission rates have dropped modestly due to differences in the reporting of remission values.

The 95 percent follow-up rate deserves comment because, under today’s rules, such validation would be impossible in the U.S. To reward patients for their return visits, they and their families were provided free outpatient care—an approach illegal today because of government procurement laws that prevent private entities from charging the government more for the same services rendered in the civilian sector. Giving free care today would violate billing regulations and potentially imperil collections for Medicare. The investigators also had a departmental van for the free transport of patients, but that service had to be stopped because of liability issues. Finally, if the surgeons could not find a patient due to changes in names and addresses, they asked the local sheriff, who would provide that information—clearly a Health Insurance Portability and Accountability Act (also known as HIPAA) violation today, but legal then.

To determine whether the correction of glucose values actually influenced long-term outcomes, MacDonald and colleagues pursued a retrospective study to compare the long-term outcomes of 154 patients with T2DM who underwent the gastric bypass with another 78 patients who were also scheduled for surgery but did not have the operation because of a lack of insurance coverage or because they changed their minds.9 These data revealed a 78 percent reduction in mortality. Similar reductions of mortality by bariatric surgery also were reported by Christou and colleagues in Canada, Sjostrom and colleagues in Sweden, and Arterburn and colleagues in U.S. veterans.10-12

These reports, in turn, stimulated a seven-year study, Longitudinal Assessment of Bariatric Surgery (LABS), funded by the National Institutes of Health (NIH), which documented the persistence and variations of weight loss, durable remission of T2DM, and the other comorbidities of the metabolic syndrome, as well as other late outcomes and complications. These extensive studies now provide the most detailed and accurate data regarding early and late outcomes of metabolic surgery in adults and adolescents.13-18 The review of the seven-year data has now been accepted for publication.

These articles and others, however, still left the question of how surgical outcomes compare with “intensive” medical care, a level not available to most patients with T2DM. Three prospective randomized controlled clinical trials by Schauer, Mingrone, Ikrammudin, and their respective colleagues19-21 provided convincing answers. Metabolic surgery proved to be more effective at all levels in terms of lowering blood glucose, HbA1C, and the need for anti-diabetic medications.

T2DM: Another expression of metabolic syndrome

The relationships between obesity, diabetes, hypertension, and dyslipidemia have been noted for years and named the “metabolic syndrome.” The concept was challenged in the past as just another correlation, but the broad response by varied organ systems to metabolic surgery has forced reconsideration of this syndrome. It has become evident through mounting data that there is a unifying underlying metabolic derangement that results in the development and propagation of these and numerous other life-threatening diseases.

The broad physiologic response to surgery is real. Even in 1984, surgeons noted that in addition to durable weight loss of about one-third of the patients’ original weight, metabolic surgery led to marked improvement in hypertension, heart disease, sleep apnea, and asthma (see Table 2).6 Blackstone and colleagues confirmed these broader outcomes, but also documented remission of hypertension in 63.3 percent; obstructive sleep apnea, 68.9 percent; gastroesophageal reflux disease, 87.6 percent; venous insufficiency, 71.0 percent; asthma, 66 percent; stress incontinence, 84 percent; depression, 31.4 percent; degenerative joint disease, 67 percent; and hyperlipidemia, 61.4 percent.22 Additional expressions of the syndrome continue to surface, including non-alcoholic steatotic hepatitis (NASH), polycystic ovary syndrome, infertility, and decreased cognition.

Table 2. Effects of metabolic surgery

Table 2. Effects of metabolic surgery

The metabolic syndrome, therefore, is real and affects most, if not all, organ systems. Accordingly, T2DM is not an individual, unique, and separate disease, but rather, only one expression of the metabolic syndrome. An additional clue that these various diseases are related is a recent review of the literature by Kelly and colleagues, which documented that each of these expressions of the metabolic syndrome presented with elevated insulin levels.23 Because patients with T2DM have high lactate as well as high glucose and insulin levels, it is likely that the basic defect of the syndrome lies in the oxidation of glucose at the level of mitochondria.

Reassessment of insulin therapy for T2DM

It is unfortunate when two disparate diseases have the same name. Diabetes represents two such entities. Although both type 1 diabetes mellitus (T1DM) and T2DM are detected by high glucose levels, they differ sharply. Patients with T1DM are unable to secrete insulin; patients with T2DM may have levels nine times normal. It is as if pneumonia and thyroid storm both had similar names because both are associated with fever. Thus, investigation and treatment of two very different diseases, both termed “diabetes,” has suffered from reduction and conflation to a single term.

To pursue the finding of elevated insulin levels in the metabolic syndrome, the ECU group analyzed a series of consecutive oral glucose tolerance tests performed in 295 patients (normal, obese, impaired [IGT], early T2DM with fasting blood sugar [FBS] <140 mg/dL, and advanced T2DM with FBS >140 mg/dL) (see Figure 1A). These data provide insights into insulin secretion with the progression of the disease. The data support the concept of “insulin resistance,” usually cited as the reason for the administration of insulin. In the obese, it appears that the islets must secrete more insulin to maintain euglycemia (see Figure 1A). The data also support the concept that maximum insulin secretion decreases with the progression of T2DM (see Figure 1B). However, the data also indicate that the maximum insulin secretion in response to a meal, even in advanced diabetes, is still more than twice that seen in euglycemic subjects. Perhaps even more importantly, basal insulin secretion, when T2DM patients are fasting and asleep, is as great as the maximum secretion in normal individuals. These observations demonstrate that the administration of drugs to increase insulin secretion even more to lower insulin resistance or to give insulin is disadvantageous.

Figure 1A. Hyperinsulinemia in T2DM patients

Figure 1A. Hyperinsulinemia in T2DM patients

Figure 1B. Effects of metabolic surgery on insulin resistance

Figure 1B. Effects of metabolic surgery on insulin resistance

Insulin resistance or resistance to insulin?

The basis for insulin therapy in T2DM patients who already have high insulin levels has been “to overcome insulin resistance;” that is, more insulin is needed to control glucose levels with the advancement of disease. Insulin resistance certainly occurs, as noted earlier in this article. However, this resistance occurs in patients without T2DM. It also can occur with sepsis, other expressions of the metabolic syndrome, and toxic agents.

The most convincing evidence that insulin resistance is not the cause of T2DM comes from another set of studies by the ECU group, which measured levels of glucose and insulin prior to the gastric bypass, and one week and three months following the operation. The data reflect the prompt reduction in glucose and the correction of insulin levels within the first week. Insulin sensitivity, however, remains unchanged even after three months in spite of full remission of T2DM.

Is the etiology of T2DM a pathologic signal from the gut?

Because the degree of T2DM remission obtained by metabolic surgery is directly related to the reduction of contact between food and the gut, it seems reasonable to conclude that the effect is due to the interruption of a diabetogenic signal(s) from the intestine. Two elegant studies by Rubino and colleagues provided support. In the first, they documented that exclusion of the duodenum in overfed, hyperglycemic rats restored euglycemia.24 In the second study, a silicone intestinal liner produced the same result, but perforating the material produced a return to high glucose values.25 Koehestanie and colleagues reported that similar liners in patients with diabetes produced euglycemia.26 Clinical application of the liners, however, is unlikely. Too many patients in the series could tolerate the devices only for a brief time.

This assessment does not include any consideration of the use of insulin for acute care. Patients with T2DM with sepsis develop severe hyperglycemia that may benefit bacterial growth and hinder a protective response. Until separate, appropriate studies evaluate the value of insulin therapy for acute disease, those practices should continue.

Reassessment of insulin therapy for T2DM

The traditional treatment of T2DM aims to maintain normal glucose levels. Exercise, diets, and metformin are effective and carry little risk. When these measures fail, as they usually do with time, therapy progresses to the administration of drugs that increase insulin secretion or insulin resistance, and various preparations of insulin—essentially feeding a vicious cycle. That insulin-centric approach needs prompt reassessment.

The hyperglycemia of T2DM is not due to a shortage of insulin. These patients are already hyperinsulinemic. Insulin is not benign. It is a powerful mitogen; its administration may be one of the reasons that T2DM is associated with a higher prevalence of cancer. It promotes synthesis of fatty acids in the liver, leading to the synthesis of fatty acids and lipoproteins that may play a role in NASH and the increased atherosclerosis in this disease. Hypoglycemic attacks are another concern. Inkster and colleagues reported the prevalence of all hypoglycemia (mild and severe) in their patients with insulin-treated T2DM to be 45 percent with an incidence of 16.4 episodes per patient per year.27

A report by Currie and colleagues indicates that insulin therapy increases mortality from T2DM.28 Although retrospective, the study raises serious concerns. They reported the mortality rates in two groups treated in the U.K. who failed metformin therapy and were then advanced, by choice of the primary care physicians, either to oral drugs (27,965 patients) or oral drugs plus insulin (20,005 patients). The mortality, stratified by HbA1C levels, was 7 percent in those patients on oral drugs alone versus 21 percent in patients who also received insulin.

This failure of the insulin-based approach is now being recognized, as reflected in Palmer’s recent meta-analysis, published in the Journal of the American Medical Association, which states, “Despite more than 300 available clinical trials involving nearly 120,000 adults and 1.4 million patient-months of treatment, there was limited evidence that any glucose-lowering drug stratified by co-existing treatments prolonged life expectancy or prevented cardiovascular disease.”29

The American Diabetes Association is well aware of these advances. In the 2017 issue of the influential Standards of Medical Care in Diabetes 2017, the recommendation has been made that “Metabolic surgery should be recommended to treat type 2 diabetes in appropriate surgical candidates…when hyperglycemia is inadequately controlled.”30

Conclusion

The use of insulin for the chronic treatment of T2DM deserves rigorous review. There is little evidence, if any, that this costly and dangerous approach effectively prevents the complications of T2DM.

Metabolic surgery is by far the most effective current therapy. It corrects the underlying metabolic dysfunction that drives this and other components of the metabolic syndrome. It provides durable control of T2DM, prevents its complications, and reduces mortality with remarkable safety, with a 90-day mortality of 0.3 percent. However, far too many patients are denied access to the treatment because of resistance from primary care physicians, insurance carriers, and the patients themselves as a result of either a lack of understanding of the treatment’s safety, efficacy, and durability or persistent negative bias. The current record of <0.7 percent of the patients who could benefit from receiving the surgery is unacceptable.

Enough data are available to indicate that the metabolic syndrome is caused by pathologic signal(s) from the gut, and that understanding of these pathways can lead to effective intervention with medications. Research to explore these opportunities should be strongly supported.

Acknowledgments

This work was supported by the American College of Surgeons (ACS). The authors declare that they have no relevant conflict of interest.

We are grateful to the ACS for their generous sponsorship of the Metabolic Surgery Symposium and associated journal publication development. We thank Jane N. Buchwald, chief scientific research writer, Medwrite Medical Communications, Maiden Rock, WI, for manuscript editing and publication coordination. And we thank Patrick Beebe and Donna Coulombe, ACS Executive Services, for their expert organization of the Metabolic Surgery Symposium.


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