bariatric surgery to cure type-2 diabetes

Abstract

Objective

To review the effect of morbid obesity surgery on type 2 diabetes mellitus, and to analyze data that might explain the mechanisms of action of these surgeries and that could answer the question of whether surgery for morbid obesity can represent a cure for type 2 diabetes in nonobese patients as well.

Summary Background Data

Diabetes mellitus type 2 affects more than 150 million people worldwide. Although the incidence of complications of type 2 diabetes can be reduced with tight control of hyperglycemia, current therapies do not achieve a cure. Some operations for morbid obesity not only induce significant and lasting weight loss but also lead to improvements in or resolution of comorbid disease states, especially type 2 diabetes.

Methods

The authors reviewed data from the literature to address what is known about the effect of surgery for obesity on glucose metabolism and the endocrine changes that follow this surgery.

Results

Series with long-term follow-up show that gastric bypass and biliopancreatic diversion achieve durable normal levels of plasma glucose, plasma insulin, and glycosylated hemoglobin in 80% to 100% of severely obese diabetic patients, usually within days after surgery. Available data show a significant change in the pattern of secretion of gastrointestinal hormones. Case reports have also documented remission of type 2 diabetes in nonmorbidly obese individuals undergoing biliopancreatic diversion for other indications.

Conclusions

Gastric bypass and biliopancreatic diversion seem to achieve control of diabetes as a primary and independent effect, not secondary to the treatment of overweight. Although controlled trials are needed to verify the effectiveness on nonobese individuals, gastric bypass surgery has the potential to change the current concepts of the pathophysiology of type 2 diabetes and, possibly, the management of this disease.

Role of Weight Loss

Most reported series show that return to euglycemia and normal insulin levels occur within days after surgery, long before there is any significant weight loss. ^15,24,25 In 1995, Pories et al ²⁴ reported the results of GBP in a series of 608 morbidly obese patients. Preoperatively, 146 patients were diabetic (type 2) and 152 had impaired glucose tolerance. GBP achieved normal levels of plasma glucose, insulin, and glycosylated hemoglobin in 83% of diabetic patients and in 98.7% of patients with impaired glucose tolerance within 4 months after surgery, without the need for any diabetic medication or special diet, and before any weight reduction occurred. In 1998, Scopinaro et al ¹⁵ reported normalization of glucose levels in 100% of their morbidly obese patients after BPD with no need for medication and on a totally free diet as early as 1 month after operation, when excess weight was still more than 80%. Hickey et al²⁵ demonstrated significantly lower levels of fasting plasma glucose, plasma insulin, and serum leptins in a group of patients maintaining stable weight after GBP compared to a group of patients matched in weight, age, and percentage of fat who did not undergo surgery. A clinical case described in detail by Pories and Albrecht ²⁹ is instructive. This woman with a fasting blood glucose of 495 mg/dL despite daily administration of 90 units insulin underwent GBP. On the first day after surgery her blood glucose fell to 281 mg/dL and her insulin requirement was only 8 units. By day 6 she no longer required insulin, and she subsequently remained euglycemic without insulin or other hypoglycemic agents on a regular diet for the following years.

Role of Decreased Food Intake

If decreased food intake explains how the GBP and BPD procedures control diabetes, gastroplasties should be effective too, since these operations significantly lower food intake by reduction of gastric volume. Gastroplasties do indeed improve glucose metabolism, ^30,31 but there is no evidence for long-term cure of diabetes in morbidly obese patients. Furthermore, vertical banded gastroplasty results in less reduction of hyperglycaemia and hyperinsulinemia than GBP does. ³² Also, patients undergoing BPD show only temporary food intake limitation; over time, their eating capacity is fully restored or even increased, ¹⁵ while blood glucose levels remain under control.

CURRENT THEORIES ABOUT THE PATHOGENESIS OF TYPE 2 DIABETES

The most recent theories portray type 2 diabetes mellitus as a heterogeneous disorder. In addition to insulin resistance, clinical studies in humans and animal data have documented a variety of defects in β-cell function, ⁴¹ and most researchers agree that both insulin secretion impairment and insulin resistance contribute to the fully established disease. ⁴²GBP and BPD restore insulin sensitivity, but the possibility of an additional incretin-mediated effect on insulin secretion cannot be ruled out.

Though insulin is the chief acute physiologic stimulus of glucose disposal, other stimuli can also activate glucose uptake and control glycemia. ⁴³ In vivo administration of IGF1 has a potent hypoglycemic effect and has been proven to effectively lower blood glucose concentrations in subjects with type 1 or type 2 diabetes. ^44,45 Decreased levels of IGF-1 have also been documented in patients with type 2 diabetes mellitus. ⁴⁶ Poulos at al ³⁵demonstrated that GBP significantly increases IGF-1 levels only in morbidly obese patients with diabetes and not in nondiabetic subjects.

Recent data indicate that leptin may directly affect glucose and fat metabolism. ⁴⁷Administration of leptin to normal, genetically obese, or diabetic rodents improved sensitivity to insulin and reduced hyperinsulinemia before any changes in food intake or body weight occurred. ^48,49 Leptin-induced increase in fatty acid oxidation could also improve glucose uptake ⁵⁰ and influence insulin sensitivity indirectly through the brain and sympathetic nervous system ^49,51 or by changes in the concentration of serum fatty acids and glucose flux in the liver. ⁵¹ In the light of these effects, it is of extreme interest that leptin levels decrease rapidly after GBP and BPD without correlation with postoperative BMI. ^25,36 This observation suggests that body fat composition is not the only factor that regulates leptin levels. It might be speculated that an unknown factor, produced in the duodenum or jejunum in response to food stimulation, is responsible for a sort of “leptin resistance” and compensatory increased plasma levels of leptins, which is a common finding in obese patients. ⁴⁷ Accordingly, when the duodenum and jejunum are bypassed, as after GBP and BPD, the cause of leptin resistance is abolished or greatly reduced, leptin resistance is resolved, and plasma leptin levels decrease. The effect of GBP and BPD on leptin may therefore in part explain their efficacy in treatment of both obesity and diabetes.

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SURGERY AS A CURE FOR TYPE 2 DIABETES?

The evidence of this extraordinary control of diabetes by obesity surgery stimulates another intriguing question: since GBP and BPD seem to achieve control of diabetes as a primary, specific, and independent effect rather than secondary to the treatment of overweight, would these operations also be effective in moderately obese or in nonobese diabetics?

In 1997, Mingrone et al ⁵² reported a case of a young diabetic woman of normal weight who underwent BPD for chylomicronemia and whose plasma insulin and blood glucose levels were normalized within 3 months, even though she gained weight due to an unrestricted diet rich in sugar and lipids. Noya et al ⁵³ reported remission of type 2 diabetes in 9 of 10 moderately obese (mean BMI 33.2) diabetic patients undergoing BPD.

Although some suggested that the etiology of type 2 diabetes mellitus might be different in obese patients because of the greater insulin resistance with respect to non-obese diabetic patients, ⁵⁴ this finding was not confirmed by most studies. ^55,56 It has been reported that the degree of insulin resistance is correlated with the degree of obesity only up to a BMI of about 30, after which there is little further change. ⁵⁷ These observations suggest that GBP and BPD might achieve control of plasma glucose levels and insulin abnormalities at least in moderately obese patients (BMI > 30). Since more than 60% of patients with type 2 diabetes have a BMI above 28, ⁵⁸ the potential is huge.

If morbid obesity surgery could become a specific treatment for type 2 diabetes, which operation should be performed? We believe that because of its low complication rate and lack of important late metabolic sequelae, GBP is more suitable than BPD for nonmorbidly obese diabetic patients. The fact that GPB is performed laparoscopically more often and in more centers is an additional advantage.

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SUMMARY AND CONCLUSIONS

GBP and BPD seem to be an effective form of therapy for type 2 diabetes, at least in morbidly obese patients. Significant changes in gastrointestinal hormones have been documented, but no clear explanation has been given yet about the mechanism of action of this surgery. The bypass of the duodenum and proximal jejunum, a common feature of both GBP and BPD, may contrasts a hormonal or neural signaling originating from the gut in response to the passage of food and responsible for the impaired action and/or secretion of insulin that characterizes type 2 diabetes. Case reports and observations on the timing of the restoration of glucose metabolism after surgery suggest that the control of diabetes occurs as a primary, specific, and independent effect of this surgery, not secondary to the treatment of overweight.

Controlled trials in centers with a wide experience of GBP surgery are needed to verify the possibility of a surgical cure specific for type 2 diabetes; however, surgeries for obesity seem to have a potential for changing the current concepts of the pathophysiology of type 2 diabetes and, possibly, the management of this disease.

The gastric bypass operation reduces the progression and mortality of non-insulin-dependent diabetes mellitus.

From Abstract: Study of 232 patients who had either bariatric surgery of none. The mortality rate in the surgery group was 1%, in those without treatment 4.5% per year. Mean glucose level in the surgery group fell for 187 to 140 mg/dl. The surgery group needing medical management of glucose fell from 31.8% to 8.6 and the non-treatment group increased from 56.4% to 87.5%.

Mechanisms of Recovery From Type 2 Diabetes After Malabsorptive Bariatric Surgery

Abstract: Currently, there are no data [2006] in the literature regarding the pathophysiological mechanisms involved in the rapid resolution of type 2 diabetes after bariatric surgery, which was reported as an additional benefit of the surgical treatment for morbid obesity. With this question in mind, insulin sensitivity, using euglycemic-hyperinsulinemic clamp, and insulin secretion, by the C-peptide deconvolution method after an oral glucose load, together with the circulating levels of intestinal incretins and adipocytokines, have been studied in 10 diabetic morbidly obese subjects before and shortly after biliopancreatic diversion (BPD) to avoid the weight loss interference. Diabetes disappeared 1 week after BPD, while insulin sensitivity (32.96 ± 4.3 to 65.73 ± 3.22 μmol · kg fat-free mass⁻¹ · min⁻¹at 1 week and to 64.73 ± 3.42 μmol · kg fat-free mass⁻¹ · min⁻¹ at 4 weeks; P < 0.0001) was fully normalized. Fasting insulin secretion rate (148.16 ± 20.07 to 70.0.2 ± 8.14 and 83.24 ± 8.28 pmol/min per m²; P < 0.01) and total insulin output (43.76 ± 4.07 to 25.48 ± 1.69 and 30.50 ± 4.71 nmol/m²; P < 0.05) dramatically decreased, while a significant improvement in β-cell glucose sensitivity was observed, Both fasting and glucose-stimulated gastrointestinal polypeptide (13.40 ± 1.99 to 6.58 ± 1.72 pmol/l at 1 week and 5.83 ± 0.80 pmol/l at 4 weeks) significantly (P < 0.001) decreased, while glucagon-like peptide 1 significantly increased (1.75 ± 0.16 to 3.42 ± 0.41 pmol/l at 1 week and 3.62 ± 0.21 pmol/l at 4 weeks; P < 0.001). BPD determines a prompt reversibility of type 2 diabetes by normalizing peripheral insulin sensitivity and enhancing β-cell sensitivity to glucose, these changes occurring very early after the operation. This operation may affect the enteroinsular axis function by diverting nutrients away from the proximal gastrointestinal tract and by delivering incompletely digested nutrients to the ileum.

Resolution of type 2 diabetes has been observed as an additional benefit of surgical treatment for morbid obesity (1). After the Greenville gastric bypass operation, 88.7% of 515 morbidly obese patients became and have remained euglycemic, and only 5.8% patients remained diabetic (2). The Swedish Obese Subjects Intervention Study (3), where the effect of bariatric surgery was compared with that of conventional medical treatment of obesity in a large sample of 1,690 obese subjects, showed that the 2-year incidence of diabetes in the surgical arm was 0% compared with 16% in the control group. Furthermore, clinical remission of type 2 diabetes occurred in 83% of 192 severely obese patients with type 2 diabetes who underwent laparoscopic Roux-en-Y gastric bypass, while a significant improvement was observed in the remaining 17%. Noticeably, this study found that a shorter history of diabetes and milder disease was associated with an increased likelihood of remission (4).

In a recent systematic review and meta-analysis of the data reported in the literature on bariatric surgery, Buchwald et al. (5) found a gradation of effects on the resolution of diabetes from 98.9% for biliopancreatic diversion (BPD) or duodenal switch technique to 83.7% for gastric bypass to 71.6% for gastroplasty and to 47.9% for gastric banding. However, up to now, there is a lack of prospective studies showing the relative merits of gastric restrictive or malabsorptive procedures for those patients with diabetes.

It should be emphasized that in these subjects, glycemic control often occurs long before a significant weight loss (6), and bariatric surgery is also effective in curing diabetes in normal-weight subjects (7), suggesting that the control of diabetes may be a direct effect of the operations rather than a secondary outcome of the weight loss. Pories and Albrecht (8) have suggested that the rapidity of the correction to euglycemia, usually a matter of days, might be the result of the exclusion of food from the intestinal transit, resulting in a secondary alteration in incretin signals from the antrum, duodenum, and proximal jejunum to the pancreatic islets.

Up to now, no data are reported in the literature regarding the pathophysiological mechanisms involved in the rapid resolution of diabetes after malabsorptive bariatric surgery, like BPD. With the purpose of providing additional evidence on this topic and in order to avoid the interference due to weight loss, we have studied 10 obese, diabetic subjects both before and shortly after BPD, i.e., 1 and 4 weeks after surgery. Insulin sensitivity was measured using the euglycemic-hyperinsulinemic clamp, and insulin secretion was derived by the C-peptide deconvolution method after a standard oral glucose load, and, in addition, circulating levels of intestinal incretins and adipocytokines were obtained.

Research Design and Methods: Ten morbidly obese women (BMI 54.55 ± 3.75 kg/m²), affected by type 2 diabetes, undergoing BPD were studied. The onset of diabetes dated 1–3 years, and the average HbA_1c was 8.5 ± 1.2%. Patients were restudied at 1 and 4 weeks after surgery.

Conclusions: In conclusion, BPD determines a prompt reversibility of type 2 diabetes by normalizing peripheral insulin sensitivity and by enhancing β-cell sensitivity to glucose; these changes occur very early after the operation.

BPD operation may affect the enteroinsular axis by diverting nutrients away from the proximal gastrointestinal tract and by delivering incompletely digested nutrients to the ileum. This, in turn, enhances the secretion of GLP-1 in the transposed ileum, while the exclusion of the duodenum and jejunum might be responsible for the downregulation of GIP and of other gut hormones involved in insulin sensitivity regulation.

In blood tests designed to measure improved function of beta cells in pancreas and insulin sensitivity all ten subjects tested at end of 1 week following bariatric surgery were cured of T2D. The study shows that the cure was affected through fasting rather than weight loss. Those who undergo bariatric surgery undergo fasting. The oral glucose load, together with the circulating levels of intestinal incretins and adipocytokines has been studied in 10 diabetic morbidly obese subjects before and shortly after biliopancreatic diversion (BPD) [bariatric surgery]to avoid the weight loss interference.

“Immediately after bariatric surgery, the patient is restricted to a clear liquid diet, which includes foods such as clear broth, diluted fruit juices or sugar-free drinks and gelatin desserts. This diet is continued until the gastrointestinal tract has recovered somewhat from the surgery. The next stage provides a blended or pureed sugar-free diet for at least two weeks. This may consist of high protein, liquid or soft foods such as protein shakes, soft meats, and dairy products. Foods high in carbohydrates are usually avoided when possible during the initial weight loss period. Post-surgery, overeating is curbed because exceeding the capacity of the stomach causes nausea and vomiting,” Wiki.

Glutamic acid decarboxylase autoantibody (GADA), islet cell autoantibody (ICA), insulinoma-associated (IA-2) autoantibody, and zinc transporter autoantibody (ZnT8) testing should be performed on all adults who are not obese who are diagnosed with diabetes.

Steatohepatitis (also known as fatty liver disease) is a type of liver disease, characterized by inflammation of the liver with concurrent fat accumulation in liver (steato-, meaning "fat", hepatitis, meaning "inflammation of the liver"). More deposition of fat in the liver is termed steatosis, and together these constitute fatty liver changes. Classically seen in alcoholics as part of alcoholic liver disease, steatohepatitis is also frequently found in people with diabetes and obesity and is related to metabolic syndrome. When not associated with excessive alcohol intake, it is referred to as nonalcoholic steatohepatitis, or NASH, and is the progressive form of the relatively benign non-alcoholic fatty liver disease.