Diet and Medical Therapy Versus Bariatric Surgery in Type 2 Diabetes
Condition: Type 2 Diabetes
MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 2
Study type: Interventional

Summary: 
      It is generally held that ß-cell function is irreversibly lost already at the time the
      disease manifests itself and thereafter continues to decline linearly with time. Several
      studies, however, have documented the possibility that ß-cell function may be restored, at
      least partially, in type 2 diabetes. Of major relevance to the issue of ß-cell recovery in
      diabetes are the following findings:

        -  bariatric surgery in morbidly obese patients with type 2 diabetes can restore
           euglycaemia, the acute insulin response to glucose and insulin sensitivity;

        -  recent studies have reported that diabetic subjects return to euglycaemia and normal
           insulin levels within days after surgery, long before a significant weight loss has
           occurred; and

        -  whereas gastric bypass (GBP) improves insulin sensitivity in proportion to weight loss,
           bilio-pancreatic diversion (BPD) improves insulin action out of proportion to weight
           loss, i.e., it normalizes it at a time when patients are still markedly obese. Because
           RYGB is a predominantly restrictive procedure involving the foregut, whereas BPD is a
           predominantly malabsorptive procedure involving the distal gastro-intestinal (GI) tract,
           these findings suggest that the control of both insulin action and ß-cell function is
           influenced by signals originating from the GI tract.

      The principal aim of this study is to verify the effect on type 2 diabetes mellitus (T2DM) of
      GBP and BPD, the two operations which have shown specific actions on glucose homeostasis
      control, in type 2 diabetic patients with BMI > 35 kg/m2, and to compare this effect with
      matched T2DM control patients receiving the standard of medical care.
    

Detailed description: 
      ß-cell dysfunction and insulin resistance are the main pathophysiological defects responsible
      for the development of hyperglycaemia [1]. Both these defects predict incident diabetes in
      high-risk subjects [2]. Insulin resistance per se is not sufficient to cause hyperglycaemia;
      mild degrees of ß-cell dysfunction, on the other hand, may not result in diabetic
      hyperglycaemia in insulin sensitive individuals. It is only when impaired ß-cell function
      occurs in the background of insulin resistance that plasma glucose levels begin to rise (as
      is the case of individuals with impaired glucose tolerance [3]). The occurrence of
      postprandial, or day-long, hyperglycaemia further compromises both ß-cell function and
      insulin action, a phenomenon called glucose toxicity [4-6]. As a consequence, the vast
      majority of patients with established type 2 diabetes present, in addition to marked insulin
      resistance, a clear defect in ß-cell function, which is generally proportional to the
      severity of the hyperglycaemia [7]. Of note is that the extent of ß-cell dysfunction in type
      2 patients may be misjudged when ß-cell function is inferred from simple measurements of
      fasting or postprandial plasma insulin concentrations. In fact, insulin secretion increases
      (in non-linear manner [8]) in insulin resistant individuals, a compensatory response aimed at
      maintaining glucose tolerance. As a consequence, the absolute insulin hypersecretion
      (particularly in the fasting state) commonly found in patients with IGT or diabetes masks the
      underlying defect in the ability of the ß-cell to cope with nutrient stimulation.

      It is generally held that ß-cell function is irreversibly lost already at the time the
      disease manifests itself and thereafter continues to decline linearly with time. Several
      studies, however, have documented the possibility that ß-cell function may be restored, at
      least partially, in type 2 diabetes [9-13]. Of major relevance to the issue of ß-cell
      recovery in diabetes are the following findings: (a) bariatric surgery in morbidly obese
      patients with type 2 diabetes can restore euglycaemia, the acute insulin response to glucose
      [14-17] and insulin sensitivity [18,19]; (b) recent studies have reported that diabetic
      subjects return to euglycaemia and normal insulin levels within days after surgery, long
      before a significant weight loss has occurred [20]; and (c) whereas RYGB improves insulin
      sensitivity in proportion to weight loss, BPD improves insulin action out of proportion to
      weight loss, i.e., it normalises it at a time when patients are still markedly obese [21].
      Because RYGB is a predominantly restrictive procedure involving the foregut whereas BPD is a
      predominantly malabsorptive procedure involving the distal GI tract, these findings suggest
      that the control of both insulin action and ß-cell function is influenced by signals
      originating from the GI tract.

      Some studies have investigated the hormonal changes that follow bariatric surgery. In most
      cases, however, clinical testing was performed after significant weight reduction, thereby
      making it difficult to establish whether any observed hormonal effect was the cause or the
      consequence of weight loss and diabetes resolution. Recently, it has been reported that RYGB
      induces rapid normalisation of blood glucose and insulin levels in concomitance with
      significant changes of the levels of hormones involved in the regulation of glucose
      metabolism (ACTH, leptin and GIP) in the early postoperative period [22]. It has been
      proposed that the incretins could be one of the key mediators of the anti-diabetic effects of
      certain types of bariatric surgery. Previous data have shown that the significant weight loss
      observed after various bariatric procedures was accompanied by improvement of diabetes
      control and increased GLP-1 levels. However, most studies were cross sectional [23,24],
      reported fasting [25] rather than post-prandial GLP-1 levels, and compared various types of
      surgery such as jejuno-ileal bypass (JIB) [26,27] or bilio-pancreatic diversion (BPD) [27],
      often leading to inconclusive results. Data on fasting GIP levels after bariatric surgery are
      inconsistent, reporting either a decrease [25,28,29] or an increase [23,24]. GLP-1 levels
      increase after a meal in patients after RY-GBP [30] or with oral glucose after BPD [30].
      Meal-stimulated GIP levels have been reported to increase after JIB [23], or to decrease
      after GBP, JIB or BPD surgery [26,29,31,32]. None of these studies, however, measured GLP-1
      and GIP simultaneously, reported the incretin levels and effect on insulin secretion (with
      the exception of the last quoted one, which reported both GIP and insulin response to meal
      markedly reduced after BPD), or was done in diabetic patients.

      Some authors have suggested that an enhanced release of GLP-1, triggered by the earlier
      presentation of undigested food to lower segments of the bowel, might be involved in the
      glycaemic improvement consequent to bypass procedures for obesity surgery.

      Collectively, these observations clearly suggest that there is a large margin for ß-cell
      recovery of function in type 2 diabetes and that different segments of the gut participate
      differentially in such recovery.

      The primary end-points of the study are the differences in the proportions of patients
      reaching partial or complete remission of type 2 diabetes between conventional therapy and
      BPD or conventional therapy and RYGB.

      In particular, according to Buse et al (Diabetes Care 2009; 32:2133-35) partial remission is
      defined as fasting glucose values of 100-125 mg/dl [5.6-6.9 mmol/l]) and HbA1c<6.5%, of at
      least 1 year's duration in the absence of active pharmacologic therapy. Complete remission is
      referred to fasting glucose <100 mg/dl [5.6 mmol/l]) and HbA1c in the normal range of at
      least 1 year's duration in the absence of active pharmacologic therapy.

      Secondary endpoints Secondary endpoints include percentage change of fasting plasma glucose
      levels, glycated hemoglobin, weight, waist circumference, blood pressure, cholesterol,
      HDL-cholesterol and triglycerides, and hard cardiovascular risk.
    

Intervention name(s): Bariatric surgery: Gastric bypass; Bariatric surgery: Bilio-pancreatic diversion; anti-diabetic drugs and behavioral suggestions
Intervention type(s): Procedure; Procedure; Behavioral
Intervention description(s): Gastric bypass (GBP): A subcardial gastric pouch with a 30±10 ml capacity will be created on a naso-gastric 36F calibrating tube by sectioning the stomach with a linear stapler 3-4 cm horizontally on the lesser curve, 4 cm distal to the e-g junction, and then vertically until attainment of the angle of Hiss. After identification of the Treitz ligament, the jejunum will be transected at 100 cm from the ligament of Treitz and the two stumps will be closed. The distal stump will be anastomosed to the distal end of the gastric pouch. The preferred gastro-jejunal anastomosis is the totally hand-sewn one, but it can be performed using any other the technique the surgeon is more familiar with. Finally, the proximal stump of the transacted bowel will be joined end-to-side to the jejunum 150 cm distal to the gastroenterostomy.; Biliopancreatic diversion (BPD): A distal two-third gastrectomy will be carried out aiming at leaving an about 400 ml gastric remnant. The gastrointestinal continuity will be re-established by sectioning the small bowel 300 cm proximal to the ileocecal valve, closing the intestinal stumps, and joining the proximal one end-to-side to the distal ileum at 50 cm from the ligament of Treitz. The distal stump of the transacted bowel will be anastomosed to the left corner of the gastric stump, preferably in a totally hand-sewn fashion.; Medical therapies (oral hypoglycemic agents and insulin) are optimized on an individual basis. Lifestyle modification programs, including reduced energy and fat (<30% total fat and <10% saturated fat, high fibre content) intake and increased physical exercise (suggested at least 30 minutes of brisk walking every day possibly associated with a moderate intensity aerobic activity twice a week), are tailor made by an experienced diabetologist assisted by a dietitian. After the two years, the patients in control group will be offered the choice to undergo one of the two surgical procedures.
Intervention MeSH terms: Hypoglycemic Agents
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: bariatric surgery; GBP; BPD; type 2 diabetes