Complete Remission Of Diabetes Research Articles

Metabolic outcomes 2 years following gastric bypass surgery in people with type 2 diabetes: an observational cohort study

Gastric bypass surgery induces early remission or significant improvement in type 2 diabetes (T2D). To assess effectiveness of stopping glucose-lowering treatment at the time of surgery. Observational cohort analysis. We identified 101 patients (62 women) with T2D who had undergone gastric bypass surgery at a mean (SD, standard deviation) age of 51.4 (9.0) years. We recorded weight, body mass index (BMI), glycosylated haemoglobin (HbA1c), blood pressure (BP), total and high-density lipoprotein (HDL) cholesterol preoperatively and at a median 4, 12 and 24 months postoperatively, and changes to glucose-lowering therapy. Mean (SD) baseline BMI was 50.3 (6.3) kg/m(2), HbA1c 65.3 (18.5) mmol/mol, systolic BP 146.0 (18.0) mmHg, diastolic BP 87.0 (10.8) mmHg and total cholesterol-to-HDL cholesterol ratio 4.0 (1.2). Mean (95% confidence interval) reduction in BMI was 16.4 (14.1-18.7) kg/m(2), HbA1c 23.6 (17.6-29.6) mmol/mol, systolic BP 12.9 (5.9-19.8) mmHg, diastolic BP 6.1 (1.8-10.5) mmHg and total cholesterol-to-HDL cholesterol ratio 1.1 (0.6-1.5) at 24 months (P < 0.001 for all measures). Although 91% of patients were receiving glucose-lowering therapies preoperatively, complete (HbA1c < 42 mmol/mol) and partial (HbA1c 42-48 mmol/mol) remissions of T2D were seen in 62.1% and 5.2% at 2 years postoperatively. Cessation of glucose-lowering therapies in people with T2D at the time of gastric bypass surgery was clinically effective. The majority of patients remained in complete or partial remission of diabetes up to 2 years postoperatively.

Perfil dos obesos sem remissão do diabete melito tipo 2 e/ou perda insuficiente de peso após bypass gástrico em Y-de-roux

The literature reports that gastrojejunal derivation with Roux-en-Y gastric bypass is highly efficient in controlling weight and resolving; but studies have shown worsened glycemic control in a considerable number of patients and associated factors that have not been fully elucidated. To analyze the profile of patients submitted to gastric bypass that did not achieve satisfactory weight loss or complete diabetes remission. Case-control study of 32 patients submitted to gastric bypass with at least two years postoperative time, unsatisfactory results in terms of weight loss or absence of complete diabetes remission. The control group was composed of another 32 patients submitted to the same operation at the same facility, matched for age and postoperative time. A structured questionnaire was applied and clinical and laboratory data were analyzed. Among the cases and controls, BMI was 38.9 kg/m² and 29.5 kg/m2, excess weight loss was 56.1% and 77.2%, % excess weight regain of initial excess weight loss, was 20.2% and 7.7%, respectively. Family history of type 2 diabetes mellitus, hypertension and food intolerance showed a significant relationship between cases and controls. Food intolerance and family history of hypertension and diabetes were associated to lower loss and weight regain or less likelihood of complete diabetes remission after gastric bypass.

Mechanism of Metabolic Advantages After Bariatric Surgery

The acute glucose-lowering effect of certain bariatric procedures—before any significant weight loss has occurred—has been known for decades (1). In a comprehensive meta-analysis by Buchwald et al. (2), type 2 diabetes remission rates after the most common bariatric procedure, Roux-en-Y gastric bypass (RYGB), were reported to be 80%. Applying the 2009 consensus criteria for the definition of diabetes remission has been reported to show complete remission of diabetes in “only” 41% of 160 RYGB-treated obese patients with type 2 diabetes (3). Importantly, bariatric surgery seems to improve several components of the metabolic syndrome, and type 2 diabetes–specific mortality rates have been demonstrated to be up to 90% lower in RYGB-treated subjects compared with nontreated control subjects (2,4). In comparison with medical therapy alone, recent clinical trials have shown that RYGB or biliopancreatic diversion resulted in better glucose control (5), RYGB achieved glycemic control in significantly more patients (6), and sleeve gastrectomy resolved the diabetic state more effectively (7). Thus, it is well established that bariatric procedures improve glycemic control or even resolve the type 2 diabetic state. However, the mechanisms by which these operations bring about their glucose-lowering effects remain much debated. Obviously, the body weight–lowering effect of these operations contributes to the long-term improvements in glucose metabolism (primarily via increased hepatic and peripheral insulin sensitivity [8]), but it is striking that amelioration of hyperglycemia after bariatric surgery occurs within days of the surgery, pointing to immediate, weight loss–independent mechanisms possibly related to surgery-induced changes in food intake (caloric restriction), gastrointestinal (GI) anatomy, or transit of nutrients. The predominant hypotheses on the physiological background for the metabolic advantages (specifically, the glucose-lowering effects) after bariatric surgery include changed release of GI hormones (increased secretion of hormones with antidiabetes properties and reduced secretion of “diabetogenic” hormones) and surgery-induced …

Association of an Intensive Lifestyle Intervention With Remission of Type 2 Diabetes

The frequency of remission of type 2 diabetes achievable with lifestyle intervention is unclear. To examine the association of a long-term intensive weight-loss intervention with the frequency of remission from type 2 diabetes to prediabetes or normoglycemia. Ancillary observational analysis of a 4-year randomized controlled trial (baseline visit, August 2001-April 2004; last follow-up, April 2008) comparing an intensive lifestyle intervention (ILI) with a diabetes support and education control condition (DSE) among 4503 US adults with body mass index of 25 or higher and type 2 diabetes. Participants were randomly assigned to receive the ILI, which included weekly group and individual counseling in the first 6 months followed by 3 sessions per month for the second 6 months and twice-monthly contact and regular refresher group series and campaigns in years 2 to 4 (n=2241) or the DSE, which was an offer of 3 group sessions per year on diet, physical activity, and social support (n=2262). Partial or complete remission of diabetes, defined as transition from meeting diabetes criteria to a prediabetes or nondiabetic level of glycemia (fasting plasma glucose <126 mg/dL and hemoglobin A1c <6.5% with no antihyperglycemic medication). RESULTS Intensive lifestyle intervention participants lost significantly more weight than DSE participants at year 1 (net difference, -7.9%; 95% CI, -8.3% to -7.6%) and at year 4 (-3.9%; 95% CI, -4.4% to -3.5%) and had greater fitness increases at year 1 (net difference, 15.4%; 95% CI, 13.7%-17.0%) and at year 4 (6.4%; 95% CI, 4.7%-8.1%) (P < .001 for each). The ILI group was significantly more likely to experience any remission (partial or complete), with prevalences of 11.5% (95% CI, 10.1%-12.8%) during the first year and 7.3% (95% CI, 6.2%-8.4%) at year 4, compared with 2.0% for the DSE group at both time points (95% CIs, 1.4%-2.6% at year 1 and 1.5%-2.7% at year 4) (P < .001 for each). Among ILI participants, 9.2% (95% CI, 7.9%-10.4%), 6.4% (95% CI, 5.3%-7.4%), and 3.5% (95% CI, 2.7%-4.3%) had continuous, sustained remission for at least 2, at least 3, and 4 years, respectively, compared with less than 2% of DSE participants (1.7% [95% CI, 1.2%-2.3%] for at least 2 years; 1.3% [95% CI, 0.8%-1.7%] for at least 3 years; and 0.5% [95% CI, 0.2%-0.8%] for 4 years). In these exploratory analyses of overweight adults, an intensive lifestyle intervention was associated with a greater likelihood of partial remission of type 2 diabetes compared with diabetes support and education. However, the absolute remission rates were modest. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00017953.

A Multisite Study of Long-term Remission and Relapse of Type 2 Diabetes Mellitus Following Gastric Bypass

Gastric bypass has profound effects on glycemic control in adults with type 2 diabetes mellitus. The goal of this study was to examine the long-term rates and clinical predictors of diabetes remission and relapse among patients undergoing gastric bypass. We conducted a retrospective cohort study of adults with uncontrolled or medication-controlled type 2 diabetes who underwent gastric bypass from 1995 to 2008 in three integrated health care delivery systems in the USA. Remission and relapse events were defined by diabetes medication use and clinical laboratory measures of glycemic control. We identified 4,434 adults with uncontrolled or medication-controlled type 2 diabetes who had gastric bypass. Overall, 68.2 % (95 % confidence interval [CI], 66 and 70 %) experienced an initial complete diabetes remission within 5 years after surgery. Among these, 35.1 % (95 % CI, 32 and 38 %) redeveloped diabetes within 5 years. The median duration of remission was 8.3 years. Significant predictors of complete remission and relapse were poor preoperative glycemic control, insulin use, and longer diabetes duration. Weight trajectories after surgery were significantly different for never remitters, relapsers, and durable remitters (p = 0.03). Gastric bypass surgery is associated with durable remission of type 2 diabetes in many but not all severely obese diabetic adults, and about one third experience a relapse within 5 years of initial remission. More research is needed to understand the mechanisms of diabetes relapse, the optimal timing of surgery in effecting a durable remission, and the relationship between remission duration and incident microvascular and macrovascular events.

Effect of the definition of type II diabetes remission in the evaluation of bariatric surgery for metabolic disorders

The American Diabetes Association recently defined remission of type II diabetes as a return to normal measures of glucose metabolism (haemoglobin (Hb) A1c below 6 per cent, fasting glucose less than 5·6 mmol/l) at least 1 year after bariatric surgery without hypoglycaemic medication. A previously used common definition was: being off diabetes medication with normal fasting blood glucose level or HbA1c below 6 per cent. This study evaluated the proportion of patients achieving complete remission of type II diabetes following bariatric surgery according to these definitions. This was a retrospective review of data collected prospectively in three bariatric centres on patients undergoing gastric bypass, sleeve gastrectomy and gastric banding. Some 1006 patients underwent surgery, of whom 209 had type II diabetes. Median follow-up was 23 (range 12-75) months. HbA1c was reduced after operation in all three surgical groups (P < 0·001). A total of 72 (34·4 per cent) of 209 patients had complete remission of diabetes, according to the new definition; the remission rates were 40·6 per cent (65 of 160) after gastric bypass, 26 per cent (5 of 19) after sleeve gastrectomy and 7 per cent (2 of 30) after gastric banding (P < 0·001 between groups). The remission rate for gastric bypass was significantly lower with the new definition than with the previously used definition (40·6 versus 57·5 per cent; P = 0·003). Expectations of patients and clinicians may have to be adjusted as regards remission of type II diabetes after bariatric surgery. Focusing on improved glycaemic control rather than remission may better reflect the benefit of this type of surgery and facilitate improved glycaemic control after surgery.

Biliopancreatic Diversion with Duodenal Switch in Patients with Type 2 Diabetes mellitus: Is the Chance of Complete Remission Dependent on Therapy and Duration of Insulin Treatment?

Background: Rapid resolution of type 2 diabetes mellitus (T2DM) is a common feature after intestinal bypass surgery bypassing the duodenum and parts of the jejunum. However, the parameters determining the individual chance of remission are imprecisely defined. Methods: Biliopancreatic diversion with duodenal switch and sleeve gastrectomy (BPD-DS) was performed in n = 86 patients with T2DM (mean age 50 years, range 26–68, 51 females; BMI 47 kg/m², range 26–71). The patients were retrospectively divided into 4 groups according to the treatment modality and the duration of insulin treatment preoperatively: n = 18 patients were treated with oral antidiabetic drugs only (group 1); n = 32, n = 24, and n = 12 patients were treated with insulin for less than 5 years, for 5–10 years, and for more than 10 years (groups 2, 3, and 4), respectively. Results: At discharge from hospital, all patients of groups 1 and 2 were free of insulin usage, 30% and 75% of the patients of groups 3 and 4 used up to 48 units of insulin per day (mean 24, n = 16). After 1 year, only 4 patients of group 4 permanently required small amounts of insulin (mean 17 units per day) to keep blood glucose below 200 mg/dl. These 4 patients had been using insulin preoperatively for 13, 15, 22, and 25 years. In 3 of these 4 patients, fasting C-peptide was measured and found to be low (<1.2 ng/ml). The rate of complete remission of diabetes for the whole study population was 91%. Conclusion: BPD-DS reliably causes rapid and complete remission of T2DM in all patients on oral antidiabetic drugs and in patients with insulin treatment for less than 5 years. In patients with insulin treatment longer than 5 or 10 years, complete remission rates decline to 88 and 66%, respectively. A low C-peptide preoperatively might be a specific adverse prognostic parameter for the chance of diabetes remission.

Long-term metabolic outcome and quality of life after laparoscopic adjustable gastric banding in obese patients with type 2 diabetes mellitus or impaired fasting glucose

The long-term outcome of type 2 diabetes mellitus after laparoscopic adjustable gastric banding (LAGB) is unknown. A longitudinal cohort study was undertaken of patients with grade 3 obesity and type 2 diabetes or impaired fasting glucose (IFG) undergoing LAGB. Metabolic outcomes and quality of life (QoL) were assessed before and 5 years after LAGB. At 5 years, data for 22 out of 23 patients with type 2 diabetes and 51 out of 53 with IFG were available. Mean(s.d.) excess weight loss was 41(25) and 41(27) per cent in patients with type 2 diabetes and IFG respectively, and was associated with a significant decrease in haemoglobin (Hb) A1c, fasting and postprandial blood glucose, insulin and triglyceride levels, and in liver steatosis. There were significant increases in insulin sensitivity, beta-cell function, disposition index, high-density lipoprotein-cholesterol and QoL (Nottingham Health Profile). Good metabolic control (HbA1c 7 per cent or less) was obtained in 13 diabetic patients, but complete diabetes remission was maintained in only four. Longer duration of diabetes, and poor preoperative glucose control and beta-cell function at baseline were associated with a less favourable outcome. LAGB improved metabolic outcomes and QoL in patients with grade 3 obesity with IFG or type 2 diabetes but rarely led to prolonged remission in long-standing diabetes.

Gastrointestinal Surgery as a Treatment for Diabetes

APPROXIMATELY ONE-THIRD OF ADULTS IN THE UNITED States are obese, and largely because of this, at least as many have diabetes or prediabetes. With these escalating twin epidemics, the health care community has been challenged to develop novel treatment strategies. In this issue of JAMA, Dixon and colleagues report a 2-year study in which patients with recently diagnosed type 2 diabetes and a body mass index (BMI) of 30 to 40 were randomly assigned to receive conventional medical/ behavioral therapy (medical therapy and a focus on weight loss through lifestyle modification) or laparoscopic adjustable gastric banding (LAGB) plus conventional medical/ behavioral therapy. The results were clear and striking. Complete remission of diabetes at 2 years was achieved in 73% of the patients in the LAGB group vs only 13% of those in the medical/behavioral therapy group, and the former experienced larger reductions in blood glucose levels, glycated hemoglobin levels, estimated insulin resistance, use of diabetes medication, and several features of the metabolic syndrome. No serious surgical complications were reported, and minor surgical mishaps seemed no worse than the adverse reactions to diabetes-related pharmacotherapy. As expected, the surgical group lost more weight than the medical/behavioral group (20.7% vs 1.7%), and the amount of weight lost was the dominant predictor of diabetes remission. The percentage weight loss generally required for diabetes resolution was 10%, which was achieved in 86% of surgical patients but in only 1 patient in the medical group. Of the 34 patients who lost less than 10% of body weight, only 4 experienced diabetes remission, and these individuals had particularly mild baseline disease. Conversely, of the 26 patients who lost more than 10% of body weight, diabetes remitted in all but 4. In short, diabetes remission after LAGB appeared attributable to weight loss, with no evidence of additional antidiabetes mechanisms; but by promoting greater weight loss, LAGB was far more effective than medical/behavioral therapy at improving diabetes. For a study in which surgery outperformed nonsurgical interventions, a natural question is whether the medical/ behavioral program was as good as it could be. Pharmacotherapy was determined individually by an experienced diabetologist, using all diabetes medications available at the time. In addition, lifestyle optimization was stressed, including reduced intake of fats, saturated fats, foods with high glycemic index, and overall calories, together with a physical activity program of more than 10 000 steps per day and 200 minutes per week of moderate-intensity exercise. Whether this program constitutes the optimal medical/behavioral intervention can be debated. However, participants visited a physician, nurse, dietician, and/or diabetes educator at least once every 6 weeks for 2 years—an intensity of follow-up unlikely to be exceeded in common practice. Moreover, because both study groups had access to the same nonsurgical interventions, the greater improvement in diabetes following surgery is attributable to the benefits of LAGB in this randomized trial. The general applicability of these findings remains to be determined. The authors’ bariatric surgical team in Melbourne, Australia, is among the most experienced groups in the world using LAGB, and their excellent results may not be readily reproducible elsewhere. Their reported postLAGB weight loss often exceeds that observed by other investigators. The discrepancy likely results from the Melbourne group’s acclaimed long-term, multidisciplinary postLAGB follow-up program. The widespread feasibility and cost of such postoperative coaching are unclear, and results in the community at large are unknown. Moreover, participants in this study had relatively mild diabetes, as characterized by less than 2 years’ duration, no retinopathy or nephropathy, a mean baseline glycated hemoglobin value of 7.7%, and only 1 patient taking insulin. It is unclear whether secondary effects from weight loss alone after LAGB, without apparent direct antidiabetes surgical mechanisms,

Polyclonal Anti-T-Cell Therapy for Type 1 Diabetes Mellitus of Recent Onset

The destruction of pancreatic beta-cells in type 1 diabetes mellitus is mediated by autoreactive T-lymphocyte clones. We initiated a prospective randomized controlled trial of polyclonal rabbit anti-T-cell globulin (ATG) in patients with type 1 diabetes within 4 weeks of diagnosis and with residual post-glucagon C-peptide levels still over 0.3 nmol/l. ATG was administered as an initial bolus of 9 mg/kg followed by 3 consecutive doses of 3 mg/kg. An interim analysis was performed to establish whether any significant changes in C-peptide production and insulin requirement had occurred that would justify the continuation of this pilot study. By May 2004, 11 subjects were assigned to treatment with ATG along with intensified insulin therapy and 6 to intensified insulin therapy with placebo, and were followed for a period of at least 6 months. During the first 12 months a significant difference in the insulin dose trends was found between the groups (p = 0.010) with a lower insulin dosage in the ATG group. There was also a difference in the glucagon stimulated C-peptide level trends of marginal significance (p = 0.068). Compared to values at screening, stimulated C-peptide levels significantly improved in the ATG group (p = 0.012) but not in the placebo group. Complete diabetes remission occurred in 2 patients in the ATG and in none of the placebo group. Glycosylated hemoglobin at 12 months tended to be lower in the ATG group (p = 0.088). Significant adverse effects of ATG treatment, mainly transient fever and moderate symptoms of serum sickness (7 and 6 subjects, respectively) were observed during the first month only. The interim analysis of this ongoing study suggests that short-term ATG therapy in type 1 diabetes of recent onset contributes to the preservation of residual C-peptide production and to lower insulin requirements in the first year following diagnosis.

CD3 antibody-induced dominant self tolerance in overtly diabetic NOD mice.

Low doses of the CD3 mAb 145 2C11 restored self tolerance to beta cell Ags in adult overtly diabetic NOD mice. Within 2 to 4 wk after treatment, complete and permanent remission of diabetes was observed. Autoreactive T cells were not deleted in CD3 Ab-protected animals as evidenced first, by the persistence of peripheral insulitis and, second, by the capacity of spleen cells from CD3 Ab-treated mice to transfer diabetes to adult irradiated syngeneic recipients. Moreover, the conferred tolerance was reproducibly reversed by a single injection of cyclophosphamide. For 5 to 7 wk after treatment, IFN-gamma production by stimulated spleen cells was significantly decreased in treated animals. One unique feature was that the CD3 Ab-induced tolerance ensued only from treatment of overtly diabetic NOD mice. Durable protection was exclusively observed when treating mice with recent onset disease (14-20 wk old). At variance with this finding, treatment of 4- and 8-wk-old mice was without effect, and complete but transient protection followed the treatment of 12-wk-old NOD mice. The tolerogenic properties of 145 2C11 did not depend on its mitogenic capacity, since nonmitogenic F(ab')2 fragments also appeared potent at inducing durable remission in overtly diabetic NOD, although nonmitogenic CD3 F(ab')2 fragments could mediate T cell signaling, as evidenced by cytokine gene transcription (IL-2, IFN-gamma, IL-4, and IL-10) assessed by PCR on splenocytes from treated mice. A concomitant cyclosporine treatment abrogated the CD3 mAb-induced protection, further pointing to the crucial role of T cell signaling in the effect observed.

The influence of genetic background on the expression of mutations at the diabetes locus in the mouse IV. Male lethal syndrome in CBA/Lt mice.

To assess whether db-induced pathogenetic changes in beta-cells were restricted to mice with H-2d haplotype, the db gene from BL/Ks was transferred into the CBA/Lt subline (H-2k). A marked sexual dimorphism was observed in the diabetes syndrome in db/db animals. Young adult db/db males exhibited an early onset and completely lethal diabetes (100% mortality by 6 mo). At 3 mo db/db males were moderately obese (43 +/- 4 g) but severely hyperglycemic (475 +/- 69 mg/dl blood glucose) and hyperglucagonemic. Islets were atrophic, showing variable leukocytic infiltration. Although hyperinsulinemic at 2 mo, mutant males had only normal or below normal plasma insulin at 4 mo. Electron microscopic examination confirmed beta-cell necrosis and the appearance, in prenecrotic beta-cells, of numerous intracisternal type A (retrovirus) particles (IAP). In contrast, db/db females became increasingly obese with age but remained healthy, suffering no mortality in 6 mo. These mice were only transiently hyperglycemic and were able to sustain hyperinsulinemia. Light and electron microscopy revealed beta-cell hypertrophy that was not accompanied by increased numbers of IAP or by necrosis. Retrovirus infection therefore seemed a consequence rather than a cause of hyperglycemia. Ovariectomy coupled with testosterone injection failed to induce severe diabetes in females; castration failed to moderate male diabetes. Instead, biweekly injections of 25 micrograms each of 17 beta-estradiol and progesterone effected complete diabetes remission in males. Experiments using cultured CBA/J islet cells did not support the hypothesis that ovarian steroids were directly protective at the beta-cell level. This study shows that db gene-induced pathogenesis is not restricted to mice with the H-2d haplotype, and that sex steroids are important modifiers of syndrome severity.