Adrian Vella

Roux-en-Y gastric bypass vs intensive medical management for the control of type 2 diabetes, hypertension, and hyperlipidemia: the Diabetes Surgery Study randomized clinical trial.

IMPORTANCE Controlling glycemia, blood pressure, and cholesterol is important for patients with diabetes. How best to achieve this goal is unknown. OBJECTIVE To compare Roux-en-Y gastric bypass with lifestyle and intensive medical management to achieve control of comorbid risk factors. DESIGN, SETTING, AND PARTICIPANTS A 12-month, 2-group unblinded randomized trial at 4 teaching hospitals in the United States and Taiwan involving 120 participants who had a hemoglobin A1c (HbA1c) level of 8.0% or higher, body mass index (BMI) between 30.0 and 39.9, C peptide level of more than 1.0 ng/mL, and type 2 diabetes for at least 6 months. The study began in April 2008. INTERVENTIONS Lifestyle-intensive medical management intervention and Roux-en-Y gastric bypass surgery. Medications for hyperglycemia, hypertension, and dyslipidemia were prescribed according to protocol and surgical techniques that were standardized. MAIN OUTCOMES AND MEASURES Composite goal of HbA1c less than 7.0%, low-density lipoprotein cholesterol less than 100 mg/dL, and systolic blood pressure less than 130 mm Hg. RESULTS All 120 patients received the intensive lifestyle-medical management protocol and 60 were randomly assigned to undergo Roux-en-Y gastric bypass. After 12-months, 28 participants (49%; 95% CI, 36%-63%) in the gastric bypass group and 11 (19%; 95% CI, 10%-32%) in the lifestyle-medical management group achieved the primary end points (odds ratio [OR], 4.8; 95% CI, 1.9-11.7). Participants in the gastric bypass group required 3.0 fewer medications (mean, 1.7 vs 4.8; 95% CI for the difference, 2.3-3.6) and lost 26.1% vs 7.9% of their initial body weigh compared with the lifestyle-medical management group (difference, 17.5%; 95% CI, 14.2%-20.7%). Regression analyses indicated that achieving the composite end point was primarily attributable to weight loss. There were 22 serious adverse events in the gastric bypass group, including 1 cardiovascular event, and 15 in the lifestyle-medical management group. There were 4 perioperative complications and 6 late postoperative complications. The gastric bypass group experienced more nutritional deficiency than the lifestyle-medical management group. CONCLUSIONS AND RELEVANCE In mild to moderately obese patients with type 2 diabetes, adding gastric bypass surgery to lifestyle and medical management was associated with a greater likelihood of achieving the composite goal. Potential benefits of adding gastric bypass surgery to the best lifestyle and medical management strategies of diabetes must be weighed against the risk of serious adverse events. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00641251.

Secular Trends in the Presentation and Management of Functioning Insulinoma at the Mayo Clinic, 1987–2007

OBJECTIVE The objective of the study was to assess changes in the presentation and diagnostic and radiological evaluation of patients with surgically confirmed insulinoma at the Mayo Clinic 1987-2007. METHODS A retrospective analysis of patients with insulinoma was conducted. Patients with prior gastric bypass were excluded. RESULTS A total of 237 patients [135 women (57%)] were identified. Hypoglycemia was reported solely in the fasting state in 73%, the fasting and postprandial state in 21%, and exclusively postprandially in 6%. There was a predominance of men in the postprandial symptom group. Considering the period of study by quartile, outpatient evaluation increased from 35 to 83% and successful preoperative localization improved from 74 to 100% comparing the first to the fourth quartiles. Although the rates of localization by noninvasive techniques remained static at approximately 75%, the addition of invasive modalities has resulted in successful preoperative localization in all patients in the past 10 yr. The sensitivity and specificity of the established diagnostic criteria using insulin, C-peptide, proinsulin, beta-hydroxybutyrate, and glucose response to iv glucagon were greater than 90% and greater than 70%, respectively. CONCLUSIONS Although fasting hypoglycemia is characteristic of patients with insulinoma, postprandial symptoms have been reported with increasing, albeit low, frequency. Trends in the evaluation and preoperative management include a shift to outpatient diagnostic testing, an emphasis on successful preoperative localization to avoid blind pancreatic exploration, and a validation of the diagnostic criteria for hyperinsulinemic hypoglycemia.

Effects of dipeptidyl peptidase-4 inhibition on gastrointestinal function, meal appearance, and glucose metabolism in type 2 diabetes.

OBJECTIVE— We sought to determine whether alterations in meal absorption and gastric emptying contribute to the mechanism by which inhibitors of dipeptidyl peptidase-4 (DPP-4) lower postprandial glucose concentrations. RESEARCH DESIGN AND METHODS— We simultaneously measured gastric emptying, meal appearance, endogenous glucose production, and glucose disappearance in 14 subjects with type 2 diabetes treated with either vildaglipitin (50 mg b.i.d.) or placebo for 10 days using a double-blind, placebo-controlled, randomized, crossover design. RESULTS— Fasting (7.3 ± 0.5 vs. 7.9 ± 0.5 mmol/l) and peak postprandial (14.1 ± 0.6 vs. 15.9 ± 0.9 mmol/l) glucose concentrations were lower (P < 0.01) after vildagliptin treatment than placebo. Despite lower glucose concentrations, postprandial insulin and C-peptide concentrations did not differ during the two treatments. On the other hand, the integrated (area under the curve) postprandial glucagon concentrations were lower (20.9 ± 1.6 vs. 23.7 ± 1.3 mg/ml per 5 h, P < 0.05), and glucagon-like peptide 1 (GLP-1) concentrations were higher (1,878 ± 270 vs. 1,277 ± 312 pmol/l per 5 h, P = 0.001) during vildagliptin administration compared with placebo. Gastric emptying and meal appearance did not differ between treatments. CONCLUSIONS— Vildagliptin does not alter gastric emptying or the rate of entry of ingested glucose into the systemic circulation in humans. DPP-4 inhibitors do not lower postprandial glucose concentrations by altering the rate of nutrient absorption or delivery to systemic circulation. Alterations in islet function, secondary to increased circulating concentrations of active GLP-1, are associated with the decreased postprandial glycemic excursion observed in the presence of vildagliptin.

Adrenal Hemorrhage: A 25-Year Experience at the Mayo Clinic

OBJECTIVE To characterize the clinical course of adrenal hemorrhage (AH) by using a systematic review of the presentation, associated conditions, and outcomes in patients with AH seen at our institution between 1972 and 1997 (a 25-year period). PATIENTS AND METHODS A computer search of recorded dismissal diagnoses identified 204 patients with a diagnosis of AH, but only 141 fulfilled our study criteria. Their records were analyzed systematically by presentation, bilateral or unilateral hemorrhage, corticosteroid treatment, and survival. RESULTS AH is a heterogeneous entity that occurs in the postoperative period, in the antiphospholipid-antibody syndrome, in heparin-associated thrombocytopenia, or in the setting of severe physical stress and multiorgan failure. Standard laboratory evaluation is not helpful in establishing the diagnosis. Of the 141 cases of AH, 78 were bilateral, and 63 were unilateral. Corticosteroid treatment in situations of severe stress or sepsis had little effect on outcome (9% vs. 6% survival with and without corticosteroid treatment, respectively). This is in sharp contrast to AH occurring postoperatively (100% vs. 17% survival with or without treatment, respectively) or in the antiphospholipid-antibody syndrome (73% vs. 0% survival, respectively). CONCLUSIONS A high index of suspicion is required to make a timely diagnosis of AH. Fever and hypotension in the appropriate clinical setting necessitate further investigation. Although the diagnosis of AH is infrequently made while the patient is alive, appropriate imaging techniques are useful for establishing a timely diagnosis. In severe physical stress or sepsis, AH may be a marker of severe, preterminal physiologic stress and poor outcome.

A Stable Isotope Breath Test with a Standard Meal for Abnormal Gastric Emptying of Solids in the Clinic and in Research

BACKGROUND & AIMS The aim of this study was to validate a [13C]-Spirulina platensis gastric emptying (GE) breath test (GEBT) with a standardized meal. METHODS Thirty-eight healthy volunteers and 129 patients with clinically suspected delayed GE underwent measurements at 45, 90, 120, 150, 180, and 240 minutes after a 238 kcal meal labeled test with 100 mg [13C]-S platensis and 0.5 mCi 99mTc. We established normal ranges for scintigraphy with this test meal, intraindividual and interindividual coefficients of variation (COVs), and the ability of the [13C] GEBT breath percent dose excreted *1000 values to predict scintigraphic half-life and to categorize GE as delayed, normal, or accelerated. RESULTS In health, the 10th and 90th percentiles of half-life for scintigraphic GE with this meal were 52 and 86 minutes; intraindividual COVs for scintigraphy and the GEBT were, respectively, 31% and 27% at 45 minutes, 17% and 21% at 90 minutes, 13% and 16% at 120 minutes, 10% and 13% at 150 minutes, and 8% and 12% at 180 minutes. Interindividual COVs at each time for the [13C] GEBT and scintigraphy were typically approximately 1%-4% lower than intraindividual COVs. Individual breath samples at 45, 150, and 180 minutes predicted GE category; at 80% specificity, 45- and 180-minute samples combined were 93% sensitive to identify accelerated GE, and 150- and 180-minute combined were 89% sensitive for delayed GE. CONCLUSIONS [13C]-S platensis GEBT is as reproducible as scintigraphy; imprecision with both tests reflects physiologic variation. With 4 breath samples, this method with an off-the-shelf meal is valid to assess GE in clinic and in research.

Contribution of Endogenous Glucagon-Like Peptide 1 to Glucose Metabolism After Roux-en-Y Gastric Bypass

The contribution of elevated glucagon-like peptide 1 (GLP-1) to postprandial glucose metabolism after Roux-en-Y gastric bypass (RYGB) has been the subject of uncertainty. We used exendin-9,39, a competitive antagonist of GLP-1, to examine glucose metabolism, islet hormone secretion, and gastrointestinal transit in subjects after RYGB and in matched control subjects. Subjects were studied in the presence or absence of exendin-9,39 infused at 300 pmol/kg/min. Exendin-9,39 resulted in an increase in integrated postprandial glucose concentrations post-RYGB (3.6 ± 0.5 vs. 2.0 ± 0.4 mol/6 h, P = 0.001). Exendin-9,39 decreased insulin concentrations (12.3 ± 2.2 vs. 18.1 ± 3.1 nmol/6 h, P = 0.002) and the β-cell response to glucose (ϕTotal, 13 ± 1 vs. 11 ± 1 × 10−9 min−1, P = 0.01) but did not alter the disposition index (DI). In control subjects, exendin-9,39 also increased glucose (2.2 ± 0.4 vs. 1.7 ± 0.3 mol/6 h, P = 0.03) without accompanying changes in insulin concentrations, resulting in an impaired DI. Post-RYGB, acceleration of stomach emptying during the first 30 min by exendin-9,39 did not alter meal appearance, and similarly, suppression of glucose production and stimulation of glucose disappearance were unaltered in RYGB subjects. These data indicate that endogenous GLP-1 has effects on glucose metabolism and on gastrointestinal motility years after RYGB. However, it remains uncertain whether this explains all of the changes after RYGB.

Effects of pramlintide, an amylin analogue, on gastric emptying in type 1 and 2 diabetes mellitus

Pramlintide delays gastric emptying, possibly by a centrally mediated mechanism. Our aim was to determine whether the effects of pramlintide on gastric emptying differ in people with type 1 or type 2 diabetes who had no history of complications. Using a randomized, three‐period, two‐dose, crossover design, we studied the effects of 0, 30, or 60 μg t.i.d. pramlintide subcutaneously for 5 days each in six type 1 and six type 2 diabetic subjects. Gastric emptying of solids was measured by 13C‐Spirulina breath test. Plasma pancreatic polypeptide (HPP) response to the test meal was also measured. Relative to placebo [t 50% 91 ± 6 min (means ± SEM)], pramlintide equally delayed gastric emptying following 30 or 60 μg t.i.d. (268 ± 37 min, 329 ± 49 min, respectively; P < 0.01]. Postprandial HPP levels were lower in response to 30 and 60 μg pramlintide compared to placebo. There were no significant differences in the effects on gastric emptying or HPP levels between type 1 and type 2 diabetic subjects. Pramlintide delays gastric emptying in diabetes unassociated with clinically detected complications. Further studies are needed in diabetic patients with impaired gastric motor function.

The Oral Minimal Model Method

The simultaneous assessment of insulin action, secretion, and hepatic extraction is key to understanding postprandial glucose metabolism in nondiabetic and diabetic humans. We review the oral minimal method (i.e., models that allow the estimation of insulin sensitivity, β-cell responsivity, and hepatic insulin extraction from a mixed-meal or an oral glucose tolerance test). Both of these oral tests are more physiologic and simpler to administer than those based on an intravenous test (e.g., a glucose clamp or an intravenous glucose tolerance test). The focus of this review is on indices provided by physiological-based models and their validation against the glucose clamp technique. We discuss first the oral minimal model method rationale, data, and protocols. Then we present the three minimal models and the indices they provide. The disposition index paradigm, a widely used β-cell function metric, is revisited in the context of individual versus population modeling. Adding a glucose tracer to the oral dose significantly enhances the assessment of insulin action by segregating insulin sensitivity into its glucose disposal and hepatic components. The oral minimal model method, by quantitatively portraying the complex relationships between the major players of glucose metabolism, is able to provide novel insights regarding the regulation of postprandial metabolism.

Common Genetic Variation in GLP1R and Insulin Secretion in Response to Exogenous GLP-1 in Nondiabetic Subjects: A pilot study

OBJECTIVE Glucagon-like peptide (GLP)-1 receptor is encoded by GLP1R. The effect of genetic variation at this locus on the response to GLP-1 is unknown. This study assessed the effect of GLP1R polymorphisms on insulin secretion in response to hyperglycemia and to infused GLP-1 in nondiabetic subjects. RESEARCH DESIGN AND METHODS Eighty-eight healthy individuals (aged 26.3 ± 0.6 years, fasting glucose 4.83 ± 0.04 mmol/l) were studied using a hyperglycemic clamp. GLP-1 was infused for the last 2 h of the study (0.75 pmol/kg/min over 121–180 min, 1.5 pmol/kg/min over 181–240 min). β-Cell responsivity (ΦTotal) was measured using a C-peptide minimal model. The effect of 21 tag single nucleotide polymorphisms (SNPs) in GLP1R on ΦTotal was examined. RESULTS Two SNPs (rs6923761 and rs3765467) were nominally associated with altered β-cell responsivity in response to GLP-1 infusion. CONCLUSIONS Variation in GLP1R may alter insulin secretion in response to exogenous GLP-1. Future studies will determine whether such variation accounts for interindividual differences in response to GLP-1–based therapy.

Surgery for Cushing’s Syndrome: An Historical Review and Recent Ten-year Experience

BackgroundCushing’s syndrome (CS), due to multiple etiologies, is a disorder associated with the ravages of cortisol excess. The purpose of this review article is to provide a historical synopsis of surgery for CS, review a recent 10-year period of operative management at a tertiary care facility, and to outline a practical approach to diagnosis and management.Materials and MethodsFrom 1996 to 2005, 298 patients underwent 322 operative procedures for CS at Mayo Clinic, Rochester, Minnesota. A retrospective chart review was carried out. Data was gathered regarding demographics, preoperative assessment, procedures performed, and outcomes. Data are presented as counts and percentages. Five-year survival rates were calculated where applicable by the Kaplan-Meier method. Statistical analysis was carried out with SAS, version 9 (SAS Institute, Inc., Cary, NC).ResultsTwo-hundred thirty-one patients (78%) had ACTH-dependent CS and 67 patients (22%) had ACTH-independent CS. One-hundred ninety-six patients (66%) had pituitary-dependent CS and 35 patients (12%) had ectopic ACTH syndrome. Fifty-four patients (18%) had cortisol-secreting adenomas, 10 patients (3%) had cortisol-producing adrenocortical carcinomas, and 1% had other causes. Cure rates for first time pituitary operations (transsphenoidal, sublabial, and endonasal) were 80% and 55% for reoperations. Most benign adrenal processes could be managed laparoscopically. Five-year survival rates (all causes) were 90%, 51%, and 23% for adrenocortical adenomas, ectopic ACTH syndrome, and adrenocortical carcinomas, respectively.ConclusionsSurgery for CS is highly successful for pituitary-dependent CS and most ACTH-independent adrenal causes. Bilateral total adrenalectomy can also provide effective palliation from the ravages of hypercortisolism in patients with ectopic ACTH syndrome and for those who have failed transsphenoidal surgery. Unfortunately, to date, adrenocortical carcinomas are rarely cured. Future successes with this disease will likely depend on a better understanding of tumor biology, more effective adjuvant therapies and earlier detection. Clearly, IPSS, advances in cross-sectional imaging, along with developments in transsphenoidal and laparoscopic surgery, have had the greatest impact on today’s management of the complex patient with CS.