Moahad S. Dar

Hypoglycemia after Roux-en-Y Gastric Bypass: The BOLD Experience

Obesity is a global epidemic associated with higher mortality and increased incidence of type 2 diabetes, hypertension, and obstructive sleep apnea [1]. Although dietary and lifestyle interventions can achieve modest weight loss, they are difficult to sustain over the long-term [2]. Patients are increasingly turning to bariatric surgery to achieve greater weight loss and increase remission of type 2 diabetes, hypertension, and obstructive sleep apnea. Roux-en-y gastric bypass (RYGB) is one of the most commonly performed bariatric procedures due to its safety (mortality ~0.5 %), efficacy in weight loss (~60% excess weight lost), and disease remission (77 % for type 2 diabetes, 62 % for hypertension, 86 % for obstructive sleep apnea) [3]. However, these impressive postoperative outcomes are tempered by the development of metabolic, nutritional, and cosmetic complications. Hypoglycemia after RYGB is a troublesome metabolic complication that typically develops 6 months or more after RYGB and usually occurs after a meal. An estimated 671,959 bariatric procedures were performed in the USA between 2003 and 2008 [4]. In 2008 alone, an estimated 344,221 bariatric procedures were performed in the world and 124,838 in the USA, respectively [4, 5]. Since RYGB is one of the most commonly performed bariatric procedures in the world, it is essential for patients to be aware of the true risk for post-RYGB hypoglycemia prior to surgery [4, 5]. Two independent studies by Marsk and Kellog estimated the incidence of post-RYGB hypoglycemia to be 0.2 % and 0.36 % in 5,040 and 3,082 subjects, respectively [6, 7]. Although the low incidence of hypoglycemia reported in these studies is reassuring, there were some methodological limitations in both studies. The Marsk study included only Swedish subjects which limits its applicability to the more ethnically diverse US population [6]. The Kellog study was from a single center which increases the odds for institutional bias [7]. A large prospective outcomes database of US patients

Amelioration of Insulin Requirement in Patients Undergoing Duodenal Bypass for Reasons Other than Obesity Implicates Foregut Factors in the Pathophysiology of Type II Diabetes

BACKGROUND Foregut diversion and weight loss have been proposed as potential mechanisms for resolution of type II diabetes mellitus (T2DM) observed in patients undergoing gastric bypass for obesity. To support or refute the role of the foregut, we analyzed glycemic control in T2DM patients before and after foregut bypass for reasons other than morbid obesity. STUDY DESIGN Using ICD9/CPT codes, we identified patients undergoing Roux-en-Y gastrojejunostomy (RY) or Billroth II (BII) reconstruction over 10 years. Fasting blood glucose, insulin or oral diabetic agent requirement, and body mass index (BMI) before and after surgery were tabulated and compared using the Students t-test. Linear regression was applied to determine specific factors predictive of resolution or improvement in glycemic control including age, duration of diabetes, antidiabetic regimen, type of operation, and surgical indication. RESULTS Between 1996 and 2006, we identified 24 patients with T2DM out of a cohort of 209 who underwent either RY (12 of 24) or BII reconstruction (12 of 24) for cancer or peptic ulcer disease and survived more than 30 days after operation. Of this group, 75% were overweight (18 of 24 with BMI < 30 kg/m(2)) and 25% were class I morbidly obese (6 of 24 with BMI 30 to 35 kg/m(2)). Seventeen patients (71%) had either complete resolution (7 of 24 or 29%) or significant reduction (10 of 24 or 42%) in medication requirements; 7 patients (29%) did not have any improvement. Logistic regression failed to identify specific factors predicting improved glycemic control. CONCLUSIONS Complete resolution of T2DM in patients undergoing duodenal diverting surgery occurs in about one-third of nonobese patients. Improved glycemic control occurs in more than two-thirds and cannot be explained by surgically related weight loss alone. Surgical cure of T2DM may be possible in carefully selected nonobese patients.

Regulator of G Protein Signaling 5 Is Highly Expressed in Parathyroid Tumors and Inhibits Signaling by the Calcium-Sensing Receptor

The molecular mechanisms responsible for aberrant calcium signaling in parathyroid disease are poorly understood. The loss of appropriate calcium-responsive modulation of PTH secretion observed in parathyroid disease is commonly attributed to decreased expression of the calcium-sensing receptor (CaSR), a G protein-coupled receptor. However, CaSR expression is highly variable in parathyroid adenomas, and the lack of correlation between CaSR abundance and calcium-responsive PTH kinetics indicates that mechanisms independent of CaSR expression may contribute to aberrant calcium sensing in parathyroid disease. To gain a better understanding of parathyroid tumors and the molecular determinants that drive parathyroid adenoma development, we performed gene expression profiling on a panel of 64 normal and neoplastic parathyroid tissues. The microarray data revealed high-level expression of genes known to be involved in parathyroid biology (PTH, VDR, CGA, CaSR, and GCM2). Moreover, our screen identified regulator of G protein signaling 5 (RGS5) as a candidate inhibitor of CaSR signaling. We confirmed RGS5 to be highly expressed in parathyroid adenomas relative to matched-pair normal glands. Transient expression of RGS5 in cells stably expressing CaSR resulted in dose-dependent abrogation of calcium-stimulated inositol trisphosphate production and ERK1/2 phosphorylation. Furthermore, we found that RGS5-nullizygous mice display reduced plasma PTH levels, an outcome consistent with attenuated opposition to CaSR activity. Collectively, these data suggest that RGS5 can act as a physiological regulator of calcium sensing by CaSR in the parathyroid gland. The abnormally elevated expression of RGS5 observed in parathyroid adenomas could thus represent a novel mechanism of CaSR desensitization in patients with primary hyperparathyroidism.

Impairments in site-specific AS160 phosphorylation and effects of exercise training

The purpose of this study was to determine if site-specific phosphorylation at the level of Akt substrate of 160 kDa (AS160) is altered in skeletal muscle from sedentary humans across a wide range of the adult life span (18–84 years of age) and if endurance- and/or strength-oriented exercise training could rescue decrements in insulin action and skeletal muscle AS160 phosphorylation. A euglycemic-hyperinsulinemic clamp and skeletal muscle biopsies were performed in 73 individuals encompassing a wide age range (18–84 years of age), and insulin-stimulated AS160 phosphorylation was determined. Decrements in whole-body insulin action were associated with impairments in insulin-induced phosphorylation of skeletal muscle AS160 on sites Ser-588, Thr-642, Ser-666, and phospho-Akt substrate, but not Ser-318 or Ser-751. Twelve weeks of endurance- or strength-oriented exercise training increased whole-body insulin action and reversed impairments in AS160 phosphorylation evident in insulin-resistant aged individuals. These findings suggest that a dampening of insulin-induced phosphorylation of AS160 on specific sites in skeletal muscle contributes to the insulin resistance evident in a sedentary aging population and that exercise training is an effective intervention for treating these impairments.

Insulin sensitivity is related to glycemic control in type 2 diabetes and diabetes remission after Roux-en Y gastric bypass.

BACKGROUND After initial onset, adequate glycemic control in patients with type 2 diabetes (T2DM) presents a continuing challenge even with aggressive pharmacologic treatment, and longer disease duration is associated with poorer resolution in response to Roux-en Y gastric bypass (RYGB). Skeletal muscle insulin sensitivity is an important determinant of glycemic control. We investigated whether skeletal muscle insulin sensitivity is predictive of T2DM resolution with RYGB and is in general lower in patients with longer-duration T2DM. METHODS Insulin sensitivity (SI) and the acute response to glucose (AIRg) were calculated by MINMOD analysis from glucose and insulin obtained during a modified frequently sampled intravenous glucose tolerance test. RESULTS Pre-RYGB SI and duration but not AIRg were predictive of T2DM resolution by RYGB. In addition, HbA1c was greater and SI and AIRg lower in long- (8+ years) compared with short-duration (1- to 7-year) T2DM. Multiple linear regression analysis demonstrated that SI explained 32% and AIRg 21% of the variance in HbA1c, respectively. CONCLUSION The current results suggest that pre-RYGB SI is predictive of T2DM resolution after RYGB, skeletal muscle insulin sensitivity and β-cell function worsen after the onset of T2DM, and low skeletal muscle insulin sensitivity as well as low β cell function contribute to poor glycemic control in T2DM.

High Incomplete Skeletal Muscle Fatty Acid Oxidation Explains Low Muscle Insulin Sensitivity in Poorly Controlled T2D.

Context Almost 50% of type 2 diabetic (T2D) patients are poorly controlled [glycated hemoglobin (HbA1c) ≥ 7%]; however, the mechanisms responsible for progressively worsening glycemic control are poorly understood. Lower skeletal muscle mitochondrial respiratory capacity is associated with low insulin sensitivity and the development of T2D. Objective We investigated if skeletal muscle insulin sensitivity (SI) was different between well-controlled T2D (WCD) and poorly controlled T2D (PCD) and if the difference was associated with differences resulting from mitochondrial respiratory function. Design Vastus lateralis muscle mitochondrial respiration, mitochondrial content, mitochondrial enzyme activity, and fatty acid oxidation (FAO) were measured. SI and the acute response to glucose (AIRg) were calculated by MINMOD analysis from glucose and insulin obtained during a modified, frequently sampled, intravenous glucose tolerance test. Results SI and AIRg were lower in PCD than WCD. Muscle incomplete FAO was greater in PCD than WCD and greater incomplete FAO was associated with lower SI and higher HbA1c. Hydroxyacyl-coenzyme A dehydrogenase expression and activity were greater in PCD than WCD. There was no difference in maximal mitochondrial respiration or content between WCD and PCD. Conclusion The current results suggest that greater skeletal muscle incomplete FAO in poorly controlled T2D is due to elevated β oxidation and is associated with worsening muscle SI.