Michael R. Rickels

Active behaviors in the rat forced swimming test differentially produced by serotonergic and noradrenergic antidepressants

This study demonstrated that distinct patterns of active behaviors are produced by antidepressants that selectively inhibit norepinephrine (NE) or serotonin (5-HT) uptake in the rat forced swimming test (FST). A behavior sampling technique was developed to score the active behaviors swimming, climbing and diving, as well as immobility. The rats behavior was recorded at the end of each 5-s period during the test session. The sampling technique was both reliable, as demonstrated by test-retest reliability and inter-rater reliability, and valid, as shown by comparison to the timing of behavior durations. Five different antidepressant drugs which block monoamine uptake and two 5-HT1A receptor agonists were shown to decrease immobility in the FST; however, they produced distinct patterns of active behaviors. The selective NE uptake inhibitors desipramine and maprotiline selectively increased climbing, whereas the selective serotonin reuptake inhibitors (SSRIs) fluoxetine, sertraline and paroxetine selectively increased swimming. The 5-HT1A receptor agonists 8-OH-DPAT and gepirone also selectively increased swimming. These results show that:1) SSRIs are not false negatives in the FST; 2) at least two behaviorally distinct processes occur in the FST; and 3) enhancement of NE neurotransmission may mediate climbing in the FST, whereas enhancement of 5-HT neurotransmission may mediate swimming.

Improvement in Outcomes of Clinical Islet Transplantation: 1999–2010

OBJECTIVE To describe trends of primary efficacy and safety outcomes of islet transplantation in type 1 diabetes recipients with severe hypoglycemia from the Collaborative Islet Transplant Registry (CITR) from 1999 to 2010. RESEARCH DESIGN AND METHODS A total of 677 islet transplant-alone or islet-after-kidney recipients with type 1 diabetes in the CITR were analyzed for five primary efficacy outcomes and overall safety to identify any differences by early (1999–2002), mid (2003–2006), or recent (2007–2010) transplant era based on annual follow-up to 5 years. RESULTS Insulin independence at 3 years after transplant improved from 27% in the early era (1999–2002, n = 214) to 37% in the mid (2003–2006, n = 255) and to 44% in the most recent era (2007–2010, n = 208; P = 0.006 for years-by-era; P = 0.01 for era alone). C-peptide ≥0.3 ng/mL, indicative of islet graft function, was retained longer in the most recent era (P < 0.001). Reduction of HbA1c and resolution of severe hypoglycemia exhibited enduring long-term effects. Fasting blood glucose stabilization also showed improvements in the most recent era. There were also modest reductions in the occurrence of adverse events. The islet reinfusion rate was lower: 48% by 1 year in 2007–2010 vs. 60–65% in 1999–2006 (P < 0.01). Recipients that ever achieved insulin-independence experienced longer duration of islet graft function (P < 0.001). CONCLUSIONS The CITR shows improvement in primary efficacy and safety outcomes of islet transplantation in recipients who received transplants in 2007–2010 compared with those in 1999–2006, with fewer islet infusions and adverse events per recipient.

Experimental Endotoxemia Induces Adipose Inflammation and Insulin Resistance in Humans

OBJECTIVE An emerging model of metabolic syndrome and type 2 diabetes is of adipose dysfunction with leukocyte recruitment into adipose leading to chronic inflammation and insulin resistance (IR). This study sought to explore potential mechanisms of inflammatory-induced IR in humans with a focus on adipose tissue. RESEARCH DESIGN AND METHODS We performed a 60-h endotoxemia protocol (3 ng/kg intravenous bolus) in healthy adults (n = 20, 50% male, 80% Caucasian, aged 27.3 ± 4.8 years). Before and after endotoxin, whole-blood sampling, subcutaneous adipose biopsies, and frequently sampled intravenous glucose tolerance (FSIGT) testing were performed. The primary outcome was the FSIGT insulin sensitivity index (Si). Secondary measures included inflammatory and metabolic markers and whole-blood and adipose mRNA and protein expression. RESULTS Endotoxemia induced systemic IR as demonstrated by a 35% decrease in Si (3.17 ± 1.66 to 2.06 ± 0.73 × 10−4 [μU · ml−1 · min−1], P < 0.005), while there was no effect on pancreatic β-cell function. In adipose, endotoxemia suppressed insulin receptor substrate-1 and markedly induced suppressor of cytokine signaling proteins (1 and 3) coincident with local activation of innate (interleukin-6, tumor necrosis factor) and adaptive (monocyte chemoattractant protein-1 and CXCL10 chemokines) inflammation. These changes are known to attenuate insulin receptor signaling in model systems. CONCLUSIONS We demonstrate, for the first time in humans, that acute inflammation induces systemic IR following modulation of specific adipose inflammatory and insulin signaling pathways. It also provides a rationale for focused mechanistic studies and a model for human proof-of-concept trials of novel therapeutics targeting adipose inflammation in IR and related consequences in humans.

Narrative Review: Effect of Bariatric Surgery on Type 2 Diabetes Mellitus

Key Summary Points The rapid improvement in glycemic control after bariatric surgery results from caloric restriction and alterations in the gut hormones that control insulin secretion. The enteroinsular axis includes the incretins glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP), ghrelin, and peptide YY (PYY) and their subsequent effect on insulin secretion and sensitivity. Restrictive, malabsorptive, and combined bariatric surgery procedures have different effects on the enteroinsular axis. Intestinal bypass procedures increase GLP-1 and PYY levels. In contrast, restrictive procedures do not increase incretin or PYY levels. Familiarity with these changes can help physicians consider the various surgical approaches and develop postoperative treatment regimens for patients. Glycemic control in diabetic patients improves markedly within days of bariatric surgery, which suggests that the procedures alter the hormones that control insulin secretion (1). The enteroinsular axis includes the gut hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP). These hormones, also known as incretins, are secreted by intestinal L and K cells, respectively, in response to nutrients and directly enhance insulin secretion (2). Restrictive, malabsorptive, and combined bariatric surgery procedures affect the enteroinsular axis differently. The various bariatric procedures also affect the secretion of other gut hormones that affect insulin sensitivity, including ghrelin and peptide YY (PYY). Thus, an altered pattern of gut hormone secretion after bariatric surgery may profoundly affect glucose tolerance. We focus on the short-term pathophysiologic changes in the enteroinsular axis and their subsequent effect on insulin secretion and sensitivity after bariatric surgery. Familiarity with these changes can help clinicians decide among the different surgical approaches and formulate treatment regimens that avoid severe postoperative hypoglycemia. Methods We searched English-language publications in PubMed and reference lists from relevant articles published between 1967 and 2008. Our main search terms were bariatric surgery, Roux-en-Y, gastric bypass, biliopancreatic diversion, gastric banding, laparoscopic adjustable gastric banding, diabetes, enteroinsular axis, incretins, GLP-1, GIP, ghrelin, PYY, insulin, and postoperative management. To determine the rates of diabetes resolution, we included studies that enrolled at least 10 diabetic patients (alone or along with nondiabetic patients) and reported diabetes-related outcomes. We retrieved randomized, controlled trials; cohort studies; and casecontrol studies that reported weight loss, diabetes resolution, and time to restoration of normoglycemia. Because we found few such studies, we also included large case series. We evaluated study quality by using the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) system (3). We used our judgment to identify high-quality studies that described gut hormone levels after bariatric surgery. Types of Bariatric Procedures and Effect on Weight Loss and Diabetes Since its inception in the 1950s, bariatric surgery has become increasingly refined. More recently, it has been touted as a cure for diabetes (4). Several procedures are now available (Figure 1). Bariatric procedures were initially classified as restrictive, malabsorptive, or combined, reflecting the purported mechanism of weight loss (1). Restrictive procedures, such as laparoscopic adjustable gastric banding (LAGB) and vertical banded gastroplasty (VBG), greatly reduce the volume of the stomach to decrease food intake and induce early satiety. Malabsorptive procedures, such as biliopancreatic diversion (BPD), shorten the small intestine to decrease nutrient absorption. Combined procedures, such as the Roux-en-Y gastric bypass (RYGB), incorporate both restrictive and malabsorptive elements. Roux-en-Y gastric bypass surgery is the current gold standard treatment for severe obesity. Both BPD and RYGB alter the secretion of orexigenic and anorexigenic gut peptides, which interact with appetitive centers in the arcuate nucleus of the hypothalamus to decrease appetite (5). Because both BPD and RYGB bypass similar segments of the small bowel, we use the term intestinal bypass procedure to refer to either. Figure 1. Surgical procedures. Reprinted with permission of the American Society for Metabolic and Bariatric Surgery, copyright 2008, all rights reserved. Weight Loss Two recent meta-analyses (6, 7) reported weight loss; operative mortality; and obesity-related comorbid conditions, including diabetes, after bariatric surgery. Buchwald and colleagues (7) reported mean excess weight loss (see Glossary) (710) of 61% across all procedures in 22094 patients; weight loss rates associated with each procedure varied (Table 1). On average, bariatric surgery reduces body mass index by 10 to 15 kg/m2 and weight by 30 to 50 kg (11). Table 1. Results of Different Types of Bariatric Surgery Several relatively poor-quality randomized, controlled trials that compared different bariatric surgery procedures (12) showed that weight loss was greater with gastric bypass than with VBG or LAGB. The SOS (Swedish Obese Subjects) study (13), a landmark observational study that followed more than 4000 obese participants, matched those who selected medical management with those undergoing various bariatric procedures, including RYGB, VBG, or LAGB. At 10 years, RYGB was associated with a 25% reduction in total body weight, whereas VBG and LAGB were associated with 16% and 14% weight loss, respectively. Diabetes Resolution and Improvement Observational evidence suggests that bariatric surgery is associated with a 60% to 80% rate of diabetes resolution (14). In 1 meta-analysis (7), approximately 15% of the patients were diabetic. In studies reporting complete resolution of diabetes (defined as normoglycemia with no diabetes medications), 1417 of 1846 patients (76.8%) met the criteria for resolution. Among studies reporting resolution or improvement of diabetes, 414 of 485 patients (mean, 86.0%) experienced either outcome. Table 1 shows rates of diabetes resolution for individual bariatric procedures. Conclusions about bariatric surgery and diabetes resolution come with an important qualifier: The studies had serious methodological weaknesses. Few are randomized, controlled trials; most surgical outcome studies are uncontrolled case series with considerable missing data (6, 10). In 1 meta-analysis (6), one quarter of the studies did not report enrolling consecutive patients and fewer than 50% reported how many enrolled patients provided follow-up data. Table 2 (4, 1422) includes selected studies that met the minimum GRADE criteria quality standards and reported follow-up rates of at least 80% (3). Paired comparisons of surgical procedures typically favored RYGB or BPD over the restrictive procedures (23). Table 2. Efficacy for Resolution of Diabetes Predictors of Diabetes Resolution Identifying preoperative predictors of diabetes resolution is critical for determining which diabetic patients will obtain the greatest benefit from surgery. In earlier studies of RYGB, longer duration of diabetes (>10 years), poor preoperative glycemic control, and preoperative insulin use reduced the probability of diabetes resolution (18, 19); however, these studies did not adjust for the effects of known confounding factors. More recently, Torquati and colleagues (24) adjusted for body mass index, sex, and preoperative hemoglobin A1c level and found that preoperative treatment with oral antidiabetic agents (as opposed to insulin) and smaller preoperative waist circumference predicted diabetes resolution (18). Shorter duration of diabetes was a weaker, statistically nonsignificant predictor, which supports earlier studies of RYGB (18). The same factors predict diabetes resolution after gastric banding. Dixon and colleagues (25) reported that diabetes for less than 3 years predicted diabetes resolution, after they controlled for age and excess weight loss. Less deterioration in -cell function at the time of surgery may maximize the effect of the surgery-altered secretion of gut peptides that enhance -cell insulin secretion. The Enteroinsular Axis Bayliss and Starling first described the connection between the gut and the pancreas in 1902, when they demonstrated that intestinal mucosa extracts contained a factor, which they called secretin, that acted through the bloodstream to stimulate exocrine secretion by the pancreas (26). Sixty-five years later, Perley and Kipnis (27) demonstrated that ingested nutrients stimulated greater insulin release than intravenously administered glucose. In 1979, Creutzfeldt (28) defined incretins as gastrointestinal hormones that stimulate insulin release after enteral nutrition. This connection between the gut and pancreatic islet cells is called the enteroinsular axis, a term first used by Unger and Eisentraut (29). The Incretins: GLP-1 and GIP By potentiating glucose-dependent insulin secretion, GLP-1 and GIP account for 50% to 60% of nutrient-stimulated insulin release (2). In animal models of diabetes, GLP-1 also increases -cell mass through regulation of proliferation, neogenesis, and apoptosis (30). Glucagon-like peptide-1 is a potent insulin secretatogue that is secreted by the L cells of the distal ileum in response to ingested nutrients and is inactivated by the enzyme dipeptidyl peptidase IV (DPP-IV) (31). By activating adenylate cyclase, GLP-1 acts on pancreatic islets to augment glucose-dependent insulin secretion. The subsequent increase in insulin levels within islets inhibits glucagon secretion, possibly through direct activation of GLP-1 receptors on cells (31). Glucagon-like peptide-1 also slows gastric emptying, which delays digestion and blunts postprandial glycemia (32), and acts on the central nervou

B lymphocyte–directed immunotherapy promotes long-term islet allograft survival in nonhuman primates

We found that an induction immunotherapy regimen consisting of rabbit anti-thymocyte globulin (Thymoglobulin) and the monoclonal antibody to CD20 rituximab (Rituxan) promoted long-term islet allograft survival in cynomolgus macaques maintained on rapamycin monotherapy. B lymphocyte reconstitution after rituximab-mediated depletion was characterized by a preponderance of immature and transitional cells, whose persistence was associated with long-term islet allograft survival. Development of donor-specific alloantibodies was abrogated only in the setting of continued rapamycin monotherapy.

Severe hypoglycemia and diabetic ketoacidosis in adults with type 1 diabetes: results from the T1D Exchange clinic registry.

CONTEXT Few studies have assessed factors associated with severe hypoglycemia (SH) and diabetic ketoacidosis (DKA) in adults with type 1 diabetes (T1D). OBJECTIVE Our objective was to determine frequency of and factors associated with the occurrence of SH and DKA in adults with T1D. DESIGN AND SETTING We conducted a cross-sectional analysis from the T1D Exchange clinic registry at 70 U.S. endocrinology centers. PATIENTS Analysis included 7012 participants in the T1D Exchange clinic registry aged 26 to 93 years old with T1D for ≥2 years. RESULTS Higher frequencies of SH and DKA were associated with lower socioeconomic status (P < .001). SH was strongly associated with diabetes duration (P < .001), with 18.6% of those with diabetes ≥40 years having an event in the past 12 months. SH frequency was lowest in those with hemoglobin A1c (HbA1c) levels of 7.0% (53 mmol/mol) to 7.5% (58 mmol/mol), being higher in those with HbA1c levels <7.0% (<53 mmol/mol) or >7.5% (>58 mmol/mol). DKA frequency increased with higher HbA1c levels (P < .001), with 21.0% of those with HbA1c ≥10.0% (≥86 mmol/mol) having an event in the past 12 months. CONCLUSIONS SH and DKA are more common in those with lower socioeconomic status. DKA, most common in those with HbA1c ≥10.0% (≥86 mmol/mol), should be largely preventable. In contrast, SH, most frequent with diabetes ≥40 years duration, cannot be abolished given the limitation of current therapies. To reduce SH in adults with longstanding diabetes, consideration should be given to modifying HbA1c goals, particularly in patients with very low HbA1c levels.

Phase 3 Trial of Transplantation of Human Islets in Type 1 Diabetes Complicated by Severe Hypoglycemia

OBJECTIVE Impaired awareness of hypoglycemia (IAH) and severe hypoglycemic events (SHEs) cause substantial morbidity and mortality in patients with type 1 diabetes (T1D). Current therapies are effective in preventing SHEs in 50–80% of patients with IAH and SHEs, leaving a substantial number of patients at risk. We evaluated the effectiveness and safety of a standardized human pancreatic islet product in subjects in whom IAH and SHEs persisted despite medical treatment. RESEARCH DESIGN AND METHODS This multicenter, single-arm, phase 3 study of the investigational product purified human pancreatic islets (PHPI) was conducted at eight centers in North America. Forty-eight adults with T1D for >5 years, absent stimulated C-peptide, and documented IAH and SHEs despite expert care were enrolled. Each received immunosuppression and one or more transplants of PHPI, manufactured on-site under good manufacturing practice conditions using a common batch record and standardized lot release criteria and test methods. The primary end point was the achievement of HbA1c <7.0% (53 mmol/mol) at day 365 and freedom from SHEs from day 28 to day 365 after the first transplant. RESULTS The primary end point was successfully met by 87.5% of subjects at 1 year and by 71% at 2 years. The median HbA1c level was 5.6% (38 mmol/mol) at both 1 and 2 years. Hypoglycemia awareness was restored, with highly significant improvements in Clarke and HYPO scores (P > 0.0001). No study-related deaths or disabilities occurred. Five of the enrollees (10.4%) experienced bleeds requiring transfusions (corresponding to 5 of 75 procedures), and two enrollees (4.1%) had infections attributed to immunosuppression. Glomerular filtration rate decreased significantly on immunosuppression, and donor-specific antibodies developed in two patients. CONCLUSIONS Transplanted PHPI provided glycemic control, restoration of hypoglycemia awareness, and protection from SHEs in subjects with intractable IAH and SHEs. Safety events occurred related to the infusion procedure and immunosuppression, including bleeding and decreased renal function. Islet transplantation should be considered for patients with T1D and IAH in whom other, less invasive current treatments have been ineffective in preventing SHEs.

Antipsychotic-Induced Insulin Resistance and Postprandial Hormonal Dysregulation Independent of Weight Gain or Psychiatric Disease

Atypical antipsychotic (AAP) medications that have revolutionized the treatment of mental illness have become stigmatized by metabolic side effects, including obesity and diabetes. It remains controversial whether the defects are treatment induced or disease related. Although the mechanisms underlying these metabolic defects are not understood, it is assumed that the initiating pathophysiology is weight gain, secondary to centrally mediated increases in appetite. To determine if the AAPs have detrimental metabolic effects independent of weight gain or psychiatric disease, we administered olanzapine, aripiprazole, or placebo for 9 days to healthy subjects (n = 10, each group) under controlled in-patient conditions while maintaining activity levels. Prior to and after the interventions, we conducted a meal challenge and a euglycemic-hyperinsulinemic clamp to evaluate insulin sensitivity and glucose disposal. We found that olanzapine, an AAP highly associated with weight gain, causes significant elevations in postprandial insulin, glucagon-like peptide 1 (GLP-1), and glucagon coincident with insulin resistance compared with placebo. Aripiprazole, an AAP considered metabolically sparing, induces insulin resistance but has no effect on postprandial hormones. Importantly, the metabolic changes occur in the absence of weight gain, increases in food intake and hunger, or psychiatric disease, suggesting that AAPs exert direct effects on tissues independent of mechanisms regulating eating behavior.

Detection, evaluation and treatment of diabetes mellitus in chronic pancreatitis: Recommendations from PancreasFest 2012

DESCRIPTION Diabetes and glucose intolerance are common complications of chronic pancreatitis, yet clinical guidance on their detection, classification, and management is lacking. METHODS A working group reviewed the medical problems, diagnostic methods, and treatment options for chronic pancreatitis-associated diabetes for a consensus meeting at PancreasFest 2012. RESULTS Guidance Statement 1.1: Diabetes mellitus is common in chronic pancreatitis. While any patient with chronic pancreatitis should be monitored for development of diabetes, those with long-standing duration of disease, prior partial pancreatectomy, and early onset of calcific disease may be at higher risk. Those patients developing diabetes mellitus are likely to have co-existing pancreatic exocrine insufficiency. Guidance Statement 1.2: Diabetes occurring secondary to chronic pancreatitis should be recognized as pancreatogenic diabetes (type 3c diabetes). Guidance Statement 2.1: The initial evaluation should include fasting glucose and HbA1c. These tests should be repeated annually. Impairment in either fasting glucose or HbA1c requires further evaluation. Guidance Statement 2.2: Impairment in either fasting glucose or HbA1c should be further evaluated by a standard 75 g oral glucose tolerance test. Guidance Statement 2.3: An absent pancreatic polypeptide response to mixed-nutrient ingestion is a specific indicator of type 3c diabetes. Guidance Statement 2.4: Assessment of pancreatic endocrine reserve, and importantly that of functional beta-cell mass, should be performed as part of the evaluation and follow-up for total pancreatectomy with islet autotransplantation (TPIAT). Guidance Statement 3: Patients with pancreatic diabetes shall be treated with specifically tailored medical nutrition and pharmacologic therapies. CONCLUSIONS Physicians should evaluate and treat glucose intolerance in patients with pancreatitis.

Total pancreatectomy and islet autotransplantation in chronic pancreatitis: recommendations from PancreasFest.

DESCRIPTION Total pancreatectomy with islet autotransplantation (TPIAT) is a surgical procedure used to treat severe complications of chronic pancreatitis or very high risk of pancreatic cancer while reducing the risk of severe diabetes mellitus. However, clear guidance on indications, contraindications, evaluation, timing, and follow-up are lacking. METHODS A working group reviewed the medical, psychological, and surgical options and supporting literature related to TPIAT for a consensus meeting during PancreasFest. RESULTS Five major areas requiring clinical evaluation and management were addressed: These included: 1) indications for TPIAT; 2) contraindications for TPIAT; 3) optimal timing of the procedure; 4) need for a multi-disciplinary team and the roles of the members; 5) life-long management issues following TPIAP including diabetes monitoring and nutrition evaluation. CONCLUSIONS TPIAT is an effective method of managing the disabling complications of chronic pancreatitis and risk of pancreatic cancer in very high risk patients. Careful evaluation and long-term management of candidate patients by qualified multidisciplinary teams is required. Multiple recommendations for further research were also identified.