Jenny Tong

Oral Disposition Index Predicts the Development of Future Diabetes Above and Beyond Fasting and 2-h Glucose Levels

OBJECTIVE—We sought to determine whether an oral disposition index (DIO) predicts the development of diabetes over a 10-year period. First, we assessed the validity of the DIO by demonstrating that a hyperbolic relationship exists between oral indexes of insulin sensitivity and β-cell function. RESEARCH DESIGN AND METHODS—A total of 613 Japanese-American subjects (322 men and 291 women) underwent a 75-g oral glucose tolerance test (OGTT) at baseline, 5 years, and 10 years. Insulin sensitivity was estimated as 1/fasting insulin or homeostasis model assessment of insulin sensitivity (HOMA-S). Insulin response was estimated as the change in insulin divided by change in glucose from 0 to 30 min (ΔI0–30/ΔG0–30). RESULTS—ΔI0–30/ΔG0–30 demonstrated a curvilinear relationship with 1/fasting insulin and HOMA-S with a left and downward shift as glucose tolerance deteriorated. The confidence limits for the slope of the loge-transformed estimates included −1 for ΔI0–30/ΔG0–30 versus 1/fasting insulin for all glucose tolerance groups, consistent with a hyperbolic relationship. When HOMA-S was used as the insulin sensitivity measure, the confidence limits for the slope included −1 only for subjects with normal glucose tolerance (NGT) or impaired fasting glucose (IFG)/impaired glucose tolerance (IGT) but not diabetes. On the basis of this hyperbolic relationship, the product of ΔI0–30/ΔG0–30 and 1/fasting insulin was calculated (DIO) and decreased from NGT to IFG/IGT to diabetes (P < 0.001). Among nondiabetic subjects at baseline, baseline DIO predicted cumulative diabetes at 10 years (P < 0.001) independent of age, sex, BMI, family history of diabetes, and baseline fasting and 2-h glucose concentrations. CONCLUSIONS—The DIO provides a measure of β-cell function adjusted for insulin sensitivity and is predictive of development of diabetes over 10 years.

Ghrelin in the regulation of body weight and metabolism

Ghrelin, a peptide hormone predominantly produced by the stomach, was isolated as the endogenous ligand for the growth hormone secretagogue receptor. Ghrelin is a potent stimulator of growth hormone (GH) secretion and is the only circulatory hormone known to potently enhance feeding and weight gain and to regulate energy homeostasis following central and systemic administration. Therapeutic intervention with ghrelin in catabolic situations may induce a combination of enhanced food intake, increased gastric emptying and nutrient storage, coupled with an increase in GH thereby linking nutrient partitioning with growth and repair processes. These qualities have fostered the idea that ghrelin-based compounds may have therapeutic utility in treating malnutrition and wasting induced by various sub-acute and chronic disorders. Conversely, compounds that inhibit ghrelin action may be useful for the prevention or treatment of metabolic syndrome components such as obesity, impaired lipid metabolism or insulin resistance. In recent years, the effects of ghrelin on glucose homeostasis, memory function and gastrointestinal motility have attracted considerable amount of attention and revealed novel therapeutic targets in treating a wide range of pathologic conditions. Furthermore, discovery of ghrelin O-acyltransferase has also opened new research opportunities that could lead to major understanding of ghrelin physiology. This review summarizes the current knowledge on ghrelin synthesis, secretion, mechanism of action and biological functions with an additional focus on potential for ghrelin-based pharmacotherapies.

Ghrelin Suppresses Glucose-Stimulated Insulin Secretion and Deteriorates Glucose Tolerance in Healthy Humans

OBJECTIVE The orexigenic gut hormone ghrelin and its receptor are present in pancreatic islets. Although ghrelin reduces insulin secretion in rodents, its effect on insulin secretion in humans has not been established. The goal of this study was to test the hypothesis that circulating ghrelin suppresses glucose-stimulated insulin secretion in healthy subjects. RESEARCH DESIGN AND METHODS Ghrelin (0.3, 0.9 and 1.5 nmol/kg/h) or saline was infused for more than 65 min in 12 healthy patients (8 male/4 female) on 4 separate occasions in a counterbalanced fashion. An intravenous glucose tolerance test was performed during steady state plasma ghrelin levels. The acute insulin response to intravenous glucose (AIRg) was calculated from plasma insulin concentrations between 2 and 10 min after the glucose bolus. Intravenous glucose tolerance was measured as the glucose disappearance constant (Kg) from 10 to 30 min. RESULTS The three ghrelin infusions raised plasma total ghrelin concentrations to 4-, 15-, and 23-fold above the fasting level, respectively. Ghrelin infusion did not alter fasting plasma insulin or glucose, but compared with saline, the 0.3, 0.9, and 1.5 nmol/kg/h doses decreased AIRg (2,152 ± 448 vs. 1,478 ± 2,889, 1,419 ± 275, and 1,120 ± 174 pmol/l) and Kg (0.3 and 1.5 nmol/kg/h doses only) significantly (P < 0.05 for all). Ghrelin infusion raised plasma growth hormone and serum cortisol concentrations significantly (P < 0.001 for both), but had no effect on glucagon, epinephrine, or norepinephrine levels (P = 0.44, 0.74, and 0.48, respectively). CONCLUSIONS This is a robust proof-of-concept study showing that exogenous ghrelin reduces glucose-stimulated insulin secretion and glucose disappearance in healthy humans. Our findings raise the possibility that endogenous ghrelin has a role in physiologic insulin secretion, and that ghrelin antagonists could improve β-cell function.

Hiatal hernia size affects lower esophageal sphincter function, esophageal acid exposure, and the degree of mucosal injury

Background Since the role of a hiatal hernia in the pathophysiology of gastroesophageal reflux disease (GERD) has not been fully elucidated, we studied the effects of hiatal hernias on the function of the lower esophageal sphincter (LES) and esophageal acid clearance. Patients and methods Ninety-five consecutive patients with GERD diagnosed by 24-hour pH monitoring underwent upper gastrointestinal series (UGI), endoscopy, and esophageal manometry. Based on the presence (H+) or absence (H-) of a hiatal hernia on UGI series, they were divided into two groups: H+ (n = 51) and H- (n = 44). Then, using the size of the hiatal hernia, the H+ group was divided into three subgroups: I, H 5 cm (n = 6). Results Esophageal manometry showed that patients with larger hiatal hernias (groups II and III) had a weaker and shorter LES and less effective peristalsis compared to patients with a small or no hiatal hernia. Prolonged pH monitoring showed that patients with larger hiatal hernias were exposed to more refluxed acid and had more severely abnormal acid clearance. Endoscopy showed more severe esophagltis among patients with GERD and hiatal hernia compared with GERD patients without hiatal hernia, and the degree of esophagitis was proportionate to the size of the hernia. Conclusions Among patients with proven GERD, those with a small hiatal hernia and those with no hiatal hernia had similar abnormalities of LES function and acid clearance. In patients with larger hiatal hernias, however, the LES was shorter and weaker, the amount of reflux was greater, and acid clearance was less efficient. Consequently, the degree of esophagitis was worse in the presence of a large hiatal hernia.

Comparison of thoracoscopic and laparoscopic Heller myotomy for achalasia.

For more than three decades experts have debated the relative merits of thoracoscopic Heller myotomy (no antireflux procedure) vs. laparoscopic Heller myotomy plus Dor fundoplication for treatment of achalasia. The aim of this study was to compare the results of these two methods with respect to (1) relief of dysphagia, (2) incidence of postoperative gastroesophageal reflux, and (3) hospital course. Sixty patients with esophageal achalasia were operated on between 1991 and 1996. Thirty underwent a thoracoscopic Heller myotomy and 30 had a laparoscopic Heller myotomy with a Dor fundoplication. The two groups were similar with respect to demographic characteristics, clinical findings, and extent of manometric abnormalities. Preoperative pH monitoring showed abnormal reflux in two patients in the laparoscopic group. Average hospital stay was 84 hours for the thoracoscopic group and 42 hours for the laparoscopic group. Excellent (no dysphagia) or good (dysphagia less than once a week) results were obtained in 87% of patients in the thoracoscopic group and in 90% of patients in the laparoscopic group. Postoperative pH monitoring showed abnormal reflux in 6 (60%) of 10 patients in the thoracoscopic group and in 1 (10%) of 10 patients in the laparoscopic group. The two patients in the laparoscopic group who had reflux preoperatively had normal reflux scores postoperatively. Laparoscopic Heller myotomy with Dor fundoplication was found to be superior to thoracoscopic Heller myotomy. Both operations relieved dysphagia, but the laparoscopic approach avoided postoperative reflux and even corrected reflux present preoperatively. In addition, the patients were more comfortable and left the hospital earlier following a laparoscopic myotomy. Whether it is truly possible to perform a Heller myotomy without an antireflux procedure in a way that relieves dysphagia and regularly avoids reflux remains questionable.

Ghrelin enhances olfactory sensitivity and exploratory sniffing in rodents and humans

Olfaction is an integral part of feeding providing predictive cues that anticipate ingestion. Although olfactory function is modulated by factors such as prolonged fasting, the underlying neural mechanisms remain poorly understood. We recently identified ghrelin receptors in olfactory circuits in the brain. We therefore investigated the role of the appetite-stimulating hormone ghrelin in olfactory processing in rodents and humans, testing the hypothesis that ghrelin lowers olfactory detection thresholds and enhances exploratory sniffing, both being related to food seeking. In rats, intracerebroventricular ghrelin decreased odor detection thresholds and increased sniffing frequency. In humans, systemic ghrelin infusions significantly enhanced sniff magnitudes in response to both food and nonfood odorants and air in comparison to control saline infusions but did not affect the pleasantness ratings of odors. This is consistent with a specific effect on odor detection and not the hedonic value of odors. Collectively, our findings indicate that ghrelin stimulates exploratory sniffing and increases olfactory sensitivity, presumably enhancing the ability to locate, identify, and select foods. This novel role is consistent with ghrelins overall function as a signal amplifier at the molecular interface between environmental and nutritional cues and neuroendocrine circuits controlling energy homeostasis.

Importance of preoperative and postoperative pH monitoring in patients with esophageal achalasia

Gastroesophageal reflux (GER) can develop in patients with esophageal achalasia either before treatment or following pneumatic dilatation or Heller myotomy. In this study we assessed the value of pre- and postoperative pH monitoring in identifying GER in patients with esophageal achalasia. Ambulatory pH monitoring was performed preoperatively in 40 patients with achalasia (18 untreated patients and 22 patients after pneumatic dilatation), 27 (68%) of whom complained of heartburn in addition to dysphagia (group A), and postoperatively in 18 of 51 patients who underwent a thoracoscopic (n=30) or laparoscopic (n=21) Heller myotomy (group B). The DeMeester reflux score was abnormal in 14 patients in group A, 13 of whom had been treated previously by pneumatic dilatation. Two types of pH tracings were seen: (1) GER in eight patients (7 of whom had undergone dilatation) and (2) pseudo-GER in six patients (all 6 of whom had undergone dilatation). Therefore 7 (32%) of 22 patients had abnormal GER after pneumatic dilatation. Postoperatively (group B) seven patients had abnormal GER (6 after thoracoscopic and 1 after laparoscopic myotomy). Six of the seven patients were asymptomatic. These findings show that (1) approximately one third of patients treated by pneumatic dilatation had GER; (2) symptoms were an unreliable index of the presence of abnormal GER, so pH monitoring must be performed in order to make this diagnosis; and (3) the preoperative detection of GER in patients with achalasia is important because it influences the choice of operation.

Early-Life Exposure to Testosterone Programs the Hypothalamic Melanocortin System

In mammals, males consume more food, which is considered a masculinized behavior, but the underlying mechanism of this sex-specific feeding behavior is unknown. In mice, neonatal testosterone (NT) is critical to masculinize the developing brain, leading to sex differences in reproductive physiology. The proopiomelanocortin (POMC) neurons of the hypothalamic arcuate nucleus (ARC) are critical to suppress energy intake and POMC innervation of hypothalamic feeding circuits develops to a large extent neonatally. We hypothesized that NT programs the masculinization of energy intake by programming POMC neurons. We tested this hypothesis by comparing control females and control males (CMs) with female mice neonatally androgenized with testosterone (NTFs). We show that increased food intake in CMs is associated with reduced POMC expression and decreased intensity of neuronal projections from POMC neurons within the ARC compared with control females. We found that NTFs display a masculinized energy intake and ARC POMC expression and innervation as observed in CMs, which can be mimicked by neonatal exposure to the androgen receptor agonist dihydrotestosterone (DHT). NTFs also exhibit hyperleptinemia and a decreased ability of leptin to up-regulate POMC, suppress food intake, and prevent adipose tissue accumulation, independent of signal transducer and activator of transcription 3. However, this leptin resistance is specific to NTFs, is not a consequence of masculinization, and is reproduced by neonatal exposure to estrogen but not DHT. Thus, NT programs a sexual differentiation of POMC neurons in female mice via DHT but also predisposes to leptin resistance and obesity in an estrogen-dependent manner.

Ghrelin and PYY in the regulation of energy balance and metabolism: lessons from mouse mutants

Effective control of body weight and energy homeostasis requires stringent regulation of caloric intake and energy expenditure. Gut-brain interactions comprise a central axis for the control of energy homeostasis by integrating the intake of nutrients with an effective utilization of ingested calories either by storage or by expenditure as cellular fuel. Ghrelin, a stomach-derived peptide, is the only known circulating orexigenic hormone. It is acylated with a medium-chain fatty acid by the enzyme ghrelin O-acetyltransferase (GOAT) and displays a broad range of activity, from central control of food intake to peripheral functions such as gastric emptying and insulin secretion. PYY, a peptide produced by L cells of the small intestine and rectum, has been shown to inhibit gut motility and is proposed to stimulate a powerful central satiety response. In recent years, pharmacological studies in animals and clinical studies in humans have contributed to our knowledge of principal ghrelin and PYY actions. However, valuable findings from studies using ghrelin-deficient mice, ghrelin receptor [growth hormone secretagogue receptor-1a (GHSR1a)]-deficient mice, double-knockout mice (for ghrelin and GHSR), and GOAT-deficient or -overexpressor mice, as well as mice deficient for PYY or neuropeptide Y receptors have allowed better definition of the actual physiological functions of ghrelin and PYY. This review summarizes findings from mutant mouse studies with emphasis on respective gene knockout and transgenic animals and describes how these studies contribute to the current understanding of how endogenous ghrelin and PYY as two major representatives of endocrine gut-brain communications may regulate energy and glucose homeostasis.

The GOAT-ghrelin system is not essential for hypoglycemia prevention during prolonged calorie restriction.

Objective Ghrelin acylation by ghrelin O-acyltransferase (GOAT) has recently been reported to be essential for the prevention of hypoglycemia during prolonged negative energy balance. Using a unique set of four different genetic loss-of-function models for the GOAT/ghrelin/growth hormone secretagogue receptor (GHSR) system, we thoroughly tested the hypothesis that lack-of-ghrelin activation or signaling would lead to hypoglycemia during caloric deprivation. Methodology Male and female knockout (KO) mice for GOAT, ghrelin, GHSR, or both ghrelin and GHSR (dKO) were subjected to prolonged calorie restriction (40% of ad libitum chow intake). Body weight, fat mass, and glucose levels were recorded daily and compared to wildtype (WT) controls. Forty-eight hour blood glucose profiles were generated for each individual mouse when 2% or less body fat mass was reached. Blood samples were obtained for analysis of circulating levels of acyl- and desacyl-ghrelin, IGF-1, and insulin. Principal Findings Chronic calorie restriction progressively decreased body weight and body fat mass in all mice regardless of genotype. When fat mass was depleted to 2% or less of body weight for 2 consecutive days, random hypoglycemic events occurred in some mice across all genotypes. There was no increase in the incidence of hypoglycemia in any of the four loss-of-function models for ghrelin signaling including GOAT KO mice. Furthermore, no differences in insulin or IGF-1 levels were observed between genotypes. Conclusion The endogenous GOAT-ghrelin-GHSR system is not essential for the maintenance of euglycemia during prolonged calorie restriction.