glucagon-like-peptide-1 and Malabsorption-Syndromes

Behavioral and pharmaceutical intervention to treat obesity and its comorbidities typically results in only a 5-10% weight loss. Thus, bariatric surgery is the most effective obesity treatment with some surgeries resulting in 30% sustained weight loss. Although this degree of weight loss has profound metabolic impact, these surgeries seem to have metabolic effects that are independent of weight loss. In support of this is the clinical literature showing rapid resolution of Type 2 diabetes mellitus (T2DM) that occurs before significant weight loss. To gain a complete understanding of the weight loss-independent effects of bariatric surgery, animal models have been developed. These are becoming more widely implemented and allow the use of pair-fed or weight-matched sham-operated controls in order to gain mechanistic insights into the mode of action of bariatric surgery. Increases in anorectic gut hormones, such as glucagon-like peptide-1 and peptide YY, or decreases in the orexigenic hormone ghrelin have been seen and are implicated as mediators of weight loss-independent actions of bariatric surgery. Changes in nutrient processing and sensing may also have a mechanistic role that is independent of, or that regulates, gut hormone responses to these surgeries. Ultimately, the hope is that understanding the mechanisms of bariatric surgeries will aid in the development of less invasive surgeries or pharmacological therapies that are more specifically, and perhaps individually, targeted at weight loss and/or resolution of T2DM.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Type 2; Gastric Bypass; Gastrointestinal Hormones; Glucagon-Like Peptide 1; Humans; Malabsorption Syndromes; Peptide YY; Weight Loss

Enteroendocrine cells secrete over a dozen different hormones responsible for coordinating digestion, absorption, metabolism, and gut motility. Loss of enteroendocrine cells is a known cause of severe congenital diarrhea. Furthermore, enteroendocrine cells regulate glucose metabolism, with the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) playing critical roles in stimulating insulin release by pancreatic β-cells. Islet1 (Isl1) is a LIM-homeodomain transcription factor expressed specifically in an array of intestinal endocrine cells, including incretin-expressing cells. To examine the impact of intestinal Isl1 on glycemic control, we set out to explore the role of intestinal Isl1 in hormone cell specification and organismal physiology. Mice with intestinal epithelial-specific ablation of Isl1 were obtained by crossing Villin-Cre transgenic animals with mice harboring a Isl1(loxP) allele (Isl1(int) model). Gene ablation of Isl1 in the intestine results in loss of GLP-1, GIP, cholecystokinin (CCK), and somatostatin-expressing cells and an increase in 5-HT (serotonin)-producing cells, while the chromogranin A population was unchanged. This dramatic change in hormonal milieu results in animals with lipid malabsorption and females smaller than their littermate controls. Interestingly, when challenged with oral, not intraperitoneal glucose, the Isl-1 intestinal-deficient animals (Isl1(int)) display impaired glucose tolerance, indicating loss of the incretin effect. Thus the Isl1(int) model confirms that intestinal biology is essential for organism physiology in glycemic control and susceptibility to diabetes.

Topics: Age Factors; Animals; Animals, Newborn; Biomarkers; Blood Glucose; Cholecystokinin; Chromogranin A; Diarrhea; Dietary Fats; Enteroendocrine Cells; Female; Gastric Inhibitory Polypeptide; Gastrins; Genotype; Ghrelin; Glucagon-Like Peptide 1; Glucose Metabolism Disorders; Glucose Tolerance Test; Integrases; Intestinal Absorption; Intestinal Mucosa; Intestine, Small; LIM-Homeodomain Proteins; Malabsorption Syndromes; Male; Mice, Inbred C57BL; Mice, Knockout; Microfilament Proteins; Phenotype; Serotonin; Somatostatin; Transcription Factors; Weight Gain

The hormone glucagon-like peptide-1 (GLP-1) is synthesized and secreted by L cells in the small intestine in response to food ingestion. After reaching the general circulation it has a half-life of 2-3 minutes due to degradation by the enzyme dipeptidyl peptidase-4. Its physiological role is directed to control plasma glucose concentration, though GLP-1 also plays other different metabolic functions following nutrient absorption. Biological activities of GLP-1 include stimulation of insulin biosynthesis and glucose-dependent insulin secretion by pancreatic beta cell, inhibition of glucagon secretion, delay of gastric emptying and inhibition of food intake. GLP-1 is able to reduce plasma glucose levels in patients with type 2 diabetes and also can restore beta cell sensitivity to exogenous secretagogues, suggesting that the increasing GLP-1 concentration may be an useful therapeutic strategy for the treatment of patients with type 2 diabetes.

Topics: Animals; Blood Glucose; Carbohydrate Metabolism, Inborn Errors; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Eating; Gastric Emptying; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucose; Homeostasis; Humans; Hyperglycemia; Incretins; Insulin; Insulin Secretion; Insulin-Secreting Cells; Malabsorption Syndromes; Mice; Mice, Knockout; Models, Biological; Obesity; Receptors, Glucagon

Carbohydrate malabsorption causes more symptoms in patients with functional gastrointestinal disorders than in healthy individuals. The purpose of this study was to investigate whether this could be explained by differences in ileal brake hormone secretion.. Eighteen consecutive patients with functional abdominal complaints, referred to our clinic for investigation of self-reported food hypersensitivity, were included in the study and compared with 15 healthy volunteers. All subjects ingested a mixture of 25 g fructose and 5 g sorbitol. Pulmonary hydrogen and methane excretion and plasma glucagon-like peptide 1 (GLP-1) and peptide YY (PYY) levels were measured during the next 3 h. Both habitual and post-test symptoms were assessed.. Malabsorption of fructose and sorbitol was present in 61% of the patients and 73% of the controls. Nevertheless, the patients experienced significantly more symptoms following carbohydrate challenge, and 78% of the patients claimed that the challenge replicated their habitual gastrointestinal complaints. No significant differences in gas excretion or GLP-1 and PYY levels were found between patients and controls or between symptomatic and asymptomatic carbohydrate malabsorbers. A weak correlation between hydrogen excretion and PYY levels was demonstrated in non-producers of methane.. Neither intestinal gas production nor ileal brake hormone secretion seems to play a role in the symptomatology of carbohydrate intolerance in patients with self-reported food hypersensitivity. Other mechanisms related to bacterial fermentation may be involved and should be investigated further.

Topics: Adult; Breath Tests; Case-Control Studies; Female; Food Hypersensitivity; Fructose; Glucagon-Like Peptide 1; Humans; Malabsorption Syndromes; Male; Middle Aged; Peptide YY; Sorbitol