Distribution and function of glucagon-like peptide 1 (GLP-1) in the digestive tract of mammals and the clinical use of its analogues

Recently, interest in glucagon-like peptide-1 (GLP-1) and other peptides derived from preproglucagon has increased significantly. GLP-1 is a 30-amino acid peptide hormone produced in L-type enteroendocrine cells as a response to food intake. GLP-1 is rapidly metabolized and inactivated by the dipeptidyl peptidase IV enzyme before the hormone leaves the intestine, which increases the likelihood that GLP-1 action is transmitted through sensory neurons in the intestine and liver through the GLP-1 receptor. The main actions of GLP-1 are to stimulate insulin secretion (i.e. act as incretin hormone) and inhibit glucagon secretion, thus contributing to the reduction of postprandial glucose spikes. GLP-1 also inhibits motility and gastrointestinal secretion, and therefore acts as part of the „small bowel brake” mechanism. GLP-1 also appears to be a physiological regulator of appetite and food intake. Because of these effects, GLP-1 or GLP-1 receptor agonists are now increasingly used to treat type 2 diabetes. Reduced GLP-1 secretion may contribute to the development of obesity, and excessive secretion may be responsible for postprandial reactive hypoglycemia. The use of GLP-1 agonists opens up new possibilities for the treatment of type 2 diabetes and other metabolic diseases. In the last two decades, many interesting studies covering both the physiological and pathophysiological role of GLP-1 have been published, and our understanding of GLP-1 has broadened significantly. In this review article, we have tried to describe our current understanding of how GLP-1 works as both a peripheral hormone and as a central neurotransmitter in health and disease. We focused on its biological effects on the body and the potential clinical application in relation to current research.

Glycemic Patterns are Distinct in Individuals with Post-Bariatric Hypoglycemia after Gastric Bypass (PBH-RYGB)

Context Severe hypoglycemia with neuroglycopenia, termed post-bariatric hypoglycemia (PBH). typically occurs postprandially, but is also reported post-activity or mid-nocturnally. Objective To quantify glycemia, glycemic variability (GV), and magnitude/duration of low sensor glucose (SG) values in patients with PBH after Roux-en-Y gastric bypass (PBH-RYGB). Design Retrospective analysis Setting Academic medical center Participants Individuals with PBH-RYGB (n=40), reactive hypoglycemia without GI surgery (Non-Surg Hypo, n=20), pre-diabetes (Pre-DM, n=14), newly-diagnosed T2D (n=5), and healthy controls (HC, n=38). Interventions Masked CGM (Dexcom G4) was used to assess patterns over 24 hours, daytime (6 AM-midnight) and nighttime (midnight-6 AM). Outcome measures: Prespecified measures included mean and median SG, variability, and percent time at thresholds of sensor glucose. Results Mean and median SG were similar for PBH-RYGB and HC (mean: 99.8±18.6 vs. 96.9±10.2 mg/dL; median: 93.0±14.8 vs. 94.5±7.4 mg/dL). PBH-RYGB had a higher coefficient of variation (27.3±6.8 vs. 17.9±2.4%, p<0.0001) and range (154.5±50.4 vs. 112.0±26.7 mg/dL, p<0.0001). Nadir was lowest in PBH-RYGB (42.5±3.7 vs. HC 49.0±11.9 mg/dL, p=0.0046), with >2-fold greater time with SG<70 mg/dL vs. HC (7.7±8.4 vs. 3.2±4.1%, p=0.0013); these differences were greater at night (12.6±16.9 vs. 1.0±1.5%, p<0.0001). Non-Surg Hypo also had 4-fold greater time with SG<70 at night vs. HC (SG <70: 4.0 ± 5.9% vs 1.0 ± 1.5%), but glycemic variability was not increased. Conclusions Patients with PBH-RYGB experience higher glycemic variability and frequency of SG<70 compared to HC, especially at night. These data suggest that additional pathophysiologic mechanisms beyond prandial changes contribute to PBH.

Surgical Remission of Acromegaly Resolves Neuroglycopenia and Paradoxical Rise in GH after OGTT

Background: Acromegaly is known to cause insulin resistance through increased gluconeogenesis and reduction in peripheral glucose use; however, hypoglycemia related to acromegaly has not been reported. Clinical Case: A 58-year old man presented for evaluation of several elevated serum IGF1 levels. The patient had reported years of increased body heat but no changes in his hands or feet and no voice deepening. He recently needed 15 dental crowns due to gaps in his teeth. He also had difficult to manage OSA and weight gain. The patient reported neuroglycopenia after a high glycemic meal or drink, although he was never able to objectively measure any low blood glucoses when they occurred; these symptoms improved but did not resolve despite adhering to a low carbohydrate diet. He also had decreased libido and erectile dysfunction. Exam was significant for coarse facial features. Prior testing revealed several elevated IGF1 serum levels, the last one being 227 ng/mL (54-194). One year prior, OGTT resulted in an initial GH level of 0.1 ng/mL with a decrease to <0.1 ng/mL after two hours. Repeat OGTT had an initial GH of 2.98 ng/mL which paradoxically rose to 12 ng/mL. Fasting BG was 90 mg/dL and peaked at 171 mg/dL. Pituitary MRI showed a 5 mm microadenoma, consistent with acromegaly from a GH secreting adenoma. He underwent a TSSC, and his heat intolerance, low libido, and symptom of hypoglycemia resolved completely. Subsequent IGF1 levels and MRI imaging normalized. Postoperatively OGTT showed a peak GH of 0.23 ng/mL with a peak glucose of 134 mg/dL. There was no paradoxical rise in GH. Discussion: Acromegaly is commonly associated with insulin resistance in ~30% of cases; however, there are no reports of associated neuroglycopenia after a carbohydrate-rich meal or OGTT, which in our patient resolved after successful removal of the pituitary microadenoma. His low glucose symptoms could have been a result of reactive hypoglycemia, which is often seen in patients with diabetes or even prediabetes. However this patient had no history of either. He did not have evidence of any tumors causing hypoglycemia and no gastric surgery to suggest a related etiology (e.g, dumping syndrome or nesidioblastosis). Conversely since GH is normally anabolic and stimulates insulin release, the patient’s elevated GH may have caused an abnormal increase in insulin, leading to his hypoglycemia symptoms. Indeed GIP, which stimulates insulin, is thought to be the cause of the paradoxical rise in GH seen in 30% of acromegaly cases. Remarkably, the patient’s hypoglycemia symptoms disappeared after treatment of the acromegaly, which leads us to consider that excess GH was the culprit.

CASE SERIES OF REACTIVE HYPOGLYCEMIA

Reactive hypoglycemia (RH) is the condition of postprandially hypoglycemia occurring 2-5 hours after food intake. This study consisted of 12 patients who were reviewed in Neurology and General medicine OPD with atypical symptoms which we couldn't explain. These patients were then observed for 14 days with CGM. The incidence of reactive hypoglycemia was found to be more in patients with a high waist hip ratio. Patients with higher BMI have a high risk for reactive hypoglycemia.

Metabolic Parameters in Patients with Suspected Reactive Hypoglycemia

Background: It remains unclear whether reactive hypoglycemia (RH) is a disorder caused by improper insulin secretion, result of eating habits that are not nutritionally balanced or whether it is a psychosomatic disorder. The aim of this study was to investigate metabolic parameters in patients admitted to the hospital with suspected RH. Methods: The study group (SG) included non-diabetic individuals with symptoms consistent with RH. The control group (CG) included individuals without hypoglycemic symptoms and any documented medical history of metabolic disorders. In both groups the following investigations were performed: fasting glucose and insulin levels, Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), 75 g five-hour Oral Glucose Tolerance Test (OGTT) with an assessment of glucose and insulin and lipid profile evaluation. Additionally, Mixed Meal Tolerance Test (MMTT) was performed in SG. Results from OGTT and MMTT were analyzed in line with the non-standardized RH diagnostic criteria. Results: Forty subjects have been enrolled into SG. Twelve (30%) of those patients had hypoglycemic symptoms and glucose level ≤55 mg/dL during five-hour OGTT and have been diagnosed with RH. Ten (25%) subjects manifested hypoglycemic like symptoms without significant glucose decline. Patients with diagnosed RH had statistically significantly lower mean glucose at first (92.1 ± 37.9 mg/dL vs. 126.4 ± 32.5 mg/dL; LSD test: p < 0.001) and second (65.6 ± 19.3 mg/dL vs. 92.6 ± 19.3 mg/dL; LSD test: p < 0.001) hour of OGTT and insulin value (22.7 ± 10.9 lU/mL vs. 43.4 ± 35.0 lU/mL; LSD test: p < 0.001) at second hour of OGTT compared to the patients who did not meet the criteria of RH. Seventeen (43%) subjects from SG reported symptoms suggesting hypoglycemia during MMTT but none of them had glucose value lower than ≤55 mg/dL (68.7 ± 4.7 mg/dL). From the entire lipid profile, only mean total cholesterol value was significantly higher (p = 0.024) in SG in comparison with CG but did not exceed standard reference range. Conclusions: No metabolic disturbances have been observed in patients with diagnosed reactive hypoglycemia. Hyperinsulinemia has not been associated with glycemic declines in patients with this condition. Occurrence of pseudohypoglicemic symptoms and lower glucose value was more common after ingestion of glucose itself rather than after ingestion of a balanced meal. This could suggest an important role that nutritionally balanced diet may play in maintaining correct glucose and insulin levels in the postprandial period.