Nutrient re-routing and altered gut-islet cell crosstalk may explain early relief of severe postprandial hypoglycaemia after reversal of Roux-en-Y gastric bypass.

BACKGROUND: Roux-en-Y gastric bypass is associated with an increased risk of postprandial hyperinsulinaemic hypoglycaemia, but the underlying pathophysiology remains poorly understood. We therefore examined the effect of re-routing of nutrient delivery on gut-islet cell crosstalk in a person with severe postprandial hypoglycaemia after Roux-en-Y gastric bypass. CASE REPORT: A person with severe postprandial hypoglycaemia, who underwent surgical reversal of Roux-en-Y gastric bypass, was studied before reversal and at 2 weeks and 3 months after reversal surgery using liquid mixed meal tests and hyperinsulinaemic-euglycaemic clamps. The nadir of postprandial plasma glucose rose from 2.8 mmol/l to 4.1 mmol/l at 2 weeks and to 4.4 mmol/l at 3 months after reversal. Concomitant insulin- and glucagon-like peptide-1 secretion (peak concentrations and area under the curve) clearly decreased after reversal, while concentrations of glucose-dependent insulinotropic polypeptide and ghrelin increased. Insulin clearance declined after reversal, whereas clamp-estimated peripheral insulin sensitivity was unchanged. The person remained without symptoms of hypoglycaemia, but had experienced significant weight gain at 15-month follow-up. DISCUSSION: Accelerated nutrient absorption may be a driving force behind postprandial hyperinsulinaemic hypoglycaemia after Roux-en-Y gastric bypass. Re-routing of nutrients by reversal of the Roux-en-Y gastric bypass diminished postprandial plasma glucose excursions, alleviated postprandial insulin and glucagon-like peptide-1 hypersecretion and eliminated postprandial hypoglycaemia, which emphasizes the importance of altered gut-islet cell crosstalk for glucose metabolism after Roux-en-Y gastric bypass.

Continuous subcutaneous infusion of glucagon-like peptide 1 lowers plasma glucose and reduces appetite in type 2 diabetic patients.

OBJECTIVE: The gut hormone glucagon-like peptide 1 (GLP-1) has insulinotropic and anorectic effects during intravenous infusion and has been proposed as a new treatment for type 2 diabetes and obesity. The effect of a single subcutaneous injection is brief because of rapid degradation. We therefore sought to evaluate the effect of infusion of GLP-1 for 48 h in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: We infused GLP-1 (2.4 pmol.kg-1.min-1) or saline subcutaneously for 48 h in randomized order in six patients with type 2 diabetes to evaluate the effect on appetite during fixed energy intake and on plasma glucose, insulin, glucagon, postprandial lipidemia, blood pressure, heart rate, and basal metabolic rate. RESULTS: The infusion resulted in elevations of the plasma concentrations of intact GLP-1 similar to those observed after intravenous infusion of 1.2 pmol.kg-1.min-1, previously shown to lower blood glucose effectively in type 2 diabetic patients. Fasting plasma glucose (day 2) decreased from 14.1 +/- 0.9 (saline) to 12.2 +/- 0.7 mmol/l (GLP-1), P = 0.009, and 24-h mean plasma glucose decreased from 15.4 +/- 1.0 to 13.0 +/- 1.0 mmol/l, P = 0.0009. Fasting and total area under the curve for insulin and C-peptide levels were significantly higher during the GLP-1 administration, whereas glucagon levels were unchanged. Neither triglycerides nor free fatty acids were affected. GLP-1 administration decreased hunger and prospective food intake and increased satiety, whereas fullness was unaffected. No side effects during GLP-1 infusion were recorded except for a brief cutaneous reaction. Basal metabolic rate and heart rate did not change significantly during GLP-1 administration. Both systolic and diastolic blood pressure tended to be lower during the GLP-1 infusion. CONCLUSIONS: We conclude that 48-h continuous subcutaneous infusion of GLP-1 in type 2 diabetic patients 1) lowers fasting as well as meal-related plasma glucose, 2) reduces appetite, 3) has no gastrointestinal side effects, and 4) has no negative effect on blood pressure.

Evaluation of beta-cell secretory capacity using glucagon-like peptide 1.

OBJECTIVE: Beta-cell secretory capacity is often evaluated with a glucagon test or a meal test. However, glucagon-like peptide 1 (GLP-1) is the most insulinotropic hormone known, and the effect is preserved in type 2 diabetic patients. RESEARCH DESIGN AND METHODS: We first compared the effects of intravenous bolus injections of 2.5, 5, 15, and 25 nmol GLP-1 with glucagon (1 mg intravenous) and a standard meal (566 kcal) in 6 type 2 diabetic patients and 6 matched control subjects. Next, we studied another 6 patients and 6 control subjects and, in addition to the above procedure, performed a combined glucose plus GLP-1 stimulation, where plasma glucose was increased to 15 mmol/l before injection of 2.5 nmol GLP-1. Finally, we compared the insulin response to glucose plus GLP-1 stimulation with that observed during a hyperglycemic arginine clamp (30 mmol/l) in 8 patients and 8 control subjects. RESULTS: Peak insulin and C-peptide concentrations were similar after the meal, after 2.5 nmol GLP-1, and after glucagon. Side effects were less with GLP-1 than with glucagon. Peak insulin and C-peptide concentrations were as follows (C-peptide concentrations are given in parentheses): for patients (n = 12): meal, 277 +/- 42 pmol/l (2,181 +/- 261 pmol/l); GLP-1 (2.5 nmol), 390 +/- 74 pmol/l (2,144 +/- 254 pmol/l); glucagon, 329 +/- 50 pmol/l (1,780 +/- 160 pmol/l); glucose plus GLP-1, 465 +/- 87 pmol/l (2,384 +/- 299 pmol/l); for control subjects (n = 12): meal, 543 +/- 89 pmol/l (2,873 +/- 210 pmol/l); GLP-1, 356 +/- 51 pmol/l (2,001 +/- 130 pmol/l); glucagon, 420 +/- 61 pmol/l (1,995 +/- 99 pmol/l); glucose plus GLP-1, 1,412 +/- 187 pmol/l (4,391 +/- 416 pmol/l). Peak insulin and C-peptide concentrations during the hyperglycemic arginine clamp and during glucose plus GLP-1 injection were as follows: for patients: 475 +/- 141 pmol/l (2,295 +/- 379 pmol/l) and 816 +/- 268 pmol/l (3,043 +/- 508 pmol/l), respectively; for control subjects: 1,403 +/- 308 pmol/l (4,053 +/- 533 pmol/l) and 2,384 +/- 452 pmol/l (6,047 +/- 652 pmol/l), respectively. CONCLUSIONS: GLP-1 (2.5 nmol = 9 microg) elicits similar secretory responses to 1 mg glucagon (but has fewer side effects) and a standard meal. Additional elevation of plasma glucose to 15 mmol/l did not enhance the response further. The incremental response was similar to that elicited by arginine, but hyperglycemia had an additional effect on the response to arginine.

Additive glucose-lowering effects of glucagon-like peptide-1 and metformin in type 2 diabetes.

OBJECTIVE: The incretin hormone glucagon-like peptide-1 (GLP-1) reduces plasma glucose in type 2 diabetic patients by stimulating insulin secretion and inhibiting glucagon secretion. The biguanide metformin is believed to lower plasma glucose without affecting insulin secretion. We conducted this study to investigate the effect of a combination therapy with GLP-1 and metformin, which could theoretically be additive, in type 2 diabetic patients. RESEARCH DESIGN AND METHODS: In a semiblinded randomized crossover study, seven patients received treatment with metformin (1,500 mg daily orally) alternating with GLP-1 (continuous subcutaneous infusion of 2.4 pmol x kg(-1) x min(-1)) alternating with a combination of metformin and GLP-1 for 48 h. Under fixed energy intake, we examined the effects on plasma glucose, insulin, C-peptide, glucagon, and appetite. RESULTS: Fasting plasma glucose (day 2) decreased from 13.9 +/- 1 (no treatment) to 11.2 +/- 0.4 (metformin) and 11.5 +/- 0.5 (GLP-1) and further decreased to 9.4 +/- 0.7 (combination therapy) (P = 0.0005, no difference between monotherapy with GLP-1 and metformin). The 24-h mean plasma glucose (day 2) decreased from 11.8 +/- 0.5 (metformin) and 11.7 +/- 0.8 (GLP-1) to 9.8 +/- 0.5 (combination) (P = 0.02, no difference between GLP-1 and metformin). Insulin levels were similar between the three regimens, but glucagon levels were significantly reduced with GLP-1 compared with metformin (P = 0.0003). Combination therapy had no additional effect on appetite scores. CONCLUSIONS: Monotherapy with GLP-1 and metformin have equal effects on plasma glucose and additive effects upon combination.

Determinants of the effectiveness of glucagon-like peptide-1 in type 2 diabetes.

GLP-1 lowers blood glucose in fasting type 2 diabetic patients. To clarify the relation of the effect of GLP-1 to obesity, blood glucose, beta-cell function, and insulin sensitivity, GLP-1 (1.2 pmol/kg.min) was infused iv for 4-6 h into 50 fasting type 2 diabetic patients with a wide range of age, body mass index, HbA1c, and fasting plasma glucose. The effectiveness of GLP-1 was evaluated by calculation of a glucose disappearance constant for each individual (Kg, linear slope of log-transformed plasma glucose), and by the lowest stable glucose level (Nadir plasma glucose) obtained during the infusion. Grouped according to fasting plasma glucose (<10, 10-15, >15 mmol/liter), Kg values were 0.45 +/- 0.03, 0.38 +/- 0.04, and 0.28 +/- 0.04%/min (P = 0.005), and Nadir plasma glucose values were 4.7 +/- 0.1 (3.9-5.9), 5.8 +/- 0.4 (4.3-8.4), and 8.7 +/- 1.4 (6.2-18.7) mmol/liter (P = 0.0003). Nonresponders were not identified. Multiple regression analysis with Kg or Nadir plasma glucose as the dependent parameter and body mass index, age, gender, diabetes duration, and significantly correlated parameters (in multiple regression for Kg: fasting plasma glucose, fasting nonesterified fatty acid, dipeptidyl peptidase activity, peak insulin, and the logarithm of beta-cell function; and for Nadir plasma glucose: fasting plasma glucose, fasting nonesterified fatty acid, dipeptidyl peptidase activity, delta glucagon decrement, F-GLP-1 total, logarithm of beta-cell function, and Kg) as independent parameters resulted in fasting plasma glucose as the only significant predictor of Kg, and fasting plasma glucose and Kg as predictors of Nadir plasma glucose. Kg and Nadir plasma glucose were neither influenced by treatment nor by neuropathy per se. In conclusion, GLP-1 lowers plasma glucose in type 2 diabetes regardless of severity, but glucose elimination is faster and obtained glycemic level lower in patients with the lower fasting plasma glucose. Not all patients can be expected to reach normoglycemia.

Determinants of the impaired secretion of glucagon-like peptide-1 in type 2 diabetic patients.

To elucidate the causes of the diminished incretin effect in type 2 diabetes mellitus we investigated the secretion of the incretin hormones, glucagon-like peptide-1 and glucose- dependent insulinotropic polypeptide and measured nonesterified fatty acids, and plasma concentrations of insulin, C peptide, pancreatic polypeptide, and glucose during a 4-h mixed meal test in 54 heterogeneous type 2 diabetic patients, 33 matched control subjects with normal glucose tolerance, and 15 unmatched subjects with impaired glucose tolerance. The glucagon-like peptide-1 response in terms of area under the curve from 0-240 min after the start of the meal was significantly decreased in the patients (2482 +/- 145 compared with 3101 +/- 198 pmol/liter.240 min; P = 0.024). In addition, the area under the curve for glucose-dependent insulinotropic polypeptide was slightly decreased. In a multiple regression analysis, a model with diabetes, body mass index, male sex, insulin area under the curve (negative influence), glucose-dependent insulinotropic polypeptide area under the curve (negative influence), and glucagon area under the curve (positive influence) explained 42% of the variability of the glucagon-like peptide-1 response. The impaired glucose tolerance subjects were hyperinsulinemic and generally showed the same abnormalities as the diabetic patients, but to a lesser degree. We conclude that the meal-related glucagon-like peptide-1 response in type 2 diabetes is decreased, which may contribute to the decreased incretin effect in type 2 diabetes.

On the treatment of diabetes mellitus with glucagon-like peptide-1.

As a therapeutic principle, the insulinotropic peptide, GLP-1, of the secretin-glucagon family of peptides, has turned out to possess some remarkably attractive properties, including the capability of normalizing blood glucose concentrations in patients with non-insulin-dependent diabetes mellitus and promoting satiety and reducing food intake in healthy volunteers. Because of rapid and extensive metabolization, the peptide is not immediately clinically applicable and, as a therapeutic principle, GLP-1 is still in its infancy. Some possible avenues for circumventing these difficulties are the development of DPP-IV-resistant analogs, the inhibition of DPP-IV, enhancement of GLP-1 secretion, GLP delivery systems using continuous subcutaneous infusion or buccal tablets, GLP-1 absorption, and orally active, stable analogs. It seems likely that one or more of these approaches could result in a clinically useful development program.