Glucagon-like peptide 1 (GLP-1) secretion and plasma dipeptidyl peptidase IV (DPP-IV) activity in morbidly obese patients undergoing biliopancreatic diversion.

BACKGROUND: The physiological inhibitory control of glucagon-like Peptide 1 (GLP-1) on gastric emptying and the contribution of this peptide in the regulation of food intake as a satiety factor suggest that impaired secretion and/or activity of GLP-1 may be involved in the pathogenesis of obesity. We investigated food-mediated GLP-1 secretion as well as plasma activity of dipeptidyl-peptidase IV (DPP-IV), the enzyme responsible for rapid inactivation of the circulating peptide, in morbidly obese patients, before and after weight loss resulting from biliopancreatic diversion. METHODS: Twenty-two morbidly obese non-diabetic patients (BMI = 47.5 +/- 1.8) and 9 age-matched healthy volunteers were studied. A mixed meal (700 kcal) was administered to all subjects and blood samples were collected at 0, 15, 30, 60, 120 min for the determination of circulating glucose, insulin, GLP-1 (7 - 36 amide) concentrations and plasma DPP-IV activity. The patients repeated the test meal after 50 % overweight reduction resulting from surgical treatment (BMI = 33.8 +/- 1.1). RESULTS: While nutrient ingestion significantly increased plasma GLP-1 levels in the control group (30', 60': p < 0.01), the test-meal failed to modify basal peptide values in the obese patients, and an overall reduction in circulating GLP-1 occurred during the observation period (p < 0.001). Plasma DPP-IV activity in the same patients resulted as being significantly higher than controls, both at fasting and in response to the meal (p < 0.05). With respect to preoperative values, an overall increase in circulating GLP-1 levels occurred in all patients following biliopancreatic diversion (p < 0.001). Plasma DPP-IV activity, on the other hand, continued to be abnormally increased, even after considerable weight loss (p < 0.05 vs. controls). CONCLUSIONS: First: In morbid obesity, the accelerated inactivation of circulating GLP-1 could at least partially account for plasma peptide levels lower than normal, the defective availability of such a satiety factor possibly contributing to eating behaviour abnormalities; Second: plasma DPP-IV hyperactivity in the obese did not seem to be affected by the overweight degree, the increase in postoperative GLP-1 levels mainly resulting from hyperstimulation of GLP-1 secretory cells due to surgical manipulation of gastrointestinal tract. If the abnormally accelerated degradation of GLP-1 in obesity is confirmed, selective DPP-IV inhibitors could actually represent an ideal approach to obesity management.

Evidence for early impairment of glucagon-like peptide 1-induced insulin secretion in human type 2 (non insulin-dependent) diabetes.

UNLABELLED: To investigate a possible role of an enteroinsular axis involvement in the pathogenesis of type 2 diabetes, plasma glucagon-like peptide 1 (GLP-1) 7-36 amide response to nutrient ingestion was evaluated in type 2 diabetics affected by different degrees of beta-cell dysfunction. METHODS: 14 patients on oral hypoglycaemic treatment (group A: HbA1C = 8.1 +/- 1.8 %) and 11 age-matched diabetic patients on diet only (group B: HbA1C = 6.4 +/- 0.9) participated in the study. 10 healthy volunteers were studied as controls. In the postabsorptive state, a mixed meal (700 kCal) was administered to all subjects, and blood samples were regularly collected up to 180' for plasma glucose, insulin, glucagon, and GLP-1 determination. RESULTS: In the control group, the test meal induced a significant increase in plasma GLP-1 at 30' and 60' (p < 0.01); the peptide concentrations then returning toward basal levels. beta-cell function estimation by HOMA score confirmed a more advanced involvement in group A than in group B (p < 0.01). In contrast, the insulin resistance degree showed a similar result in the two groups (HOMA-R). In group A, first-phase postprandial insulin secretion (0 - 60') resulted, as expected, in being significantly reduced compared to healthy subjects (p < 0.001). In the same patients the mean fasting GLP-1 value was similar to controls, but the meal failed to increase plasma peptide levels, which even tended to decrease during the test (p < 0.01). In group B, food-mediated early insulin secretion was higher than in group A (p < 0.001), although significantly reduced when compared to controls (p < 0.01). Like group A, no GLP-1 response to food ingestion occurred in group B patients in spite of maintained basal peptide secretion. Whereas the test-meal did not significantly modify plasma glucagon levels in the control group, glucagon concentrations increased at 30' and 60' in both diabetic groups (p < 0.01). CONCLUSIONS: 1) The functional integrity of GLP-1 cells results as being seriously impaired even in the condition of mild diabetes; 2) the early peptide failure could contribute to the development of beta-cell deterioration which characterizes overt type 2 diabetes.

Urinary excretion of glucagon-like peptide 1 (GLP-1) 7-36 amide in human type 2 (non-insulin-dependent) diabetes mellitus.

The urinary excretion of insulinotropic glucagon-like peptide 1 (GLP-1) was investigated as an indicator of renal tubular integrity in 10 healthy subjects and in 3 groups of type 2 diabetic patients with different degrees of urinary albumin excretion rate. No significant difference emerged between the groups with respect to age of the patients, known duration of diabetes, metabolic control, BMI, or residual beta-cell pancreatic function. Endogenous creatinine clearance was significantly reduced under conditions of overt diabetic nephropathy, compared with normo and microalbuminuric patients (p < 0.01). Urinary excretion of GLP-1 was significantly higher in normoalbuminuric patients compared to controls (490.4 +/- 211.5 vs. 275.5 +/- 132.1 pg/min; p < 0.05), with further increase under incipient diabetic nephropathy conditions (648.6 +/- 305 pg/min; p < 0.01). No significant difference resulted, in contrast, between macroproteinuric patients and non-diabetic subjects. Taking all patients examined into account, a significant positive relationship emerged between urinary GLP-1 and creatinine clearance (p = 0.004). In conclusion, an early tubular impairment in type 2 diabetes would occur before the onset of glomerular permeability alterations. The tubular dysfunction seems to evolve with the development of persistent microalbuminuria. Finally, the advanced tubular involvement, in terms of urinary GLP1 excretion, under overt diabetic nephropathy conditions would be masked by severe concomitant glomerular damage with the coexistence of both alterations resulting in a peptide excretion similar to control subjects.

Effect of nutrient ingestion on glucagon-like peptide 1 (7-36 amide) secretion in human type 1 and type 2 diabetes.

Exogenous glucagon-like peptide 1(GLP-1) bioactivity is preserved in type 2 diabetic patients, resulting the peptide administration in a near-normalization of plasma glucose mainly through its insulinotropic effect. GLP-1 also reduces meal-related insulin requirement in type 1 diabetic patients, suggesting an impairment of the entero-insular axis in both diabetic conditions. To investigate this metabolic dysfunction, we evaluated endogenous GLP-1 concentrations, both at fasting and in response to nutrient ingestion, in 16 type 1 diabetic patients (age = 40.5 +/- 14yr, HbA1C = 7.8 +/- 1.5%), 14 type 2 diabetics (age = 56.5 +/- 13yr, HbA1C = 8.1 +/- 1.8%), and 10 matched controls. In postabsorptive state, a mixed breakfast (230 KCal) was administered to all subjects and blood samples were collected for plasma glucose, insulin, C-peptide and GLP-1 determination during the following 3 hours. In normal subjects, the test meal induced a significant increase of GLP-1 (30', 60': p < 0.01), returning the peptide values towards basal concentrations. In type 2 diabetic patients, fasting plasma GLP-1 was similar to controls (102.1 +/- 1.9 vs. 97.3 +/- 4.01 pg/ml), but nutrient ingestion failed to increase plasma peptide levels, which even decreased during the test (p < 0.01). Similarly, no increase in postprandial GLP-1 occurred in type 1 diabetics, in spite of maintained basal peptide secretion (106.5 +/- 1.5 pg/ml). With respect to controls, the test meal induced in both diabetic groups a significant increase in plasma glucagon levels at 60' (p < 0.01). In conclusion, either in condition of insulin resistance or insulin deficiency chronic hyperglycemia, which is a common feature of both metabolic disorders, could induce a progressive desensitization of intestinal L-cells with consequent peptide failure response to specific stimulation.

Food-related sensory stimuli are able to promote pancreatic polypeptide elevation without evident cephalic phase insulin secretion in human obesity.

The data concerning the cephalic phase of insulin secretion (CPIS) in human obesity are controversial. We investigated the effect of a variety of sensory challenges on CPIS in 17 non-diabetic obese patients (four males, 13 females, mean age 41.1 years, mean BMI 38.7). Water, saccharin, and lemon juice were used as oral stimuli, and a complete meal was simply presented as visual and olfactory stimulations. Twelve healthy normal-weight subjects (four men, eight women, mean age 39.9, mean BMI 22.5) also underwent oral stimulation as controls, and the patients who underwent the sight and smell stimulations were also tested for pancreatic polypeptide (PP) changes in order to verify the occurrence of truly cephalic reflex during the test. Insulin levels were measured before and after each stimulation (every min for the first 5 min, and then after 10, 20, and 30 min). None of the stimuli (saccharin, lemon juice or water retained in the mouth for 2 min and were then spat out; the combined and separate sight and smell of a meal for 2 min) led to a significant increase in insulin in the obese patients (except in the case of one woman after oral stimulation). The oral stimuli led to a variable CPIS in one female and three male controls. Despite the absence of CPIS, the five obese patients undergoing all three sensory stimulations related to the meal (combined sight and smell, sight alone and smell alone) showed an early and significant increase in plasma PP concentrations within the first 3 min; this was more pronounced after the combined than after the separate exposure. Although only preliminary, these results underline the variability but substantial lack of CPIS in obese patients, thus suggesting that it can be considered a relatively rare and unrelevant event even in the presence of a true brain-mediated reflex revealed by the rapid and consistent increase in PP found in our experiments.

[Severe diabetic retinopathy and renal function in non-insulin-dependent (type-2) diabetes mellitus]. / Retinopatia diabetica ingravescente e funzionalità renale nel diabete mellito non insulino-dipendente (tipo 2).

The existence of a linkage between retinal and renal microvascular complications in type 2 diabetes has been so far little investigated. For this purpose we evaluated the presence and degree of renal dysfunction in the most serious clinical conditions of diabetic retinopathy. On the basis of the alterations evidenced by fluorescein angiography 73 type 2 diabetic patients were recruited and divided into the following groups: 19 patients were affected by "clinically significant" Macular Edema (ME), 25 subjects had Preproliferative Retinopathy (PrePR) and 29 patients showed Proliferative Retinopathy (PR). Mean values (M +/- SD) of glycosylated hemoglobin, plasma basal C-peptide, lipid profile, blood pressure, glomerular filtration rate, body mass index, age and known duration of diabetes were similar between the groups. Urinary albumin excretion rate (UAE) was determined for each patient on three consecutive overnight collections (pg/min). Even though the distribution of normo (UAE < 20 micrograms/min), micro (UAE:20-200) and macroalbuminuric (UAE > 200) patients did not significantly differ between the groups, mean values of UAE increased significantly in PrePR (371.1 +/- 532.2) and PR (300.7 +/- 717.3) with respect to ME (35.4 +/- 73.1; p < 0.05). The evaluation of all patients recruited for the study, independently of the kind of retinal alteration, showed that 56.8% of them had no sign of even incipient renal dysfunction, in spite of the advanced retinal damage. When considering those patients affected by both retinal and renal complications (43.2%) the prevalence of renal involvement resulted different in the three conditions investigated.(ABSTRACT TRUNCATED AT 250 WORDS)

Glucose metabolism and larger molecule removal in long-term high efficiency hemofiltration.

High efficiency hemofiltration (HF) was carried out for 9 months in 6 patients on hemodialysis (HD). Comparative studies on carbohydrate metabolism and 500- to 1,500-dalton serum solute concentrations were performed during HD and HF. After 5 months of HF, intravenous glucose tolerance tests showed an improved peripheral glucose utilization, with unchanged insulin secretion. Larger solute concentrations, measured by gel chromatography, simultaneously dropped in serum suggesting that HF removes some toxic substances that inhibit peripheral insulin action. After 9 months of HF, an unexpected increase in the larger solute concentration coincided with an impaired glucose tolerance, stressing the probable toxic rule of such solutes. Changes in other glucoregulatory hormone secretions were not unequivocal. On account of the later increase in 500- to 1,500-dalton solute concentrations, HF failed to prevent larger toxic molecules accumulating in uremic sera.

Renal metabolism of C-peptide in man.

Renal metabolism of C-peptide was studied in nine nondiabetic nonobese patients with normal renal function by the arterial-venous difference technique before and after the oral administration of an amino acid mixture simulating an animal protein meal. In the basal state, the kidney removed 25.7 +/- 7.5% (+/- SD) of the arterial plasma C-peptide. Renal uptake was approximately 7-fold greater than urinary excretion, and thus, more than 85% of the amount extracted was metabolized by the kidney. Renal C-peptide clearance was very high and approximated the glomerular filtration rate, whereas urinary C-peptide clearance was only 14% of its renal clearance. Shortly after amino acid ingestion, arterial C-peptide levels increased by 107%, and C-peptide renal fractional extraction, uptake, and net metabolism also increased markedly (67%, 278%, and 328%, respectively); urinary clearance and excretion did not change. Renal clearance became 2-fold greater than the glomerular filtration rate, indicating that in this phase the kidney removed substantial amounts of C-peptide from peritubular blood as well as by filtration. Both renal uptake and urinary excretion of C-peptide were related to its arterial levels (P less than 0.001 and P less than 0.05, respectively), but renal uptake increased much more than urinary excretion for each increment in arterial C-peptide levels. These results indicate that renal C-peptide metabolism is considerable in the postabsorptive state and is even more marked during the postprandial period. The kidney, therefore, plays a key role in both the regulation of circulating plasma levels and the metabolic clearance of C-peptide.

Diabetic autonomic neuropathy and impaired human pancreatic polypeptide secretion in response to food.

In normal subjects, the early human pancreatic polypeptide (hPP) increase induced by food is mainly dependent on vagal activity. Parasympathetic function and plasma hPP response to a standard mixed meal were evaluated in 10 long term insulin-dependent (type I) diabetic patients (group A), 6 age-matched newly diagnosed type I diabetic patients (group B), and 8 normal subjects. The indices of vagal function (beat to beat heart rate variation during deep breathing and the Valsalva maneuver) were uniformly altered in group A, while they were in the normal range in group B, thus excluding in these latter patients the presence of vagal damage. Plasma hPP in response to standard mixed meal was measured at 5, 15, 30, 60, and 120 min. Fasting plasma hPP concentrations (determined by RIA) in groups A and B (mean +/- SEM, 113 +/- 21 and 83 +/- 21 pg/ml, respectively) did not significantly differ from normal (59 +/- 12 pg/ml). In group A, the initial meal-induced hPP increase was significantly lower than normal (5 min, 139 +/- 12; 15 min, 173 +/- 24; 30 min, 137 +/- 17 pg/ml; P less than 0.01 vs. 5 min, 412 +/- 76; 15 min, 446 +/- 57; 30 min, 325 +/- 56 pg/ml). All group B patients had a marked early increase in the peptide, similar to that in the normal subjects. These results suggest that diabetic autonomic neuropathy is associated with dysfunction of hPP secretion, and the evaluation of hPP in response to SMM may be considered a sensitive and nonstressful method for the assessment of parasympathetic impairment in diabetes.

Plasma and skeletal muscle free amino acids in type I, insulin-treated diabetic subjects.

Insulin-dependent diabetes mellitus (IDDM) induces plasma amino acid (AA) abnormalities, including low alanine and high branched-chain (BCAA). While insulin treatment restores plasma AA pattern, proline, methionine, valine, isoleucine, and total BCAA remain elevated in skeletal muscle intracellular water. This suggests that the restoration of plasma AA concentrations is not a satisfactory index of recovered AA metabolism in IDDM.

Human pancreatic polypeptide and somatostatin in chronic renal failure.

Human pancreatic polypeptide is the only hormone so far reported which clearly suppresses somatostatin release, suggesting that this peptide may have a role in controlling somatostatin secretion from the gut and pancreas. In this study endogenous high circulating human pancreatic polypeptide concentrations in patients with chronic renal failure do not decrease somatostatin circulating levels. The reduced clearance rate of somatostatin in chronic renal failure may partially account for the normal circulating levels of somatostatin observed in our patients with respect to controls. Renal insufficiency may, itself, induce an increase in some gastrointestinal peptides capable of stimulating somatostatin secretion.

[Behavior of blood amino acids after acute administration of glucagon in humans]. / Comportamento degli aminoacidi plasmatici dopo somministrazione acuta di glucagone nell'uomo.

The authors have studied the behavior of Aminoacids (AA), GH, Prolactin (PRL), Insulin (IRI) and blood sugar (BS) after fast intravenous injection of 1 mg of Glucagon (G), in eight normal volunteers. The rise in BS levels soon after G. administration at time 10', 20', 30', 45', 60' prompted to consider the initial phase of the experimental to be under G predominance, although IRI did respond to the infusion with a sharp rise, at time 10', 20', 30', 45'. Glycine, serine, threonine, alanine, lysine, phenylalanine and arginine displayed a significant reduction already at time 10' or 20', when G metabolic effects were dominant, a selective G influence on these AA can be supposed. At time 45' and 60' tyrosine, histidine, methionine, valine, leucine, isoleucine, proline, decreased significantly and glycine, serine, threonine, lysine, alanine, phenylalanine, evidenced further reduction. GH and PRL were not affected by the administration of G.

Variation of blood glucose and serum growth hormone, prolactin and insulin in subjects with insulin-dependent diabetes, after OGTT and pretreatment with 2-Br-alpha-ergocryptine.

In insulin-dependent diabetics high GH values are usually observed. The OGTT does not modify these levels. It was observed that CB 154 (2-Br-alpha ergocryptine) seems capable of lowering GH in acromegalics. We thought it pertinent to check whether or not CB 154 could reduce GH also in diabetics. OGTT was performed in insulin-dependent diabetic patients; 5 days later the same test was repeated after pretreatment with 2.5 mg of CB 154. Serum IRI, GH, hPRL levels and blood glucose values were checked during the test. Significant GH and hPRL variations were not observed after OGTT in the diabetic subjects examined; IRI was always absent, and glycemia followed the model of the diabetic curve. On the contrary, after pretreatment with CB 154, we observed: 1) hPRL reduction; 2) GH increase, sometimes as early as 30 min after OGTT; 3) IRI was never present and blood glucose levels were lower than the values observed with glucose alone. Contrary to what is observed in acromegalics, CB 154 is unable to lower the increased GH levels normally present in insulin-dependent diabetics. After pretreatment with CB 154, OGTT seems to release GH, which is not observed after glucose alone. This can be accounted for only by postulating an antagonism at the hypothalamic level between the adrenergic and serotoninergic pathways of GH stimulation.