Role of orlistat in the treatment of obese patients with type 2 diabetes. A 1-year randomized double-blind study.

OBJECTIVE: Obesity is an important risk factor for type 2 diabetes. Weight loss in patients with type 2 diabetes is associated with improved glycemic control and reduced cardiovascular disease risk factors, but weight loss is notably difficult to achieve and sustain with caloric restriction and exercise. The purpose of this study was to assess the impact of treatment with orlistat, a pancreatic lipase inhibitor, on weight loss, glycemic control, and serum lipid levels in obese patients with type 2 diabetes on sulfonylurea medications. RESEARCH DESIGN AND METHODS: In a multicenter 57-week randomized double-blind placebo-controlled study, 120 mg orlistat or placebo was administered orally three times a day with a mildly hypocaloric diet to 391 obese men and women with type 2 diabetes who were aged > 18 years, had a BMI of 28-40 kg/m2, and were clinically stable on oral sulfonylureas. Changes in body weight, glycemic control, lipid levels, and drug tolerability were measured. RESULTS: After 1 year of treatment, the orlistat group lost 6.2 +/- 0.45% (mean +/- SEM) of initial body weight vs. 4.3 +/- 0.49% in the placebo group (P < 0.001). Twice as many patients receiving orlistat (49 vs. 23%) lost > or = 5% of initial body weight (P < 0.001). Orlistat treatment plus diet compared with placebo plus diet was associated with significant improvement in glycemic control, as reflected in decreases in HbA1c (P < 0.001) and fasting plasma glucose (P < 0.001) and in dosage reductions of oral sulfonylurea medication (P < 0.01). Orlistat therapy also resulted in significantly greater improvements than placebo in several lipid parameters, namely, greater reductions in total cholesterol, (P < 0.001), LDL cholesterol (P < 0.001), triglycerides (P < 0.05), apolipoprotein B (P < 0.001), and the LDL-to-HDL cholesterol ratio (P < 0.001). Mild to moderate and transient gastrointestinal events were reported with orlistat therapy, although their association with study withdrawal was low. Fat-soluble vitamin levels generally remained within the reference range, and vitamin supplementation was required in only a few patients. CONCLUSIONS: Orlistat is an effective treatment modality in obese patients with type 2 diabetes with respect to clinically meaningful weight loss and maintenance of weight loss, improved glycemic control, and improved lipid profile.

Dose-response effects of dietary marine oil on carbohydrate and lipid metabolism in normal subjects and patients with hypertriglyceridemia.

Recent studies indicate that marine (omega-3) fatty acids decrease hypertriglyceridemia but worsen hyperglycemia in diabetes. We studied dose-response relationships between omega-3 intake and indices of carbohydrate and lipid metabolism in 21 hypertriglyceridemic patients with (n = 6) or without (n = 15) diabetes, and 6 normal volunteers. All subjects consumed isocaloric diets of 65% carbohydrate, 20% fat, and 15% protein. The basal diet contained 15% of total calories as vegetable oil (omega-6), and the test diets included 15%, 7.5%, or 3.75% calories as fish oil (MaxEPA). After three months of the basal diet, patients were randomized to receive two 3-month omega-3 diets in the following sequences: 15%/7.5%, 7.5%/15%, 7.5%/3.75%, or 3.75%/7.5%. Both 15% and 7.5% diets, regardless of sequence, significantly decreased serum triglycerides but increased low-density lipoprotein (LDL)-cholesterol levels as much as 98% and LDL/high-density lipoprotein (HDL)-cholesterol ratio as much as 1.6-fold. Daily insulin requirements of three diabetic patients increased progressively while they received an omega-3-enriched diet for up to 2 years. In healthy controls, favourable changes induced by an omega-3 fatty acid diet in serum lipids and lipoproteins were associated with a tendency toward an inhibition of C-peptide secretion following a meal challenge. We conclude that substitution of commercially available omega-3 for omega-6 fatty acids improves hypertriglyceridemia but may worsen other lipoproteins indices and may increase insulin requirements in diabetic hypertriglyceridemic subjects.

Gastric inhibitory polypeptide hypersecretion in diabetes mellitus: effect of sulfonylurea treatment.

We studied gastric inhibitory peptide (GIP) in response to a mixed meal in both adult-onset diabetics and normal controls. The adult-onset diabetic group was also studied for immunoreactive GIP (IR-GIP), insulin, and glucose with a test meal before and after tolazamide therapy. Mean basal and meal-stimulated IR-GIP concentrations were greater (P less than 0.05) in the adult-onset diabetic group than in normal controls. With treatment, mean fasting glucose significantly decreased (P less than 0.05) from 206 +/- 14 to 162 +/- 11 mg/dl, and postprandial glucose concentrations were reduced (P less than 0.05) between 5-180 min. In contrast, after 1 month of treatment with tolazamide, IR-GIP concentrations were not significantly altered. Further, basal and postmeal serum insulin levels were significantly higher (P less than 0.05) after tolazamide therapy. We conclude that the enteroinsular axis in terms of IR-GIP is overactive in adult-onset diabetics; tolazamide therapy does not appear to effect its meal-stimulated response.

The effect of increasing doses of ingested glucose on insulin and gastric inhibitory polypeptide (GIP) concentrations in man.

Gastric inhibitory polypeptide (GIP) is insulinotropic in vivo and in vitro. It is released following glucose ingestion and is a leading candidate as a mediator of the enteroinsular axis. To investigate the GIP response to increasing amounts of oral glucose, and its relationship to glucose levels and insulin secretion, fourteen normal volunteers ingested 25, 50 and 75 g of glucose at random with 5-7 days between each test. Serum insulin, glucose and GIP concentrations were measured and total integrated incremental responses were determined. Peak mean responses to glucose, insulin and GIP occurred at 30 min following each glucose ingestion. There were no significant differences in glucose concentrations at any interval with the varying glucose doses. Mean peripheral insulin concentrations were significantly increased after 50 or 75 g of glucose as compared with the 25 g dose (P less than 0.02). Mean GIP concentrations were significantly greater (P less than 0.03) between 15 and 180 min with both the 50 and 75 g glucose stimulus. Total integrated areas under the response curves for glucose, insulin and GIP showed a graded increase in circulating insulin and GIP (P less than 0.01) as the amount of ingested glucose was increased from 25 to 75 g. These findings show that increasing doses of glucose stimulated greater levels of GIP and insulin and further support the insulinotropic properties of endogenous GIP in man.

Gastric inhibitory polypeptide (GIP) and insulin release in duodenal ulcer patients.

To investigate the role of gastric inhibitory polypeptide (GIP) in the hypersecretion of glucose-stimulated insulin release in duodenal ulcer disease, serum glucose, insulin, and immunoreactive GIP (IR-GIP) were measured in 18 healthy subjects and 10 duodenal ulcer patients after glucose ingestion. Although the serum glucose and insulin were significantly greater (P less than 0.05) at 15 and 60 min in the ulcer group, the total integrated glucose areas were similar (20,552 +/- 837 vs. 19,154 +/- 745 mg-min/ml). In contrast, the total integrated insulin area was significantly greater (P less than 0.05) in the ulcer patients (12,873 +/- 2,082 vs. 8,216 +/- 1,072 micro U-min/ml). Mean IR-GIP levels were significantly greater (P less than 0.05) in the ulcer group at 15-120 min of the study, as was the total integrated area (244,755 +/- 34,934 vs. 126,595 +/- 17,468 pg-min/ml). The exaggerated insulin release to oral glucose may be due to the synergistic action of higher blood glucose and greater IR-GIP release in this disease.

Insulin-induced attenuation of glucose-stimulated gastric inhibitory polypeptide secretion.

Administration of exogenous insulin before and after intraduodenal glucose results in blunting of the GIP response to glucose. Physiologic levels of serum insulin were attained. Therefore, the present study suggests the existence of negative feedback regulation of GIP release by endogenous insulin (pancreatico-GIP axis).

Gastric inhibitory polypeptide (GIP) in maturity-onset diabetes mellitus.

Serum GIP, insulin, and glucose concentrations were determined during a standard oral glucose tolerance test in 80 individuals, 45 of whom were normal and 35 of whom had adult-onset diabetes mellitus according to USPHS criteria. As a group, the diabetics had fasting hyperglycemia (219 +/- 17 mg./dl.) and, in response to glucose, displayed a peak serum glucose of 373 +/- 23 mg./dl. and sustained hyperglycemia (315 +/- 24 mg./dl.) at 180 minutes. There were no statistically significant differences in absolute serum insulin levels between the two groups. However, insulin secretion was delayed, IRI increments were smaller, and the IRI concentrations were inappropriately low for the simultaneous serum glucose concentrations in the diabetics at every time interval tested. Mean fasting serum GIP was 335 +/- 30 pg./ml. in the diabetics as against 262 +/- 15 pg./ml. in normal individuals (p less than 0.025). After the ingestion of glucose, diabetics had significantly higher (p less than 0.001) mean serum GIP levels between five and 120 minutes. By 180 minutes, serum GIP levels remained above fasting in both groups, but the diabetics had higher than normal serum concentrations (p less than 0.05). Peak serum GIP concentrations, which occurred at 30 minutes in both groups, were 1,376 +/- 106 and 806 +/- 75 pg./ml. in the diabetics and normals, respectively (p less than 0.001). Total integrated serum GIP was also greater in diabetics than normals (140,852 +/- 14,208 vs. 64,602 +/- 8,719 pg.-min./ml.-1, p less than 0.001). The higher serum GIP concentrations observed following glucose ingestion in diabetics could not be attributed to obesity or age. We conclude that both fasting and glucose-stimulated GIP concentrations are higher than normal in obese adult-onset diabetics. The significance of this observation is uncertain. However, since our current understanding suggests the GIP may be an important enteric signal for the release of insulin in man, and because GIP has been shown to stimulate the release of immunoreactive glucagon, GIP may play a role in the pathogenesis of diabetes mellitus.

The insulinotropic effect of endogenous gastric inhibitory polypeptide in normal subjects.

Intravenously administered porcine GIP is insulinotropic in man. This study was designed to investigate the effects of simultaneous fat ingestion, a potent stimulus for GIP release, and intravenous glucose infusion upon endogenous serum GIP and insulin concentrations in normal subjects. Seven normal volunteers were studied on three separate occasions following: a) the ingestion of 67 grams of emulsified corn oil, b) constant intravenous infusion of glucose, and c) simultaneous administration of corn oil and glucose as in parts (a) and (b) of the study. Serum glucose, insulin (IRI), and GIP concentrations were measured at intervals between 15 and 180 minutes following each stimulus. With corn oil, mean serum GIP concentrations increased from a fasting level of 290 +/- 40 (SE) pg/ml to 1936 +/- 402 pg/ml at 60 minutes without a significant change in serum IRI or glucose concentrations. The infusion of intravenous glucose alone was associated with no rise in serum GIP levels despite a substantial increase in serum IRI and glucose concentrations. With the combined stimuli, mean serum GIP increased less (P is less than .05) between 30 and 90 minutes, and total integrated incremental GIP was significantly less (P is less than .025) than that after corn oil ingestion alone. Following the combined stimuli, incremental insulin levels were higher (P is less than .05) between 15 and 90 minutes, total integrated incremental insulin was greater (P is less than .025), and glucose homeostasis was significantly enhanced (P is less than .05) at 120 and 180 minutes compared with the effects on insulin of glucose infusion alone. We conclude that the potentiation of glucose-stimulated insulin secretion induced by the ingestion of fat is associated with serum GIP levels that are within the insulinotropic range. The augmented secretion of insulin may be mediated partially or completely by endogenous GIP. The lower serum GIP concentrations observed following the combined stimuli suggest a feedback inhibition of GIP release which is perhaps mediated by insulin.

Stimulation of secretion of gastric inhibitory polypeptide and insulin by intraduodenal amino acid perfusion.

The effect of intraduodenal or intravenous administration of a 30-gm mixed amino acid solution of serum gastric inhibitory polypeptide (GIP), alpha-amino nitrogen (AAN), glucose, and insulin concentrations was studied in 10 normal subjects. Initially, an intraduodenal amino acid perfusion (15 ml per min X 60 min) was performed in each subject and was followed in 1 to 2 weeks by an intravenous infusion. Peak AAN concentrations occurred at 60 min after both routes of administration, but were greater with intravenous infusion, 145 +/- 5.7 mug per ml vs. 89 +/- 4.4 mug per ml (P less than 0.001). Although serum AAN levels were significantly lower after intraduodenal administration, incremental insulin concentrations were greater after intraduodenal perfusion, 77.3 +/- 8.8 muM per ml vs. 43.1 +/- 5.6 muU per ml (P less than 0.005). Total integrated insulin secretion was also greater after intraduodenal amino acids, 5000 vs. 2400 muU-min ml-1 (P less than 0.005). With intravenous amino acid infusion, serum GIP concentrations remained below the assay detection limit. After intraduodenal perfusion, a mean maximum GIP increment of 468 pg per ml occurred at 15 min. In all subjects peak GIP concentrations occurred at 15 min and preceded the maximum insulin rise by 15 to 30 min. Total integrated GIP secretion was significantly greater after intraduodenal amino acid perfusion, 13,000 pg-min ml-1 vs. no measurable response with intravenous infusion. In separate studies performed in 12 subjects, no significant changes in serum GIP concentrations occurred after intraduodenal perfusion of 0.45% saline, 0.9% saline, or 10% mannitol. The results of this study demonstrate that intraduodenal amino acid administration stimulates the secretion of GIP and suggest that endogenously released GIP may be important in the enteric mediated release of insulin.

Gastric inhibitory polypeptide (GIP) stimulated by fat ingestion in man.

Ten normal volunteers ingested emulsified corn oil and the immunoreactive GIP, insulin (IRI) and nonesterified fatty acid (NEFA) responses were measured. Serum GIP levels increased after the ingestion of corn oil in all subjects, rising from a mean fasting level of 272 pg/ml to 856 +/- 272 pg/ml (P less than 0.05) by 30 minutes. The peak mean serum GIP concentration of 1,345 +/- 291 pg/ml occurred at 60 minutes; and mean serum GIP levels at 180 minutes remained significantly elevated over fasting values. Serum IRI, glucose and NEFA concentrations did not change during the 180 minutes of study. No changes in serum GIP concentrations occurred when, for control purposes, six volunteers ingested water on another day. We conclude: 1) Fat is a potent stimulus for the release of GIP in normal individuals. 2) Endogenously released GIP is not insulinotropic under the conditions of this study.