Search

Aim: To investigate the acute and longer-term effects of low (LGI) versus high glycaemic index (HGI) diets on hepatic fat and glycogen accumulation and related blood measures in healthy volunteers., Methods: Eight healthy men (age 20.1 ± 0.4 years, body mass index 23.0 ± 0.9 kg/m 2 ) attended a test day before and after a 7-day macronutrient- and energy-matched HGI or LGI diet, followed by a minimum 4-week wash-out period, and then returned to repeat the intervention with the alternative diet. During test days, participants consumed either an HGI or an LGI test meal corresponding to their diet week, and liver fat [ 1 H magnetic resonance spectroscopy (MRS)], glycogen ( 13 C MRS) and gastric content volume (MRI) were measured. Blood samples were obtained regularly throughout the test day to assess plasma glucose and insulin levels., Results: Plasma glucose and insulin peak values and area under the curve were significantly greater after the HGI test meal compared with the LGI test meal, as expected. Hepatic glycogen concentrations increased more after the HGI test meal ( P < .05) and peak levels were significantly greater after 7 days of HGI dietary intervention compared with those at the beginning of the intervention ( P < .05). Liver fat fractions increased significantly after the HGI dietary intervention compared with the LGI dietary intervention (two-way repeated-measures analysis of variance P ≤ .05)., Conclusions: Compared with an LGI diet, a 1-week HGI diet increased hepatic fat and glycogen stores. This may have important clinical relevance for dietary interventions in the prevention and management of non-alcoholic fatty liver disease., (© 2016 John Wiley & Sons Ltd.)

Background: The ability to simulate in silico experiments is crucial for fast and cost-effective preliminary studies prior to clinical trials. We present an in silico approach to the design of optimal pramlintide-to-insulin (P/I) ratios, using our computer simulator of the human metabolic system, with a population of virtual adult type 1 diabetes mellitus patients and with individual parameters modified to account for the dynamic effects of pramlintide., Materials and Methods: A model of pramlintide action on gastric emptying was built using data of 15 type 1 diabetes mellitus subjects studied twice with a standardized dual-tracer meal on placebo and pramlintide, which was incorporated in our type 1 diabetes simulator. Extensive in silico experiments on 100 virtual subjects were performed to optimize the co-administration of pramlintide and insulin prior to its submission to clinical trials; several P/I ratios were tested in terms of efficacy, in attenuating postprandial hyperglycemia, and in hypoglycemia safety., Results: In silico experiments estimated the optimal P/I ratio to be 9 μg of pramlintide per unit (U) of insulin. Additional simulations narrowing the investigated range indicated that P/I ratios of 8 and 10 μg/U would achieve similar performance. Moreover, simulation results suggested that in clinical trials, insulin boluses should be reduced by approximately 21% at a P/I ratio of 9 μg/U to account for the effects of pramlintide and avoid postprandial hypoglycemia., Conclusions: We can assert that a valid simulation model of pramlintide action was developed, leading to in silico estimation of optimal pramlintide:insulin co-administration ratio. Clinical trials will confirm (or adjust) this initial estimation.

Objective: Synthetic glucagon-like peptide-1 (7-36)amide (GLP-1) lowers postprandial (pp) glycemia by stimulating insulin and inhibiting glucagon release and delaying gastric emptying (GE). However, the biological effects of the endogenous peptide and their relative contributions to pp glycemia remain to be defined in detail. Using the specific GLP-1 receptor antagonist exendin(9-39)amide [Ex(9-39)], we studied the exact impact of GLP-1 after an oral meal in humans., Research Design and Methods: After a 50-min basal period, 12 healthy subjects ingested a 412-kcal mixed semisolid meal containing 30 g oatmeal, labeled with 99mTc-Sn-colloid. GE was measured by high-resolution scintigraphy until 210 min after meal ingestion. In random order, saline or Ex(9-39) at 900 pmol/kg·min was infused iv. Additionally, in six subjects gastric motility was measured by antroduodenal manometry and a gastric barostat in parallel., Results: Ex(9-39) increased pp blood glucose excursions during the first 60 min after the meal (43.9 ± 5.4 vs. 35.9 ± 3.6 mg/dl, P = 0.008; pp peak glucose 154.0 ± 5.5 vs.141.0 ± 4.7 mg/dl, P = 0.009). Insulin increased slightly with Ex(9-39), whereas the insulin to glucose ratio was unchanged. pp glucagon was significantly increased with Ex(9-39) (7.5 ± 2.4 vs. 3.2 ± 2.1 pg/ml, P = 0.024). GE and accordingly gastric motility did not change with Ex(9-39). Multiple linear regression analysis revealed only changes of pp glucagon to be significantly associated with increased pp glycemia under Ex(9-39) (R = 0.678, P = 0.015)., Conclusions: Released after an oral meal, GLP-1 lowers pp glycemia. In this study, the inhibition of glucagon release was a major determinant of the acute GLP-1 action in healthy subjects. In contrast, gastric emptying was not changed by GLP-1 receptor antagonism.

Objective: Regulation of postprandial (pp) plasma glucose excursions is complex. Insulin and glucagon are thought to play the predominant role. Nevertheless, only 50% of the variation in pp plasma glucose excursions is explained by variations by the latter. Theoretically, gastric emptying (GE) should be another important factor. However, its impact on pp glucose homeostasis is unknown., Research Design and Methods: We examined the consequences of pramlintide-induced delay in GE on pp glycemia and glucose fluxes, determined isotopically. GE was recorded by scintigraphy. Fourteen healthy subjects (8 men, 6 women; age 40 +/- 3 yr, body mass index 27.8 +/- 1.1 kg/m2) ate a mixed meal, and 30 microg of pramlintide (PRAM) or placebo (PBO) were injected subcutaneously., Results: At 60 min, greater proportions of the initial gastric contents remained in the stomach (PBO vs. PRAM). Thereafter, GE slopes paralleled until 240 min. Fifty percent retention times were lower when PBO was given (P < 0.001). GE was greater from 240 min to the end of the PRAM experiments, so that only slightly greater proportions of the meal remained in the stomach at 330 min. Reductions of GE lowered pp glucose (7.5 +/- 0.3 vs. 6.0 +/- 0.2 mmol/l, P < 0.001), even though plasma insulin was lower with PRAM (164 +/- 13 vs. 138 +/- 13 pmol/ml, both P < 0.01). Reduction in total glucose appearance (P < 0.001) was due to reduced meal-derived glucose appearance (10.2 +/- 0.5 vs. 7.0 +/- 0.4 micromol.kg(-1).min(-1), P < 0.001). Endogenous glucose appearance was greater with PRAM (P < 0.001). Splanchnic glucose uptake was greater with PRAM (26.5 +/- 1.6 vs. 32.5 +/- 2.1%, P = 0.014)., Conclusions: These data support the concept that GE is an important physiological regulator of pp glucose homeostasis in humans.

Objective: HbA1c values reflect overall glycemic exposure over the past 2-3 months and are determined by both fasting (FPG) and postprandial plasma glucose (PPG) levels. Cross-sectional studies suggest that attainment of HbA1c goals requires specific targeting of postprandial hyperglycemia., Research Design and Methods: We undertook a prospective intervention trial to assess the relative contribution of controlling FPG and PPG for achieving recommended HbA1c goals. One hundred and sixty-four patients (90 male and 74 female) with unsatisfactory glycemic control (HbA1c >/=7.5%) were enrolled in an individualized forced titration intensified treatment program., Results: After 3 months HbA1c levels decreased from 8.7+/-0.1 to 6.5+/-0.1% (p<0.001); FPG decreased from 174+/-4 to 117+/-2mg/dl (p<0.001); PPG decreased from 224+/-4 to 159+/-3mg/dl (p<0.001) and daylong hyperglycemia (average of premeal, postprandial and bedtime plasma glucose excluding FPG) decreased from 199+/-4 to 141+/-2mg/dl (p<0.0001). Patients' weight remained unchanged (84.0+/-1.4kg versus 82.9+/-1.5kg, p=0.36). No severe hypoglycemia occurred. Only 64% of patients achieving FPG targets of <100mg/dl achieved an HbA1c target of <7% whereas 94% of patients achieving the postprandial target of <140mg/dl did. Decreases in PPG accounted for nearly twice as much for the decreases in HbA1c as did decreases in FPG. PPG accounted approximately 80% of HbA1c when HbA1c was <6.2% and only about 40% when HbA1c was above 9.0%., Conclusions: Control of fasting hyperglycemia is necessary but usually insufficient for achieving HbA1c goals <7%. Control of postprandial hyperglycemia is essential for achieving recommended HbA1c goals.

A functional connection between the small intestine and endocrine pancreas was proved in the sixties, after it became possible to determine the exact amount of insulin in plasma. The insulin response after oral doses of glucose is substantially stronger than after intravenous doses of sugar, even when identical glucose plasma levels are attained. This incretin effect is explained by the connection of the entero-insular axis. The intestinal hormones, that are released by the small intestine after meals, circulate measurably in plasma, and strengthen the glucose-induced insulin secretion, are responsible for this effect. In addition to the classical incretin hormone "Gastric inhibitory polypeptide-1" (GIP), "Glucagon-like peptide-1" (GLP-1) is very interesting to investigators today. In a relatively short amount of time, GLP-1 has matured from a physiologically interesting incretin hormone candidate to a potentially therapeutical alternative for the treatment of diabetes mellitus. GLP-1 stimulates glucose-dependent insulin secretion, decreases plasma glucagon levels, delays gastric emptying, and putatively exerts an additional effect on peripheral glucose utilization. On top of that, GLP-1 has effects on the central nervous system thereby impacting on feeding behavior.