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Articles by J. J Holst
Total Records ( 6 ) for J. J Holst
  S Bonuccelli , E Muscelli , A Gastaldelli , E Barsotti , B. D Astiarraga , J. J Holst , A Mari and E. Ferrannini

Improved glucose tolerance to sequential glucose loading (Staub-Traugott effect) is an important determinant of day-to-day glycemic exposure. Its mechanisms have not been clearly established. We recruited 17 healthy volunteers to receive two sequential oral glucose tolerance tests (OGTTs), at time 0 min and 180 min (Study I). The protocol was repeated on a separate day (Study II) except that plasma glucose was clamped at 8.3 mmol/l between 60 and 180 min. β-Cell function was analyzed by mathematical modeling of C-peptide concentrations. In a subgroup, glucose kinetics were measured by a triple-tracer technique (infusion of [6,6-2H2]glucose and labeling of the 2 glucose loads with [1-2H]glucose and [U-13C]glucose). In both Studies I and II, the plasma glucose response to the second OGTT equaled 84 ± 2% (P = 0.003) of the response to the first OGTT. Absolute insulin secretion was lower (37.8 ± 4.3 vs. 42.8 ± 5.1 nmol/m2, P = 0.02), but glucose potentiation (i.e., higher secretion at the same glycemia) was stronger (1.08 ± 0.02- vs. 0.92 ± 0.02-fold, P = 0.006), the increment being higher in Study II (+36 ± 5%) than Study I (+19 ± 6%, P < 0.05). In pooled data, a higher glucose area during the first OGTT was associated with a higher potentiation during the second OGTT (rho=0.60, P = 0.002). Neither insulin clearance nor glucose clearance differed between loads, and appearance of glucose over 3 h totalled 60 ± 6 g for the first load and 52 ± 5 g for the second load (P = not significant). Fasting endogenous glucose production [13.3 ± 0.6 µmol·min–1·kg fat-free mass (FFM)–1] averaged 6.0 ± 3.8 µmol·min–1·kg FFM–1 between 0 and 180 min and 1.7 ± 2.6 between 180 and 360 min (P < 0.03). Glucose potentiation and stronger suppression of endogenous glucose release are the main mechanisms underlying the Staub-Traugott effect.

  R. W Gelling , P. M Vuguin , X. Q Du , L Cui , J Romer , R. A Pederson , M Leiser , H Sorensen , J. J Holst , C Fledelius , P. B Johansen , N Fleischer , C. H. S McIntosh , E Nishimura and M. J. Charron

In addition to its primary role in regulating glucose production from the liver, glucagon has many other actions, reflected by the wide tissue distribution of the glucagon receptor (Gcgr). To investigate the role of glucagon in the regulation of insulin secretion and whole body glucose homeostasis in vivo, we generated mice overexpressing the Gcgr specifically on pancreatic β-cells (RIP-Gcgr). In vivo and in vitro insulin secretion in response to glucagon and glucose was increased 1.7- to 3.9-fold in RIP-Gcgr mice compared with controls. Consistent with the observed increase in insulin release in response to glucagon and glucose, the glucose excursion resulting from both a glucagon challenge and intraperitoneal glucose tolerance test (IPGTT) was significantly reduced in RIP-Gcgr mice compared with controls. However, RIP-Gcgr mice display similar glucose responses to an insulin challenge. β-Cell mass and pancreatic insulin content were also increased (20 and 50%, respectively) in RIP-Gcgr mice compared with controls. When fed a high-fat diet (HFD), both control and RIP-Gcgr mice developed similar degrees of obesity and insulin resistance. However, the severity of both fasting hyperglycemia and impaired glucose tolerance (IGT) were reduced in RIP-Gcgr mice compared with controls. Furthermore, the insulin response of RIP-Gcgr mice to an IPGTT was twice that of controls when fed the HFD. These data indicate that increased pancreatic β-cell expression of the Gcgr increased insulin secretion, pancreatic insulin content, β-cell mass, and, when mice were fed a HFD, partially protected against hyperglycemia and IGT.

  K. J Hare , T Vilsboll , J. J Holst and F. K. Knop

Hyperglucagonemia following oral glucose ingestion in patients with type 1 diabetes (and type 2 diabetes) has been claimed to result from impaired intraislet insulin inhibition of glucagon. We looked at plasma glucagon responses to the oral glucose tolerance test (OGTT) and isoglycemic intravenous glucose infusion (IIGI) in patients with type 1 diabetes. Nine patients without residual β-cell function [age: 25 ± 9 yr; body mass index (BMI): 24 ± 2 kg/m2; fasting plasma glucose (FPG): 9.5 ± 2.1 mM; Hb A1c: 8.4 ± 1.2% (mean ± SD)] and eight healthy subjects (age: 28 ± 5 yr; BMI: 24 ± 3 kg/m2; FPG: 5.3 ± 0.2 mM; Hb A1c: 5.0 ± 0.1%) were examined on two separate occasions: 4-h 50-g OGTT and IIGI. Isoglycemia during IIGIs was obtained using 53 ± 5 g of glucose in patients with type 1 diabetes and 30 ± 3 g in control subjects (P < 0.001), resulting in gastrointestinal-mediated glucose disposal [100% x (glucoseOGTT – glucoseIIGI/glucoseOGTT)] of –6 ± 9 and 40 ± 6% (P < 0.01), respectively. Equal glucagon suppression during the two glucose stimuli was observed in healthy subjects, whereas patients with type 1 diabetes exhibited less inhibition in response to OGTT compared with IIGI (AUC: 1,519 ± 129 vs. 1,240 ± 86 pM·4 h; P = 0.03). This difference was even more pronounced during the initial 40 min with paradoxical hypersecretion of glucagon during OGTT and suppression during IIGI (AUC: 37 ± 13 vs. –33 ± 16 pM·40 min; P = 0.02). These results suggest that the inappropriate glucagon response to glucose in patients with type 1 diabetes occurs as a consequence of the oral administration way, suggesting a role of the gastrointestinal tract, possibly via glucagonotropic signaling from gut hormones (e.g., glucose-dependent insulinotropic polypeptide), in type 1 diabetic hyperglucagonemia.

  L. S Mortensen , J Schrezenmeir , J. J Holst and K. Hermansen

Background: Enhanced and prolonged postprandial triglyceride responses involve increased cardiovascular disease risk in type 2 diabetes. Dietary fat and carbohydrates profoundly influence postprandial hypertriglyceridemia, whereas little information exists on the effect of proteins.

Objective: The objective was to compare the effects of the proteins casein, whey, cod, and gluten on postprandial lipid and incretin responses to a high-fat meal in persons with type 2 diabetes.

Design: A crossover study was conducted in 12 patients with type 2 diabetes. Blood samples were collected over 8 h after ingestion of a test meal containing 100 g butter and 45 g carbohydrate in combination with 45 g casein (Cas-meal), whey (Whe-meal), cod (Cod-meal), or gluten (Glu-meal). We measured plasma concentrations of triglycerides, retinyl palmitate (RP), free fatty acids, insulin, glucose, glucagon, glucagon-like peptide 1, and glucose-dependent insulinotropic peptide.

Results: The incremental area under the curve for triglyceride was significantly lower after the Whe-meal than after the other meals. The RP response was lower after the Whe-meal than after the Cas-meal and Cod-meal in the chylomicron-rich fraction and higher after the Whe-meal than after Cod- and Glu-meals in the chylomicron-poor fraction. Free fatty acids were most pronouncedly suppressed after the Whe-meal. The glucose response was lower after the Whe-meal than after the other meals, whereas no significant differences were found in insulin, glucagon, glucagon-like peptide 1, and glucose-dependent insulinotropic peptide responses.

Conclusion: The data suggest that as a supplement to a fat-rich meal in patients with type 2 diabetes, whey protein seems to outperform other proteins in terms of postprandial lipemia improvement, possibly because of the formation of fewer chylomicrons or increased clearance of chylomicrons. The trial was registered at as NCT00817973.

  B Holst , K. L Egerod , C Jin , P. S Petersen , M. V Ostergaard , J Hald , A. M. E Sprinkel , J Storling , T Mandrup Poulsen , J. J Holst , P Thams , C Orskov , N Wierup , F Sundler , O. D Madsen and T. W. Schwartz

G protein-coupled receptor (GPR)-39 is a seven-transmembrane receptor expressed mainly in endocrine and metabolic tissues that acts as a Zn++ sensor signaling mainly through the Gq and G12/13 pathways. The expression of GPR39 is regulated by hepatocyte nuclear factor (HNF)-1 and HNF-4, and in the present study, we addressed the importance of GPR39 for glucose homeostasis and pancreatic islets function. The expression and localization of GPR39 were characterized in the endocrine pancreas and pancreatic cell lines. Gpr39(–/–) mice were studied in vivo, especially in respect of glucose tolerance and insulin sensitivity, and in vitro in respect of islet architecture, gene expression, and insulin secretion. Gpr39 was down-regulated on differentiation of the pluripotent pancreatic cell line AR42J cells toward the exocrine phenotype but was along with Pdx-1 strongly up-regulated on differentiation toward the endocrine phenotype. Immunohistochemistry demonstrated that GRP39 is localized selectively in the insulin-storing cells of the pancreatic islets as well as in the duct cells of the exocrine pancreas. Gpr39(–/–) mice displayed normal insulin sensitivity but moderately impaired glucose tolerance both during oral and iv glucose tolerance tests, and Gpr39(–/–) mice had decreased plasma insulin response to oral glucose. Islet architecture was normal in the Gpr39 null mice, but expression of Pdx-1 and Hnf-1 was reduced. Isolated, perifused islets from Gpr39 null mice secreted less insulin in response to glucose stimulation than islets from wild-type littermates. It is concluded that GPR39 is involved in the control of endocrine pancreatic function, and it is suggested that this receptor could be a novel potential target for the treatment of diabetes.

  E. A Ozer , J. J Holst , N Duman , A Kumral and H. Ozkan

Glucagon-like peptide 2 (GLP-2) is a hormone produced primarily in the distal intestine, stimulated by enteral nutrients, and playing diverse roles in the intestinal adaptation and growth. We aimed to investigate whether GLP-2 may play a role in the development of feeding intolerance which is a common problem in preterm newborns resulting from the intestinal immaturity. The study included 20 term and 28 preterm neonates. Of preterm babies, 13 showed feeding intolerance fulfilling at least one of the following criteria: abdominal distension, increased gastric residual volume and presence of bile in the gastric aspirate. The plasma GLP-2 levels measured prior to enteral feeding (fasting level) and at 60 min after the beginning of the feeding (post-pradial level) were correlated with of clinical parameters. There was no statistical difference between GLP-2 levels of overall preterm babies and those of term newborns. However, preterm neonates with feeding intolerance showed significantly lower levels of GLP-2 and increased duration to achieve full enteral feeding and hospitalization. It is suggested that GLP-2 plays a significant role in the regulation of feeding in newborns and that preterm babies with low levels of GLP-2 carry a risk for development of feeding intolerance. It may, therefore, be of relevance to investigate the therapeutic and prophylactic effects of GLP-2 administration in the preterm babies.

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