Comment on: Godsland IF, Jeffs JAR, Johnston DG (2004) Loss of beta cell function as fasting glucose increases in the non-diabetic range. Diabetologia 47:1157–1166

Ionescu-Tîrgovişte, C

doi:10.1007/s00125-004-1610-5

Cited by 4 publications

(1 citation statement)

References 5 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Stimulation of b-cells containing immature insulin vesicles and subsequent secretion of these vesicles increases the level of intact proinsulin in the blood. Elevated levels of proinsulin have been found both at the onset of type 1 diabetes [50][51][52][53][54] and in type 2 diabetes, [54][55][56][57][58][59][60][61][62][63][64][65][66][67][68][69][70][71] as well. Two hypotheses have been suggested to explain the increased amount of proinsulin in the blood: 72,73 (i) a dysfunction of the enzymatic proinsulin processing mechanism and (ii) lack of maturation of insulin vesicles due to an intense hyperglycemic stimulation.…”

Section: Discussionmentioning

confidence: 99%

Biophysical alteration of the secretory track in β-cells due to molecular overcrowding: the relevance for diabetes

Ionescu-Tîrgovişte¹,

Despa²

2011

Integr. Biol.

View full text Add to dashboard Cite

Recent data demonstrate that accumulation of misfolded proteins within the early part of the secretory track of β-cells causes impaired insulin synthesis and development of diabetes. The molecular mechanism of this cellular dysfunction remains largely unknown. Using basic molecular principles and computer simulations, we suggested recently that hyperglycemic conditions can generate substantial molecular crowding effects in the secretory track of β-cells leading to significant alterations of the insulin biosynthesis capabilities. Here, we review the major molecular mechanisms that may be implicated in the alteration of insulin synthesis in susceptible β-cells. Steric repulsions and volume exclusion in the endoplasmic reticulum (ER) increase the propensity of misfolding of proinsulin (the precursor molecule of insulin). In addition, similar forces might act in the next secretory compartments (Golgi and vesicles) leading to (i) altered packaging of proinsulin in vesicles (ii) entrapment of proinsulin convertases and/or restricted accessibility for these convertases to the cleavage sites on the surface of the proinsulin and (iii) depressed kinetic rate of the transformation of the native proinsulin in active insulin and C-peptide. These concepts are expressed in simple mathematical terms relating the kinetic coefficient of proinsulin to insulin conversion to the levels of proinsulin misfolding and hyperglycemic stress. The present approach is useful for understanding molecular phenomena associated with the pathogenesis of diabetes. It also offers practical means for predicting the state of pancreatic β-cells from measurements of the insulin to proinsulin ratio in the blood. This is of immediate clinical relevance and may improve the diagnosis of diabetes.

show abstract

Section: Discussionmentioning

confidence: 99%

Biophysical alteration of the secretory track in β-cells due to molecular overcrowding: the relevance for diabetes

Ionescu-Tîrgovişte¹,

Despa²

2011

Integr. Biol.

View full text Add to dashboard Cite

show abstract

β-Cell Dysfunction under Hyperglycemic Stress: A Molecular Model

Despa

Berry

2010

J Diabetes Sci Technol

View full text Add to dashboard Cite

Together with previous experimental data, the present study can help us to better understand chemistry aspects related to the secondary translational mechanisms in β cells and how hyperglycemic stress can alter secretory function. This can give a further impetus to the development of novel software to be used in a clinical setup for prediction and assessment of diabetic states in susceptible patients.

show abstract

Plasma dipeptidyl peptidase-IV activity in patients with type-2 diabetes mellitus correlates positively with HbAlc levels, but is not acutely affected by food intake

Ryskjær¹,

Deacon²,

Carr³

et al. 2006

eur j endocrinol

173

155

View full text Add to dashboard Cite

Objective: Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide are incretin hormones, secreted in response to meal ingestion. The incretin hormones stimulate insulin secretion and are essential for the maintenance of normal plasma glucose concentrations. Both incretin hormones are metabolized quickly by the enzyme dipeptidyl peptidase-IV (DPP-IV). It is well known that type-2 diabetic patients have an impaired incretin effect. Therefore, the aim of the present study was to investigate plasma DPP-IV activity in the fasting and the postprandial state in type-2 diabetic patients and control subjects. Design: The study included two protocols. Protocol one involved 40 fasting type-2 diabetic patients (28 men); age 61G1.4 (meanGS.E.M.) years; body mass index (BMI) 31G0.6 kg/m 2 ; HbAlc 7.2G0.2%; and 20 matched control subjects (14 men) were studied. Protocol two involved eight type-2 diabetic patients (six men); age 63G1.2 years; BMI 33G0.5 kg/m 2 ; HbAlc 7.5G0.4%; eight matched control subjects were included. Methods: In protocol one, fasting values of DPP-IV activity were evaluated and in protocol two, postprandial DPP-IV activity during a standard meal test (566 kcal) was estimated. Results: Mean fasting plasma DPP-IV activity (expressed as degradation of GLP-1) was significantly higher in this patient group compared with the control subjects (67.5G1.9 vs 56.8G2.2 fmol GLP-1/h (meanGS.E.M.); PZ0.001). In the type-2 diabetic patients, DPP-IV activity was positively correlated to FPG and HbAlc and negatively to the duration of diabetes and age of the patients. No postprandial changes were seen in plasma DPP-IV activity in any of the groups. Conclusions: Plasma DPP-IV activity increases in the fasting state and is positively correlated to FPG and HbAlc levels, but plasma DPP-IV activity is not altered following meal ingestion and acute changes in plasma glucose. 155 485-493 European Journal of Endocrinology

show abstract

Comment on: Godsland IF, Jeffs JAR, Johnston DG (2004) Loss of beta cell function as fasting glucose increases in the non-diabetic range. Diabetologia 47:1157–1166

Cited by 4 publications

References 5 publications

Biophysical alteration of the secretory track in β-cells due to molecular overcrowding: the relevance for diabetes

Biophysical alteration of the secretory track in β-cells due to molecular overcrowding: the relevance for diabetes

β-Cell Dysfunction under Hyperglycemic Stress: A Molecular Model

Plasma dipeptidyl peptidase-IV activity in patients with type-2 diabetes mellitus correlates positively with HbAlc levels, but is not acutely affected by food intake

Contact Info

Product

Resources

About