“…Based on the thresholds set by the ADA for fasting glucose, HbA 1c and 2 h glucose level during an OGTT in the days immediately before surgery, participants were classified as NGT ( n =5), IGT ( n =9) or with disease onset longer than 1 year ( n =4). All 18 participants underwent both an OGTT and an MMT to evaluate insulin secretion (from C-peptide deconvolution) [ 7 ] (Table 1 ). Fig.…”
Section: Methodsmentioning
confidence: 99%
“…Using a human model of partial pancreatectomy, we recently demonstrated that beta cell function and patterns of insulin secretion differed significantly among nondiabetic individuals, and that only pre-existing impairments in beta cell function, i.e. reduced first-phase insulin release (model-derived reduced glucose sensitivity and rate sensitivity) and defective proinsulin processing in the granules, predicted impairment in glucose tolerance and diabetes [5][6][7]. Thus, the actual determinant of diabetes development is the presence of a dysfunctional milieu, in which both morphological and functional alterations directly impact the beta cell secretory system [6,8].…”
Aims/hypothesis
Endoplasmic reticulum (ER) stress and beta cell dedifferentiation both play leading roles in impaired insulin secretion in overt type 2 diabetes. Whether and how these factors are related in the natural history of the disease remains, however, unclear.
Methods
In this study, we analysed pancreas biopsies from a cohort of metabolically characterised living donors to identify defects in in situ insulin synthesis and intra-islet expression of ER stress and beta cell phenotype markers.
Results
We provide evidence that in situ altered insulin processing is closely connected to in vivo worsening of beta cell function. Further, activation of ER stress genes reflects the alteration of insulin processing in situ. Using a combination of 17 different markers, we characterised individual pancreatic islets from normal glucose tolerant, impaired glucose tolerant and type 2 diabetic participants and reconstructed disease progression.
Conclusions/interpretation
Our study suggests that increased beta cell workload is accompanied by a progressive increase in ER stress with defects in insulin synthesis and loss of beta cell identity.
Graphical abstract
“…Based on the thresholds set by the ADA for fasting glucose, HbA 1c and 2 h glucose level during an OGTT in the days immediately before surgery, participants were classified as NGT ( n =5), IGT ( n =9) or with disease onset longer than 1 year ( n =4). All 18 participants underwent both an OGTT and an MMT to evaluate insulin secretion (from C-peptide deconvolution) [ 7 ] (Table 1 ). Fig.…”
Section: Methodsmentioning
confidence: 99%
“…Using a human model of partial pancreatectomy, we recently demonstrated that beta cell function and patterns of insulin secretion differed significantly among nondiabetic individuals, and that only pre-existing impairments in beta cell function, i.e. reduced first-phase insulin release (model-derived reduced glucose sensitivity and rate sensitivity) and defective proinsulin processing in the granules, predicted impairment in glucose tolerance and diabetes [5][6][7]. Thus, the actual determinant of diabetes development is the presence of a dysfunctional milieu, in which both morphological and functional alterations directly impact the beta cell secretory system [6,8].…”
Aims/hypothesis
Endoplasmic reticulum (ER) stress and beta cell dedifferentiation both play leading roles in impaired insulin secretion in overt type 2 diabetes. Whether and how these factors are related in the natural history of the disease remains, however, unclear.
Methods
In this study, we analysed pancreas biopsies from a cohort of metabolically characterised living donors to identify defects in in situ insulin synthesis and intra-islet expression of ER stress and beta cell phenotype markers.
Results
We provide evidence that in situ altered insulin processing is closely connected to in vivo worsening of beta cell function. Further, activation of ER stress genes reflects the alteration of insulin processing in situ. Using a combination of 17 different markers, we characterised individual pancreatic islets from normal glucose tolerant, impaired glucose tolerant and type 2 diabetic participants and reconstructed disease progression.
Conclusions/interpretation
Our study suggests that increased beta cell workload is accompanied by a progressive increase in ER stress with defects in insulin synthesis and loss of beta cell identity.
Graphical abstract
“…In T2D rats fed with fructose, ALA did not affect insulin sensitivity but induced greater insulin excursions after glucose administration [ 50 ]. In a more recent study, the co-administration of lypo-polisaccharide S (LPS) (an inducer of chronic subacute hepatic inflammation, which can also impair pancreatic insulin secretion) [ 51 ] and ALA produced no changes in insulin sensitivity [ 52 ], assessed by euglycemic hyper-insulinemic clamp [ 53 ], but determined a restoration of first-phase and second-phase insulin secretion [ 54 ] (assessed by hyperglycaemic clamp), compared to rats treated with LPS alone. In aged rat islets, ALA significantly increased insulin secretion and decreased reactive oxygen species [ 55 ].…”
Alpha-lipoic acid (ALA) is a natural compound with antioxidant and pro-oxidant properties which has effects on the regulation of insulin sensitivity and insulin secretion. ALA is widely prescribed in patients with diabetic polyneuropathy due to its positive effects on nerve conduction and alleviation of symptoms. It is, moreover, also prescribed in other insulin resistance conditions such as metabolic syndrome (SM), polycystic ovary syndrome (PCOS) and obesity. However, several cases of Insulin Autoimmune Syndrome (IAS) have been reported in subjects taking ALA. The aim of the present review is to describe the main chemical and biological functions of ALA in glucose metabolism, focusing on its antioxidant activity, its role in modulating insulin sensitivity and secretion and in symptomatic peripheral diabetic polyneuropathy. We also provide a potential explanation for increased risk for the development of IAS.
“…A loss of glucose-induced first-phase insulin release (FPIR) has been found to be a particularly sensitive marker of the onset of decompensation and risk of progression to diabetes, thus causing it to receive considerable attention [8][9][10][11][12][13]. The changes in FPIR are striking but poorly understood.…”
Section: Gaps In Our Understanding Of How β-Cells Progress From Succe...mentioning
confidence: 99%
“…Another example of impaired FPIR are the individuals who have undergone a 50% pancreatectomy as donors for islet transplantation [65] or for neoplasms [7,8,66] Not only were these donors found to have increased risk of developing either impaired glucose tolerance or diabetes, but a recent study by Mezza et al [8] found that reduction of FPIR in particular was a strong predictor of progression to diabetes. The variability among these subjects was not surprising because many observations in both humans and animals indicate that a 50% reduction of β-cell mass is a tipping point for progression to diabetes [2,[66][67][68][69][70][71].…”
Section: Reduction Of Glucose-induced First-phase Insulin Release (Fp...mentioning
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