Role of Intact Proinsulin in Diagnosis and Treatment of Type 2 Diabetes Mellitus

Pfützner, Andreas; Pfützner, A.; Larbig, Martin; Forst, Thomas

doi:10.1089/152091504774198124

Cited by 61 publications

(91 citation statements)

References 59 publications

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“…An unfolded protein response could be initiated if such demand exceeds capacity, potentially leading to cell apoptosis (Pfützner et al 2004, Prentki & Nolan 2006. Elevated circulating proinsulin is an indicator for risk of developing diabetes in humans (Wareham et al 1999, Pfützner et al 2005, Prentki & Nolan 2006, Strawbridge et al 2011, von Berghes et al 2011.…”

Section: Discussionmentioning

confidence: 99%

Five stages of progressive β-cell dysfunction in the laboratory Nile rat model of type 2 diabetes

Yang

Gotzmann

Kuny

et al. 2016

Journal of Endocrinology

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We compared the evolution of insulin resistance, hyperglycemia, and pancreatic β-cell dysfunction in the Nile rat (Arvicanthis niloticus), a diurnal rodent model of spontaneous type 2 diabetes (T2D), when maintained on regular laboratory chow versus a high-fiber diet. Chow-fed Nile rats already displayed symptoms characteristic of insulin resistance at 2 months (increased fat/lean mass ratio and hyperinsulinemia). Hyperglycemia was first detected at 6 months, with increased incidence at 12 months. By this age, pancreatic islet structure was disrupted (increased α-cell area), insulin secretion was impaired (reduced insulin secretion and content) in isolated islets, insulin processing was compromised (accumulation of proinsulin and C-peptide inside islets), and endoplasmic reticulum (ER) chaperone protein ERp44 was upregulated in insulin-producing β-cells. By contrast, high-fiber-fed Nile rats had normoglycemia with compensatory increase in β-cell mass resulting in maintained pancreatic function. Fasting glucose levels were predicted by the α/β-cell ratios. Our results show that Nile rats fed chow recapitulate the five stages of progression of T2D as occurs in human disease, including insulinresistant hyperglycemia and pancreatic islet β-cell dysfunction associated with ER stress. Modification of diet alone permits long-term β-cell compensation and prevents T2D. 343-356229:3 β-cell phenotype in type 2 diabetic Nile rats k yang and others

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Section: Discussionmentioning

confidence: 99%

Five stages of progressive β-cell dysfunction in the laboratory Nile rat model of type 2 diabetes

Yang

Gotzmann

Kuny

et al. 2016

Journal of Endocrinology

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“…18 Intact proinsulin was shown by us to be a marker of severe ß-cell dysfunction following exhaustion of the ß-cell proinsulin processing capacity and a highly specific indicator of clinically significant insulin resistance. 20,21 The search for genes that are downregulated by thiazolidinediones in mouse adipocytes resulted in the detection of an adipose-specific protein called resistin by Steppan and co-workers. 4 Formation of resistin is induced during adipogenesis, and the peptide is secreted by white and brown fat tissue of C57B1/6J mice into the serum.…”

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confidence: 99%

Impact of Treatment with Rosiglitazone or Metformin on Biomarkers for Insulin Resistance and Metabolic Syndrome in Patients with Polycystic Ovary Syndrome

Steiner

Jensterle

Reisinger

et al. 2007

J Diabetes Sci Technol

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Background:There is increasing evidence that insulin resistance (IR) has an important implication in the pathogenesis of polycystic ovary syndrome (PCOS), a common endocrinopathy in women. This study was performed to investigate the impact of different treatments for IR on five currently discussed markers for insulin resistance: intact proinsulin, adiponectin, retinol-binding protein 4 (RBP4), resistin, and visfatin in patients with PCOS. Methods:Thirty-five women with clinically confirmed PCOS diagnosis were included in the study [age (mean±SD): 24.7±4.8 years; body mass index: 27.4±6.0 kg/m 2 ]. They were randomized to receive either metformin (850 mg twice a day) or rosiglitazone (4 mg once a day). Blood samples for measurement of the HOMA IR score, visfatin, RBP4, intact proinsulin, resisitin, and adiponectin were taken at baseline and after 6 months of treatment. Results:Both drugs improved ovulation, and an increase in insulin sensitivity was observed, especially in the rosiglitazone arm. Adiponectin levels increased in both treatment arms (metformin: 8.6±3.3 to 16.7±7.2 mg/liter, p < 0.001; rosiglitazone: 8.2±3.5 to 26.2±9.5 mg/liter, p < 0.001), but the increase was more pronounced with rosiglitazone (p < 0.001). While no changes of visfatin concentrations were observed during rosiglitazone therapy (15.4±6.9 ng/ml vs 17.4±4.8 ng/ml, n.s.), there was an increase in the metformin treatment arm (11.9±4.0 to 21.8±8.3 ng/ml, p < 0.001). Significant increases demonstrated for RBP4 in both treatment arms were more pronounced in the metformin group (metformin: +66%, rosiglitazone: +33%). All patients were in stage I or II of ß-cell dysfunction and none of them showed increased intact proinsulin levels or changes in resisitin at baseline or end point. Journal of Diabetes Science and Technology

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“…These results suggest that the deterioration of beta-cell function is accelerated by this combination, since elevated intact proinsulin levels and P/I ratio are indicators of beta-cell dysfunction and predictors of the progression of insulin resistance. 40,41) Cisplatin is known to inhibit glucose uptake in various cells. 42,43) In fact, cisplatin rapidly decreases the function of glucose transporter 1 by changing its intracellular localization in ovarian cancer cells.…”

Section: Discussionmentioning

confidence: 99%

Administration of Olanzapine as an Antiemetic Agent Changes Glucose Homeostasis in Cisplatin-Treated Rats

Machida

Miyamura

Machida

et al. 2015

Biological & Pharmaceutical Bulletin

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We investigated the effects of olanzapine on cisplatin-induced pica (the consumption of non-nutrient materials such as kaolin) and glucose homeostasis in rats to clarify the effects of olanzapine when used as an anti-emetic drug. Rats were injected intraperitoneally (i.p.) with either 5 mg/kg cisplatin or saline. Additionally, 2 or 10 mg/kg olanzapine were administered i.p. to the rats 10 min before the administration of cisplatin and subsequently administered every 24 h for 3 d. Kaolin and food intake was measured using an automatic monitoring apparatus. Plasma glucose levels were measured by an enzyme electrode method. The plasma levels of insulin and intact proinsulin were measured by enzyme-linked immunosorbent assay (ELISA). The proinsulin-to-insulin (P/I) ratio was calculated. Cisplatin significantly increased kaolin intake, but decreased food intake and body weight up to 72 h. Olanzapine had no effect on these parameters. Neither olanzapine nor cisplatin alone had a significant effect on the plasma levels of glucose, insulin, or proinsulin. However, a combination of olanzapine and cisplatin significantly decreased plasma insulin levels, but increased plasma intact proinsulin levels and the P/I ratio. Our results suggest that an additive deterioration of insulinsecreting beta-cell function and disturbance of glucose homeostasis should be considered during treatment of patients with olanzapine for cisplatin-induced nausea and vomiting.Key words chemotherapy-induced nausea and vomiting; olanzapine; cisplatin; pica; glucose homeostasis Chemotherapy-induced nausea and vomiting (CINV) is a major adverse event that affects patients' quality of life and is closely related to tolerance of chemotherapy and the rate of success. Therefore, the outcome of chemotherapy itself is influenced by anti-emetic treatments for CINV.1) Animal experimental models and human studies show that acute emesis, which is evoked within the first 24 h after highly emetogenic chemotherapy (HEC), is controlled by the use of selective 5-hydroxytryptamine 3 (5-HT 3 ) receptor antagonists, such as granisetron and ondansetron.2,3) Delayed emesis, occurring at 1 d to 1 week after HEC, cannot be controlled by serotonin 5-HT 3 receptor antagonists alone, but can be controlled by the combination of a 5-HT 3 receptor antagonist, dexamethasone, and/or a tachykinin NK 1 receptor antagonist in both human patients 4,5) and ferrets. [6][7][8] In fact, the use of these drugs is widely recommended in the guidelines for CINV prevention, including those of the National Comprehensive Cancer Network. However, CINV is still experienced by patients: approximately 20% of patients experience acute emesis and approximately 30% experience delayed emesis that is uncontrolled by the antiemetic therapy recommended in these guidelines. [9][10][11] Currently, the use of olanzapine is recommended as an alternative option for CINV prophylaxis in such patients. [12][13][14] The detailed mechanism by which olanzapine reduces CINV is still unknown. However, blockade of the ac...

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Role of Intact Proinsulin in Diagnosis and Treatment of Type 2 Diabetes Mellitus

Cited by 61 publications

References 59 publications

Five stages of progressive β-cell dysfunction in the laboratory Nile rat model of type 2 diabetes

Five stages of progressive β-cell dysfunction in the laboratory Nile rat model of type 2 diabetes

Impact of Treatment with Rosiglitazone or Metformin on Biomarkers for Insulin Resistance and Metabolic Syndrome in Patients with Polycystic Ovary Syndrome

Administration of Olanzapine as an Antiemetic Agent Changes Glucose Homeostasis in Cisplatin-Treated Rats

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