Nicolae Constantin Paulescu: prvi eksplicitni opis unutarnjeg izlučivanja gušterače

The purpose of this article is to describe the research of Nicolae Constantin Paulescu and to emphasize his role in the discovery of insulin. Methods: We made a thorough review of the literature and research in the Romanian Academy Archive in order to find adequate references. Results: In 1912 N.C. Paulescu analysed the clinical and biochemical alterations in diabetic patients and in dogs after performing a pancreatectomy, that apart hyperglycemia and glycosuria (carbohydrate metabolism), had noted also changes in lipid and protein metabolism. In 1916 he started the experiments with a pancreas extract obtained by his original method, that was injected intravenously to the diabetic dogs. The results of his first experiments showed: “The pancreatic extract injected into a peripheral vein produce: 1) A diminution and even a temporary suppression of diabetic hyperglycemia, which may be replaced by hypoglycemia; 2) A diminution or even temporary suppression of glycosuria; 3) A diminution of blood urea; 4) A diminution of urinary urea. In other words, the intravenous injection of the pancreatic extract has as effect the disappearance of diabetic symptoms. The attenuation of the diabetic syndrome begins immediately after the injection. It reaches a maximum after 2 hours,- and it lasts for about 12 hours”. He concluded as such: “This discovery,- which sheds a bright light over the pathogenesis of diabetes gives us also the key for the treatment of this syndrome”. In 1921, Paulescu had published extensively his data in two outstanding French journals 8 months before the first publication of Banting and Best from February 1922. It is clear that insulin has been discovered in Europe. Conclusion: Paulescu thought that a new hormone – Pancreine, that he discovered is the key element in the treatment of diabetes, but his outstanding research was unfairly neglected.Svrha je ovog članka opisati istraživanje Nicolaea Constantina Paulescua i istaknuti njegovu ulogu u otkriću inzulina. Metode: Temeljito smo pregledali literaturu i istraživanja u rumunjskoj akademskoj arhivi kako bismo pronašli odgovarajuće reference. Rezultati: N. C. Paulescu je 1912. analizirao kliničke i biokemijske promjene kod pacijenata s dijabetesom i kod pasa nakon izvođenja pankreatektomije, koji su osim hiperglikemije i glikozurije (metabolizam ugljikohidrata) zabilježili i promjene u metabolizmu lipida i proteina. Godine 1916. Paulescu je započeo eksperiment s ekstraktom gušterače dobivenim njegovom izvornom metodom, koji je intravenski ubrizgan u pse koji su bolovali od dijabetesa. Rezultati njegovih prvih eksperimenata pokazali su: “Ekstrakt gušterače ubrizgan u perifernu venu proizvodi: 1. smanjenje, pa čak i privremenu supresiju dijabetičke hiperglikemije, koja može biti zamijenjena hipoglikemijom; 2. smanjenje ili čak privremenu supresiju glikozurije; 3. smanjenje uree u krvi; 4. smanjenje uree urina. Drugim riječima, intravenozna injekcija ekstrakta gušterače ima za posljedicu nestanak simptoma dijabetesa. Smanjenje dijabetičkog sindroma počinje odmah nakon ubrizgavanja, a maksimum doseže nakon dva sata – i traje oko 12 sati.” Zaključio je: “Ovo otkriće, koje baca novo svjetlo na patogenezu dijabetesa, daje nam i ključ za liječenje ovog sindroma.” Paulescu je 1921. objavio svoje podatke u dva izvanredna francuska časopisa i to osam mjeseci prije prve publikacije Bantinga i Besta u veljači 1922. Jasno je da je inzulin otkriven u Europi. Zaključak: Paulescu je smatrao da je novootkriveni hormon, nazvan pancrein, ključni element u liječenju dijabetesa, ali njegovo izvanredno istraživanje nepravedno je zanemareno

Vascular risk factors and diabetic neuropathy

Background: Other than glycemic control, there are no treatments for diabetic neuropathy. Thus, identifying potentially modifiable risk factors for neuropathy is crucial. We studied risk factors for the development of distal symmetric neuropathy in 1172 patients with type 1 diabetes mellitus from 31 centers participating in the European Diabetes (EURODIAB) Prospective Complications Study. Methods: Neuropathy was assessed at baseline (1989 to 1991) and at follow-up (1997 to 1999), with a mean (±SD) follow-up of 7.3±0.6 years. A standardized protocol included clinical evaluation, quantitative sensory testing, and autonomic-function tests. Serum lipids and lipoproteins, glycosylated hemoglobin, and the urinary albumin excretion rate were measured in a central laboratory. Results: At follow-up, neuropathy had developed in 276 of 1172 patients without neuropathy at baseline (23.5 percent). The cumulative incidence of neuropathy was related to the glycosylated hemoglobin value and the duration of diabetes. After adjustment for these factors, we found that higher levels of total and low-density lipoprotein cholesterol and triglycerides, a higher body-mass index, higher von Willebrand factor levels and urinary albumin excretion rate, hypertension, and smoking were all significantly associated with the cumulative incidence of neuropathy. After adjustment for other risk factors and diabetic complications, we found that duration of diabetes, current glycosylated hemoglobin value, change in glycosylated hemoglobin value during the follow-up period, body-mass index, and smoking remained independently associated with the incidence of neuropathy. Cardiovascular disease at baseline was associated with double the risk of neuropathy, independent of cardiovascular risk factors. Conclusions: This prospective study indicates that, apart from glycemic control, the incidence of neuropathy is associated with potentially modifiable cardiovascular risk factors, including a raised triglyceride level, body-mass index, smoking, and hypertension

Vascular risk factors and diabetic neuropathy

Background: Other than glycemic control, there are no treatments for diabetic neuropathy. Thus, identifying potentially modifiable risk factors for neuropathy is crucial. We studied risk factors for the development of distal symmetric neuropathy in 1172 patients with type 1 diabetes mellitus from 31 centers participating in the European Diabetes (EURODIAB) Prospective Complications Study. Methods: Neuropathy was assessed at baseline (1989 to 1991) and at follow-up (1997 to 1999), with a mean (±SD) follow-up of 7.3±0.6 years. A standardized protocol included clinical evaluation, quantitative sensory testing, and autonomic-function tests. Serum lipids and lipoproteins, glycosylated hemoglobin, and the urinary albumin excretion rate were measured in a central laboratory. Results: At follow-up, neuropathy had developed in 276 of 1172 patients without neuropathy at baseline (23.5 percent). The cumulative incidence of neuropathy was related to the glycosylated hemoglobin value and the duration of diabetes. After adjustment for these factors, we found that higher levels of total and low-density lipoprotein cholesterol and triglycerides, a higher body-mass index, higher von Willebrand factor levels and urinary albumin excretion rate, hypertension, and smoking were all significantly associated with the cumulative incidence of neuropathy. After adjustment for other risk factors and diabetic complications, we found that duration of diabetes, current glycosylated hemoglobin value, change in glycosylated hemoglobin value during the follow-up period, body-mass index, and smoking remained independently associated with the incidence of neuropathy. Cardiovascular disease at baseline was associated with double the risk of neuropathy, independent of cardiovascular risk factors. Conclusions: This prospective study indicates that, apart from glycemic control, the incidence of neuropathy is associated with potentially modifiable cardiovascular risk factors, including a raised triglyceride level, body-mass index, smoking, and hypertension

Dietary carbohydrates and breast cancer risk: A prospective study of the roles of overall glycemic index and glycemic load

We examined breast cancer risk in association with overall glycemic index (GI), glycemic load (GL), and dietary carbohydrate and sugar intake in a prospective cohort of 49,613 Canadian women enrolled in the National Breast Screening Study who completed a self‐administered food frequency questionnaire between 1980 and 1985. Linkages to national mortality and cancer databases yielded data on deaths and cancer incidence, with follow‐up ending between 1998 and 2000. During a mean follow‐up of 16.6 years, we observed 1,461 incident breast cancer cases. GI, GL, total carbohydrate and total sugar intake were not associated with breast cancer risk in the total cohort. However, there was evidence of effect modification of the association between GI and breast cancer risk by menopausal status (p = 0.01), the hazard ratio for the highest versus the lowest quintile level of GI being 0.78 (95% CI = 0.52–1.16; ptrend = 0.12) in premenopausal women and 1.87 (95% CI = 1.18–2.97; ptrend = 0.01) in postmenopausal women. The associations between GI and GL were not modified by body mass index (BMI) or by vigorous physical activity among pre‐ or postmenopausal women. Similarly, the associations between GI/GL and risk in postmenopausal women were not modified by BMI, vigorous physical activity, or ever use of hormone replacement therapy (HRT), although the associations were slightly stronger among those who reported no vigorous physical activity (ptrend = 0.02), among those who reported ever using HRT (ptrend = 0.02) and among normal‐weight women (BMI \u3c 25 kg/m2; ptrend = 0.03). Our data suggest that consumption of diets with high GI values may be associated with increased risk of breast cancer among postmenopausal women, possibly more so among subgroups defined by participation in vigorous physical activity, ever use of HRT and those who are not overweight

Glucose-Raising Genetic Variants in MADD and ADCY5 Impair Conversion of Proinsulin to Insulin

Recent meta-analyses of genome-wide association studies revealed new genetic loci associated with fasting glycemia. For several of these loci, the mechanism of action in glucose homeostasis is unclear. The objective of the study was to establish metabolic phenotypes for these genetic variants to deliver clues to their pathomechanism.) and insulin resistance (HOMA-IR, Matsuda-Index) were assessed.. on proinsulin-to-insulin conversion. These effects may also be related to neighboring regions of the genome

Efficacy and Safety of Lacosamide in Painful Diabetic Neuropathy

OBJECTIVE: To evaluate efficacy and safety of lacosamide compared with placebo in painful diabetic polyneuropathy. RESEARCH DESIGN AND METHODS: Diabetic patients with at least moderate neuropathic pain were randomized to placebo or lacosamide 400 (in a slow or standard titration) or 600 mg/day over 6-week titration and 12-week maintenance periods. Primary efficacy criterion was intra-individual change in average daily Numeric Pain Rating Scale score from baseline to the last 4 weeks. RESULTS: For the primary end point, pain reduction was numerically but not statistically greater with lacosamide compared with placebo (400 mg/day, P = 0.12; 600 mg/day, P = 0.18). Both doses were significantly more effective compared with placebo over the titration (P = 0.03, P = 0.006), maintenance (P = 0.01, P = 0.005), and entire treatment periods (P = 0.03, P = 0.02). Safety profiles between titration schemes were similar. CONCLUSIONS: Lacosamide reduced neuropathic pain and was well tolerated in diabetic patients, but the primary efficacy criterion was not met, possibly due to an increased placebo response over the last 4 weeks.status: publishe

Plasma levels of matrix metalloproteinase-2, -3, -10, and tissue inhibitor of metalloproteinase-1 are associated with vascular complications in patients with type 1 diabetes: The EURODIAB Prospective Complications Study

Impaired regulation of extracellular matrix remodeling by matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinase (TIMP) may contribute to vascular complications in patients with type 1 diabetes. We investigated associations between plasma MMP-1, -2, -3, -9, -10 and TIMP-1, and cardiovascular disease (CVD) or microvascular complications in type 1 diabetic patients. We also evaluated to which extent these associations could be explained by low-grade inflammation (LGI) or endothelial dysfunction (ED). Methods: 493 type 1 diabetes patients (39.5 ± 9.9 years old, 51% men) from the EURODIAB Prospective Complications Study were included. Linear regression analysis was applied to investigate differences in plasma levels of MMP-1, -2, -3, -9, -10, and TIMP-1 between patients with and without CVD, albuminuria or retinopathy. All analyses were adjusted for age, sex, duration of diabetes, Hba1c and additionally for other cardiovascular risk factors including LGI and ED. Results: Patients with CVD (n = 118) showed significantly higher levels of TIMP-1 [β = 0.32 SD (95%CI: 0.12; 0.52)], but not of MMPs, than patients without CVD (n = 375). Higher plasma levels of MMP-2, MMP-3, MMP-10 and TIMP-1 were associated with higher levels of albuminuria (p-trends were 0.028, 0.004, 0.005 and 0.001, respectively). Severity of retinopathy was significantly associated with higher levels of MMP-2 (p-trend = 0.017). These associations remained significant after further adjustment for markers of LGI and ED. Conclusions: These data support the hypothesis that impaired regulation of matrix remodeling by actions of MMP-2, -3 and-10 and TIMP-1 contributes to the pathogenesis of vascular complications in type 1 diabetes

Relationship Between Risk Factors and Mortality in Type 1 Diabetic Patients in Europe: The EURODIAB Prospective Complications Study (PCS)

OBJECTIVE—The purpose of this study was to examine risk factors for mortality in patients with type 1 diabetes