c-peptide and Fibrosis

Insulin is synthesised as a pro-hormone with an interconnecting C-peptide, cleaved during post-translational modification. This review discusses growing evidence which indicates that C-peptide is biologically active, benefiting microvascular complications associated with diabetes.. To explore the renoprotective role of C-peptide in diabetic nephropathy (DN), we reviewed the literature using PubMed for English language articles that contained key words related to C-peptide, kidney and DN.. Numerous studies have demonstrated that C-peptide ameliorates a number of the structural and functional renal disturbances associated with uncontrolled hyperglycaemia in human and animal models of type 1 diabetes mellitus that lead to the development and progression of nephropathy, including abrogation of glomerular hyperfiltration, reduced microalbuminuria, decreased mesangial expansion and increased endothelial nitric oxide synthase levels. The in vitro exposure of kidney proximal tubular cells to physiological concentrations of C-peptide activates extracellular signal-regulated kinase, phosphatidylinositol 3-kinase, protein kinase C, elevates intracellular calcium, and stimulates transcription factors NF-kappaB and peroxisome proliferator-activated receptor-gamma.. Burgeoning studies suggest that C-peptide is more than merely a link between the A and B chains of the proinsulin molecule and represents a future therapeutic tool in reducing complications of DN.

Topics: Animals; C-Peptide; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Disease Progression; Fibrosis; Humans; Hyperglycemia; Models, Biological; NF-kappa B; Nitric Oxide Synthase Type III; Phosphatidylinositol 3-Kinases; Protein Kinase C; Sodium-Potassium-Exchanging ATPase

Diabetic retinopathy is a leading cause of vision impairment. Surging diabetic population and poor visual care raises the need for better diagnostic tools. Hence, it is worthwhile to look for biomarkers associated with the disease pathogenesis. Periostin and tenascin-C are matricellular proteins mediating fibrillogenesis in retinopathy. Their serum levels and association with the presence and severity of retinopathy in diabetics is of importance to be explored.. The study involved two groups of type 2 diabetes patients, 38 controls without retinopathy and 38 cases with retinopathy. We obtained serum sample and performed biochemical autoanalysis for routine parameters. Special parameters periostin, tenascin-C, and C-peptide were estimated by ELISA.. Periostin and tenascin-C were significantly elevated in the retinopathy group. Periostin progressively increased among subgroups. C-peptide decreased significantly in retinopathy group and had a negative correlation with duration of DM, duration of retinopathy, HbA1c and tenascin-C. We observed a positive correlation for periostin and tenascin-C with duration of diabetes. The AUC for C-peptide was the highest (0.750) amongst our parameters. HOMA 2 (%B) index was significantly lower in retinopathy group.. Serum Levels of PO and TnC increased in retinopathy. As the disease advances, periostin level increases, indicating continuing fibrosis and fibrovascular membrane formation. Periostin and tenascin-C increase with duration of retinopathy whereas levels of C-peptide decrease. C-peptide has a better differentiating potential for DR from DM. Reduced insulin production as indicated by declined HOMA 2-%BETA in retinopathy favors hyperglycemia and chronic inflammatory state for the disease progression.

Topics: C-Peptide; Diabetes Mellitus, Type 2; Diabetic Retinopathy; Fibrosis; Humans; Tenascin

Studies evaluating endocrine and exocrine functions in fibrocalculous pancreatic diabetes (FCPD) are scarce.. Insulin, C-peptide, glucagon, incretin hormones (glucagon-like peptide 1 [GLP-1] and gastric inhibitory peptide [GIP]), and dipeptidyl peptidase IV (DPP-IV) were estimated in patients with FCPD (n = 20), type 2 diabetes mellitus (T2DM) (n = 20), and controls (n = 20) in fasting and 60 minutes after 75 g glucose.. Fasting and post-glucose C-peptide and insulin in FCPD were lower than that of T2DM and controls. Plasma glucagon decreased after glucose load in controls (3.72, 2.29), but increased in T2DM (4.01, 5.73), and remained unchanged in FCPD (3.44, 3.44). Active GLP-1 (pmol/L) after glucose load increased in FCPD (6.14 to 9.72, P = <.001), in T2DM (2.87 to 4.62, P < .001), and in controls (3.91 to 6.13, P < .001). Median active GLP-1 in FCPD, both in fasting and post-glucose state (6.14, 9.72), was twice that of T2DM (2.87, 4.62) and 1.5 times that of controls (3.91, 6.13) (P < .001 for all). Post-glucose GIP (pmol/L) increased in all: FCPD (15.83 to 94.14), T2DM (21.85 to 88.29), and control (13.00 to 74.65) (P < .001 for all). GIP was not different between groups. DPP-IV concentration (ng/mL) increased in controls (1578.54, 3012.00) and FCPD (1609.95, 1995.42), but not in T2DM (1204.50, 1939.50) (P = .131). DPP-IV between the three groups was not different. Fecal elastase was low in FCPD compared with T2DM controls.. In FCPD, basal C-peptide and glucagon are low, and glucagon does not increase after glucose load. GLP-1, but not GIP, in FCPD increases 1.5 to 2 times as compared with T2DM and controls (fasting and post glucose) without differences in DPP-IV.. 背景: 评价纤维结石性胰腺糖尿病(FCPD)内分泌和外分泌功能的研究很少。 方法: 测定FCPD组(n=20)、2型糖尿病(T2 DM)组(n=20)和对照组(n=20)空腹和75g葡萄糖后60min的胰岛素、C肽、胰高血糖素、肠泌素(胰高血糖素样肽1[GLP-1]和胃抑制肽[GIP])、二肽基肽酶IV(DPP-IV)水平。 结果: FCPD组空腹和糖负荷后C肽、胰岛素水平均低于T2 DM组和对照组。对照组糖负荷后胰高血糖素(pmol/L)降低(3.72; 2.29); T2 DM组升高(4.01; 5.73); FCPD组(3.44; 3.44)无明显变化。FCPD组(6.14~9.72; P=<0.001)、T2 DM组(2.87~4.62; P<0.001)和对照组(3.91~6.13; P<0.001)糖负荷后活性GLP-1(pmol/L)升高。FCPD组空腹和糖负荷后GLP-1(pmol/L)活性中位数(6.14; 9.72)是T2 DM组(2.87; 4.62)的两倍; 是对照组(3.91; 6.13)的1.5倍(P<0.001)。糖负荷后GIP(pmol/L)在所有组别中都升高:FCPD(15.83~94.14)、T2DM(21.85~88.29)、对照组(13.00~74.65), P<0.01。不同组间GIP差异无统计学意义。对照组(1578.54,3012.00)和FCPD组(1609.95,1995.42)的DPP-IV浓度(ng/mL)升高; 而T2 DM组(1204.50,1939.50)的DPP-IV浓度无明显变化(P=0.131)。DPP-IV于三组间差异无统计学意义。FCPD组中粪弹性蛋白酶低于T2 DM组对照组。 结论: FCPD患者糖负荷后基础C肽和胰高血糖素降低; 在糖负荷后胰高血糖素不升高。FCPD的GLP-1; 而不是GIP; 与T2 DM和对照组(空腹和糖负荷后)相比升高了1.5-2倍; 而DPP-IV没有差异.

Topics: Adolescent; Adult; Biomarkers; Blood Glucose; C-Peptide; Calcinosis; Case-Control Studies; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Female; Fibrosis; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Insulin; Male; Middle Aged; Pancreatitis, Chronic; Time Factors; Young Adult

Islet transplantation has been proved to be effective in delaying early stage of DN. This study was established to observe the mechanism of islet transplantation on early diabetic nephropathy (DN).. The diabetes mellitus (DM) rat model was established by an injection of a single-dose streptozotocin. According to the treatment, the rats were randomly divided into 4 groups: the untreated DN rats (DN group); the C-peptide treated rats (CP group); the islet transplanted rats (IT group); the normal control rats (NC group). Renal function and structure of glomerular filtration barrier (GFB) were evaluated by urinalysis and histopathological examination, respectively. The renal fibrotic factors, TGF- β1 and CTGF, as well as the anti-renal fibrosis factor HGF were assessed by immunohistochemical staining and western blotting methods.. After C-peptide treatment and islet transplantation, the GFB structure was obviously improved. The blood glucose significantly decreased in the IT group. The 24h urine protein and glomerular basement membrane thickness decreased, the pathological changes of podocytes improved, TGF- β1 and CTGF decreased and HGF increased in the CP group and the IT group compared with that in the DN group (P < 0.05), especially in the IT group.. Islet transplantation could ameliorate the structure of GFB of early DN in a rat model, and the treatment effect was partly attributed to the restoration of C-peptide concentration. Suppressing the fibrosis system can be the potential mechanism of islet transplantation, which is independent of blood glucose control.

Topics: Animals; C-Peptide; Diabetes Mellitus; Diabetic Nephropathies; Disease Models, Animal; Fibrosis; Glomerular Filtration Barrier; Humans; Islets of Langerhans Transplantation; Male; Rats; Rats, Sprague-Dawley; Streptozocin; Transforming Growth Factor beta1; Urinalysis

Cardiovascular and renal complications are the predominant causes of morbidity and mortality amongst patients with diabetes. Development of novel treatments have been hampered by the lack of available animal models recapitulating the human disease. We hypothesized that experimental diabetes in rats combined with a cardiac or renal stressor, would mimic diabetic cardiomyopathy and nephropathy, respectively. Diabetes was surgically induced in male Sprague Dawley rats by 90% pancreatectomy (Px). Isoprenaline (Iso, 1 mg/kg, sc., 10 days) was administered 5 weeks after Px with the aim of inducing cardiomyopathy, and cardiac function and remodeling was assessed by echocardiography 10 weeks after surgery. Left ventricular (LV) fibrosis was quantified by Picro Sirius Red and gene expression analysis. Nephropathy was induced by Px combined with uninephrectomy (Px-UNx). Kidney function was assessed by measurement of glomerular filtration rate (GFR) and urine albumin excretion, and kidney injury was evaluated by histopathology and gene expression analysis. Px resulted in stable hyperglycemia, hypoinsulinemia, decreased C-peptide, and increased glycated hemoglobin (HbA1c) compared with sham-operated controls. Moreover, Px increased heart and LV weights and dimensions and caused a shift from α-myosin heavy chain (MHC) to β-MHC gene expression. Isoprenaline treatment, but not Px, decreased ejection fraction and induced LV fibrosis. There was no apparent interaction between Px and Iso treatment. The superimposition of Px and UNx increased GFR, indicating hyperfiltration. Compared with sham-operated controls, Px-UNx induced albuminuria and increased urine markers of kidney injury, including neutrophil gelatinase-associated lipocalin (NGAL) and podocalyxin, concomitant with upregulated renal gene expression of NGAL and kidney injury molecule 1 (KIM-1). Whereas Px and isoprenaline separately produced clinical endpoints related to diabetic cardiomyopathy, the combination of the two did not accentuate disease development. Conversely, Px in combination with UNx resulted in several clinical hallmarks of diabetic nephropathy indicative of early disease development.

Topics: Albuminuria; Animals; C-Peptide; Diabetes Mellitus, Experimental; Diabetic Cardiomyopathies; Diabetic Nephropathies; Disease Models, Animal; Fibrosis; Glomerular Filtration Rate; Heart; Isoproterenol; Kidney; Lipocalin-2; Male; Pancreatectomy; Rats; Rats, Sprague-Dawley; Renal Insufficiency

The therapeutic potential of adipose-derived stem cell conditioned medium (ASC-CM) was studied in the rabbit model of critical limb ischemia (CLI).. Rabbits received treatment with ASC-CM or placebo. Gastrocnemius muscle tissue was collected 35 days after ischemia induction. Ischemic changes were evaluated in hematoxylin-eosin stained tissues for early (necrotic lesions/granulation tissue) and late (fibrous scars) phases of tissue repair. The expression of proangiogenic miR-126 was also evaluated using in situ hybridization. The levels of cytokines, insulin, and C-peptide were measured in blood.. Early repair phases were observed more often in placebo-treated samples (45.5%) than in ASC-CM-treated ones (22.2%). However, the difference was not statistically significant. We demonstrated a statistically significant positive correlation between the early healing phases in tissue samples and C-peptide levels in peripheral blood. The expression of proangiogenic miR-126 was also shown in a number of structures in all phases of ischemic tissue healing.. Based on our results, we believe that treatment with ASC-CM has the potential to accelerate the healing process in ischemic tissues in the rabbit model of CLI. The whole healing process was accompanied by miR-126 tissue expression. C-peptide could be used to monitor the course of the tissue healing process.

Topics: Adult; Animals; C-Peptide; Cicatrix; Culture Media, Conditioned; Cytokines; Diabetes Mellitus, Experimental; Diabetic Foot; Disease Models, Animal; Fibrosis; Granulation Tissue; Hindlimb; Humans; In Situ Hybridization; Insulin; Ischemia; Male; Mesenchymal Stem Cells; MicroRNAs; Muscle, Skeletal; Necrosis; Neovascularization, Physiologic; Rabbits; Wound Healing

Adipose stem cell (ASC) transplantation is a promising therapeutic strategy for diabetic renal fibrosis. Hypoxia-inducible factor 1α (HIF1α) is a negative regulatory factor of mitochondrial function. In the current study, we aimed to explore if HIF1α deletion protects against hyperglycemia-induced ASC damage and enhances the therapeutic efficiency of ASCs in diabetic renal fibrosis. Our data indicated that HIF1α was upregulated in ASCs in response to high glucose stimulation. Higher HIF1α expression was associated with ASC apoptosis and proliferation arrest. Loss of HIF1α activated mitophagy protecting ASCs against high glucose-induced apoptosis via preserving mitochondrial function. Transplanting HIF1α-deleted ASCs in db/db mice improved the abnormalities in glucose metabolic parameters, including the levels of glucose, insulin, C-peptide, HbA1c, and inflammatory markers. In addition, the engraftment of HIF1α-modified ASCs also reversed renal function, decreased renal hypertrophy, and ameliorated renal histological changes in db/db mice. Functional studies confirmed that HIF1α-modified ASCs reduced renal fibrosis. Collectively, our results demonstrate that ASCs may be a promising therapeutic treatment for ameliorating diabetes and the development of renal fibrosis and that the loss of HIF1α in ASCs may further increase the efficiency of stem cell-based therapy. These findings provide a new understanding about the protective effects of HIF1α silencing on ASCs and offer a new strategy for promoting the therapeutic efficacy of ASCs in diabetic renal fibrosis.

Topics: Adipocytes; Animals; Apoptosis; Blood Glucose; C-Peptide; Cell Proliferation; Diabetes Complications; Diabetes Mellitus, Experimental; Fibrosis; Gene Deletion; Glucose; Glycated Hemoglobin; Hyperglycemia; Hypoxia-Inducible Factor 1, alpha Subunit; Insulin; Kidney; Mice; Mitophagy; Stem Cells; Up-Regulation

The effect of exocrine pancreatic function on the glucose-mediated insulin response and glucose utilization were studied in an exocrine pancreas-insufficient (EPI) pig model. Five 10-week-old EPI pigs after pancreatic duct ligation and 6 age-matched, non-operated control pigs were used in the study. Blood glucose, plasma insulin and C-peptide concentrations were monitored during meal (MGTT), oral (OGTT) and intravenous (IVGTT) glucose tolerance tests. Upon post-mortem examination, the pancreatic remnants of the EPI pigs showed acinar fibrotic atrophy but normal islets and β-cell morphology. The EPI pigs displayed increased fasting glucose concentrations compared with control animals (6.4 ± 0.4 versus 4.8 ± 0.1 mmol l(-1) , P < 0.0001) but unchanged insulin concentrations (2.4 ± 0.6 versus 2.1 ± 0.2 pmol l(-1) ). During the OGTT and IVGTT, the EPI pigs showed slower, impaired glucose utilization, with the disruption of a well-timed insulin response. Plasma C-peptide concentrations confirmed the delayed insulin response during the IVGTT in EPI pigs. Oral pancreatic enzyme supplementation (PES) of EPI pigs improved glucose clearance during IVGTT [AUC(glucose) 1295 ± 70 mmol l(-1) × (120 min) in EPI versus 1044 ± 32 mmol l(-1) × (120 min) in EPI + PES, P < 0.0001] without reinforcing the release of insulin [AUC(C-peptide) 14.4 ± 3.8 nmol l(-1) × (120 min) in EPI versus 6.4 ± 1.3 nmol l(-1) × (120 min) in EPI + PES, P < 0.002]. The results suggest the existence of an acino-insular axis regulatory communication. The presence of pancreatic enzymes in the gut facilitates glucose utilization in an insulin-independent manner, indicating the existence of a gut-derived pancreatic enzyme-dependent mechanism involved in peripheral glucose utilization.

Topics: Animals; Atrophy; Blood Glucose; C-Peptide; Eating; Fibrosis; Glucose Tolerance Test; Insulin; Insulin-Secreting Cells; Islets of Langerhans; Ligation; Pancreas, Exocrine; Pancreatic Ducts; Sus scrofa; Swine; Weight Gain

Previous studies have demonstrated that renoprotective effects of C-peptide in experimental models of diabetes-induced renal disease may be mediated via lowering blood glucose. The present study examined the renoprotective effects of C-peptide in a model of nondiabetic renal disease, the Dahl salt-sensitive (SS/jr) rat. SS/jr rats were placed on a 2% NaCl diet for 2 wk (HS2, resulting in mild to moderate renal injury) or 4 wk (HS4, resulting in advanced renal injury) and then received either vehicle (veh) or C-peptide (Cpep) for additional 4 wk. Urine albumin (UAE) and protein (UPE) excretion rates were measured at baseline (i.e., before initiation of veh or Cpep treatment) and 4 wk later (i.e., at the time of death). Glomerular permeability, indexes of glomerulosclerosis and tubulointerstitial fibrosis, the presence of inflammatory cells, and protein expression of transforming growth factor-β (TGF-β) and podocin were measured at the time of death. In HS2 + veh rats, UAE and UPE increased by 74 and 92%, respectively, from baseline and the time of death. While HS2 + Cpep attenuated this increase in UAE and UPE, HS4 + Cpep had no effect on these parameters. Similarly, HS2 + Cpep reduced glomerular permeability, tubulointerstitial fibrosis, renal inflammation, TGF-β, and podocin protein expression, while HS4 + Cpep had no effect. These studies indicate that C-peptide is renoprotective in nondiabetic experimental models with mild to moderate renal injury.

Topics: Albuminuria; Animals; C-Peptide; Fibrosis; Glomerulosclerosis, Focal Segmental; Intracellular Signaling Peptides and Proteins; Kidney Glomerulus; Male; Membrane Proteins; Nephritis, Interstitial; Permeability; Rats; Rats, Inbred Dahl; Sodium Chloride, Dietary; Transforming Growth Factor beta

Topics: Albuminuria; Bilirubin; Blood Glucose; Blood Proteins; C-Peptide; Cyclosporine; Diabetes Mellitus, Type 2; Fibrosis; Glucocorticoids; Humans; Hypoglycemic Agents; Immunosuppressive Agents; Insulin; Liver Transplantation; Male; Middle Aged; Nutritional Status; Prednisone; Radioimmunoassay; Triglycerides; Uric Acid

beta-Cell function (plasma C-peptide) in 17 fibrocalculous pancreatic diabetic (FCPD) subjects (14 newly diagnosed) was not different at presentation from that in 14 matched insulin-dependent diabetic subjects. After insulin treatment and improvement in the patients' nutritional and metabolic status, fasting and postglucose plasma C-peptide concentrations showed a significant increase (fasting 0.06 +/- 0.01 to 0.17 +/- 0.03 nM, peak 0.11 +/- 0.02 to 0.29 +/- 0.06 nM, mean +/- SE; P less than 0.01 for both). Thus, severely diminished beta-cell function in FCPD is partially reversible after treatment. This could contribute to the clinical metabolic peculiarities of this group of patients.

Topics: Adult; C-Peptide; Diabetes Mellitus; Diabetes Mellitus, Type 1; Female; Fibrosis; Follow-Up Studies; Fructose; Glucose Tolerance Test; Glycated Hemoglobin; Humans; Insulin; Male; Pancreatic Diseases