c-peptide and Arteriosclerosis

The accumulation of Nxi-(carboxymethyl)lysine (CML), a product of glycoxidation and lipoxidation reactions, on tissue proteins is related to the formation and acceleration of diabetic and nondiabetic atherosclerotic lesions. Yet, little is known about the levels of circulating serum CML-containing protein in nondiabetic patients with clinical symptoms of advanced atherosclerosis. We measured the levels of immunoreactive CML in sera from non-diabetic patients with accelerated symptoms of coronary heart disease, from diabetic patients with no late complications, and from healthy individuals. Serum CML was significantly higher in non-diabetic patients with coronary heart disease than in healthy control subjects and was comparable to serum CML in patients with type 2 diabetes mellitus without late complications and coronary heart disease. In nondiabetic patients with coronary heart disease, a significant inverse correlation was found between serum levels of CML and proinsulin C-peptide, a marker of pancreatic beta cells activity that affects microvascular function. Serum levels of CML and high density lipoprotein (HDL) were positively correlated in this group. We conclude that glycoxidation and lipoxidation are associated with serum HDL levels and the secretive capacity of pancreatic beta cells in nondiabetic patients with coronary heart disease.

Topics: Arteriosclerosis; C-Peptide; Carbohydrate Metabolism; Cholesterol, HDL; Coronary Disease; Diabetes Mellitus; Enzyme-Linked Immunosorbent Assay; Female; Glucose; Humans; Islets of Langerhans; Lipid Metabolism; Lipoproteins, HDL; Lysine; Male; Middle Aged; Oxidation-Reduction

The aim of this study was to examine the association between intact insulin, insulin propeptides, and femoral artery intima-media thickness. The design was a cross-sectional study and the study group (n = 391) consisted of randomly recruited clinically healthy 58-year-old Swedish men. The intima-media thickness of the common femoral artery was measured with ultrasound. Fasting plasma insulin; intact insulin; proinsulin; 32,33 split-proinsulin; and C-peptide concentrations were assessed. The results showed that the common femoral artery intima-media thickness correlated significantly and univariately with waist-hip ratio, systolic blood pressure, serum total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, ApoB, low-density lipoprotein peak particle size, and cigarette years. Furthermore, of intact insulin and insulin propeptides, only intact insulin and C-peptide were univariately associated with common femoral artery intima-media thickness (r= 0.14, p < 0.01; r= 0.18, p < 0.01; respectively). In a multiple regression analysis, common femoral artery intima-media thickness was independently associated with systolic blood pressure (beta-coefficient = 0.004, p = 0.002), ApoB (beta-coefficient = 0.338, p < 0.001 ) and cigarette years (beta-coefficient = 0.0004, p < 0.001), (R2= 25%, p

Topics: Apolipoproteins B; Arteriosclerosis; Biomarkers; Blood Pressure; C-Peptide; Cholesterol; Cross-Sectional Studies; Femoral Artery; Humans; Insulin; Insulin Resistance; Male; Middle Aged; Proinsulin; Protein Precursors; Radioimmunoassay; Reference Values; Risk Factors; Triglycerides; Tunica Intima; Ultrasonography

To evaluate the glycemic control, lipid effects, and safety of pioglitazone in patients with type 2 diabetes mellitus.. Patients (n = 197) with type 2 diabetes mellitus, a hemoglobin A1c (HbA1c) > or = 8.0%, fasting plasma glucose (FPG) > 7.7 mmol/l (140 mg/dl), and C-peptide > 0.331 nmol/l (1 ng/ml) were enrolled in this 23-week multi-center (27 sites), double-blind clinical trial and randomized to receive either a placebo or pioglitazone HCl 30 mg (pioglitazone), administered once daily, as monotherapy. Patients were required to discontinue all anti-diabetic medications 6 weeks before receiving study treatment. Efficacy parameters included HbA1c fasting plasma glucose (FPG), serum C-peptide, insulin, triglycerides (Tg), and cholesterol (total cholesterol [TC], high-density lipoprotein-cholesterol [HDL-C], low-density lipoprotein-cholesterol [LDL-C]). Adverse event rates, serum chemistry, and physical examinations were recorded.. Compared with placebo, pioglitazone significantly (P= 0.0001) reduced HbA1c (-1.37% points), FPG (-3.19 mmol/l; -57.5 mg/dl), fasting C-peptide (-0.076+/-0.022 nmol/l), and fasting insulin (-11.88+/-4.70 pmol/l). Pioglitazone significantly (P < 0.001) decreased insulin resistance (HOMA-IR; -12.4+/-7.46%) and improved beta-cell function (Homeostasis Model Assessment (HOMA-BCF); +47.7+/-11.58%). Compared with placebo, fasting serum Tg concentrations decreased (-16.6%; P = 0.0178) and HDL-C concentrations increased (+12.6%; P= 0.0065) with pioglitazone as monotherapy. Total cholesterol and LDL-C changes were not different from placebo. The overall adverse event profile of pioglitazone was similar to that of placebo, with no evidence of drug-induced elevations of serum alanine transaminase (ALT) concentrations or hepatotoxicity.. Pioglitazone improved insulin resistance and glycemic control, as well as Tg and HDL-C - which suggests that pioglitazone may reduce cardiovascular risk for patients with type 2 diabetes.

Topics: Adult; Aged; Arteriosclerosis; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Double-Blind Method; Endpoint Determination; Female; Follow-Up Studies; Glycated Hemoglobin; Humans; Hyperlipidemias; Hypoglycemic Agents; Insulin; Insulin Resistance; Islets of Langerhans; Lipids; Lipoproteins; Male; Middle Aged; Pioglitazone; Single-Blind Method; Thiazoles; Thiazolidinediones; Treatment Outcome; United States

Twenty-four middle-aged healthy men were given a low-fat high-carbohydrate (5.5 g fat; L), or a moderately-fatty, (25.7 g fat; M) breakfast of similar energy contents for 28 d. Other meals were under less control. An oral glucose tolerance test (OGTT) was given at 09.00 hours on day 1 before treatment allocation and at 13.30 hours on day 29. There were no significant treatment differences in fasting serum values, either on day 1 or at the termination of treatments on day 29. The following was observed on day 29: (1) the M breakfast led to higher OGTT C-peptide responses and higher areas under the curves (AUC) of OGTT serum glucose and insulin responses compared with the OGTT responses to the L breakfast (P < 0.05); (2) treatment M failed to prevent OGTT glycosuria, eliminated with treatment L; (3) serum non-esterified fatty acid (NEFA) AUC was 59% lower with treatment L than with treatment M, between 09.00 and 13.20 hours (P < 0.0001), and lower with treatment L than with treatment M during the OGTT (P = 0.005); (4) serum triacylglycerol (TAG) concentrations were similar for both treatments, especially during the morning, but their origins were different during the afternoon OGTT when the Svedberg flotation unit 20-400 lipid fraction was higher with treatment L than with treatment M (P = 0.016); plasma apolipoprotein B-48 level with treatment M was not significantly greater than that with treatment L (P = 0.086); (5) plasma tissue plasminogen-activator activity increased after breakfast with treatment L (P = 0.0008), but not with treatment M (P = 0.80). Waist:hip circumference was positively correlated with serum insulin and glucose AUC and with fasting LDL-cholesterol. Waist:hip circumference and serum TAG and insulin AUC were correlated with factors of thrombus formation; and the OGTT NEFA and glucose AUC were correlated. A small difference in fat intake at breakfast has a large influence on circulating diurnal NEFA concentration, which it is concluded influences adversely glucose tolerance up to 6 h later.

Topics: Adult; Aged; Area Under Curve; Arteriosclerosis; Blood Glucose; Body Constitution; C-Peptide; Cholesterol, LDL; Dietary Fats; Fatty Acids, Nonesterified; Glucose Tolerance Test; Humans; Insulin; Male; Middle Aged; Risk Factors; Thrombosis; Time Factors; Tissue Plasminogen Activator; Triglycerides

C-peptide is a proinsulin cleavage product released from the pancreas in amounts equimolar to insulin, and elevated levels of C-peptide have been found in patients with insulin resistance and early type 2 diabetes mellitus. Recent data suggest that C-peptide could play a causal role in the pathophysiology of vascular disease, but nothing is known about the prognostic value of C-peptide concentrations in the circulation.. We examined whether C-peptide is associated with cardiovascular and total mortality in 2,306 patients from the Ludwigshafen Risk and Cardiovascular Health Study who underwent coronary angiography at baseline (1997-2000).. During a mean follow-up of 7.6 years, 440 deaths (19.1%) occurred, 252 (10.9%) of which were due to cardiovascular causes. Age- and sex-adjusted hazard ratios (HRs) in the third compared with the first tertile of C-peptide were 1.46 (95% CI 1.15-1.85; P = 0.002) for all cause and 1.58 (1.15-2.18; P = 0.005) for cardiovascular mortality. After further adjustment for common risk factors as well as markers of glucose metabolism, these HRs remained significant at 1.46 (1.10-1.93; P = 0.008) and 1.55 (1.07-2.24; P = 0.022), respectively. Moreover, patients in higher tertiles of C-peptide exhibited higher levels of markers of endothelial dysfunction and atherosclerosis as well as a more severe extent of coronary lesions.. In patients undergoing coronary angiography, C-peptide levels are independently associated with all cause and cardiovascular mortality as well as presence and severity of coronary artery disease. Further studies are needed to examine a potential causal role of C-peptide in atherogenesis in humans.

Topics: Aged; Arteriosclerosis; C-Peptide; Cardiovascular Diseases; Coronary Angiography; Female; Humans; Male; Middle Aged; Mortality

Patients with insulin resistance and early type 2 diabetes exhibit an increased propensity to develop a diffuse and extensive pattern of arteriosclerosis. Typically, these patients show elevated serum levels of the proinsulin cleavage product C-peptide and immunohistochemical data from our group revealed C-peptide deposition in early lesions of these individuals. Moreover, in vitro studies suggest that C-peptide could promote atherogenesis. This study examined whether C-peptide promotes vascular inflammation and lesion development in a mouse model of arteriosclerosis. ApoE-deficient mice on a high fat diet were treated with C-peptide or control injections for 12 weeks and the effect on lesion size and plaque composition was analysed. C-peptide treatment significantly increased C-peptide blood levels by 4.8-fold without having an effect on glucose or insulin levels, nor on the lipid profile. In these mice, C-peptide deposition in atherosclerotic plaques was significantly increased compared with controls. Moreover, lesions of C-peptide-treated mice contained significantly more macrophages (1.6 ± 0.3% versus 0.7 ± 0.2% positive area; P < 0.01) and more vascular smooth muscle cells (4.8 ± 0.6% versus 2.4 ± 0.3% positive area; P < 0.01). Finally, lipid deposition measured by Oil-red-O staining in the aortic arch was significantly higher in the C-peptide group compared with controls. Our results demonstrate that elevated C-peptide levels promote inflammatory cell infiltration and lesion development in ApoE-deficient mice without having metabolic effects. These data obtained in a mouse model of arteriosclerosis support the hypothesis that C-peptide may have an active role in atherogenesis in patients with diabetes and insulin resistance.

Topics: Amino Acid Sequence; Animals; Apolipoproteins E; Arteriosclerosis; C-Peptide; Disease Models, Animal; In Vitro Techniques; Macrophages; Mice; Mice, Knockout; Molecular Sequence Data

Increased levels of C-peptide, a cleavage product of proinsulin, circulate in patients with insulin resistance and early type 2 diabetes mellitus. Recent data suggest a potential causal role of C-peptide in atherogenesis by promoting monocyte and T-lymphocyte recruitment into the vessel wall. The present study examined the effect of C-peptide on vascular smooth muscle cells (VSMCs) proliferation and evaluated intracellular signaling pathways involved. In early arteriosclerotic lesions of diabetic subjects, C-peptide colocalized with VSMCs in the media. In vitro, stimulation of human or rat VSMCs with C-peptide induced cell proliferation in a concentration-dependent manner with a maximal 2.6+/-0.8-fold induction at 10 nmol/L human C-peptide (P<0.05 compared with unstimulated cells; n=9) and a 1.8+/-0.2-fold induction at 0.5 nmol/L rat C-peptide (P<0.05 compared with unstimulated cells; n=7), respectively, as shown by [H3]-thymidin incorporation. The proliferative effect of C-peptide on VSMCs was inhibited by Src short interference RNA transfection, PP2, an inhibitor of Src-kinase, LY294002, an inhibitor of PI-3 kinase, and the ERK1/2 inhibitor PD98059. Moreover, C-peptide induced phosphorylation of Src, as well as activation of PI-3 kinase and ERK1/2, suggesting that these signaling molecules are involved in C-peptide-induced VSMC proliferation. Finally, C-peptide induced cyclin D1 expression as well as phosphorylation of Rb in VSMCs. Our results demonstrate that C-peptide induces VSMC proliferation through activation of Src- and PI-3 kinase as well as ERK1/2. These data suggest a novel mechanism how C-peptide may contribute to plaque development and restenosis formation in patients with insulin resistance and early type 2 diabetes mellitus.

Topics: Animals; Arteriosclerosis; C-Peptide; Cell Proliferation; Cells, Cultured; Cyclin D1; Diabetic Angiopathies; Enzyme Activation; Humans; Intracellular Membranes; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Phosphatidylinositol 3-Kinases; Phosphorylation; Phosphotransferases; Proto-Oncogene Proteins c-akt; Rats; Retinoblastoma Protein; Signal Transduction; src-Family Kinases

Increased levels of C-peptide, a cleavage product of proinsulin, circulate in patients with insulin resistance and early type 2 diabetes, a high-risk population for the development of a diffuse and extensive pattern of arteriosclerosis. This study tested the hypothesis that C-peptide might participate in atherogenesis in these patients.. We demonstrate significantly higher intimal C-peptide deposition in thoracic aorta specimens from young diabetic subjects compared with matched nondiabetic controls as determined by immunohistochemical staining. C-peptide colocalized with monocytes/macrophages in the arterial intima of artery specimen from diabetic subjects. In vitro, C-peptide stimulated monocyte chemotaxis in a concentration-dependent manner with a maximal 2.3+/-0.4-fold increase at 1 nmol/L C-peptide. Pertussis toxin, wortmannin, and LY294002 inhibited C-peptide-induced monocyte chemotaxis, suggesting the involvement of pertussis toxin-sensitive G-proteins as well as a phosphoinositide 3-kinase (PI3K)-dependent mechanism. In addition, C-peptide treatment activated PI3K in human monocytes, as demonstrated by PI3K activity assays.. C-peptide accumulated in the vessel wall in early atherogenesis in diabetic subjects and may promote monocyte migration into developing lesions. These data support the hypothesis that C-peptide may play an active role in atherogenesis in diabetic patients and suggest a new mechanism for accelerated arterial disease in diabetes.

Topics: Adolescent; Adult; Androstadienes; Aorta, Thoracic; Aortic Diseases; Arteriosclerosis; C-Peptide; Cells, Cultured; Chemotaxis; Chromones; Diabetes Mellitus, Type 2; Disease Progression; Enzyme Inhibitors; Female; GTP-Binding Proteins; Humans; Hyperinsulinism; Insulin Resistance; Macrophages; Male; Metabolic Syndrome; Models, Biological; Monocytes; Morpholines; Pertussis Toxin; Phosphatidylinositol 3-Kinases; Wortmannin

To evaluate the effect of massive weight loss on insulin sensitivity, soluble adhesion molecules, and markers of the insulin resistance syndrome (IRS).. Eighteen morbidly obese patients underwent gastric banding and were evaluated before and 6 and 12 months after surgery. Total insulin secretion, hepatic insulin extraction, and insulin sensitivity were analyzed by oral glucose-tolerance test model analysis. In addition, soluble intercellular adhesion molecule-1, vascular cell adhesion molecule-1, E-selectin, leptin, high-sensitivity C-reactive protein, plasminogen activating factor-1 (PAI-1), and tissue plasminogen activator were measured.. BMI dropped from 45.22 +/- 5.62 to 36.99 +/- 4.34 kg/m(2) after 6 months and 33.72 +/- 5.55 kg/m(2) after 12 months (both p < 0.0001). This intervention resulted in a significant reduction of blood pressure (p < 0.00001), triglycerides (p < 0.01), fasting blood glucose (p = 0.03), basal insulin (p < 0.001), and basal C-peptide (p = 0.008) levels. Total insulin secretion decreased (p < 0.05), whereas hepatic insulin extraction (p < 0.05) and oral glucose insulin sensitivity index (p < 0.0001) increased compared with baseline. Leptin (p < 0.0001) and E-selectin levels decreased significantly after 6 and 12 months (p = 0.05), whereas significantly lower levels of intercellular adhesion molecule-1 and PAI-1 were only seen after 6 months. Subclinical inflammation, measured by high-sensitivity C-reactive protein, was lowered to normal ranges. No changes were observed in vascular cell adhesion molecule-1 and tissue plasminogen activator levels.. Although gastric banding ameliorates several features of the IRS, including 29.05% improvement in insulin sensitivity and blood pressure and reduction of soluble adhesion molecules and PAI-1, considerable weight loss did not normalize all components of the IRS in morbidly obese patients.

Topics: Adult; Arteriosclerosis; C-Peptide; Cell Adhesion Molecules; E-Selectin; Female; Glucose Tolerance Test; Humans; Hypertension; Insulin; Insulin Resistance; Intercellular Adhesion Molecule-1; Leptin; Male; Obesity, Morbid; Plasminogen Activators; Stomach; Vascular Cell Adhesion Molecule-1; Weight Loss

Increased levels of C-peptide, a cleavage product of proinsulin, circulate in patients with insulin resistance and early type 2 diabetes, a high-risk population for the development of a diffuse and extensive pattern of arteriosclerosis. The present study examined the effect of C-peptide on CD4(+) lymphocyte migration, an important process in early atherogenesis. C-peptide stimulated CD4(+) cell chemotaxis in a concentration-dependent manner. This process involves pertussis toxin-sensitive G-proteins as well as activation of phosphoinositide 3-kinase (PI 3-K). Biochemical analysis showed that C-peptide induced recruitment of PI 3-K to the cell membrane as well as PI 3-K activation in human CD4(+) cells. In addition, antidiabetic peroxisome proliferator-activated receptor gamma-activating thiazolidinediones inhibited C-peptide-induced CD4(+) cell chemotaxis as well as PI 3-Kgamma activation. Finally, immunofluorescence staining of thoracic artery specimen of diabetic patients showed intimal CD4(+) cells in areas with C-peptide deposition. Thus, C-peptide might deposit in the arterial intima in diabetic patients during early atherogenesis and subsequently attract CD4(+) cells to migrate into the vessel wall.

Topics: Arteriosclerosis; C-Peptide; CD4-Positive T-Lymphocytes; Cell Movement; Cells, Cultured; Chemotaxis; Diabetic Angiopathies; Enzyme Activation; GTP-Binding Proteins; Humans; Pertussis Toxin; Phosphatidylinositol 3-Kinases; Thiazolidinediones

Subclinical inflammation has been implicated in the initiation and/or progression of atherosclerosis. Diabetes mellitus and obesity are risk factors for atherosclerosis, and asymptomatic low grade inflammation occurs prior to overt vascular lesions in these patients. In contrast to adults, little information exists concerning low grade inflammation in young type 1 diabetes and juvenile obesity.. To investigate low grade inflammation and immune activation in juvenile diabetes mellitus and obesity.. hs-CRP, soluble interleukin-2 receptor (sIL-2R), C-peptide, insulin, cortisol, vitamin B12, folic acid, leptin, and homocysteine were determined in 148 patients with juvenile type 1 diabetes, 86 obese children and 142 normal weighted age-matched healthy controls. Intima-media thickness (IMT) and lumen diameter of both common carotid arteries (CCA) was measured by ultrasonography in 52 healthy pediatric controls, 10 diabetics, and 34 obese juveniles.. Serum hs-CRP was significantly elevated in patients with type 1 diabetes (p < 0.0001), and obese children (p < 0.0001) as compared to the control group. The obese juveniles (p < 0.0001) and the diabetics (p < 0.0001) showed significantly increased values for IMT of CAAs. Levels of homocysteine, sIL-2R, insulin, cortisol, vitamin B12, and folic acid did not differ from the controls. The elevation of hs-CRP was more pronounced in obesity as compared to type 1 diabetes (p < 0.0001), and the hs-CRP values correlated significantly with body mass index standard deviation score (BMI-SDS) values. Furthermore, the IMT and the luminal diameter of CCAs showed significant correlations with BMI-SDS values.. A low grade inflammation as determined by serum hs-CRP is significantly increased in children with type 1 diabetes, and even more pronounced in apparently healthy juveniles with obesity. The increased IMT of CCAs strongly argues for an association between this low grade inflammation and early atherosclerotic vessel injury.

Topics: Adolescent; Arteriosclerosis; Body Mass Index; C-Peptide; C-Reactive Protein; Carotid Artery, Common; Child; Diabetes Mellitus, Type 1; Female; Folic Acid; Homocysteine; Humans; Inflammation; Leptin; Male; Obesity; Receptors, Interleukin-2; Tunica Intima; Vitamin B 12

The effects of tibolone on body weight, body composition, and fasting carbohydrate measures in surgically postmenopausal cynomolgus monkeys were compared to those of conjugated equine estrogens (CEE) with and without medroxyprogesterone acetate (MPA). Monkeys were fed a moderately atherogenic diet with either no hormones (control n = 29), CEE (0.042 mg/kg, n = 27), CEE + MPA (0.167 mg/kg, n = 29), low-dose tibolone (LoTib, 0.05 mg/kg, n = 30), or high-dose tibolone (HiTib, 0.20 mg/kg, n = 31) daily for 2 years. Body weight (BW) was measured throughout the study, and dual-energy x-ray absorptiometry (DEXA) scans of the abdominal region (lumbar vertebrae 1 through 5) were performed at the end of the trial to assess abdominal body composition. Fasting carbohydrate measures (glucose, insulin, C-peptide, and fructosamine) were determined at baseline and after 2 years of treatment. Compared to controls, BW significantly increased and abdominal soft tissue mass was greater (analysis of variance [ANOVA], P <.001, P = 0.003, respectively) in all but the CEE-treated group (P =.78, P =.94, respectively). HiTib-treated monkeys had greater abdominal lean mass compared to controls (P =.008), while there was no significant treatment effect on abdominal fat mass (analysis of covariance [ANCOVA], P =.29). Fasting insulin concentrations and fasting insulin/glucose ratios were greater in CEE + MPA- (P =.002, P =.03, respectively) and HiTib-treated monkeys (P =.03, P =.02, respectively) compared to controls. There was a strong trend for a treatment effect on fasting blood glucose concentration (ANCOVA, P =.06) with CEE + MPA-treated animals having the greatest values, despite no difference in fructosamine concentration (ANCOVA, P =.57). Using these fasting measures, the homeostasis model assessment (HOMA-IR) revealed significant insulin resistance with CEE + MPA treatment compared to controls (P =.008), while the quantitative insulin sensitivity check index (QUICKI) showed significantly impaired insulin sensitivity in all hormone replacement therapy (HRT) groups (all P values <.03), except CEE (P =.12). In conclusion, HRT with CEE + MPA or tibolone results in greater BW, abdominal soft tissue, and insulin resistance (CEE + MPA and HiTib) compared to control-treated monkeys.

Topics: Animals; Arteriosclerosis; Blood Glucose; Body Composition; Body Weight; C-Peptide; Carbohydrates; Dietary Fats; Energy Intake; Estrogen Replacement Therapy; Estrogens, Conjugated (USP); Fasting; Female; Fructosamine; Insulin; Insulin Resistance; Macaca fascicularis; Medroxyprogesterone Acetate; Norpregnenes; Ovariectomy; Postmenopause

Iron is an important factor in the process of oxidation stress and atherogenesis which is as a rule potentiated in subjects with the insulin resistance syndrome. Hypertension is one of the main components of this syndrome. Ferritin due to its relationship with impaired insulin sensitivity becomes a candidate for a new indicator of insulin resistance. The subject of the present study was to assess whether we shall find in young healthy offspring of hypertensive parents changes in the ferritin level, oxidizability of LDL and whether these are related to parameters of glucose tolerance, insulin secretion and sensitivity. Twelve young (27 +/- 3.6 years) non-obese, normotesive offspring of hypertensive parents were compared with a group of 14 controls. Glucose tolerance, insulin secretion and sensitivity were examined by means of a hyperglycaemic clamp and oGTT. As to the ferritin level, the offspring of hypertensive parents did not differ significantly from controls, differences were not fond in the oxidizability of LDL-C. The glucose tolerance was comparable in the two groups. Offspring of hypertensive parents had however a significantly higher insulin and C peptide level when using the clamp and during the glucose tolerance test (p < 0.05), and a reduced insulin sensitivity (p < 0.05). The negative correlation between the index of insulin sensitivity and ferritin suggests that ferritin could be associated with the syndrome of insulin resistance.

Topics: Adult; Arteriosclerosis; C-Peptide; Ferritins; Glucose Tolerance Test; Humans; Hypertension; Insulin; Insulin Resistance; Lipoproteins, LDL; Male; Oxidative Stress; Risk Factors

In 18 patients with pernicious anaemia (PA) the authors assessed the blood glucose level, C-peptide level and immunoreactive insulin (IRI) during the oral glucose tolerance test (o-GTT). They calculated the body mass index (BMI), assessed the level of the thyroid-stimulating hormone (s-TSH), free thyroxine (fT4), triiodothyronine (T3) and took repeatedly blood pressure readings. In one female patient they confirmed the diagnosis of insulin dependent diabetes mellitus (IDDM), in another six subjects they detected non-insulin dependent diabetes mellitus (NIDDM), incl. two persons where it was detected newly. In four patients impaired glucose tolerance was revealed. In the remaining seven patients non-classifiable glucose tolerance was found, none of the patients had a quite normal o-GTT. In five patients, hitherto not diagnosed latent hypothyroidism was detected. Eleven subjects were obese, four patients suffered from hypertension, another six from systolic hypertension, in eight patients a significantly elevated C-peptide level on fasting was found, in the majority of patients an elevated, or protracted response of C-peptide and insulin to orally administered glucose was found. Patients with pernicious anaemia must be considered subjects with cumulation of risk factors for atherosclerosis; these risk factors must be actively sought and treated.

Topics: Aged; Aged, 80 and over; Anemia, Pernicious; Arteriosclerosis; Blood Glucose; C-Peptide; Diabetes Complications; Female; Glucose Tolerance Test; Humans; Hyperinsulinism; Insulin; Male; Middle Aged; Risk Factors

To identify the clinical characteristics of early-onset NIDDM patients with severe diabetic complications.. The clinical cases of a large number of diabetic patients who visited a diabetes center within the period 1970-1990 were reviewed. Of a total of 16,842 diabetic patients, 1,065 (6.3%) had early-onset NIDDM (diabetes diagnosed before 30 years of age). These 1,065 patients were divided into two groups, those who developed proliferative retinopathy before the age of 35 (n = 135) and those who did not (n = 930). Development of proliferative retinopathy, nephropathy, renal failure, blindness, and atherosclerotic vascular disease were compared between the two groups.. The subgroup of 135 patients was characterized by poor glycemic control, often requiring insulin therapy and a higher familial prevalence of diabetes, and contained a greater proportion of women than the subgroup of 930 patients. Of the 135 patients, 99 (67%) developed proliferative retinopathy before the first visit. The 135 patients developed severe progressive complications in contrast to the 930 patients. A total of 81 patients (60%) developed diabetic nephropathy at a mean age of 31 years, 31 (23%) developed renal failure requiring dialysis at a mean age of 35 years, 32 (24%) became blind at a mean age of 32 years, and 14 (10%) developed atherosclerotic vascular disease at a mean age of 36 years.. Some Japanese early-onset NIDDM patients develop severe diabetic complications in their youth. Most of them had no symptoms nor regular treatment regarding diabetes until they were noticed to have developed severe diabetic complications. Although the relevant prevalence and the pathogenetic mechanism underlying the rapid onset of the complications remain to be determined, prolonged inadequate treatment of and familial predisposition to diabetes may be contributing factors. Careful diabetes care in the twenties, not only for IDDM but also for NIDDM patients, is warranted.

Topics: Adult; Age Factors; Age of Onset; Arteriosclerosis; Blindness; Body Mass Index; C-Peptide; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diabetic Nephropathies; Diabetic Retinopathy; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Japan; Kidney Failure, Chronic; Male; Middle Aged; Retrospective Studies

To examine the hypothesis that hyperinsulinaemia promotes atherosclerosis, cholesterol-fed rabbits were injected subcutaneously with 6 i.u. of human insulin (n = 16) or placebo (n = 20) daily for 24 weeks; injection of insulin resulted in hyperinsulinaemia for up to 16 h after injection. Compared to placebo rabbits, insulin-treated rabbits had higher levels of insulin antibodies in plasma, similar levels of intermediate density, low density and high density lipoprotein cholesterol and similar activities of hepatic and lipoprotein lipase in post-heparin plasma, but lower levels of plasma C-peptide, blood glucose, postprandial plasma triglycerides, plasma cholesterol and very low density lipoprotein cholesterol. On univariate analysis, with and without adjustment for differences in plasma cholesterol levels between the two groups, there were no significant differences in extent or severity of atherosclerosis between insulin and placebo rabbits. Furthermore, after combining the results from all the rabbits to examine plasma insulin levels and the other variables mentioned above as predictors of atherosclerosis severity, plasma insulin level was not a predictor, on univariate or multiple linear regression analysis; the first ranked independent predictors were postprandial intermediate density lipoprotein cholesterol in the arch, and postprandial plasma triglyceride in both the thoracic and abdominal aorta. These results suggest that exogenous hyperinsulinaemia does not promote atherogenesis in cholesterol-fed rabbits, but that postprandial levels of intermediate density lipoprotein cholesterol or plasma triglycerides may be involved in atherogenesis.

Topics: Animals; Aorta; Arteriosclerosis; Blood Glucose; C-Peptide; Cholesterol; Cholesterol, Dietary; Diet, Atherogenic; Female; Humans; Hyperinsulinism; Insulin; Insulin Antibodies; Lipase; Lipoprotein Lipase; Lipoproteins; Lipoproteins, HDL; Lipoproteins, IDL; Liver; Placebos; Predictive Value of Tests; Rabbits; Recombinant Proteins; Time Factors; Triglycerides

High insulin levels are a recognized risk factor for atherosclerosis. Microvascular endothelium is more susceptible to metabolic and mitogenic effects of insulin than large-vessel endothelium. Besides their atherogenic effect, high insulin levels impair fibrinolysis by enhancing plasminogen activator inhibitor-1. We undertook this study to evaluate the hypothesis that elevated serum insulin and C-peptide levels are related to cerebral small-vessel disease rather than large-vessel pathology.. One hundred ninety-four consecutive patients presenting with symptomatic cerebrovascular disease were assigned to three subgroups that were differentiated by clinical presentations, brain imaging studies, and extracranial as well as transcranial vascular ultrasound findings: (1) patients with lacunes (n = 20), (2) patients with subcortical arteriosclerotic encephalopathy (n = 35), and (3) patients with strokes due to large-vessel disease (n = 99). Patients who had suffered a cryptogenic (n = 9) or cardioembolic (n = 16) stroke or who showed characteristics of the microangiopathy and macroangiopathy groups (n = 15) were not further evaluated. Thirty patients without manifestations of cerebrovascular disease were also examined. Fasting blood glucose, insulin, and C-peptide levels were determined in all subjects.. There were no significant differences in age or sex among the three groups and control patients. Insulin levels were significantly higher in the lacunar group compared with the subcortical arteriosclerotic encephalopathy group, the macroangiopathy group, and the control patients (median [interquartile range]: 103.8 [198.6], 72.0 [103.2], 66.0 [57.0], and 52.2 [57.0] pmol/L, respectively; all P < .05, Mann-Whitney test). There was a statistically significant difference in insulin concentrations between the microangiopathy group (subcortical arteriosclerotic encephalopathy and lacunes) and the macroangiopathy and control groups (81.0 [110.4], 66.0 [57.0], and 55.2 [57.0] pmol/L, respectively; all P < .05, Mann-Whitney). The same was true for the distribution of C-peptide levels and to a minor extent blood glucose values, but these differences failed to reach statistical significance.. Elevated insulin levels potentially represent a pathogenetic factor in the development of cerebral small-vessel disease, predominantly in patients presenting with lacunes. Whether this is due solely to atherosclerotic changes of the small penetrating arteries or whether changes in hemorheology are operative as well remains to be evaluated.

Topics: Aged; Arteriosclerosis; Blood Glucose; C-Peptide; Cerebrovascular Circulation; Cerebrovascular Disorders; Diabetes Mellitus; Female; Humans; Hyperinsulinism; Hypertension; Insulin; Male; Microcirculation; Middle Aged; Prevalence; Risk Factors

The relation between the C-peptide concentration in twenty-four-hour urine specimens and atherogenic risk factors was investigated in 38 patients with noninsulin-dependent diabetes mellitus in an attempt to determine the significance of urine C-peptide in diagnosing "syndrome X," which is characterized by insulin resistance. Weak positive correlations between twenty-four-hour urine C-peptide concentration and body mass index, systolic blood pressure (BP), diastolic BP, serum total cholesterol, and serum triglyceride were detected. A weak negative correlation was also apparent between urine C-peptide and serum high-density lipoprotein (HDL). The body mass index and serum triglyceride of patients with urine C-peptide excretion of > 100 micrograms/day were significantly higher than those in patients with normal urine C-peptide excretion (< 100 micrograms/day) (P < 0.01 and P < 0.02, respectively). Systolic BP, diastolic BP, serum total cholesterol, and serum HDL did not differ significantly between the two groups of patients. Results indicate that twenty-four-hour urine C-peptide concentration is of significance in determining whether a patient has a tendency to insulin resistance but has only limited value as a quantitative measure of endogenous insulin secretion.

Topics: Adult; Aged; Aged, 80 and over; Arteriosclerosis; Body Mass Index; C-Peptide; Diabetes Mellitus, Type 2; Female; Humans; Insulin Resistance; Male; Microvascular Angina; Middle Aged; Risk Factors; Triglycerides

Both vascular disease and elevated concentrations in plasma of plasminogen activator inhibitor type-1 (PAI-1) are prominent in patients with non-insulin-dependent diabetes mellitus (NIDDM). We and others have hypothesized that the increased PAI-1 may contribute to acceleration of atherosclerosis in this condition and in other states characterized by insulin resistance as well. Surprisingly, however, elevations of PAI-1 decrease when type II diabetic patients are treated with exogenous insulin, as do circulating concentrations of the precursor of insulin, proinsulin, in plasma. Accordingly, the increased PAI-1 in patients with NIDDM may reflect effects of precursors of insulin rather than or in addition to those of insulin itself. To assess this possibility directly, this study was performed to identify potential direct effects of proinsulin and proinsulin split products on synthesis of PAI-1 in liver cells, thought to be the major source of circulating PAI-1 in vivo.. Hep G2 cells (highly differentiated human hepatoma cells) were exposed to human proinsulin, des(31,32)proinsulin and des(64,65)proinsulin (split products of proinsulin), or C-peptide. Accumulation of PAI-1 in conditioned media increased in a time- and concentration-dependent fashion in response to the two des-intermediates [3.3-fold with des(31,32)proinsulin and 4.5-fold with des(64,65)proinsulin]. C-peptide elicited no increase. Stimulation was transduced at least in part by the insulin receptor as shown by inhibition of stimulation by insulin receptor antibodies, mediated at the level of PAI-1 gene expression as shown by the 2.2- to 2.9-fold increases in steady-state concentrations of PAI-1 mRNA, and indicative of newly synthesized protein as shown by results in metabolic labeling experiments.. Our results are consistent with the hypothesis that precursors of insulin (proinsulin and proinsulin split products), known to be present in relatively high concentrations in plasma in patients with NIDDM and conditions characterized by insulin resistance, may directly stimulate PAI-1 synthesis, thereby attenuating fibrinolysis and accelerating atherogenesis.

Topics: Arteriosclerosis; C-Peptide; Culture Media; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Gene Expression; Humans; Liver; Plasminogen Activator Inhibitor 1; Proinsulin; Protein Precursors; Risk Factors; RNA, Messenger; Tumor Cells, Cultured

We have previously demonstrated that women who had given birth to large infants had a six-fold increased risk of developing Type 2 (non-insulin-dependent) diabetes mellitus compared with a control group matched for age and parity. However, the patients were extremely obese which explained, in part, the increased risk. In the present investigation we studied whether the delivery of large infants correlated with risk factors for atherosclerotic vascular disease other than obesity and diabetes, and therefore could serve as early markers for syndrome X. The study consisted of 73 women who 20-27 years earlier had given birth to large infants weighing 4,500 g or more. Another group of 73 women matched for age, parity and BMI who had delivered infants weighing less than 4,500 g within a 3-month period served as a control group. Of these 73 patient/control pairs, 48 (66%) were able to participate in the investigation. Mean age was 52.2 years (range 40-66 years). No differences were noted for family history of diabetes and medication prescribed for vascular disease between the groups. An oral glucose tolerance test was performed and glucose, insulin and C-peptide at 0 and 2 h were estimated. Triglycerides, cholesterol, LDL and HDL cholesterol were analysed at baseline. We found no tendency towards hyperinsulinaemia and hyperglycaemia in the patients and both groups had the same relative increase in levels of insulin and C-peptide. No difference between the groups regarding manifest symptoms of vascular disease, either in blood pressure or in proteinuria were observed.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Arteriosclerosis; Biomarkers; Birth Weight; Blood Glucose; C-Peptide; Cholesterol, HDL; Cholesterol, LDL; Female; Glucose Tolerance Test; Humans; Incidence; Insulin; Middle Aged; Predictive Value of Tests; Risk Factors; Triglycerides

Microalbuminuria predicts cardiovascular events in diabetic and nondiabetic patients. For a better understanding of the physiopathological importance of microalbuminuria in atherosclerotic disease, we evaluated the relation between urinary albumin excretion and arterial blood pressure, left ventricular mass, insulin, and lipid levels. The studies were conducted in patients with atherosclerotic peripheral vascular disease. Urinary albumin excretion (studied by nephelometry; an average of triplicate collections from 8 PM to 8 AM), causal blood pressure, echocardiographic left ventricular mass index and wall thickness, plasma immunoreactive insulin and C-peptide (both basally and after a 75-g oral glucose load), blood lipids, and fibrinogen were studied in eight normal subjects and 20 nonobese, nondiabetic male patients with angiographically documented atherosclerotic peripheral vascular disease and preserved renal function, 12 of whom were either hypertensive or on antihypertensive treatment. Eight patients were microalbuminuric (urinary albumin > 20 micrograms/min) and 12 were not. Ankle-arm index and calf and foot transcutaneous oxygen tension were reduced in comparison with normal control subjects but superimposable between the two patient groups to indicate a comparable clinical progression of the vascular disease. In the microalbuminuric subjects, left ventricular mass index was greater, interventricular septum was thicker, and cardiac hypertrophy was more frequent than in nonmicroalbuminuric patients. The prevalence of hypertension tended to be greater and systolic blood pressure values were higher in the presence of microalbuminuria. Overall, a highly significant relation existed between urinary albumin excretion and left ventricular mass. Systolic blood pressure was greater and a history of arterial hypertension was more frequent among microalbuminurics, whereas diastolic blood pressure values showed a statistically significant correlation with both variables.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Administration, Oral; Aged; Albuminuria; Angiography; Arteriosclerosis; Blood Glucose; Blood Pressure; C-Peptide; Echocardiography; Fibrinogen; Glucose; Humans; Hyperinsulinism; Hypertrophy, Left Ventricular; Insulin; Lipids; Male; Middle Aged; Peripheral Vascular Diseases

In an attempt to define the pancreatic B cell function in the elderly, we subjected 88 non-obese individuals (aged between 21 and 88) to an oral glucose tolerance test (OGTT), a simple glucagon test (SGT) and OGTT-glucagon test, in which the plasma glucose, insulin and serum C-peptide (CPR) were measured. We investigated heterogeneity in glucose intolerance in the elderly and its relationship to atherosclerosis. In the OGTT and SGT test, the insulin responses (SIRI/SPG ratios) for normal, borderline and DM1 (fasting plasma glucose less than 140 mg/dl and 2 h-PG greater than or equal to 200 mg/dl) groups of the elderly (60 and above) were not significantly different from those for normal group of young and middle-aged (below 60) and were significantly higher for elderly group than for the young and middle-aged group in each glucose tolerance group. But the insulin responses for the DM2 (fasting plasma glucose greater than or equal to 140 mg/dl and 2 h-PG greater than or equal to 200 mg/dl) group of the elderly were not significantly different from those for the DM1 and DM2 groups of young and middle-aged. The insulin responses of normal, borderline and DM1 groups of the elderly with atherosclerosis were significantly higher than those of the comparable groups without atherosclerosis, while the insulin responses of the borderline and DM1 groups of the elderly with atherosclerosis were similar to those of the control group of the young. In the OGTT-glucagon test, there were no differences in the insulin response or serum CPR response among the normal, borderline and DM1 groups of the elderly, and these responses were significantly higher for the elderly group than the for young and middle-aged group in each glucose tolerance group. But these responses for the DM2 group of the elderly were not significantly different from those for the DM1 and DM2 groups of the young and middle-aged. These results indicate that the pancreatic B cell function of the normal group in the elderly remains favorable while mildly impaired glucose tolerance was exhibited by the borderline and DM1 groups, who are comparable with the normal group of the young and middle-aged. But this function was clearly reduced in the DM2 group of the elderly. These findings suggest that there is a subgroup in the elderly, which has clinically evident atherosclerosis, mild glucose intolerance and high insulin response. Their pancreatic B cell function remains favorable.

Topics: Adult; Aged; Aged, 80 and over; Aging; Arteriosclerosis; Blood Glucose; C-Peptide; Female; Glucose Tolerance Test; Humans; Insulin; Islets of Langerhans; Male; Middle Aged; Pancreatic Function Tests

Using a radioimmunoassay a low C-peptide fasting level was revealed in children, pregnant and lying-in women as well as in patients with insulin-dependent diabetes mellitus. After breakfast and insulin administration with curative purposes the IRI concentration in children increased whereas the C-peptide level changed insignificantly. Changes of the insulin secretion were more noticeable in severe diabetes mellitus with vascular complications and in disease decompensation. The atherogenic nature of the lipid metabolism (an increase in the cholesterol, triglyceride and beta-lipoprotein levels), changes in the liver and a tendency to vascular involvement are the results of insulin effect inadequacy. Such metabolic derangements in pregnant women create unfavorable conditions for the development of fetus and may lead to early atherogenic processes.

Topics: Adult; Arteriosclerosis; C-Peptide; Child; Diabetes Mellitus, Type 1; Female; Fetal Blood; Humans; Insulin; Insulin Secretion; Lipids; Pregnancy; Pregnancy in Diabetics; Radioimmunoassay