The association between leptin and proinsulin is lost with central obesity

OBJECTIVE: Hyperproinsulinaemia and hyperleptinaemia are interrelated features of the insulin resistance syndrome that are linked to the prospective risk of cardiovascular diseases. Whether the association between leptin and proinsulin is different between groups displaying different degrees of risk for cardiovascular diseases is not known. We therefore examined this association in men versus women and in pre- versus postmenopausal women from a population-based sample. DESIGN AND SUBJECTS: Healthy subjects (n = 158; 85 men and 73 pre- and postmenopausal women) from the Northern Sweden Monitoring of Trends and Determinants in Cardiovascular Disease population were studied with a cross-sectional design. METHODS: Anthropometric measurements (body mass index and waist circumference) and oral glucose tolerance tests were performed. Enzyme-linked immunosorbent assays were used for the analyses of specific insulin and proinsulin, and radioimmunoassay for leptin. Insulin resistance and beta-cell function were calculated according to the homeostasis assessment model. Partial correlation coefficients adjusted for age and measures of adiposity were calculated and multiple linear regression analyses were performed with leptin as dependent variable. RESULTS: In nonobese men and premenopausal women and in obese postmenopausal women, leptin was significantly associated with proinsulin after stratification for waist circumference. Furthermore, a multivariate analyses taking age and measures of adiposity into account, showed that high fasting proinsulin was a significant predictor of high leptin in these groups. In contrast, this association was lost with increasing central obesity in men and premenopausal women. CONCLUSIONS: This study shows that both the degree of adiposity and the hormonal milieu influence the association between circulating leptin and proinsulin in a normal population. Therefore, the insulin resistance syndrome seems to be characterized by lost association between leptin and proinsulin, which may be explained by dysfunction in the adipoinsular axis.     

血清IGF—1、IGFBP—1，GH水平与糖尿病慢性并发症关系的研究

目的：揭示胰岛素样生长因子－1,胰岛素样生长因子结合蛋白－1,生长激素对糖尿病慢性并发症的发生,发展的影响。方法：测定20例健康对照者和62例2例糖尿病,10例1例糖尿病患者的胰岛素样生长因子－1（IGF－1）,胰岛素样生长因子结合蛋白－1（IGFBP－1）,生长激素（GH）及血浆胰岛素（INS）,C肽（C－P）,糖化血红蛋白（HbAlc)指标,结果：（1）IGF－1水平,1型糖尿病患者显著低于对照组（P＜0．05）,2型糖尿病患者显著低于对照组（P＜0．05）,（2）IGFBP－1水平,1型糖尿病患者显著高于对照组（P＜0．05）,2型糖尿病肥胖型伴高胰岛素血症者显著低于对照组（P＜0．05）;（3）GH水平,1型糖尿病患者显著高于对照组（P＜0．05）,2型糖尿病与对照组无显著差异（P＞0．05）,（4）合并糖尿病肾病及视网膜病变患者IGF－1水平均较对照组增高（P＜0．05）,（5）IGF－1水平与HbAlc间呈负相关（P＜0．01 2型r=-0.62 1型r=-0.73)。结 论：IGF－1,IGFBP－1,GH水平的检测对糖尿病慢性并发症,特别是微血管病变的发生,发展有重要的临床意义。     

The serum concentration of insulin, C-peptide, and proinsulin in patients with acute pancreatitis

Summary In 14 patients with acute pancreatitis during 16 episodes of the disease the concentrations of blood glucose, serum insulin (IRI), C-peptide (CP), and proinsulin (Pro) were determined in the fasting state on d 1, 2, 3, 5, and 10 after the attack. The peptides were measured using RIAs, and for determination fo CP two antibodies: Byk-Mallinckrodt’s and more specific M-1221 Novo antibodies were used. Apart from sporadic rises in the initial period of the disease, the blood glucose level did not change significantly and had a decreasing trend. On d 1 the mean serum IRI level was 0.17±0.04 (SD) nM, and it decreased on d 5 to 0.06±0.04 nM, rising again to 0.11±0.15 nM on d 10. The serum Pro concentration was on the same days: 11.1±12.6, 4.2±2.4 and 7.5±10.8 pM, whereas the serum CP values determined with M-1221 antibodies were 0.48±0.50, 0.34±0.19, and 0.52±0.25 nM, respectively. However, when serum CP was determined using Byk-Mallinckrodt kits, the concentration on d 1 was 1.90±1.12 nM and over the following days it decreased to 1.08±0.98 nM on d 5 and on d 10 it was 1.11±0.46 nM. In one patient (not included in the calculation of the mean values), in whom the second attack of acute pancreatitis had a fatal outcome, the serum levels of all three peptides were very high, with a particularly evident difference of CP-values, dependent on the antibodies used: 2.47 nM with M-1221 antibodies and 9.90 mM with Byk-Mallinckrodt kits on d 5. We hypothesize that the transient decrease of the serum peptides released into the blood in the process of insulin biosynthesis observed in the early period of acute pancreatitis is owing to their breakdown by the activated pancreatic proteases. Our observation suggests also that in acute pancreatitis in blood appeared an unidentified protein reacting with less specific antibodies to C-peptide.     

肥胖儿童血清 CT、25-OHD 水平变化及其与胰岛素抵抗的关系

目的观察不同程度、类型肥胖儿童血清卡尼汀（CT）、25-羟基维生素D（25-OHD）水平,并分析其与胰岛素抵抗的关系。方法单纯性肥胖儿童60例（观察组,其中轻度肥胖23例,中度肥胖30例,重度肥胖7例;腹型37例,周围型33例）,健康体检儿童30例（对照组）。采用高效液相色谱法测定两组血清CT水平,免疫化学发光法检测25-OHD水平,葡萄糖氧化酶法检测空腹血糖（FBG）,放射免疫分析法检测空腹胰岛素（FINS）水平,ELISA法检测瘦素（LP）、脂联素（ADPN）水平,计算体质量指数（BMI）、腰臀比（WHR）,按HOMA模型计算胰岛素抵抗指数（InRI）,并分析观察组血清CT、25-OHD与其余观察指标的相关性。结果与对照组比较,观察组CT、25-OHD、ADPN水平降低,BMI、WHR、FBG、FINS、InRI、LP水平升高（P〈0．05或0．01）;与重度比较,观察组轻度、中度肥胖患儿血清CT、25-OHD水平升高（P均〈0．05）;与周围型比较,观察组腹型肥胖患儿血清CT、25-OHD水平降低（P均〈0．05）;观察组儿童血清CT与ADPN（r：0．364,P〈0．01）、25-OHD（r=0．251,P〈0．05）呈正相关,与WHR（r=0．351,P〈0．01）、FINS（r=0．270,P〈0．05）、InRI（r=0．395,P〈0．01）、IJP（r=0．273,P〈0．01）呈负相关。血清25-OHD与ADPN呈正相关（r=0．417,P〈0．01）,与WHR（r=-0．435,P〈0．01）、InRI（r=-0．317,P〈0．01）、LP（r=-0．291,P〈0．01）呈负相关。结论不同类型及程度肥胖患儿血清CT、25-OHD水平不同,CT、25-OHD与肥胖儿童胰岛素抵抗有关。     

Gastric bypass alters the dynamics and metabolic effects of insulin and proinsulin secretion.

AIMS: Hyperproinsulinaemia is associated with obesity and is a risk factor for Type 2 diabetes. We explored the dynamics of proinsulin and insulin and postprandial effects on glucose and lipids in subjects who had undergone gastric bypass (GBP) surgery compared with morbidly obese (MO) subjects and normal weight control subjects (NW). METHODS: Subjects free from diabetes were recruited: 10 previously MO subjects [body mass index (BMI) +/- sd, 34.8 +/- 6.2 kg/m2] who had undergone GBP surgery, 10 MO subjects (BMI 44 +/- 3.1 kg/m2) and 12 NW control subjects (BMI 23.2 +/- 2.4 kg/m2). After an overnight fast, a standard meal (2400 kJ) was ingested and glucose, proinsulin, insulin free fatty acids and triglycerides were determined up to 180 min. RESULTS: Fasting proinsulin was similar in the GBP group and NW control subjects, but threefold increased in MO subjects (P < 0.05). Postprandial AUC for glucose was similar in the three groups and AUC for proinsulin was high in MO, intermediate in the GBP group and lowest in NW control subjects (P for trend = 0.020). Postprandial proinsulin at 60 min was similar in the GBP group and MO subjects and twofold higher than in NW control subjects. Postprandial proinsulin at 180 min was normal in the GBP group, but fivefold increased in MO subjects (P = 0.008). Insulin increased rapidly at 30 min in the GBP group and was normal at 90 min, whereas insulin was still increased at 90-180 min in the MO subjects (P < 0.001). CONCLUSIONS: MO subjects, free from diabetes, have elevated proinsulin concentrations in the fasting as well as the postprandial phase. After GBP surgery markedly lower fasting and postprandial proinsulin concentrations were observed, although BMI was higher compared with NW control subjects.     

Plasma leptin is not associated with insulin resistance and proinsulin in non-diabetic South Asian Indians

In an earlier study, we observed only a weak association between plasma insulin (non-specific assay) and leptin in South Asian Indians. This was in contrast to the observations in many other ethnic groups. With the availability of measurements of specific insulin (SI) and proinsulin (PI) in the same study group, we have reanalysed the data to look for possible correlation of leptin with proinsulin and with insulin resistance calculated from the fasting values of specific insulin and glucose using the HOMA model. Subjects with normoglycaemia (n = 117) and impaired glucose tolerance (n = 27, WHO criteria) were included in the analysis. Leptin values were higher in women. Multiple linear regression analysis showed that the variations in leptin concentrations in men were associated with BMI, WHR, and 2 h SI values (R² = 56.2 %) while fasting SI and proinsulin concentrations had no significant association. In women BMI and age showed a significant association with serum leptin values (R² = 40.1 %). Univariate and multivariate analyses using insulin resistance as the dependent variable showed that it had no association with leptin in both genders. Leptin had no correlation with proinsulin also. This study confirmed that in Asian Indians the association between plasma leptin and insulin concentrations is weak and that leptin has no influence on insulin resistance. Proinsulin and leptin are also not correlated in this population. Insulin resistance shows correlation with the β-cell function both in men and women. © 1998 John Wiley & Sons, Ltd.     

Serum IGF-1 and IGFBP-3 levels in healthy children between 0 and 6 years of age

Objective: Along with growth hormone (GH) levels, measurements of serum insulin-like growth factor-1 (IGF-1) and IGF-binding protein-3 (IGFBP-3) are used in the diagnosis of GH deficiency and in monitoring the efficacy and safety of long-term GH treatment. The purpose of the present study was to establish reference values for serum IGF-1 and IGFBP-3 in healthy Turkish children less than 6 years of age.Methods: This study was designed as a multicenter project. Five hundred sixty-seven healthy children younger than 6 years of age from different geographical regions of Turkey, with weight and height values between the 10th and 90th percentiles according to the national standards were included in the study. In addition to anthropometric parameters, serum IGF-1 and IGFBP-3 levels were measured in all subjects.Results: Although not statistically significant, the serum IGF-1 levels in infants at age 6 months were lower than those in infants at age 3 months. The IGF-1 levels showed a slow increase with age. Serum IGF-1 levels were lower in girls as compared to boys only at age 6 months. No correlation was found between either serum IGFBP-3 levels and body mass index (BMI) or serum IGFBP-3 and weight and height standard deviation scores (SDS). A weak correlation was observed between serum IGF-1 and IGFBP-3 concentrations.Conclusions: The age- and gender-specific reference values for serum IGF-1 and IGFBP-3 reported in this study will aid in the diagnosis of GH deficiency and in the monitoring of children receiving GH treatment.Conflict of interest:None declared.     

Specific and direct radioimmunoassay for human proinsulin in serum

Summary A routine radioimmunoassay for human proinsulin in serum has been developed. The reagents used were: antibodies against the C-peptide part of the proinsulin molecule, human proinsulin as the standard and¹²⁵I-labelled synthetic human Tyr-C-peptide as the tracer. The first step in this assay comprises the binding of proinsulin to insulin antibodies covalently coupled to Sepharose (S-AIS). Although bound to the solid-phase S-AIS, the proinsulin retains its second immunogenic site, viz., the C-peptide part of the molecule, accessible. Hence a surplus of C-peptide antibodies is added to the S-AIS-bound proinsulin, and the residual amount of C-peptide antibody is determined by addition of¹²⁵I-Tyr-C-peptide. The detection limit is approximately 0.01 pmol/ml. The advantages of this method are: (1) its high specificity (proinsulin is determined as a molecule having both an insulin and a C-peptide moiety), (2) its simplicity and rapid performance, and (3) the low detection limit of the assay. Fasting sera from 24 nondiabetics, 9 maturityonset diabetics and 10 newly diagnosed insulin requiring diabetics showed the following concentrations of proinsulin: 0.009±0.005, 0.022±0.23 and 0.010±0.009 pmol/ml (mean±SD). One hour after 1.75 g/kg oral glucose, the values increased to 0.052±0.023, 0.046±0.022 and 0.032±0.022 pmol/ml. The fasting proinsulin constituted 19, 23 and 17% of the IRI, respectively, whereas 1 h post glucose these values changed to 8, 9 and 31% of IRI. Serum from 10 insulin-treated diabetics containing insulin antibodies contained from 0–1.80 pmol/ml, whereas the C-peptide levels in the same patients were 0–0.35 pmol/ml. It is suggested that insulin requiring diabetics hypersecrete proinsulin due to the inability of their B-cell to arrange proinsulin in secretory granules for adequate proinsulin/insulin conversion.     

Proinsulin levels in newborn siblings of Type 1 (insulin-dependent) diabetic children and their mothers

Summary Elevated proinsulin levels have been observed in healthy first degree relatives of Type 1 (insulin-dependent) diabetic patients. This elevation could reflect a sequele after a previous attack on the beta-cells not necessarily leading to diabetes, or represent a family trait related to the development of diabetes. When cord plasma levels of proinsulin, insulin and C-peptide from 14 newborn siblings of Type 1 diabetic patients were compared with 21 newborn control siblings unrelated to diabetic subjects, no differences were observed. Neither were any differences observed between their mothers at delivery when comparing the same parameters. In cord plasma the proinsulin levels (median and range) were higher than those in plasma from 35 adult fasting women unrelated to diabetic subjects (10, 5–83 pmol/l vs 4, 2–33 pmol/l;p<0.001) whereas the C-peptide levels (median and range) were lower (0.20, 0.11–0.56 nmol/l vs 0.37, 0.21–0.69 nmol/l;p<0.001). No differences in insulin levels using a highly specific insulin assay were observed. The results suggest that newborn children have high proinsulin and low C-peptide levels unrelated to heredity of diabetes and that the previously described elevated proinsulin level observed in older first degree relatives of diabetic subjects occurs later in life.     

Hypersecretion of proinsulin in thyrotoxicosis

Summary The plasma insulin, C-peptide and proinsulin concentrations were investigated in thyrotoxic patients and in normal controls after an overnight fast, during a 36 h fasting period, an intravenous glucose tolerance test and an oral glucose tolerance test. The main finding was a significantly raised concentration of proinsulin in plasma of patients with thyrotoxicosis. After an overnight fast the plasma proinsulin was 0.048±0.005 pmol/ml in 15 thyrotoxic patients compared with 0.023±0.012 pmol/ml in 15 euthyroid controls. A twofold rise of plasma proinsulin concentration was also found in thyrotoxic patients during a prolonged fast, and during intravenous and oral glucose tolerance tests. The immunoreactivity of proinsulin in the insulin radioimmunoassay gave rise to slightly elevated concentrations of immunoreactive insulin in thyrotoxic patients in all the conditions investigated. When insulin values were corrected for proinsulin crossreactivity, they were similar in euthyroid controls and thyrotoxic patients. The concentration of plasma C-peptide was not significantly altered in thyrotoxic patients during intravenous and oral glucose tolerance tests.     

Fasting proinsulin and 2-h post-load glucose levels predict the conversion to NIDDM in subjects with impaired glucose tolerance: The Hoorn Study

Summary The aims of the present study were to observe the natural history of impaired glucose tolerance and to identify predictors for development of non-insulin-dependent diabetes mellitus (NIDDM). A survey of glucose tolerance was conducted in subjects aged 50–74 years, randomly selected from the registry of the middle-sized town of Hoorn in the Netherlands. Based on the mean values of two oral glucose tolerance tests subjects were classified in categories of glucose tolerance according to the World Health Organization criteria. All subjects with impaired glucose tolerance (n=224) were invited to participate in the present study, in which 70% (n=158) were subsequently enrolled. During follow-up subjects underwent a repeated paired oral glucose tolerance test. The mean follow-up time was 24 months (range 12–36 months). The cumulative incidence of NIDDM was 28.5% (95% confidence interval 15–42%). Age, sex, and anthropometric and metabolic characteristics at baseline were analysed simultaneously as potential predictors of conversion to NIDDM using multiple logistic regression. The initial 2-h post-load plasma glucose levels and the fasting proinsulin levels were significantly (p<0.05) related to the incidence of NIDDM. Anthropometric characteristics, the 2-h post-load specific insulin levels and the fasting proinsulin/fasting insulin ratio were not related to the incidence of NIDDM. These results suggest that beta-cell dysfunction rather than insulin resistance plays the most important role in the future development of diabetes in a high-risk Caucasian population.Abbreviations IGT Impaired glucose tolerance - NIDDM non-insulin-dependent diabetes mellitus - OGTT oral glucose tolerance test - CI confidence interval - W/H ratio waist/hip ratio - BMI body mass index - OR odds ratio     

Long-term effect of lifestyle intervention on adiposity,metabolic parameters,inflammation and physical fitness in obese children: a randomized controlled trial

Background:

Behavioral lifestyle intervention, combined with parental involvement, is preferred over standard care or self-help in childhood obesity. The short-term results of such interventions are promising, but long-term follow-up results are equivocal.

Objective:

The objective of the present study was the short (3 months) and long-term (1 and 2 years follow-up) effect evaluation of a family-based multidisciplinary cognitive behavioral lifestyle intervention on markers of adiposity, metabolism, inflammation and physical fitness compared with standard care in children with obesity. Also the association between these outcome variables was determined.

Methods:

In this prospective longitudinal clinical trial, obese children were randomly assigned to a 3-month family-based cognitive behavioral multidisciplinary lifestyle treatment (n=40; body mass index-standard deviation score (BMI-SDS) 4.2±0.7; age; 13.3±2.0 years) or to a control group receiving an initial advice on physical activity and nutrition (n=39; BMI-SDS 4.3±0.6; age 13.1±1.9 years). Anthropometric data, physical fitness, metabolic parameters and inflammatory state were evaluated at baseline, after intervention (at 3 months) and at 1-year follow-up. At 2-year follow-up, anthropometric data and physical fitness were measured in the intervention group.

Results:

An intervention effect after 1 year was found for adiposity (P=0.02 for BMI-SDS, P=0.03 for waist circumference (WC)-SDS), physical fitness (absolute measured peak value of oxygen uptake (ml min⁻¹), standardized for age and gender (VO_2peak-SDS), P<0.01) and insulin resistance (HOMA-SDS, P=0.04). No significant intervention effect was found for serum lipid profile, high-sensitive C-reactive protein or for adiponectin. At 2-year follow-up, BMI-SDS in the intervention group (n=31) was 3.8±1.2 SDS, significantly less than at baseline (P=0.02).

Conclusion:

A positive 1-year follow-up treatment effect was found for adiposity, physical fitness and glucose homeostasis, but not for inflammatory markers. There was a significant long-term treatment effect on adiposity, although almost all children remained obese.     

高血压家族遗传因素、超重与胰岛素抵抗的关系及其相加作用的研究

为探讨高血压家族遗传因素、超重与胰岛素抵抗（ＩＲ）关系及其相加作用，本研究采用家系调查法，对比分析高血压家系直系亲属正常血压者和对照家系直系亲属的有关参数。两家系均按超重和非超重（ＢＭＩ≥２５ｋｇ／ｍ２或ＢＭＩ＜２５ｋｇ／ｍ２）分组。结果表明：四组间除血糖外，胰岛素及其对数转换值、胰岛素敏感指数均有显著的统计学差异；高血压家系非超重组胰岛素敏感指数显著低于对照家系相应组，调整年龄、性别后，各组间胰岛素水平呈高血压家系超重组＞对照家系超重组＞高血压家系非超重组＞对照家系非超重组，而且，无论高血压或对照家系，超重组胰岛素均显著高于非超重组，高血压家系超重组与其它各组间差异均达到统计学显著性水平。这些结果提示，有家族遗传因素者在高血压发生前就可能存在ＩＲ，且遗传因素和超重对ＩＲ具有相加作用。     

Association of proinsulin and insulin resistance with coronary artery disease in non-diabetic south Indian men.

AIMS: To evaluate the association of plasma proinsulin and insulin resistance (IR) with coronary artery disease (CAD) in non-diabetic subjects. METHODS: In this case control study, 41 normoglycaemic men with angiographic evidence of CAD were compared with 41 control men matched for age and glycaemia and with no history or evidence of cardiac diseases. Estimations of plasma glucose, lipids, fasting plasma specific insulin (SI) and proinsulin (PI) were performed. IR was calculated by the homeostasis model assessment (HOMA) method. Multiple logistic regression analysis was performed to test the association of the variables with the prevalence of CAD. RESULTS: Subjects with CAD had a higher body mass index (BMI) (25.4 +/- 4.3 vs. 22.9 +/- 3.2 kg/m2, P = 0.003) and waist to hip ratio (WHR) (0.95 +/- 0.05 vs. 0.89 +/- 0.09, P = 0.001) and a lower high-density lipoprotein (HDL) cholesterol level (0.97 +/- 0.2 vs. 1.1 +/- 0.2 mmol/l, P = 0.002). They also had higher mean SI values (107.5 vs. 62.3 pmol/l, P = 0.002), PI values (19.3 vs. 5.7 pmol/l, P < 0.0001), PI/SI ratios (21.4 vs. 10.3, P < 0.0001) and HOMA IR (4.2 vs. 2.4, P = 0.004) compared with non-CAD subjects. These variables were associated with CAD in the unadjusted multiple regression analysis. In the multiple regression with the forward entry of the variables, WHR and PI only showed independent association with CAD. CONCLUSIONS: Subjects with CAD had higher levels of obesity and WHR. CAD showed an association with low HDL cholesterol, circulating PI, PI/SI ratios and IR.     

Hyperinsulinaemia in obesity is not accompanied by an increase in serum proinsulin/insulin ratio in groups of human subjects with and without glucose intolerance

Summary Serum proinsulin is disproportionately elevated compared to insulin in Type 2 (non-insulin-dependent) diabetes mellitus. We studied the effect of obesity on serum proinsulin with varying degrees of glucose intolerance. Serum proinsulin and insulin were measured during a 75 g oral glucose tolerance test in 73 obese and 74 non-obese subjects with normal, borderline or diabetic-type glucose tolerance. Proinsulin was assayed by a direct radioimmunoassay using proinsulin-specific antiserum. Fasting serum proinsulin and insulin and the summed values of proinsulin and insulin during oral glucose tolerance test were significantly, or tended to be, higher in obese subjects than in those without obesity in each category of glucose tolerance. However, the molar ratio of proinsulin to insulin was nearly the same between obese and non-obese groups with a similar degree of glucose tolerance. On the other hand, the proinsulin/insulin ratio increased progressively with the deterioration of glucose tolerance. We conclude that proinsulin secretion is disproportionately increased in the presence of glucose intolerance but not by obesity itself. Each Beta cell seems to function normally in obese subjects while glucose tolerance remains normal.This work was presented at the 6th International Congress on Obesity in October 1990, Kobe, Japan     

Indirect two-site immunoradiometric assay of rat and mouse proinsulin

Summary An indirect two-site immunoradiometric assay for rat and mouse proinsulin using a rabbit antibody to synthetic rat C-peptide has been developed. The sensitivity of the assay is 0.006 pmol/ml. Proinsulin was 4.95% of the total proinsulin and insulin in extracts of rat pancreas and 5.45% in extracts of isolated rat islets. The mean fasting rat insulin and proinsulin concentrations were 0.13±0.09 pmol/ml (n=5) and 0.008±0.002 pmol/ml (n=5) respectively. The mean fasting mouse proinsulin concentration was 0.019±0.006 pmol/ml (n=8). In rats intravenous glucose produced a biphasic insulin response but proinsulin rose progressively to 0.021±0.011 pmol/ml at 45 min. In mouse oral glucose increased the proinsulin concentration to 0.13 pmol/ ml at 30 min. Proinsulin release from isolated rat islets was studied during intermittent or continuous high glucose (20 mmol/l) stimulation in static incubation. Significant increases in proinsulin release were only observed 90 min after initial exposure to high glucose whether glucose stimulation was continuous or intermittent. Both in vivo and in vitro glucose stimulation led initially to a fall in the proinsulin/ insulin molar ratio but later upon prolonged stimulation this progessively increased to above the basal value.     

Elevated intact proinsulin levels are indicative of Beta-cell dysfunction, insulin resistance, and cardiovascular risk: impact of the antidiabetic agent pioglitazone

Background:

Insulin resistance (IR) and deterioration of beta-cell secretion are main features in the development of type 2 diabetes, which is reflected in increasing serum intact proinsulin levels in later disease stage. Introduction of stable assays that are able to distinguish between intact proinsulin and its specific and unspecific cleavage products has resulted in the finding that serum intact proinsulin values can serve as a direct marker for beta-cell dysfunction, are a highly specific indicator of IR, and can predict cardiovascular risk.

Method:

Determination of fasting intact proinsulin may be used to monitor and optimize antidiabetic therapeutic approaches. Our study group has been involved in a variety of clinical studies investigating drug effects on beta-cell secretory capacity, IR, and intact proinsulin levels. One focus was on the impact of insulin-sensitizing therapy with pioglitazone on the pancreatic beta-cell load.

Results:

Treatment with pioglitazone resulted in significant decreases in elevated proinsulin levels in type 2 diabetes patients. This effect was independent from glycemic control.

Conclusions:

Measurement of fasting intact proinsulin values allows a staging of beta-cell dysfunction and evaluation of IR, thus providing an interesting diagnostic tool for both selection of appropriate therapy and monitoring of treatment success.