Serum Proinsulin Levels Research Articles

Serum proinsulin levels as peripheral blood biomarkers in patients with cognitive impairment

Insulin has long been associated with dementia. Insulin affecting the clearance of amyloid-β peptide and phosphorylation of tau in the CNS. Proinsulin is a precursor of insulin and its elevated serum levels are associated with peripheral insulin resistance that may reduce brain insulin levels. Our study aimed to assess differences in serum proinsulin levels between normal and cognitive impairment groups. Prospective recruitment of elderly participants was initiated from October 2019 to September 2023. Patients were divided into “cognitive impairment” and “normal cognition” group. All participants had blood drawn and serum proinsulin was measured at baseline and 12 months. Neurocognitive testing was performed every 6 months. A total of 121 participants were recruited. Seventy-seven were in the normal cognition group and 44 in the cognitive impairment group. The glycemic control and prevalence of diabetes type 2 was similar between groups. Baseline serum proinsulin levels were higher in the cognitively impaired group compared to the normal group at baseline (p = 0.019) and correlated with worse cognitive scores. We identified cognitive status, age, and BMI as potential factors associated with variations in baseline proinsulin levels. Given the complex interplay between insulin and dementia pathogenesis, serum biomarkers related to insulin metabolism may exhibit abnormalities in cognitive impaired patients. Here we present the proinsulin levels in individuals with normal cognitive function versus those with cognitive impairment and found a significant difference. This observation may help identifying non-diabetic patients suitable for treatment with novel AD drugs that related to insulin pathway.

Association of common variants of TCF7L2 and PCSK2 with gestational diabetes mellitus in West Bengal, India

The genetic etiology of gestational diabetes mellitus (GDM) was suggested to overlap with type-2 diabetes(T2D). Transcription factor 7-like 2 (TCF7L2) and Proprotein Convertase Subtilisin/Kexin type 2 (PCSK2) are T2D susceptibility genes of the insulin synthesis/processing pathway. We analyzed associations of TCF7L2 and PCSK2 variants with GDM risk and evaluated their potential impact on impaired insulin processing in an eastern Indian population. The study included 114 GDM (case) and 228 non-GDM pregnant women (control). rs7903146, rs4132670, rs12255372 of TCF7L2, and rs2269023 of PCSK2 were genotyped by PCR-RFLP, and genotype distributions were compared between case and control. Fasting serum proinsulin and C-peptide levels were measured by ELISA and the Proinsulin/C-peptide ratio was considered an indicator of proinsulin conversion. Significantly higher frequency of risk allele (T) of rs12255372 (p = 0.02, OR = 2.0, 95%CI = 1.11–3.64) and rs4132670 (p = 0.002, OR = 2.26, 95%CI = 1.32–3.87) of TCF7L2 was found in GDM cases than non-GDM controls; TT genotype was associated with significantly increased disease risk. In rs7903146 (TCF7L2) and rs2269023 (PCSK2), although the frequency of risk allele (T) was not significantly higher in cases than controls, an association of TT for both variants remained significant with higher GDM risk in the recessive model. Increased serum pro-insulin and proinsulin:c-peptide ratio was found in GDM than non-GDM women and the phenomenon showed significant association with careers of risk alleles for TCF7L2 variants. In conclusion, TCF7L2 and PCSK2 variants are related to GDM risk in the studied population and hence may serve as potential biomarkers for assessing the disease risk. TCF7L2 variants contribute to impaired insulin processing.

RELATIONSHIPS BETWEEN OSTEOCALCIN LEVEL AND HORMONAL METABOLIC DISORDERS IN TYPE 2 DIABETIC MEN WITH VARIOUS DEGREES OF OBESITY (LITERATURE REVIEW AND OWN RESEARCH)

The bone hormone osteocalcin is formed by osteoblasts and is partially released into the bloodstream during bone resorption, being a biomarker of bone remodeling. Osteocalcin also plays an important role in the endocrine regulation of metabolic and energy processes in the body and in their coordination. Osteocalcin uses a feedback mechanism to regulate insulin secretion, insulin sensitivity of peripheral tissues, and adipokine levels. In general, the secretion of osteocalcin and insulin are important factors in the formation of hormonal-metabolic phenotype, body composition, determination of regional distribution and metabolic activity of both bone and adipose tissue.The aim of this study was to establish the relationship between osteocalcin concentration and hormonal changes in men with type 2 diabetes with and without obesity on the background of involutive changes. Results. 64 men with type 2 diabetes, older than 50 years, were divided into 2 groups by BMI: 1) non-obese, BMI <30 kg / m2 (n = 31); 2) -obese, BMI ≥ 30 kg / m2 (n = 33). Lower levels of insulin secretion (lower serum C-peptide and insulin levels) were observed in non-obese patients in the absence of a compensatory increase in proinsulin levels. It can be assumed that the increase in the concentration of osteocalcin in group 1 is compensatory, although it does not have a significant effect on blood glucose levels. However, it may have a protective effect on the severity of insulin resistance syndrome and related metabolic disorders. Lower levels of osteocalcin in the obese group were associated with a higher degree of insulin resistance and insulin secretion. There was no significant difference between the two groups in serum proinsulin levels, as well as in androgen supply, which was assessed by the levels of total testosterone, testosteronestradiol-binding globulin, and free testosterone index. Conclusion. Lower levels of osteocalcin may be a marker of an increased risk of adverse metabolic changes in obese patients with type 2 diabetes, followed by complications compared to non-overweight patients

A comparison of glycemic parameters and their relationship with C-peptide and Proinsulin levels during partial remission and non-remission periods in children with type 1 diabetes mellitus - a cross-sectional study

BackgroundCurrently, there is a lack of data relating to glycemic parameters and their relationship with C-peptide (CP) and proinsulin (PI) during the partial remission period (PRP) in type 1 diabetes mellitus (T1D). The aim of this study was to evaluate glycemic parameters in children with T1D who are in the PRP using intermittently scanned continuous glucose monitoring systems (isCGMS) and to investigate any relationships between CP and PI levels.MethodsThe study included 21 children who were in the PRP and 31 children who were not. A cross-sectional, non-randomized study was performed. Demographic, clinical data were collected and 2 week- isCGMS data were retrieved.ResultsThe Serum CP showed a positive correlation with time-in-range in the PRP (p:0.03), however PI showed no correlations with glycemic parameters in both periods. The Serum CP and PI levels and the PI:CP ratio were significantly higher in the PRP group than in the non-PRP group. In the non-PRP group, the PI level was below 0.1 pmol/L (which is the detectable limit) in only 2 of the 17 cases as compared with none in the PRP group. Similarly, only 2 of the 17 children in the non-PRP group had CP levels of less than 0.2 nmol / L, although both had detectable PI levels. Overall time-in-range (3. 9-1.0 mmol/L) was significantly high in the PRP group. In contrast, the mean sensor glucose levels, time spent in hyperglycemia, and coefficient of variation levels (32.2vs 40.5%) were significantly lower in the PRP group.ConclusionsAlthough the mean glucose and time in range during the PRP was better than that in the non-PRP group, the glycemic variability during this period was not as low as expected. While the CP levels showed an association with TIR during the PRP, there was no correlation between PI levels and glycemic parameters. Further studies are needed to determine if PI might prove to be a useful parameter in clinical follow-up.

2268-PUB: Relationship between Serum Free Fatty Acid and Proinsulin Concentrations

Background: The causes of pancreatic beta-cell dysfunction include glucose toxicity and lipotoxicity. Basic research has suggested that free fatty acids (FFAs) damage pancreatic beta-cells. However, the relationship between FFAs and pancreatic beta-cell dysfunction has not been clarified in humans. Therefore, we investigated the relationship between the serum concentrations of FFA and proinsulin (PI), a marker of pancreatic beta-cell dysfunction, in a general Japanese population. Methods: This was a cross-sectional study of 489 people (226 men, 263 women; age 35-79 years) from a rural community in Hokkaido, Japan who were not taking diabetic medication and who provided fasting blood samples. Serum PI was measured by a radioimmunoassay, and was compared among quartiles defined with respect to FFA concentration. Because the serum FFA and PI levels showed skewed distributions, univariable and multivariable regression analyses were performed after logarithmic transformation. Results: PI, age, body mass index, and fasting blood glucose and insulin were positively associated with serum FFA quartile: for PI, median (first quartile, third quartile): Q1 8.1 (6.0, 11.7), Q2 8.5 (6.9, 13.1), Q3 9.2 (6.7, 14.5), and Q4 11.2 (7.6, 16.7); p<0.01. Univariable regression analysis showed that ln(FFA) was positively associated with ln(PI) (partial regression coefficient: 0.19, 95% confidence interval (CI): 0.07, 0.31, p<0.01). This positive association remained after adjustment for age and sex (partial regression coefficient: 0.19, 95% CI: 0.07, 0.31, p<0.01), and also after adjustment for age, sex, and HbA1c (partial regression coefficient: 0.12, 95% CI: 0.01, 0.23, p<0.05). Conclusion: Serum FFA was positively associated with PI in a general Japanese population. Thus, FFA may play a role in pancreatic beta-cell dysfunction. Disclosure K. Chiba: None. A. Nakamura: None. H. Miyoshi: Research Support; Self; Astellas Pharma Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo, Eli Lilly Japan K.K., Novo Nordisk Inc., Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Co., Ltd. Speaker’s Bureau; Self; Astellas Pharma Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo, Eli Lilly Japan K.K., Kowa Company, Ltd., MDS CO. LTD., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sanofi K.K., Sumitomo Dainippon Pharma Co., Ltd. Other Relationship; Self; Abbott, Boehringer Ingelheim Pharmaceuticals, Inc., Kowa Company, Ltd., Mitsubishi Tanabe Pharma Corporation, Ono Pharmaceutical Co., Ltd. S. Ukawa: None. K. Nakamura: None. T. Nakagawa: None. Y. Terauchi: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo, Eli Lilly Japan K.K., Novo Nordisk A/S, Sanofi. Consultant; Self; Astellas Pharma Inc. Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo, Eli Lilly Japan K.K., Merck Sharp & Dohme Corp., Novartis Pharmaceuticals Corporation, Novo Nordisk A/S, Ono Pharmaceutical Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Company Limited. Speaker’s Bureau; Self; Astellas Pharma Inc., AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo, Eli Lilly Japan K.K., Kowa Company, Ltd., Medscape, Medtronic, Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novartis Pharmaceuticals Corporation, Novo Nordisk A/S, Ono Pharmaceutical Co., Ltd., Sanofi, Sanwa Kagaku Kenkyusho, Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited, Terumo Medical Corporation. A. Tamakoshi: None. T. Atsumi: Consultant; Self; Chugai Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., GlaxoSmithKline plc., Pfizer Inc., UCB Japan Co. Ltd. Speaker’s Bureau; Self; AbbVie Inc., Alexion Pharmaceuticals, Inc., Astellas Pharma Inc., Bristol-Myers Squibb, Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo, Eisai Co., Ltd., Eli Lilly Japan K.K., Gilead Sciences, Inc., Mitsubishi Tanabe Pharma Corporation, Otsuka Pharmaceutical Co., Ltd., Pfizer Inc., Takeda Pharmaceutical Company Limited, UCB Japan Co. Ltd.

Correlation between serum proinsulin levels and fatty liver: The Dynamics of Lifestyle and Neighborhood Community on Health Study.

Aims/IntroductionWe explored the association between fatty liver and pancreatic β‐cell dysfunction in a general population.Materials and MethodsThis cross‐sectional study included 489 (53.8% women) community‐dwelling Japanese adults. The extent of fatty liver was estimated using the fatty liver index (FLI). After all participants were divided into three groups – low (FLI <30), moderate (30 ≤FLI <60) or high (FLI ≥ 60) degree of fatty liver – serum proinsulin levels transformed into natural logarithms were compared among the three groups. To determine whether obesity modified the association of interest, the participants were stratified into two groups according to the median body mass index. Next, to determine whether hyperinsulinemia modified the association of interest, a similar stratified analysis was carried out using the median serum insulin level.ResultsLogarithm (proinsulin) was significantly higher in the high FLI group than in the moderate and low groups, and it was significantly higher in the moderate group than in the low group after adjustment for age and sex (P < 0.05). Logarithm (proinsulin) was significantly higher in the high FLI group than in the low FLI group, regardless of body mass index, after adjustment for age and sex. A similar pattern was observed regardless of serum insulin levels.ConclusionsThe degree of fatty liver was positively associated with proinsulin level, regardless of the presence of obesity or hyperinsulinemia, suggesting that fatty liver reflects pancreatic β‐cell dysfunction.

SUN-234 Effect of Testosterone Undecanoate on Metabolic Syndrome Parameters in a Cohort of Hypogonadism

Objective: To study the prevalence of metabolic syndrome (MS) and whole-body composition in hypogonadism and studied the effects of replacement of testosterone. Methods: In a single centre prospective case control study, 33 patients with hypogonadism patients (ages 20-39 years) were studied for the effect of testosterone replacement on MS and its components and whole body composition. Results: The prevalence of MS was similar in patients and controls (21% vs. 9.1%, p = 0.3). Prevalence of hypertension was higher in patients than the control (33% vs. 3%, p = 0.00). There was no difference between patients and control in weight, BMI, waist circumference (WC) and whole body composition except for an increase in lean body mass in patients (45908 ± 7969 gm/cm2 vs. 50712 ±7458 gm/cm2, p=0.02). After testosterone replacement, there was significant decrease in WC (88.5 ± 13.0 cm vs. 83.9 ± 12.8 cm, p < 0.01), truncal fat, total body fat, fat mass index, fasting C-peptide (2.1 ± 0.78 ng/ml vs. 0.68 ± 0.23 ng/ml, p<0.01), serum pro insulin (1.43 pmol/l (0.32-13.4) vs. 0.5 (0.5-3.2) and a significant increase in lean mass (46906 ± 8876 gm/cm2 vs. 50083 ± 7590 gm/cm2, p <0.001). HOMA-IR (4.6±1.7 vs. 0.5±0.17, p<0.001), HOMA% β (330 ± 103 vs. 66 ± 20, p<0.001) were decreased significantly following testosterone replacement. Conclusion: Testosterone replacement resulted in significant decrease in WC and truncal fat leading to improved insulin sensitivity as evidenced by decreasing serum C-peptide, serum proinsulin levels, decreased beta cell function and decreased insulin resistance.

Hypoglycemic Syndrome without Hyperinsulinemia. A Diagnostic Challenge.

The most common cause of organic fasting hypoglycemia in adults is the presence of an insulin-producing pancreatic adenoma, but when high insulin levels are not found, the differential diagnosis is challenging. Misdiagnosis can lead to an unnecessary pancreatectomy. Insulin concentrations may be low in some cases despite a clinical history suggestive of insulinoma. In these cases, a proinsulinoma should be suspected, although the rarity of this condition requires an extensive workup before reaching a final diagnosis. We describe an unusual case of a 38-year-old man with a severe hypoglycemic syndrome due to a proinsulin-secreting pancreatic adenoma. Insulin was measured by the specific assay and suppressed under the lower detection limit during fasting hypoglycemia. Serum proinsulin and C-peptide levels were abnormally elevated, and further tests revealed an islet cell tumor. The tumor was surgically removed, relieving the fasting hypoglycemia. Histopathological study showed a conventional well-differentiated neuroendocrine tumor with high immunoreactivity against proinsulin and with lesser intensity against insulin. Interestingly, GS-9A8 antibody clone used for immunostaining proinsulin did not cross-react with human insulin or C-peptide, providing an unbiased picture of proinsulin secretion. The resolution of symptoms, the fall of proinsulin concentrations after tumor removal and the histopathology study confirmed the diagnosis of proinsulinoma.

Surgery Versus Snacking as Treatment of Insulinoma

From the Department of Internal Medicine, University of Oklahoma, Tulsa. A 19-year-old man presented with a generalized tonic-clonic seizure and serum glucose of 19 mg/dL. The seizure was aborted with dextrose and resolution of hypoglycemia. The patient had begun experiencing episodes of lightheadedness, fatigue, and seizures at age 16. Physicians in Mexico attributed his symptoms to poor nutritional intake and instructed him to increase his meal frequency and intake of soda and candy. He remained symptomatic for 3 years despite consuming 8 to 12 sodas daily supplemented by candy bars. Laboratory testing showed elevated serum insulin (200.8 mlU/mL), C-peptide (13.7 ng/ mL), proinsulin (296 pmol/L), and betahydroxybutyrate (0.3 mg/dL) levels. The sulfonylurea panel results were negative, and the serum calcium, intact parathyroid hormone, corticotropin, thyrotropin, and cortisol levels were within the normal range. A 72-hour fast revealed a glucose level of 30 mg/dL at 5 hours without neuroglycopenic or adrenergic symptoms. Computed tomography of the abdomen

The proinsulin level in the blood of children with type 1 diabetes mellitus of various duration

Proinsulin content was measured in the serum of 82 children (aged from 3 to 14 years) with type 1 diabetes mellitus of various duration. Three groups of patients characterized by low (54%), normal (42%) and high (4%) levels of this prohormone were recognized. No dependence the proinsulin level on the disease term was found. The serum proinsulin level may be used as a parameter specifying the pathogenesis of type 1 diabetes mellitus.

Relationship between proinsulin and beta cell function in different states of glucose tolerance

To measure proinsulin concentrations in different states of glucose tolerance and examine the relationship between proinsulin and beta cell function. Serum true insulin (TI), proinsulin (PI), immunoreactive insulin (IRI), C peptide (CP) and blood glucose (BG) levels were measured in the fasting state and during an oral glucose tolerance test (OGTT) in 32 individuals with normal glucose tolerance (NGT), 42 individuals with impaired glucose tolerance (IGT), and 54 individuals with newly diagnosed type 2 diabetes mellitus. All participants were also subdivided into nonobese [body mass index (BMI) <25 kg/m2] and obese (BMI ≥25 kg/m2) subgroups. The levels of TI, PI, IRI and CP were higher in obese patients compared with the corresponding NGT subgroup, whereas there was no difference in PI/TI. The levels of IRI, PI and PI/TI were higher in nonobese patients with type 2 diabetes mellitus than in the corresponding NGT subgroup. The levels of PI and TI increased in obese patients with NGT and IGT, whereas PI/TI did not change. In contrast, PI increased but TI did not in subjects with newly diagnosed diabetes mellitus, which led to an increase in PI/TI, and a decrease in beta cell function. Therefore, PI and the PI/TI ratio could offer markers for beta cell dysfunction in DM.

Independent relationships of obesity and insulin resistance with serum proinsulin level in prepubertal children with normal glucose tolerance

We compared the fasting serum proinsulin levels in lean, overweight, and obese prepubertal children with normal glucose tolerance (NGT). We also evaluated the relationship between fasting proinsulin level and indices of insulin resistance (IR). One hundred nine prepubertal children (mean age, 8.6 yr) with NGT were included. The indices of IR included the homeostasis model assessment of IR (HOMA-IR) and adiponectin level. We recorded the presence of one or more of the following metabolic derangements: triglycerides ≥ 150 mg/dL, HDL-cholesterol < 35 mg/dL, and hypertension. Fasting proinsulin levels significantly increased with body mass index (BMI) category from lean (n = 52, 7.22 ± 3.01 pmol/L) to overweight (n = 14, 12.31 ± 2.91 pmol/L) to obese (n = 43, 16.51 ± 7.27 pmol/L) (p < 0.001), after controlling for HOMA-IR. The ratio of the fasting levels of proinsulin to insulin did not differ significantly between the three groups. Both BMI z-score and HOMA-IR were significant independent factors related to the fasting proinsulin level (p < 0.001 for each). A significant inverse association was found between fasting proinsulin level and adiponectin level (r = -0.464, p < 0.001). Children with NGT who had at least one metabolic derangement had higher proinsulin levels than those without metabolic derangement. Obesity itself or obesity-related IR may independently impose β-cell overload on prepubertal children with NGT, leading to hyperproinsulinemia without causing failure to convert proinsulin to insulin when some degree of IR and metabolic derangement appears.

IL-12 serum levels in patients with type 2 diabetes treated with sulphonylureas

Interleukin-12 (IL-12) has been identified as a pro-inflammatory cytokine which is thought to contribute to the development of atherosclerosis. However, to date, the various associations between factors related to the course of type 2 diabetes, like metabolic compensation, beta cell secretory dysfunction, insulin resistance and IL-12 serum levels, remain unclear. Our study involved 41 patients with type 2 diabetes, 19 patients with coronary artery disease (CAD), and 19 healthy controls. We measured serum levels of fasting glucose, HbA 1c, 1,5-anhydro- d-glucitol, and lipids. In addition, serum levels of C-peptide, insulin, proinsulin and IL-12 were assayed. HOMA IR score was calculated. The serum concentrations of IL-12 were higher in diabetics than in either patients with CAD or healthy controls, and were correlated with BMI, C-peptide, insulin, HOMA IR, proinsulin and HDL serum levels. Multiple regression analysis revealed that the IL-12 serum level in type 2 diabetics primarily is dependent upon fasting proinsulin concentration. Our results demonstrate that elevated IL-12 serum levels in type 2 diabetics treated with sulphonylureas are induced especially by peripheral insulin resistance and beta cells dysfunction, as expressed by fasting serum proinsulin levels. This finding gives us hope that treatment to decrease peripheral insulin resistance and to avoid excessive proinsulin secretion might be successful in the prevention of IL-12-induced atherosclerosis.

Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing pioglitazone therapy in patients with type 2 diabetes: A 24-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group study

Objective: The efficacy and tolerability of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing pioglitazone therapy were assessed in patients with type 2 diabetes and inadequate glycemic control (glycosylated hemoglobin [HbA 1c] ≥7% and ≤10%) while receiving a stable dose of pioglitazone. Methods: This was a 24-week, multicenter, ran domized, double-blind, placebo-controlled, parallel group study in patients aged ≥18 years (ClinicalTrials. gov NCT00086502). At screening, all patients began a diet/exercise program that continued throughout the study period. Patients taking antihyperglycemic therapy other than pioglitazone underwent a washout of this therapy and entered an 8- to 14-week open-label pioglitazone dose-titration/stabilization period. Patients with an HbA 1c ≥7% and ≤10% at the end of this period entered a 2-week, single-blind, placebo run-in period (total duration of run-in period, up to 21 weeks). Patients who had been receiving pioglitazone monotherapy (30 or 45 mg/d) and had an HbA 1c ≥7% and ≤10% entered the 2-week, single-blind, placebo run-in period directly. Thus, at the time of randomization, all patients were receiving ongoing pioglitazone (30 or 45 mg/d). Patients were randomized in a 1:1 ratio to receive sitagliptin 100 mg once daily or placebo for 24 weeks. The primary efficacy end point was the change from baseline in HbA 1c at week 24. Secondary efficacy end points included the change from baseline in fasting plasma glucose (FPG), insulin, and proinsulin; the Homeostasis Model Assessment β-cell function and insulin-resistance indexes; the proinsulin/ insulin ratio; the Quantitative Insulin Sensitivity Check Index; the percent changes from baseline in selected lipid parameters; the proportion of patients meeting the American Diabetes Association HbA 1c, goal of <7.0%; the proportion of patients requiring metformin rescue therapy; and the time to the initiation of rescue therapy. Results: One hundred seventy-five patients were randomized to receive sitagliptin, and 178 were randomized to receive placebo. The mean (SD) baseline HbAlc value was 8.1% (0.8) in the sitagliptin group and 8.0% (0.8) in the placebo group. After 24 weeks, sitagliptin added to pioglitazone therapy was associated with significant reductions compared with placebo in HbA 1c (between-treatment difference in least squares [LS] mean change from baseline. −0.70 %; 95 % CI, −0.85 to −0.54; P < 0.001) and FPG (−17.7 mg/dL; 95% CI, −24.3 to -11.0; P < 0.001). Mean HbA 1c values at end point were 7.2% (0.9) and 7.8% (1.1) in the respective treatment groups, and the proportions of patients reaching a target HbA 1c of <7.0% were 45.4% and 23.0% ( P < 0.001). Significant reductions in fasting serum proinsulin levels and the proinsulin/insulin ratio were seen with sitagliptin treatment compared with placebo (both, P < 0.01). Sitagliptin was generally well tolerated, with no increased risk of hypoglycemia compared with placebo (2 vs 0 patients, respectively).

Indices of insulin sensitivity, beta cell function and serum proinsulin levels in the polycystic ovary syndrome

Background The study aim was to investigate the relationship between insulin resistance (IR), β-cell function (βF), hyperandrogenism and proinsulin levels during an oral glucose tolerance test (OGTT) in women with polycystic ovary syndrome (PCOS). Methods One hundred and twenty-six selected women were classified as follows: PCOS, BMI > 25 kg/m 2 ( n = 39); PCOS, BMI < 25 kg/m 2 ( n = 54); controls, BMI > 25 kg/m 2 ( n = 14); controls, BMI < 25 kg/m 2 ( n = 19). Blood samples were collected between the third and sixth day of a spontaneous menstrual cycle, at 9:00 a.m., after an overnight fast. Serum levels of FSH, LH, PRL, 17α-OH-progesterone, SHBG, testosterone, Δ 4-androstenedione, insulin, proinsulin and glucose were measured. A 75 g OGTT was performed, and concentrations of glucose, insulin and proinsulin were also measured at t = 30, 60, 90, and 120 min. Results The markers of insulin secretion and the AUC for proinsulin were higher in obese and overweight women and in women with PCOS, respectively. The AUC for proinsulin was positively correlated with markers of IR, βF and androgen levels. An inverse relationship between PI/I values and indices of IR and βF was observed. Conclusions Increased proinsulin levels reflect, most probably, insulin resistance, which is the key disorder in PCOS-associated metabolic abnormalities. β-Cell function, pre-proinsulin mRNA processing and proinsulin conversion to insulin could be initially increased as a result of IR. An interaction between circulating proinsulin and androgen biosynthesis or action might also exist.

Insulin Resistance and Risk of Congestive Heart Failure

[HR], 1.44; 95% confidence interval [CI], 1.08-1.93), fasting serum proinsulin level (HR, 1.29; 95% CI, 1.02-1.64), body mass index (HR, 1.35; 95% CI, 1.11-1.65), and waist circumference (HR, 1.36; 95% CI, 1.10-1.69), whereas a 1-SD increase in clamp glucose disposal rate decreased the risk (HR, 0.66; 95% CI, 0.51-0.86). When adding clamp glucose disposal rate to these models as a covariate, the obesity variables were no longer significant predictors of subsequent CHF.

The serum levels of proinsulin and their relationship with IGFBP‐1 in obese children

Serum proinsulin (PI) levels were investigated in obese children to determine whether PI is a sensitive indicator of insulin resistance, as previously shown in adults with type 2 diabetes mellitus (DM), and to evaluate their relationship with insulin-like growth factor-binding protein-1 (IGFBP-1) known as a predictor of the development of cardiovascular disease in diabetic adults. Forty-two obese children without DM (age, 12.1 +/- 1.5 year) and 42 age-matched control children were included in the study. The serum levels of PI, immunoreactive insulin (IRI), IGFBP-1 and free insulin-like growth factor-1 (IGF-1) were measured in the fasting state. The fasting levels of serum PI and IRI were significantly higher in obese children than in controls (PI, 10.5 +/- 6.8 vs. 5.6 +/- 2.0 pmol/l, p < 0.001; IRI, 72.0 +/- 41.8 vs. 32.7 +/- 19.5 pmol/l, p < 0.001). Serum IGFBP-1 levels were significantly lower in obese children than in controls (37.7 +/- 24.6 vs. 76.3 +/- 26.5 microg/l, p < 0.001). The ratio of PI to IRI (calculated as molar ratios) did not differ significantly between obese and control subjects (0.16 +/- 0.08 vs. 0.19 +/- 0.11, p = 0.08). For the whole group, serum PI levels correlated positively with IRI and inversely with IGFBP-1 (IRI, r = 0.67, p < 0.001; IGFBP-1, r = -0.49, p < 0.001). Serum IGFBP-1 levels correlated inversely with both BMI and IRI (BMI, r = -0.73, p < 0.001; IRI, r = -0.60, p < 0.001). Multiple regression analysis revealed that the best predictive parameters for IGFBP-1 were BMI and PI (R2 = 0.57, p < 0.001 and p < 0.05, respectively). These findings suggest that fasting serum PI levels may be a better predictor than fasting insulin levels for the future development of type 2 DM and cardiovascular disease in obese children, and PI, in addition to insulin, contributes to the suppression of hepatic IGFBP-1 production.

Insulin Resistance and Risk of Congestive Heart Failure

Diabetes and obesity are established risk factors for congestive heart failure (CHF) and are both associated with insulin resistance. To explore if insulin resistance may predict CHF and may provide the link between obesity and CHF. The Uppsala Longitudinal Study of Adult Men, a prospective, community-based, observational cohort in Uppsala, Sweden. We investigated 1187 elderly (>or=70 years) men free from CHF and valvular disease at baseline between 1990 and 1995, with follow-up until the end of 2002. Variables reflecting insulin sensitivity (including euglycemic insulin clamp glucose disposal rate) and obesity were analyzed together with established risk factors (prior myocardial infarction, hypertension, diabetes, electrocardiographic left ventricular hypertrophy, smoking, and serum cholesterol level) as predictors of subsequent incidence of CHF, using Cox proportional hazards analyses. First hospitalization for heart failure. One hundred four men developed CHF during a median follow-up of 8.9 (range, 0.01-11.4) years. In multivariable Cox proportional hazards models adjusted for established risk factors for CHF, increased risk of CHF was associated with a 1-SD increase in the 2-hour glucose value of an oral glucose tolerance test (hazard ratio [HR], 1.44; 95% confidence interval [CI], 1.08-1.93), fasting serum proinsulin level (HR, 1.29; 95% CI, 1.02-1.64), body mass index (HR, 1.35; 95% CI, 1.11-1.65), and waist circumference (HR, 1.36; 95% CI, 1.10-1.69), whereas a 1-SD increase in clamp glucose disposal rate decreased the risk (HR, 0.66; 95% CI, 0.51-0.86). When adding clamp glucose disposal rate to these models as a covariate, the obesity variables were no longer significant predictors of subsequent CHF. Insulin resistance predicted CHF incidence independently of established risk factors including diabetes in our large community-based sample of elderly men. The previously described association between obesity and subsequent CHF may be mediated largely by insulin resistance.

Cardiovascular risk factors for stable angina pectoris versus unheralded myocardial infarction

Background Ischemic heart disease can vary substantially in its clinical presentation. Some patients have acute myocardial infarction (MI) without any previous signs of myocardial ischemia, whereas other patients may have stable angina pectoris for years without periods of acute unstability. This study compared baseline risk factors between subjects in whom stable angina pectoris developed and subjects in whom unheralded fatal or nonfatal MI developed during the follow-up period. Methods In 1970 to 1973, all 50-year-old men in Uppsala, Sweden, were invited to participate in a health survey aimed at identifying risk factors for cardiovascular disease. The present study is a nested case-control study of subjects who were free of coronary heart disease (CHD) at baseline and who then underwent revascularization (percutaneous transluminal coronary angioplasty or coronary artery bypass grafting) because of angina pectoris without preceding MI (n = 70) or in whom fatal or nonfatal MI developed without prior known CHD (n = 372) during the period until 1998. Results In multivariate Cox proportional hazard models, low-density lipoprotein and high-density lipoprotein levels (protective) were significant independent risk factors for stable angina pectoris demanding revascularization, whereas smoking, diastolic blood pressure, serum proinsulin levels, and serum lipid levels were significant independent predictors of subsequent unheralded MI. When comparing hazard ratios (HR), significantly higher HR for diastolic blood pressure (1.40 vs 1.00, for 1 SD increase) and serum proinsulin (1.82 vs1.20, for 1 SD increase) were found in the group in which unheralded MI developed than in the group with stable angina pectoris. Conclusions Serum lipid levels were important risk factors for the development of both stable and acute coronary heart disease. In addition, proinsulin levels and blood pressure were independent predictors of unheralded MI only, which suggests that these factors are involved in thrombosis, plaque rupture, or both.

Human liver-derived cells stably modified for regulated proinsulin secretion function as bioimplants in vivo.

Insulin deficiency is currently treated with pharmacological insulin secretagogues, insulin injections or islet transplants. Secondary failure of pharmacological agents is common; insulin injections often fail to achieve euglycemic control; and islet transplants are rare. Non-beta cells capable of regulated insulin secretion in vivo could be a functional cure for diabetes. Hepatocytes are good candidates, being naturally glucose-responsive, protein-secreting cells, while the liver is positioned to receive direct nutrient signals that regulate insulin production. Human liver-derived Chang cells were modified with a plasmid construct in which a bifunctional promoter comprising carbohydrate response elements and the human metallothionein IIA promoter controlled human proinsulin cDNA expression. Secretory responses of stable cell clones were characterized in vitro and in vivo by proinsulin radioimmunoassay. Transfected Chang cells secreted 5-8 pmol proinsulin/10(6) cells per 24 h in continuous passage for at least a year in response to 5-25 mM glucose and 10-90 microM zinc in vitro. Glucose and zinc synergistically increased proinsulin production by up to 30-fold. Non-glucose secretagogues were also active. Glucose transporter 2 (GLUT2) and glucokinase cDNA co-transfection enhanced glucose responsiveness. Intraperitoneally implanted Chang cells secreted proinsulin in scid and Balb/c mice. Serum proinsulin levels were further increased 1.3-fold (p<0.05) after glucose and 1.4- to 1.6-fold (p<0.005) after zinc administration in vivo. These results are the first to demonstrate stable proinsulin production in a human liver-derived cell line with activity in vitro and in vivo and provide a basis for engineering hepatocytes as in vivo bioimplants for future diabetes treatment.