Molar Ratio Of C-peptide Research Articles

The Application of the Insulin to C-Peptide Molar Ratio (ICPR) in Primary Screening for Insulin Antibodies in Type 2 Diabetes Mellitus Patients: A Further Quantitative Study on the Relationship Between ICPR and Insulin Antibodies.

This study aimed to further quantify the relationship between insulin antibodies (IAs) and the 2-hour insulin to C-peptide molar ratio (2h-ICPR) using a multiple linear regression model in T2DM patients. A total of 274 T2DM patients from April 2019 to December 2022 in Xiang'an Hospital of Xiamen University were included in this study. Multiple Linear Model Fitting was conducted on the candidate independent variables (age, BMI, HbA1c, and 2h-ICPR) for the multiple linear regression. The linear relationship between insulin antibodies (IAs) and the significant independent variables was presented by making multiple linear regression equations. The total demographic characteristics of the included patients were as follows: age (51.92±13.10 years), BMI (24.94±3.99 kg/m2), HbA1c (9.70±2.39%), 2h-ICPR (0.12±0.11), and IAs (0.37±1.12COI). Linear relationships of independent variables: age (r=0.163, p=0.007), 2h-ICPR (r=0.259, p=0.001), BMI (r=0.007, p=0.907) and 2h-ICPR (r=0.092, p=0.129). Multiple linear regression: age (unstandardized β=0.014, 95% CI: 0.004-0.024, p=0.004), 2h-ICPR (unstandardized β=2.758, 95% CI: 1.555-3.962, p≤0.001). The regression equation: . The quantitative relationship between 2h-ICPR and insulin antibodies was . 2h-ICPR can be a preliminary screening indicator for insulin antibody testing in patients with type 2 diabetes.

Characteristics of OGTT and Correlation Between the Insulin to C-Peptide Molar Ratio, HOMA-IR, and Insulin Antibodies in T2DM Patients.

PurposeThe purpose of our study was to analyze the characteristics of OGTT and the correlation between the insulin to C-peptide molar ratio (ICPR), HOMA-IR and insulin antibodies (IAs) in T2DM patients.Patients and MethodsA total of 77 T2DM patients were included and divided into the IA+ group (25 patients) and IA- group (52 patients). The values of serum glucose, insulin, and C-peptide testing during 2-h OGTT were summarized comparatively, and ROC was made to analyze the predictive value of ICPR for IAs.ResultsAt each time point of OGTT, there was no significant difference in serum glucose and C-peptide changes (p>0.05). Serum insulin levels in positive patients were elevated or not at different time points of the OGTT but ICPR was significantly different (P<0.05) in the two groups. Spearman correlation coefficient analysis showed that the presence of insulin antibodies was correlated with ICPR, but not with HOMA-IR, and ICPR-2h had a better prediction capacity (AUC=0.735, the optimal cutoff-point=0.11, Se=0.760, Sp=0.635).ConclusionT2DM patients with IAs showed no difference in serum glucose and serum C-peptide changes, but elevated or not insulin levels on the OGTTs, compared with negative patients. ICPR-2h can be a preliminary diagnostic index to timely predict IAs in T2DM patients.

Higher Prevalence and Degree of Insulin Resistance in Patients With Rheumatoid Arthritis Than in Patients With Systemic Lupus Erythematosus.

Since insulin resistance (IR) is highly prevalent in patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA), we aimed to determine whether differences in IR exist between the two conditions. We conducted a cross-sectional study comprising 413 subjects without diabetes (186 with SLE and 227 with RA). Glucose, insulin, and C-peptide serum levels, as well as IR by the homeostatic model assessment (HOMA2) were studied. A multivariable regression analysis was performed to evaluate the differences in IR indexes between patients with SLE and RA, as well as to determine if IR risk factors or disease-related characteristics are differentially associated with IR in both populations. The insulin:C-peptide molar ratio was upregulated in patients with RA compared to patients with SLE (β 0.009, 95% CI 0.005-0.014, P < 0.001) after multivariable analysis. HOMA2 indexes related to insulin sensitivity (HOMA2-%S) were found to be lower (β -27, 95% CI -46 to -9, P = 0.004) and β cell function (HOMA2-%B) showed higher IR indexes (β 38, 95% CI 23-52, P < 0.001) in RA than in SLE patients after multivariable analysis. Patients with RA more often fulfilled the definition of IR than those with SLE (OR 2.15, 95% CI 1.25-3.69, P = 0.005). The size effect of IR factors on IR indexes was found to be equal in both diseases. IR sensitivity is lower and β cell function is higher in RA than in SLE patients. The fact that traditional IR factors have an equal effect on IR in both SLE and RA supports the contention that these differences are related to the diseases themselves.

Management of Insulin Autoimmune Hypoglycaemia: Single-centre experience from Western India with systematic review of world literature.

Awareness about Insulin Autoimmune Hypoglycaemia (IAH) and its management remains limited. We describe two cohorts: Cohort 1 (n=7) included patients with IAH from a tertiary care centre in India and Cohort 2 (n=294) included systematic review of published English literature from PubMed. They were compared with our insulinoma patients (n=41). Cohort 1 included seven female patients where two had drugs (carbimazole and thiocolchicoside) as triggering factors. Except for one patient requiring oral prednisolone, others had spontaneous remission. The unique features from our series are being first case series of IAH from India and reporting of second case of thiocolchicoside triggered IAH. Cohort 2 had 294 patients identified from 149 publications. Mean age was 54±19years. Thirty-five different triggers were identified from 160 cases. Antithyroid drugs were most common triggers in Japanese patients and most common HLA allele was DRB1*0406, while it was alpha-lipoic acid and HLA DRB1*0403 in non-Asians. Serum Insulin >100µIU/mL and insulin to C-peptide molar ratio (ICMR) >0.25 had specificity of 100% and 97.5%, respectively, for IAH as compared to insulinoma.56%patients had remission with complex carbohydrate diet and trigger removal while 43% required immunosuppressants. 70% achieved remission within 6months. Middle age remains most common age group. Sulfhydryl drugs are most common triggers. Serum Insulin >100µIU/mL and ICMR>0.25 in critical sample are good predictors for diagnosis of IAH, which needs to be confirmed by IAA. Conservative management with dietary modification and trigger removal usually suffices in majority. Rests need immunosuppressants.

Insulin Autoimmune Syndrome Diagnosis and Therapy in a Single Chinese Center

PurposeInsulin autoimmune syndrome (IAS) is a relatively rare cause of hypoglycemia characterized by endogenous hyperinsulinism and autoantibodies against endogenous insulin despite no prior exposure to exogenous insulin. We present a series of IAS cases and describe the clinical characteristics of these cases. MethodsThe medical records of inpatients with the final diagnosis of IAS were collected from August 2007 to August 2017 in Peking Union Medical College Hospital. Clinical characteristics and laboratory test results were summarized. The results of serum glucose, insulin, true insulin, and C-peptide testing during 5-h oral glucose tolerance tests were also summarized. Circulating immune complexes were assessed qualitatively by precipitation with polyethylene glycol (PEG) in some patients. FindingsSixteen patients were included in this study. Insulin autoimmune antibody test results were found positive in 12 patients and weakly positive in 1 patient. Nine patients had an insulin to C-peptide molar ratio >1, whereas 6 patients had an insulin to C-peptide molar ratio <1. Circulating immune complexes were verified in all 4 patients who had been assessed with PEG. During 5-h oral glucose tolerance tests, the C-peptide level responded earlier to the glucose tolerance and had a shorter peak value period compared with insulin, although C-peptide's fluctuation still lagged behind the glucose fluctuation. Three patients presented with self-limited disease courses or limited disease course after discontinuing use of the sulfhydryl group drugs. Some patients' symptoms were relieved after small frequent meals, and some were relieved after taking acarbose. Only 3 patients took glucocorticoids as the anti-immune therapy. ImplicationsThe insulin to C-peptide molar ratios were not consistently >1 in patients with confirmed diagnoses of IAS in our study, which suggested the low sensitivity of insulin to C-peptide molar ratio to detect IAS. The therapy in our study also revealed the self-limited disease course of IAS, and despite the effectiveness of anti-immunity therapy, convenient therapy, such as frequent small meals and adding acarbose, performed well in many patients.

Relationship Between Insulin Sensitivity and β-Cell Secretion in Nondiabetic Subjects with Rheumatoid Arthritis.

In nondiabetic healthy individuals, insulin secretion and sensitivity are linked by a negative feedback loop characterized by a hyperbolic function. We aimed to study the association of traditional insulin resistance (IR) factors with insulin secretion and sensitivity, and to determine whether the hyperbolic equilibrium of this relation is preserved in patients with rheumatoid arthritis (RA). This was a cross-sectional study encompassing 361 nondiabetic individuals: 151 with RA and 210 controls. Insulin, C-peptide, and IR indices by homeostatic model (HOMA2) were assessed. A multivariable analysis was performed to evaluate the differences in the correlation of traditional IR-related factors with glucose homeostasis molecules, as well as IR indices between patients and controls. Nonlinear regression analysis was used to assess the hyperbolic relation of insulin sensitivity and secretion. HOMA2-IR indices were higher in patients with RA than controls. Hepatic insulin extraction, as assessed by the insulin:C-peptide molar ratio, was lower in patients with RA after multivariable analysis (0.08 ± 0.02 vs 0.14 ± 0.07, p < 0.001). Traditional IR-related factors showed significantly lower adjusted correlation coefficients with IR indices in patients with RA. The association between insulin sensitivity and secretion showed a different hyperbolic relation in patients with RA: the variability explained by the curve was lower in RA (nonlinear r2 = 0.845 vs r2 = 0.928, p = 0.001) and β coefficients (-0.74, 95% CI -0.77 to -0.70 vs -1.09, 95% CI -1.17 to -1.02, ng/ml, p < 0.001) were different in RA. The traditional factors associated with IR in healthy individuals are less related to IR in patients with RA. Insulin sensitivity and secretion yield a different hyperbolic equilibrium in RA.

Increased Insulin following an Oral Glucose Load, Genetic Variation near the Melatonin Receptor MTNR1B, but No Biochemical Evidence of Endothelial Dysfunction in Young Asian Men and Women.

AimTo identify biochemical and genetic variation relating to increased risk of developing type 2 diabetes mellitus and cardiovascular disease in young, lean male and female adults of different ethnicities.MethodFasting blood and urine and non-fasting blood following oral glucose intake were analysed in 90 Caucasians, South Asians and South East/East Asians.ResultsThere were no differences in age, birthweight, blood pressure, body mass index, percent body fat, total energy, percentage of macronutrient intake, microalbumin, leptin, cortisol, adrenocorticotropic hormone, nitric oxide metabolites, C-reactive protein, homocysteine, tumor necrosis factor-α, interleukin-6, von Willebrand factor, vascular cell adhesion molecule-1, plasminogen activator inhibitor-1, and tissue plasminogen activator. Fasting total cholesterol (P = .000), triglycerides (P = .050), low density lipoprotein (P = .009) and non-fasting blood glucose (15 min) (P = .024) were elevated in South Asians compared with Caucasians, but there was no significant difference in glucose area under curve (AUC). Non-fasting insulin in South Asians (15–120 min), in South East/East Asians (60–120 min), and insulin AUC in South Asians and South East/East Asians, were elevated compared with Caucasians (P≤0.006). The molar ratio of C-peptide AUC/Insulin AUC (P = .045) and adiponectin (P = .037) were lower in South Asians compared with Caucasians. A significant difference in allele frequency distributions in Caucasians and South Asians was found for rs2166706 (P = 0.022) and rs10830963 (P = 0.009), which are both near the melatonin receptor MTNR1B.ConclusionsElevated non-fasting insulin exists in young South Asians of normal fasting glucose and insulin. Hepatic clearance of insulin may be reduced in South Asians. No current biochemical evidence exists of endothelial dysfunction at this stage of development. MTNR1B signalling may be a useful therapeutic target in Asian populations in the prevention of type 2 diabetes mellitus.

Recurrent Hypoglycemia from Insulin Autoimmune Syndrome

Insulin autoimmune syndrome (IAS) is an uncommon cause of hyperinsulinemic hypoglycemia characterized by autoantibodies to endogenous insulin in individuals without previous exposure to exogenous insulin. IAS is the third leading cause of spontaneous hypoglycemia in Japan, and is increasingly being recognized worldwide in non-Asian populations. We report a case of IAS in a Caucasian woman with recurrent complaints of hypoglycemia, with laboratory findings of serum glucose 2.5 mmol/L (45 mg/dL), insulin 54,930 pmol/L (7,909 μIU/mL), connecting peptide (C-peptide) 4,104 pmol/L (12.4 ng/mL), and a corresponding insulin to C-peptide molar ratio of 13.4 during a spontaneous hypoglycemic event. Autoantibodies to insulin were markedly elevated at > 50 kU/L (> 50 U/mL). IAS should be considered in the differential diagnosis of hypoglycemia in non-diabetic individuals. Distinction from insulinoma is especially crucial to prevent unwarranted invasive procedures and surgical interventions in hypoglycemic patients.

Decreased plasma C-peptide to insulin molar ratio after oral glucose in elderly subjects.

To evaluate the effect of aging on hepatic extraction of insulin, peripheral plasma insulin and C-peptide levels after an oral glucose ingestion were measured in 39 non-obese healthy subjects with normal glucose tolerance test. The subjects were divided into two groups. One age group was below 30 years (n = 17) and another was above 50 years (n = 22). Blood glucose level was significantly higher in elderly subjects than in young at 30 and 60 min, and insulin level was also significantly higher in elderly subjects than in young subjects at 60 min after glucose ingestion. C-peptide response after glucose ingestion was similar in both groups. The molar ratio of C-peptide to insulin after glucose ingestion in elderly subjects was slightly lower than that in young subjects, and the difference between the incremental areas of C-peptide and insulin divided by the incremental area of C-peptide were significantly lower in elderly subjects. These results suggest that hepatic insulin extraction after glucose loading is decreased in elderly subjects and this may partly be responsible for the slightly altered glucose metabolism in elderly subjects with normal glucose tolerance test.

Metabolic effects of chronic glipizide gastrointestinal therapeutic system on serum glucose, insulin secretion, insulin sensitivity, and hepatic insulin extraction in glucose-tolerant, first-degree relatives of African American patients with type 2 diabetes: New insights on mechanisms of action

We examined the long-term metabolic effects of a potent sulfonylurea (SU), glipizide gastrointestinal therapeutic system (glipizide GITS) in normal glucose-tolerant (NGT), first-degree relatives of African American patients with type 2 diabetes in a randomized, placebo-controlled, double-blind manner for 24 months and 6 months after discontinuation of glipizide GITS. Fifty NGT African American first-degree relatives (n = 50)) were randomized to receive either glipizide GITS (GITS, 5 mg/d) or identical placebo (PLAC). The NGT consisted of NGT/GITS (n = 16; mean age, 43.1 ± 8.7years; body mass index [BMI], 34.8 ± 10) and NGT/PLAC (n = 34; 45.5 ± 9.7 years; BMI, 31.3 ± 3.1years). Each of the subjects underwent an oral glucose tolerance test (OGTT) and frequently sampled intravenous glucose tolerance test (FSIGT) at baseline and at yearly intervals for 2 years. Insulin sensitivity (Si) and glucose effectiveness (Sg) were determined by Bergman's minimal model method. Hepatic insulin extraction (HIE) was calculated as the molar ratio of C-peptide and insulin. The mean fasting serum glucose, insulin, and C-peptide levels in the NGT/GITS were not different from that of the NGT/PLAC. After oral glucose challenge, mean serum glucose responses slightly increased (P = not significant [NS]) at 12 and 24 months in the NGT/GITS group when compared with the baseline, 0 month, but remained unchanged in the NGT/PLAC group. In addition, serum insulin and C-peptide responses significantly increased in the NGT/GITS group, but were unchanged in the NGT/PLAC group at 12 and 24 months versus 0 month. The HIE, during OGTT, decreased by 30% from the baseline (0 month) values in the NGT/ GITS, but remained unchanged in the NGT/PLAC group at 12 and 24 months. Mean Si decreased by 30% from the baseline in the NGT/GITS group by 12 and 24 months, but remained unchanged in the NGT/PLAC group. However, the disposition index (DI) remained normal in the NGT/GITS and the NGT/PLAC groups. The DI data in the NGT/GITS group suggested that β cells maintained the ability to compensate for the lower Si during the chronic GITS administration in our high risk African Americans. Chronic GITS was well tolerated without any symptoms of either hypoglycemia or weight gain in the NGT/IGTS group. After discontinuation of GITS, the altered metabolic parameters significantly improved, returning to baseline values in the NGT/IGTS group in 6 months. In summary, chronic glipizide GITS administration (5 mg/d) was associated with increased β-cell secretion, peripheral hyperinsulinemia, reduced Si, and reduced HIE in glucose-tolerant, first-degree relatives of African American patients with type 2 diabetes. These metabolic changes were reversible within 6 months after discontinuation of glipizide GITS. Our study defines a unique mode of action of glipizide GITS in African Americans at high risk for type 2 diabetes. We conclude that the use of glipizide GITS in the primary prevention of type 2 diabetes in nondiabetic first-degree relatives of patients with type 2 diabetes impaired glucose homeostasis. © 2003 Elsevier Inc. All rights reserved.

Circulating proinsulin levels in insulin-dependent diabetic patients after whole pancreas-kidney transplantation

Disproportional hyperproinsulinemia is a sensitive marker for β-cell dysfunction. The objective of this study was to assess the proinsulin profile in persons with insulin-dependent diabetes mellitus (IDDM) after pancreas-kidney transplantation. We determined serum insulin, C-peptide, and proinsulin concentrations during an oral glucose challenge in five pancreas-kidney transplant recipients, nine nondiabetic kidney transplant recipients, and 17 normal subjects. Basal proinsulin concentrations were significantly increased in pancreas-kidney recipients (geometric mean [± 1 SE range], 6.0 [5.5 to 6.4] pmol/L) and kidney recipients (6.4 [5.4 to 7.5] pmol/L) compared with the normal subjects (2.8 [2.5 to 3.2] pmol/L). Integrated proinsulin concentrations during the oral glucose load were also higher in pancreas-kidney recipients (1.4 [1.1 to 1.8] nmol/L · min) and kidney recipients (1.5 [1.2 to 2.0] nmol/L · min) versus normal subjects (0.8 [0.7 to 0.9] nmol/L · min). There was no difference in basal or integrated proinsulin concentrations between the two transplant groups. Even after adjustment for the glomerular filtration rate (GFR), basal and incremental proinsulin concentrations continued to be higher in the transplant groups than in the normal subjects. Proinsulin to C-peptide molar ratios both before and after the glucose load were similar in the three groups. From these findings, we conclude that pancreas-kidney transplantation provokes proportional hyperproinsulinemia, which is closely associated with its reduced clearance in the kidneys.

From Clinical Studies of Diabetes to Molecular Biology. Identification of Abnormal Insulin "Insulin Wakayama".

The recent development of molecular biology enables us to identify three abnormal insulins (insulin Chicago, insulin LosAngeles and insulin Wakayama). In Japan, three pedigrees in which affected individuals secrete [LeuA3] insulin (insulin Wakayama) have been identified. In each family, hyperinsulinemia associated with an abnormally elevated insulin to C-peptide molar ratio was demonstrated to occur in an autosomal dominant pattern of inheritance. In accordance with in vivo observations, semisynthetic [LeuA3] insulin demonstrated reduced in vitro receptor binding and biological activity relative to the human standard. The development of diabetes mellitus in affected family members was not uniform, was influenced by aging, and was different among families. Patients with impaired glucose tolerance demonstrated reduced insulin secretory reserve. Some of these features are thought to resemble the nature of noninsulin dependent diabetes mellitus (NIDDM).Therefore, insulin Wakayama may be an useful model for the study of the development of NIDDM.

Hyperproinsulinaemia in acromegaly: evidence for abnormal pancreatic beta-cell function?

We investigated whether pancreatic beta-cell dysfunction has a role in the pathogenesis of glucose intolerance in acromegaly by comparing plasma intact proinsulin, immunoreactive insulin, C-peptide and glucose concentrations during a 75 g oral glucose load in six patients with active acromegaly and eight healthy volunteers. Only acromegalic patients with normal glucose tolerance were studied. Glucose concentrations were similar in acromegalic patients and controls. Acromegalic patients had higher fasting insulin (P < 0.005) and fasting C-peptide (P < 0.005) concentrations than controls. Although fasting proinsulin levels were higher in acromegalic patients than controls, this did not achieve statistical significance. Integrated insulin (P < 0.05), C-peptide (P < 0.05) and proinsulin (P < 0.005) concentrations were greater in acromegalic patients than control subjects. Integrated (P < 0.05) proinsulin:insulin molar ratios were higher in acromegalic patients than controls. Fasting and integrated insulin:C-peptide molar ratios were similar in acromegalic patients and controls. These results indicate that hyperproinsulinaemia contributes to the hyperinsulinaemia which characterizes active acromegaly. The disproportionate hyperproinsulinaemia in acromegaly suggests that prolonged and excessive growth hormone secretion may result in pancreatic beta-cell dysfunction which may predispose acromegalic subjects to glucose intolerance.

Mechanisms of Hyperinsulinemia and Hyperglucagonemia after Liver Transplantation

These studies were undertaken to evaluate the mechanisms for changes in plasma insulin and glucagon levels observed post-liver transplantation. Two groups of pigs were studied: a control group (n= 8) underwent laparotomy and catheter placement in the carotid artery and portal and hepatic veins. Hepatic blood flow was measured by ultrasonic flow probes placed around the hepatic artery and portal vein. An experimental group (n= 8) underwent orthotopic liver transplantation and similar instrumentation. On Day 1 after surgery, an estimate of insulin and glucagon secretion and hepatic extraction was determined using arteriovenous difference techniques. Serum assays were performed for markers of hepatic and renal function. Plasma insulin levels of the transplanted pigs were higher in the carotid artery (4 ± 1 μU/ml vs 7 ± 1 μU/ml), but not in the hepatic vein (5 ± 1 μU/ml vs 7 ± 1 μU/ml) and in the portal vein (10 ± 2 μU/ml vs 12 ± 2 μU/ml). Arterial plasma C-peptide was significantly greater in the transplanted group (0.23 ± 0.02 ng/ml vs 0.42 ± 0.03 ng/ml); however, the molar ratio of C-peptide and insulin was not different between the two groups (3.6 ± 0.9 vs 3.4 ± 0.4). Plasma glucagon levels of the transplanted pigs were significantly elevated in the carotid artery (111 ± 11 pg/ml vs 323 ± 65 pg/ml), portal vein (221 ± 27 pg/ml vs 495 ± 69 pg/ml), and hepatic vein (142 ± 15 pg/ml vs 395 ± 58 pg/ml). The estimate of pancreatic secretion of insulin (115 ± 28 μU/kg·min) vs 71 ± 21 μU/kg·min) and glucagon (2.0 ± 0.4 ng/kg·min vs 2.7 ± 0.7 ng/kg·min) and the fractional hepatic extraction rate of insulin (35 ± 8% vs 32 ± 5%) were not different between the two groups. However, the hepatic fractional extraction rate of glucagon was significantly decreased in the transplanted group (25 ± 5% vs 11 ± 3%). Therefore, the hyperglucagonemia observed 24 hr following liver transplantation is partly due to reduced hepatic fractional extraction of glucagon while the hyperinsulinemia is mainly due to the nonhepatic clearance of insulin. We speculate that decreased renal function may contribute to the hyperinsulinemia, elevated C-peptide concentrations, and hyperglucagonemia.

The entero-insular axis in polycystic ovarian syndrome.

We investigated the contributions made by the entero-insular axis, proinsulin and the fractional hepatic extraction of insulin to the hyperinsulinaemia characteristic of polycystic ovarian syndrome (PCOS). We measured plasma glucose, gastric inhibitory polypeptide (GIP), glucagon-like peptide-1 (7-36 amide) (GLP-1(7-36) amide), immunoreactive insulin (IRI), intact proinsulin (IPI), and C-peptide concentrations during a 75 g oral glucose tolerance test in seven normal weight women with PCOS and eight healthy women. Women with PCOS had higher fasting (P = 0.05) and integrated (P < 0.01) IRI concentrations than controls. Fasting C-peptide levels were similar in both groups but integrated C-peptide (P < 0.05) concentrations were greater in PCOS subjects than controls. Fasting and integrated concentrations of glucose, GIP and GLP-1(7-36) amide were similar in subjects with PCOS and controls. Although fasting IPI concentrations were similar in both groups, integrated IPI concentrations were higher (P = 0.05) in patients with PCOS. Women with PCOS had similar fasting but higher (P < 0.05) integrated IRI:C-peptide molar ratios than controls. Fasting and integrated IPI:IRI molar ratios were similar in both groups. These results confirm that lean women with PCOS have peripheral hyperinsulinaemia. The mild fasting hyperinsulinaemia is due to increased pancreatic secretion, whereas the stimulated hyperinsulinaemia is due to both pancreatic hypersecretion and reduced fractional hepatic extraction of insulin. Hyperproinsulinaemia is modest and appropriate in PCOS, GIP and GLP-1(7-36) amide do not contribute to the stimulated hyperinsulinaemia in PCOS.

The contribution of proinsulin and des-31,32 proinsulin to the hyperinsulinemia of diabetic and nondiabetic cirrhotic patients

We used specific, monoclonal antibody-based, two-site immunoradiometric assays to test the hypothesis that serum levels of proinsulin and des-31,32 proinsulin would be increased in cirrhosis, particularly in those with overt diabetes. A 75-g oral glucose tolerance test was performed after an overnight fast in eight cirrhotic patients with diabetes (fasting blood glucose, 7.8 +/- 2.2 [SE] mmol/L), seven nondiabetic cirrhotic patients, and eight normal control subjects. Fasting serum immunoreactive insulin levels were approximately six times higher in cirrhotics than in controls, but were not different between diabetic and nondiabetic cirrhotic patients. After oral glucose, the incremental area under the serum insulin concentration curve was 3,475 +/- 1,009 pmol.L-1.h in nondiabetic cirrhotic patients, significantly higher than in controls (761 +/- 48, P < .001) or diabetic cirrhotic patients (881 +/- 186, P < .05). Fasting serum proinsulin levels in diabetic cirrhotic patients (24.0 +/- 5.7 pmol/L) were higher than in controls (2.3 +/- .05, P < .001) or nondiabetic cirrhotic patients (4.4 +/- 0.8, P < .005). Fasting serum levels of des-31,32 proinsulin were also much higher in diabetic cirrhotic patients than in nondiabetic cirrhotic patients or controls (P < .02 and P < .005, respectively). Fasting proinsulin plus des-31,32 proinsulin constituted 12.5% +/- 1.4% of serum immunoreactive insulin in diabetic cirrhotics, higher than in nondiabetic cirrhotics (3.7% +/- 0.5%, P < .001) and normal controls (7.8% +/- 1.5%, P = .035).(ABSTRACT TRUNCATED AT 250 WORDS)

Abnormal insulinemia

The recent development of molecular biology enables us to identify three abnormal insulins (insulin Chicago, insulin Los Angeles and insulin Wakayama). In Japan, three pedigrees in which affected individuals secrete [ LeuA3]insulin (insulin Wakayama) have been identified. In each family, hyperinsulinemia associated with an abnormally elevated insulin to C-peptide molar ratio was demonstrated to occur in an autosomal dominant pattern of inheritance. In accordance with in vivo observations, semisynthetic [ LeuA3] insulin demonstrated reduced in vitro receptor binding and biological activity relative to the human standard. The development of diabetes mellitus in affected family members was not uniform, was influenced by aging, and was different among families. Patients with impaired glucose tolerance demonstrated reduced insulin secretory reserve. Some of these features are thought to resemble the nature of non-insulin dependent diabetes mellitus (NIDDM). Therefore, insulin Wakayama may be a useful model for the study of the development of NIDDM.

Proinsulin and C-peptide at onset and during 12 months cyclosporin treatment of Type 1 (insulin-dependent) diabetes mellitus

An increased proinsulin to C-peptide molar ratio at the onset of Type 1 (insulin-dependent) diabetes mellitus has been suggested. We studied fasting proinsulin levels and proinsulin/C-peptide ratios in the newly diagnosed diabetic subjects participating in the Canadian/European placebo controlled cyclosporin study at entry, during the one year treatment period and six months of follow-up. Available entry data from 176 out of the 188 allocated patients were compared to 60 age and weight matched control subjects. Fasting proinsulin was significantly elevated in male patients compared to male control subjects (p less than 0.01), whereas the levels only tended to be elevated in female patients. The proinsulin/C-peptide ratio was three to fourfold elevated in the diabetic groups of both sexes, (p less than 0.001). Further, proinsulin and C-peptide were studied in 83 cyclosporin and 86 placebo-treated subjects during the trial and follow-up. An additional increase of proinsulin/C-peptide ratio was observed during the first three months of placebo treatment. It remained constantly high for nine months and then declined to entry level. This pattern was not seen in the cyclosporin-treated group, where the ratio was unchanged during the 12 months trial and follow-up. The effect of cyclosporin on the induction of non-insulin requiring remission was unrelated to fasting and glucagon stimulated C-peptide levels at entry, whereas 64% of the cyclosporin-treated against 28% of the placebo-treated subjects (p less than 0.01) went into remission if the proinsulin/C-peptide ratio at entry was above 0.024.(ABSTRACT TRUNCATED AT 250 WORDS)

Immunoreactive C-peptide in spontaneous syndromes of obesity and diabetes in mice.

Immunoreactive C-peptide was evaluated in the plasma and pancreas of Aston ob/ob and C57BL/KsJ db/db mice in relation to disturbances in pancreatic B-cell function. At 18-24 weeks of age, ob/ob and db/db mice displayed hyperglycaemia (1.6 and 3.8 fold increases respectively) and hyperinsulinaemia (10.8 and 5.1 fold increases respectively) despite a similar pancreatic insulin content to their respective non-diabetic lean control mice. Immunoreactive C-peptide concentrations in the plasma and pancreas of the mutants corresponded with the degree of hyperinsulinaemia and pancreatic insulin content, and the insulin: C-peptide molar ratios in both mutants were similar to lean controls. In ob/ob mice parenteral glucose administration decreased plasma insulin and C-peptide concentrations, despite markedly raised glucose concentrations. However, administration of a low dose of insulin (5 U/kg) to lean mice and much higher doses of insulin (50 and 120 U/kg) to ob/ob mice markedly decreased plasma glucose and C-peptide concentrations. When the rate and extent of insulin-induced glucose suppression observed in ob/ob mice was mimicked in lean mice, an almost complete (95%) inhibition of C-peptide was achieved compared with a 57% decrease in the ob/ob mutant. Injection of ob/ob mice with glucose to counter the insulin-induced hypoglycaemia failed to affect the fall of C-peptide concentrations. The data suggest that the metabolic processing of insulin and C-peptide are undisturbed in obese-diabetic mice, and that the impaired suppression of circulating C-peptide by insulin-hypoglycaemia in ob/ob mice predominantly reflects impaired feedback inhibition by insulin.

Clinical application of the 24-H urinary C-peptide excretion rate and its relationship to metabolic control in diabetics.

In this study, we evaluated in normal subjects, insulin-dependent (IDD) and non-insulin-dependent (NIDD) diabetics, the diurnal urinary C-peptide excretion rate (CPR-U) and its relationship to serum C-peptide concentration and glucose:C-peptide molar ratio, and to the common parameters of metabolic control. The CPR-U (and CPR-U/g creatinine) were significantly lower in IDD and higher in NIDD compared to control subjects. Moreover, a good and significant correlation with serum C-peptide concentrations and the glucose:C-peptide ratio in diabetic subjects as well as in controls and diabetics considered together was found. A slight but significant correlation was present in diabetic subjects between CPR-U and body mass index (r = 0.45), 24-h glycosuria (r = 0.36), HbA1 levels (r = 0.31), post-prandial glucose concentrations (r = 0.26) and per cent glucose variation after each meal (r = 0.34). No differences were found in CPR-U and the degree of metabolic control between obese and non-obese NIDD. In conclusion, CPR-U may be a useful and simple method of defining the secretory activity of the B-cell. Metabolic control in diabetics is slightly correlated to the degree of B-cell function as evaluated by the diurnal excretion rate of C-peptide in urine.