Plasma C-peptide Values Research Articles

301-OR: Effect of Vitamin D Supplementation on Insulin Sensitivity and Beta-Cell Function in Prediabetes

Vitamin D is believed to regulate pathways in glucose homeostasis, but effects of vitamin D supplementation on insulin sensitivity and β-cell function in humans remain uncertain. We completed a secondary analysis of the Vitamin D and type 2 diabetes (D2d) study to investigate the effects of vitamin D supplementation on insulin sensitivity and β-cell function. Participants at high risk for type 2 diabetes, meeting at least 2-out-of-3 ADA criteria for prediabetes, were randomly assigned to 4000 IU/day of vitamin D3 or placebo. Insulin sensitivity and β-cell function were estimated using data from 75-gram oral glucose tolerance tests (OGTT). We used the University of Oxford HOMA2 Calculator to estimate insulin sensitivity from simultaneously measured fasting plasma glucose and C-peptide values. Early C-peptide and insulin responses were calculated as the ratio of C-peptide or insulin increment to glucose level changes during the first 30 minutes of the OGTT. The disposition index (DI) as an estimate of β-cell function was calculated as the product of C-peptide response and HOMA2%S. The response to vitamin D3 was evaluated in 1,774 participants over 24 months. Baseline characteristics [mean age 60.5±9.8 years, BMI 31.9±4.4 kg/m2, 56.4% male, 69.1% white, 25-hydroxyvitamin D (25-OH D) 28.2±10.2 ng/ml, HbA1c 5.9%±0.2, FPG 107.7±7.2 mg/dl, 2hrOGTT glucose 137.1±34.1 mg/dl] were similar between the vitamin D and placebo groups. Serum 25-OH D increased from 27.9±10.3 ng/ml to 54.9±14.4 ng/ml at 24 months in the vitamin D group and remained unchanged with placebo (p<0.05 between group changes from baseline). There were no significant differences in changes in HOMA2%S, C-peptide or insulin responses and DI between the two groups. In conclusion, in this pre-specified analysis from the D2d study, supplementation with vitamin D for 24 months did not alter insulin sensitivity or β-cell function in people with prediabetes who were not selected based on their baseline vitamin D levels. Disclosure N. Rasouli: Consultant; Self; Novo Nordisk, Research Support; Self; Allergan plc, Lilly Diabetes, Novo Nordisk. I. Brodsky: None. R. Chatterjee: Research Support; Self; Bristol-Myers Squibb Company, Epigenomics AG, Verily Life Sciences. S. H. Kim: Advisory Panel; Self; Bayer U. S., GI Dynamics, Stock/Shareholder; Spouse/Partner; Dexcom, Inc. R. E. Pratley: Other Relationship; Self; Hanmi Pharmaceutical, Merck Sharp & Dohme Corp., Metavention, Monster Energy Company, Inc., Novo Nordisk, Pfizer Inc., Poxel SA, Sanofi, Scohia Pharma Inc., Sun Pharmaceutical Industries Ltd. M. Staten: None. J. P. Nelson: None. A. G. Pittas: None. D2d research group: n/a. Funding American Diabetes Association (1-14-D2d-01 to A.G.P.); National Institute of Diabetes and Digestive and Kidney Diseases (U34DK091958); Office of Dietary Supplements (U01DK098245)

Role of maternal glucose metabolism in the association between maternal BMI and neonatal size and adiposity.

One potential mechanism by which maternal obesity impacts fetal growth is through hyperglycemia below the threshold for gestational diabetes. Data regarding which measures of maternal glucose metabolism mediate this association is sparse. The objectives of this study were to (i) quantify the associations of maternal pre-pregnancy body mass index (BMI) with neonatal size and adiposity and (ii) examine the role of markers of maternal glucose metabolism as mediators in these associations. This is a secondary analysis of 6,379 mother-infant dyads from the Hyperglycemia and Adverse Pregnancy Outcome cohort. Markers of glucose metabolism, including plasma glucose and c-peptide values, Stumvoll first-phase estimate, modified Matsuda index, and oral disposition index were measured and calculated from an oral glucose tolerance test (OGTT) between 24- and 32-weeks' gestation. We calculated the direct effect of maternal BMI category, measured at the time of the OGTT and regressed to estimate pre-pregnancy BMI, on neonatal (1) birth weight (BW), (2) fat mass (FM), (3) % body fat (BF%), and (4) sum of skinfold thickness (sSFT). We then calculated the indirect effect of BMI category on these measures through markers of glucose metabolism. Maternal BMI category was positively associated with neonatal BW, FM, BF%, and sSFT. Additionally, mothers who were overweight or obese had higher odds of delivering an infant with BW, FM, BF%, or sSFT >90th percentile. Fasting glucose and c-peptide values were the strongest mediators in the linear associations between maternal BMI category and neonatal size and adiposity. Maternal overweight and obesity were associated with higher odds of neonatal BW and adiposity >90th percentile. Fasting measures of glucose metabolism were the strongest mediators of these associations, suggesting that future studies should investigate whether incorporation of these markers in pregnant women with obesity may improve prediction of neonatal size and adiposity.

Discriminatory ability of simple OGTT-based beta cell function indices for prediction of prediabetes and type 2 diabetes: the CODAM study

Aims/hypothesisThe hyperglycaemic clamp technique and the frequently sampled IVGTT are unsuitable techniques to assess beta cell function (BCF) in large cohorts. Therefore, the aim of this study was to evaluate the discriminatory ability of simple OGTT-based BCF indices for prediction of prediabetes (meaning impaired fasting glucose and/or impaired glucose tolerance) and type 2 diabetes.MethodsGlucose metabolism status was assessed by 2 h 75 g OGTT at baseline (n = 476, mean age 59.2 years, 38.7% women) and after 7 years of follow-up (n = 416) in the Cohort on Diabetes and Atherosclerosis Maastricht (CODAM) study (1999–2009). Baseline plasma glucose, insulin and C-peptide values during OGTTs were used to calculate 21 simple indices of BCF. Disposition indices (BCF index × Matsuda index), to compensate for the prevailing level of insulin resistance, were calculated for the BCF indices with the best discriminatory abilities. The discriminatory ability of the BCF indices was estimated by the area under the receiver operating characteristics curve (ROC AUC) with an outcome of incident prediabetes (n = 73) or type 2 diabetes (n = 60 and n = 18 cases, respectively, in individuals who were non-diabetic or had normal glucose metabolism at baseline).ResultsFor incident prediabetes (n = 73), all ROC AUCs were less than 70%, whereas for incident type 2 diabetes, I30/I0, CP30/CP0, ΔI30/ΔG30, ΔCP30/ΔG30 (where I, CP and G are the plasma concentrations of insulin, C-peptide and glucose, respectively, at the times indicated), and corrected insulin response at 30 min had ROC AUCs over 70%. In at-baseline non-diabetic individuals, disposition indices ΔI30/ΔG30, ΔCP30/ΔG30 and corrected insulin response at 30 min had ROC AUCs of over 80% for incident type 2 diabetes. Moreover, these BCF disposition indices had significantly better discriminatory abilities for incident type 2 diabetes than the Matsuda index alone.Conclusions/interpretationBCF indices reflecting early-phase insulin secretion have the best ability to discriminate individuals who will develop prediabetes and type 2 diabetes. Of these, ΔCP30/ΔG30, often referred to as the C-peptidogenic index, performed consistently well.

Attenuated improvements in adiponectin and fat loss characterize type 2 diabetes non-remission status after bariatric surgery.

To identify the metabolic determinants of type 2 diabetes non-remission status after bariatric surgery at 12 and 24 months. A total of 40 adults [mean ± sd body mass index 36 ± 3 kg/m(2) , age 48 ± 9 years, glycated haemoglobin (HbA1c) 9.7 ± 2%) undergoing bariatric surgery [Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy (SG)] were enrolled in the present study, the Surgical Treatment and Medication Potentially Eradicate Diabetes Efficiently (STAMPEDE) trial. Type 2 diabetes remission was defined as HbA1c <6.5% and fasting glucose <126 mg/dl (i.e. <7 mmol/l) without antidiabetic medication. Indices of insulin secretion and sensitivity were calculated from plasma glucose, insulin and C-peptide values during a 120-min mixed-meal tolerance test. Body fat, incretins (glucagon-like polypeptide-1, gastric inhibitory peptide, ghrelin) and adipokines [adiponectin, leptin, tumour necrosis factor-α, high-sensitivity C-reactive protein (hs-CRP)] were also assessed. At 24 months, 37 patients had available follow-up data (RYGB, n = 18; SG, n = 19). Bariatric surgery induced type 2 diabetes remission rates of 40 and 27% at 12 and 24 months, respectively. Total fat/abdominal fat loss, insulin secretion, insulin sensitivity and β-cell function (C-peptide0-120 /glucose0-120 × Matsuda index) improved more in those with remission at 12 and 24 months than in those without remission. Incretin levels were unrelated to type 2 diabetes remission, but, compared with those without remission, hs-CRP decreased and adiponectin increased more in those with remission. Only baseline adiponectin level predicted lower HbA1c levels at 12 and 24 months, and elevated adiponectin correlated with enhanced β-cell function, lower triglyceride levels and fat loss. Smaller rises in adiponectin level, a mediator of insulin action and adipose mass, characterize type 2 diabetes non-remission up to 2 years after bariatric surgery. Adjunctive strategies promoting greater fat loss and/or raising adiponectin may be key to achieving higher type 2 diabetes remission rates after bariatric surgery.

Fasting Plasma C-Peptide and Micro- and Macrovascular Complications in a Large Clinic-Based Cohort of Type 1 Diabetic Patients

OBJECTIVE—A protective effect of residual β-cell function on microvascular complications of type 1 diabetes has been suggested. Our aim was to retrospectively evaluate the association of fasting plasma C-peptide values with micro- and macrovascular complications.RESEARCH DESIGN AND METHODS—We recruited a clinic-based cohort of 471 type 1 diabetic patients born after 1945 and cared for in the period 1994–2004. Centralized measurements and standardized procedures of ascertainment of micro- and macrovascular complications were employed. Individual cumulative averages of A1C up to 2007 were calculated.RESULTS—Residual β-cell secretion was detected even many years after diabetes diagnosis. In multivariate linear regression analysis, fasting plasma C-peptide values were positively associated with age at diagnosis (β = 0.02; P < 0.0001) and triglycerides (β = 0.20; P = 0.05) and inversely associated with diabetes duration (β = −0.03; P < 0.0001) and HDL cholesterol (β = −0.006; P = 0.03). The final model explained 21% of fasting C-peptide variability. With respect to fasting C-peptide values in the lowest tertile (<0.06 nmol/l), higher values were associated with lower prevalence of microvascular complications (odds ratio [OR] 0.59 [95% CI 0.37–0.94]) independently of age, sex, diabetes duration, individual cumulative A1C average during the study period, hypertension, and cardiovascular diseases. No association was evident with macrovascular complications (0.77 [0.38–1.58]).CONCLUSIONS—Our study shows an independent protective effect of residual β-cell function on the development of microvascular complications in type 1 diabetes, suggesting the potential beneficial effect of treatment that allows the preservation of even modest β-cell function over time.

Residual β-Cell Function and Male/Female Ratio Are Higher in Incident Young Adults Than in Children

The hypothesis of age-dependent variations in epidemiologic and clinical features at onset of type 1 diabetes has been assessed in the registry of the province of Turin, Italy. The study base is the population 0-29 years of age of the province of Turin, in the period from 1984 to 2000. Islet cell antibody (ICA), GAD antibody (GADA), antibodies to protein tyrosine phosphatase (IA2), and C-peptide were measured in subgroups of the cohort. One thousand fifty-six incident cases have been identified (completeness of ascertainment 98.1%). Rates per 100,000 person-years were similar in males and females in the age-group 0-14 years (10.7, 95% CI 9.5-12.0 vs. 9.8, 8.6-11.1). In the age-group 15-29 years, males had higher risk than females (7.7, 6.9-8.6 vs. 5.3, 4.6-6.1; rate ratio, 1.46, 95% CI 1.23-1.74; P = 0.00002). Fasting plasma C-peptide values (n = 575) were twofold lower in the age-group 0-14 years than in the age-group 15-29 years (0.10 vs. 0.23 nmol/l; P < 0.0001). Frequencies of ICA and IA2 positivities (n = 183) decreased with increasing age, whereas frequency of GADA positivity increased. Idiopathic cases were 12.6% and had higher mean values of fasting (0.28 vs. 0.14 nmol/l; P = 0.043) and stimulated C-peptide (0.59 vs. 0.34 nmol/l; P = 0.05). In logistic regression analyses, subjects with fasting C-peptide values in the upper quartile had higher likelihood of being older (odds ratio 1.20 for year, 95% CI 1.11-1.28), ICA negative (0.26, 0.10-0.70), and female (1.29, 0.48-3.42). This study shows 1) sex differences in incidence rates in young adults; 2) better preserved beta-cell function in young adults, in idiopathic cases (12%), and in ICA-negative cases; and 3) lower frequencies of ICA and IA2 positivities and higher frequency of GADA positivity in young adults than in children.

Partial androgen deficiency in aging type 2 diabetic men and its relationship to glycemic control

Aging in the male is associated with both a higher incidence of type 2 diabetes and hypogonadism. However, little information is available about the complex of symptoms and hormonal changes related to partial androgen deficiency in aging (called andropause) in type 2 diabetic men. Here, for the first time, we used a combination of clinical and hormonal criteria to define andropause and to analyze the relationships between the androgen environment and glucose metabolism in 55 type 2 diabetic men (63.6 ± 7.9 years, mean ± SD). Low plasma levels of total testosterone (≤3.4 ng/mL) and free testosterone (≤11 pg/mL) were found in 20% and 54.5%, respectively, of the diabetic men. The fraction of diabetic men with subnormal levels of total testosterone increased with aging: 14.2% (50 to 59 years), 17.4% (60 to 69 years) and 36% (> 70 years). The corresponding figures for subnormal values of free testosterone were 38%, 69.6%, and 54.5%, respectively. In the whole group of type 2 diabetic men, no significant linear correlations between total or free testosterone with fasting plasma glucose, insulin, C-peptide, or fructosamine values could be established. Total testosterone was positively correlated with glycosylated haemoglobin (HbA 1c) levels ( r = .322, P = .01). Although fasting plasma glucose was marginally higher in aging type 2 diabetic patients with andropause than in those without andropause (162 ± 6.9 v 139 ± 8.9, mean ± SEM, P = .05), there were no differences between both subgroups for plasma fasting insulin, C-peptide, fructosamine, or HbA 1c levels. Replacement therapy (150 mg intramuscular [IM] of enanthate of testosterone every 14 days for 6 months) was applied in 10 type 2 diabetic men with clinical features of andropause associated with subnormal concentrations of serum testosterone. The treatment induced significant increases in total plasma testosterone (baseline: 3.9 ± 0.3; at 6 months: 7.1 ± 0.9 ng/mL, mean ± SEM, P = .003) and free testosterone (baseline: 9.3 ± 0.6; at 6 months 17.6 ± 2.4 pg/mL, P = .003), but had a neutral effect on overall glycemic control. These data show a high prevalence of andropause in aging type 2 diabetic men and suggest that the endogenous androgen environment, as well as correction of the partial androgen deficiency, do not have a meaningful effect on glycemic control.

Cytokine production in women with antiretroviral treatment-associated breast fat accumulation and limb wasting.

To test the cytokine production of peripheral blood mononuclear cells in a group of HIV-infected women with breast enlargement and lower limb wasting while receiving antiretroviral therapy (ART) including a protease inhibitor. Case-control study including 20 women with fat tissue alterations and 20 matched controls treated with comparable ART. Adipose tissue alterations (ATA) were defined by increased breast size (> or = 2 bra sizes) accompanied by lower limb fat wasting. A randomly selected subset of patients underwent analyses including: dual energy X-ray absorptiometry, metabolic and endocrine assays, in vitro cytokine production testing [interferon-gamma, interleukin (IL)-2, IL-4, IL-10, IL-12, tumor necrosis factor-alpha (TNF-alpha)] after appropriate stimulation; T-cell phenotyping, T-helper function after stimulation with either tetanus toxoid, influenza antigen, allogeneic peripheral blood lymphocytes, and phytohemagglutinin. Endocrinological study included the determination of plasma concentrations of prolactin, growth hormone, testosterone, adrenocorticotropic hormone, cortisol and C-peptide. In vitro production of IL-12 was higher (P = 0.0001), and TNF-alpha (P = 0.0093) and IL-10 (P < 0.0001) production were lower in stimulated peripheral blood mononuclear cells of ATA-positive women compared with ATA-negative women. ATA-positive women also showed a better response to tetanus toxoid (P = 0.021) and a lower median fluorescence intensity of CD14/DR (P=0.033). Plasma C-peptide values were higher in ATA-positive women compared with ATA-negative women (P = 0.033), even if in the normal range (< 4 ng/ml) in all but one of the ATA-positive patients. HIV-1-infected women who developed breast enlargement and lower limb fat wasting while receiving ART had a favorable immunological profile with efficient IL-12 production and T-helper function, and with TNF-a production in the range of a HIV-negative reference population. These findings suggest that the rescue of some immune functions under ART may be involved in the pathogenesis of this particular adipose tissue disorder.

The occurrence of diabetic ketoacidosis in adults.

To analyze the occurrence of DKA in Chinese adults. We retrospectively reviewed the medical records of adults presenting with DKA in a tertiary referral center from January 1992 to December 1997. We classified these patients into 3 groups: type 1, type 2 and new-onset diabetes. Clinical features and follow-up treatment were analyzed. One hundred and twenty patients with 141 episodes of DKA were included; 77 episodes (54.6%) were classified as being caused by type 2, 32 (22.7%) by type 1 and 32 (22.7%) by new-onset DM. The average age of type 2 patients was significantly higher. Of the 25 new-onset patients with follow-up for at least 12 months, 11 were not taking insulin. Of these 11 patients, 6 had a family history of DM and 5 had BMI greater than 26.4 kg/m2. The fasting plasma C-peptide values at various times of follow-up varied from 2.3 to 9.5 ng/ml in 6 of the 11 DKA-onset patients. In type 2 patients, the occurrence of DKA is usually associated with old age and another severe illness. "DKA-onset type 2 DM" reported in African-Americans and in Japanese is also observed in Chinese.

Microalbuminuria in type 2 diabetic patients: a cross-sectional study of frequency, sex distribution and relation to hypertension.

We studied 112 type 2 diabetic patients. Fourteen patients had frank proteinuria, and 37 of the remaining 98 had microalbuminuria which was more frequent in men than in women (P < 0.02). Hypertension was found in 47 of the patients, equally distributed between sexes. Male diabetics with microalbuminuria had higher systolic blood pressure than diabetics without microalbuminuria (P < 0.02). Body mass index was higher in both sexes with hypertension compared to patients without hypertension. In the hypertensive men plasma C-peptide values were higher compared to patients without hypertension (P < 0.01) irrespective of the presence of microalbuminuria. A positive correlation between blood pressure and C-peptide was found (P < 0.01) in the men. We suggest that gender should be taken into account in the analysis and interpretation of microalbuminuria in type 2 diabetes.

Islet cell antibodies are associated with beta-cell failure also in obese adult onset diabetic patients.

To clarify the utility of islet cell antibodies (ICA) to correctly classify and predict insulin treatment in newly diagnosed diabetic subjects, ICA, body mass index (BMI), glycated hemoglobin (HbA1c), and fasting plasma C-peptide values were evaluated at and 3 years after diagnosis in 233 new, consecutively diagnosed, adult diabetic patients classified as obese or nonobese (National Diabetes Data Group, NDDG criteria). Among the 233 patients, 31 were nonobese ICA-positive (mean age at diagnosis 43 +/- 3 years), 55 nonobese ICA-negative (mean age at diagnosis 58 +/- 2 years), 7 obese ICA-positive (mean age at diagnosis 57 +/- 5 years), and 139 obese ICA-negative (mean age at diagnosis 58 +/- 1 years). Fasting C-peptide decreased (P < 0.05) in nonobese ICA-positive patients who after 3 years showed lower BMI (22.6 +/- 0.6 versus 24.5 +/- 0.4; P < 0.05), lower fasting C-peptide (0.14 +/- 0.06 nmol/l versus 0.71 +/- 0.07 nmol/l; P < 0.001), and higher frequency of insulin treatment [28/31 (90%) versus 6/45 (13%); P < 0.001] than nonobese ICA-negative patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Relationship of insulin secretory pulses to sex hormone-binding globulin in normal men.

Insulin has emerged as a regulator of sex hormone-binding globulin (SHBG) production in vitro and in vivo. A role for insulin in regulating SHBG exists in insulin resistant states such as obesity and polycystic ovary syndrome. The relationship of in vivo insulin secretion rates to SHBG levels in healthy normal men is less well documented. Hepatic synthesis of SHBG may be influenced by quantitative insulin exposure as well as qualitative characteristics such as frequency and amplitude of insulin secretory pulses. The present study was undertaken to assess these relationships in 10 normal men. Adiposity was determined by the body mass index and fat distribution by the waist hip ratio. Peripheral insulin sensitivity was determined by the euglycemic clamp technique at an insulin infusion rate of 287 pmol/min.m2. SHBG levels were determined in the fasting state by RIA. Arterialized venous samples for C-peptide were obtained every 2 min for 90 min in the basal state. Individual C-peptide kinetics were derived after a bolus injection of biosynthetic human C-peptide and a previously validated two compartmental model. Insulin secretion rates at each time point were calculated using the plasma C-peptide values and the C-peptide kinetics. Insulin secretion rates were unrelated to SHBG concentrations (r = -0.29, P > 0.05). The insulin secretory pulse interval had a significant positive association with SHBG levels (r = 0.86, P < 0.05). Insulin secretory pulse amplitude, body mass index, waist hip ratio, and peripheral insulin sensitivity were not associated with SHBG concentrations in a regression analysis. We postulate that insulin secretory pulse frequency may be an important determinant of SHBG synthesis in normal man.

Primary pancreatic beta-cell secretory defect caused by mutations in glucokinase gene in kindreds of maturity onset diabetes of the young

Maturity-onset diabetes of the young (MODY), characterised by non-insulin-dependent diabetes mellitus (NIDDM) with an early age of onset, is a genetically heterogeneous disorder. In most MODY kindreds described in France, chronic hyperglycaemia is caused by mutations in the gene encoding pancreatic beta-cell and liver glucokinase (GCK). We here report the beta-cell secretory profiles of nine patients from four GCK-linked MODY kindreds. First-phase insulin secretion assessed by an intravenous glucose test was comparable in patients and seven controls. However, beta-cell secretory response to continuous glucose stimulus during a hyperglycaemic glucose clamp was significantly reduced: mean plasma insulin values of 12 (SD 7) vs 40 (11) mU/l (p=0·0001) and mean plasma C-peptide values 1·20 (0·30) vs 2·61 (0·37) (p=0·0001). This secretory profile is different from those for NIDDM with late age of onset or MODY not linked to GCK. Fasting plasma insulin and C-peptide in patients were inappropriately low in relation to concomitant plasma glucose level. Furthermore, during a hyperinsulinaemic euglycaemic clamp, endogenous insulin secretion at euglycaemia (5 mmol/l) was suppressed in patients but not in controls. These results suggest that mutant GCK may lead to chronic hyperglycaemia by raising the threshold of circulating glucose level which induces insulin secretion. These data provide the first demonstration of a primary pancreatic secretory defect associated with a form of NIDDM.

Prolonged Maximal Stimulation of Insulin Secretion in Healthy Subjects Does Not Provoke Preferential Release of Proinsulin

Release of immature secretory granules rich in incompletely processed proinsulin has been proposed to explain the relative hyperproinsulinemia in type 2 diabetic and insulinoma patients because of a constant secretory drive resulting from hyperglycemia and autonomous secretion, respectively. To test this hypothesis, insulin secretion was stimulated by a combination of hyperglycemia (11 mmol/L clamp), intravenous (i.v.) tolbutamide (1 g), and i.v. glucagon (initial bolus 10 micrograms/kg body weight, maintenance infusion 2 micrograms/kg body weight per hour) for 3 h. Circulating IR-insulin and IR-C-peptide concentrations increased 89-fold and 14-fold over basal values, respectively, but IR-proinsulin concentrations increased only ninefold over basal values. Estimation of the amount of insulin secreted (based on deconvolution analysis of plasma C-peptide values) showed that approximately 76 +/- 21 U were secreted during the stimulation period. This amount is a significant proportion of pancreatic insulin content in normal humans. In molar terms, IR-proinsulin (integrated incremental response multiplied by metabolic clearance rate of proinsulin) relative to IR-C-peptide (= insulin) secretion (deconvolution analysis) was estimated to be equal or even lower than the known proportion in islets (0.22 +/- 0.05%). Thus, using a near-maximal stimulation of insulin secretion maintained long enough to cause release of amounts of insulin approaching the estimated pancreatic content, no preferential release of proinsulin was observed in normal humans. Therefore, the hyperproinsulinemia of type 2 diabetes and in insulinoma patients may be caused by additional defects in the proinsulin to insulin conversion process.

Comparative Responses of Plasma Glucose, Insulin and C-Peptide Following Ingestion of Isocaloric Glucose, a Modified Urban Saudi Breakfast and Dates in Normal Saudi Persons

Diabetic patients are commonly advised without scientific basis to avoid ingestion of dates. Prior to undertaking studies in diabetic persons, we considered it important to establish the metabolic consequences of date ingestion in normal Saudi subjects. Nineteen normal subjects, 11 males and 8 females, aged 29.4 +/- 1.5 (mean +/- SEM) with a body mass index (BMI) of 22.1 +/- 0.5 were fed in a random order: a) a date meal (DM) consisting of approximately 300 calories (Carbohydrates - CHO 74.5 g, proteins 3.7 g and fats 0.66 g), b) a modified urban Saudi breakfast (SBF) 300 calories (oral glucose tolerance test - OGTT), on 3 different days at least 1 week apart. Plasma glucose (G), insulin (I) and C-peptide (C) values were determined at -30,0 and then every 30 minutes for 180 minutes. Glycemic indices for DM and SBF were also determined. G, I and C area profiles were not different between DM and SBF but were when compared with OGTT. This is the first documentation of the glycemic index for dates. For the "Khalas" variety it was found to be 57.7 +/- 8.5 and was significantly lower than that for SBF which was 79.0. Contrary to the usual belief, this study refutes the notion that ingestion of date adversely affects glucose tolerance compared with SBF in normal subjects. Similar results are observed in preliminary studies in diabetic subjects in our laboratory.

Sensitivity and Reproducibility of Urinary C‐peptide as Estimate of Islet B‐cell Function in Insulin‐treated Diabetes

The aims of the present study were to evaluate the ability of urinary C-peptide determination to demonstrate presence of residual insulin secretion, and to evaluate the reproducibility of urinary C-peptide excretion in 125 insulin-treated diabetic patients. C-peptide was determined in two consecutive 24-h urine specimens and related to plasma C-peptide 6 min after the intravenous injection of 1 mg glucagon. The detection limit of C-peptide in plasma was defined analytically (greater than or equal to 0.02 nmol l-1) and from pancreatectomized patients (greater than or equal to 0.06 nmol l-1), and in urine only analytically (greater than or equal to 0.1 nmol l-1). If the analytical detection limit of plasma C-peptide was used as indicator of residual insulin secretion, islet B-cell function was preserved in all patients. In patients with stimulated plasma C-peptide levels from 0.02- less than 0.06 nmol l-1 no increase was found in plasma C-peptide values after stimulation with glucagon. This unresponsiveness of islet B-cells is in good agreement with the existence of a biological detection limit of C-peptide in plasma of 0.06 nmol l-1. Using this biological plasma C-peptide detection limit, 49 of 125 patients were without residual insulin secretion. In contrast to this, only 7 patients were diagnosed as C-peptide nonsecretors using the analytical detection limit of urinary C-peptide. Eighty-four per cent of patients considered to have Type 1 (insulin-dependent) diabetes with a duration of diabetes of more than 15 years had detectable C-peptide in the urine.(ABSTRACT TRUNCATED AT 250 WORDS)

Urinary C-peptide: a useful tool for evaluating the endogenous insulin reserve in cohort and longitudinal studies of diabetes in childhood.

Increasing research into the remission phase of type I diabetes mellitus stresses the importance of a non-traumatic and reliable method for the evaluation of endogenous insulin production. We compared 24-h urinary C-peptide excretion (UCE) with plasma C-peptide values before and after stimulation with 1 mg glucagon in 24 type I diabetic children. Fasting plasma C-peptide values and stimulated plasma C-peptide values showed a linear correlation with 24 h UCE. Mean plasma C-peptide levels correlated inversely with the exogenous insulin dose. A slightly better correlation was found between the exogenous insulin dose and 24 h UCE. Control data of 24 h UCE were obtained from healthy siblings. A linear correlation with age was found up to 10 years of age above which UCE values seem to reach a plateau. This effect of age, as well as the frequency of sampling was taken into account in the derivation of 95% reference intervals for UCE. The measurement of 24 h UCE appears to be a useful parameter to assess endogenous insulin production in diabetic children, provided that age is taken into account.

Factors influencing the magnitude, duration, and rate of fall of B-cell function in type 1 (insulin-dependent) diabetic children followed for two years from their clinical diagnosis.

The pattern of fall in B-cell function measured as plasma and 24 h urinary C-peptide excretion, as well as levels of islet cell antibodies, insulin antibodies and metabolic parameters, were followed for two years in 39 children aged 1-17 years prospectively from clinical onset of Type 1 (insulin-dependent) diabetes. At onset 32/36 patients had measurable plasma C-peptide (median 0.13 nmol/l). Maximum values of fasting and postprandial plasma C-peptide were reached at a median duration of three months. Thereafter both plasma and urinary C-peptide declined linearly. The median value of the rate of fall in postprandial plasma C-peptide was 0.019 nmol.1-1.month-1. Age at onset was positively correlated to the maximum value of postprandial plasma C-peptide in each patient (rs = 0.57, p = 0.0001) and throughout the observation time positively correlated to fasting and postprandial C-peptide and to the 24 h urinary C-peptide excretion (rs range 0.35-0.70, p = 0.03-0.0001). The rate of fall of postprandial C-peptide was unrelated to age at onset and was strikingly parallel in different age groups. Islet cell antibodies were present in 87% of the patients at onset and decreased to 38% at 24 months. Islet cell antibody titres were not correlated to age at onset or to plasma or urinary C-peptide at any single observation. However, islet cell antibody negative patients had significantly higher (p less than 0.05) postprandial plasma C-peptide values at 1, 9, and 12 months of duration, compared to islet cell antibody positive patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Classification of newly diagnosed diabetic patients as insulin-requiring or non-insulin-requiring based on clinical and biochemical variables.

In a prospective study of 41 consecutively referred newly diagnosed diabetic patients, we evaluated the predictive value of fasting and glucagon-stimulated C-peptide values, ketonuria, age, and body weight in the classification of subjects as insulin-requiring (IR) or non-insulin-requiring (NIR). The patients were followed up for greater than or equal to 12 mo and classified as NIR if adequate glycemic control could be achieved without insulin (i.e., fasting plasma glucose less than 8 mM and no glycosuria). Patients who needed insulin to obtain this status were classified as IR. We found that all subjects with plasma C-peptide values greater than 0.60 nM 6 min after intravenous glucagon were NIR, whereas all IR subjects together with 3 NIR subjects had C-peptide values below this limit. All NIR subjects but 1 had fasting C-peptide values greater than 0.30 nM, and all IR subjects but 1 had C-peptide values below this limit. Seventy-five percent of the subjects could be correctly classified by use of age and percent desirable body weight. Thus, all subjects greater than 40 yr old and greater than 100% ideal body weight were NIR, and all subjects below both these limits were IR. Ketonuria was found in 10 of 12 IR subjects and in 10 of 29 NIR subjects. We conclude that 1) 75% of the subjects could be correctly classified by use of age and percent desirable body weight only and 2) C-peptide measurements are useful in the classification of newly diagnosed diabetes, whereas presence of ketonuria is of limited value.

Insulin action and insulin secretion in identical twins with MODY. Evidence for defects in both insulin action and secretion.

To evaluate the pathogenetic mechanisms responsible for development of diabetes in the genetically inherited disease maturity-onset diabetes of the young (MODY), we have investigated a pair of identical twins (19 yr old) from a MODY family. One twin had nondiabetic fasting plasma glucose values but impaired glucose tolerance (IGT), whereas the other suffered from frank diabetes (fasting plasma glucose 12.5 mM). Differences in insulin secretion pattern and/or insulin action between the twins is supposed to be responsible for development of hyperglycemia in MODY. On the other hand, identical defects in insulin secretion and action in the twins may point to the primary genetic defect in MODY. Therefore, our aim was to investigate insulin secretion and insulin action in the twins to find these differences and similarities. We found that fasting plasma insulin and C-peptide values were slightly increased in the twins, whereas the responses of insulin and C-peptide to oral glucose tolerance tests (OGTT) and meals were similar in the twins and within normal range. The insulin responses to OGTT were, however, lower than expected from the glucose values, indicating a beta-cell defect. Despite elevated plasma insulin levels, basal hepatic glucose output (HGO) was normal in the IGT twin but increased by 75% in the diabetic twin. The maximally inhibitory effect of insulin on HGO, when estimated at euglycemia, was normal in the IGT twin but reduced by 60% in the diabetic twin. Furthermore, the maximal insulin-mediated glucose uptake in peripheral tissues was reduced by 40% in the diabetic twin.(ABSTRACT TRUNCATED AT 250 WORDS)