C-peptide Profiles Research Articles

58-LB: Antidiabetic Effects of Pediococcus acidilactici pA1c on HFD-Induced Mice

Prediabetes (PreD) , which is associated with impaired glucose tolerance and fasting blood glucose, is a potential risk factor for type 2 diabetes mellitus (T2D) . Growing evidence suggests the role of the gastrointestinal microbiota in both PreD and T2D, which opens the possibility for a novel nutritional approach, based on probiotics, for improving glucose regulation and delaying disease progression of PreD to T2D. In this light, the present study aimed to assess the antidiabetic properties of Pediococcus acidilactici pA1c (pA1c) in a murine model of high-fat diet (HFD) -induced T2D. For that purpose, C57BL/6 mice were given HFD enriched with either probiotic (1×10E10 CFU/day) or placebo for 12 weeks. We determined body weight, fasting blood glucose, glucose tolerance, HOMA-IR and HOMA-β index, C-peptide, GLP-1, leptin, and lipid profile. We also measured hepatic gene expression (G6P, PEPCK, GCK, IL-1β, and IL-6) and ex-amined pancreatic and intestinal histology (% of GLP-1+ cells, % of goblet cells and villus length) . We found that pA1c supplementation significantly attenuated body weight gain, mitigated glucose dysregulation by reducing fasting blood glucose levels, glucose tolerance test, leptin levels, and insulin resistance, increased C-peptide and GLP-1 levels, enhanced pancreatic function, and improved intestinal histology. These findings indicate that pA1c improved HFD-induced T2D derived insulin resistance and intestinal histology, as well as protected from body weight increase. Together, our study proposes that pA1c may be a promising new dietary management strategy to improve metabolic disorders in PreD and T2D. Disclosure M. Cabello: None. M. Oneca: Employee; GENBIOMA APLICACIONES SL. M. J. Pajares: None. J. Ayo: Board Member; Genbioma Aplicaciones S. L., Employee; Genbioma Aplicaciones S. L. I. J. Encío: Other Relationship; Genbioma Aplicaciones SL. M. Araña: None. M. Barajas: None. Funding Government of Navarre (Ref 0011-1365-2020-000290) and the European Regional Development Fund (ERDF) . Maria Oneca is supported by Torres-Quevedo grants from the Spanish Ministry of Science and innovation (Ayudas para contratos Torres Quevedo PTQ2019-010384/AEI/10.13039/501100011033)

Effects of Low-Carbohydrate versus Mediterranean Diets on Weight Loss, Glucose Metabolism, Insulin Kinetics and β-Cell Function in Morbidly Obese Individuals

Low-calorie Mediterranean-style or low-carbohydrate dietary regimens are widely used nutritional strategies against obesity and associated metabolic diseases, including type 2 diabetes. The aim of this study was to compare the effectiveness of a balanced Mediterranean diet with a low-carbohydrate diet on weight loss and glucose homeostasis in morbidly obese individuals at high risk to develop diabetes. Insulin secretion, insulin clearance, and different β-cell function components were estimated by modeling plasma glucose, insulin and C-peptide profiles during 75-g oral glucose tolerance tests (OGTTs) performed at baseline and after 4 weeks of each dietary intervention. The average weight loss was 5%, being 58% greater in the low-carbohydrate-group than Mediterranean-group. Fasting plasma glucose and glucose tolerance were not affected by the diets. The two dietary regimens proved similarly effective in improving insulin resistance and fasting hyperinsulinemia, while enhancing endogenous insulin clearance and β-cell glucose sensitivity. In summary, we demonstrated that a low-carbohydrate diet is a successful short-term approach for weight loss in morbidly obese patients and a feasible alternative to the Mediterranean diet for its glucometabolic benefits, including improvements in insulin resistance, insulin clearance and β-cell function. Further studies are needed to compare the long-term efficacy and safety of the two diets.

The relationship between red blood cell distribution and islet \u03b2-cell function indexes in patients with type 2 diabetes

BackgroundRed cell distribution width (RDW) is a predicter of infections, cancer and diabetes. However, the relationship between RDW and β-cell function and insulin resistance remains unclear in patients with type 2 diabetes mellitus (T2DM). The aim of the study was to explore the relationship between RDW and β-cell function in patients with T2DM.MethodsA total of 559 T2DM patients were enrolled in this cross-sectional study. Patients were divided into three groups according to RDW tertiles. Clinical and biochemical characteristics such as age, duration of diabetes, blood pressure, RDW, glycosylated hemoglobin A1c (HbA1c), C-peptide and lipid profiles were collected. Homeostasis model assessment of insulin resistance (HOMA2IR) and homeostasis model assessment of β-cell function (HOMA2%B) were assessed using homeostasis model assessment (HOMA) based on fasting blood glucose (FBG) and fasting C-peptide index (FCPI). Correlations and multiple linear regressions were performed to explore the association between RDW and islet function indexes in total population and in different gender subgroups.ResultsThe HOMA2%B gradually increased according to RDW tertiles (lowest, second, highest RDW tertiles; 47.1(32.9–75.4), 54.05(34.1–81), and 57.9(38.65–95.4), respectively; P = 0.036). Correlation analysis indicated that there were significant correlations between RDW and age, diabetes duration, diastolic blood pressure (DBP), triglycerides (TG), aspartate transaminase (AST), FBG, HbA1c and HOMA2%B in all subjects. In male subjects, RDW correlated positively with age, high-density lipoprotein cholesterol (HDL) and AST, and it correlated negatively with body mass index (BMI), DBP and TG. In female subjects, RDW correlated positively with age, duration, serum creatinine (Cr), FCPI and HOMA2%B, and it correlated negatively with alanine transaminase (ALT), FBG and HbA1c. Multiple linear regressions indicated that RDW was significantly correlated with HOMA2%B and HbA1c in the total population in both unadjusted and adjusted analysis. This finding could be reproduced in the subgroup of men for HOMA2%B only and in women for HbA1c only.ConclusionsRDW is associated with β-cell function assessed by HOMA2%B after adjusting for covariates in male T2DM patients.

MON-623 Pattern of C-Peptide Response to Oral Glucose Tolerance Test: Interest and Cut-Off Values

Introduction: Oral glucose tolerance test (OGTT) allows classification of subjects in 3 groups, depending on glycaemia 120 minutes after 75g glucose ingestion: normal (glycaemia < 1.4 g/L), glucose intolerant (1.4-2 g/L) and diabetic (>2g/L). Five insulin profiles following OGTT associated with different incidence rates of diabetes over 10 years of follow-up have also previously been described (Kraft J et al, Laboratory Medicine, 1975; Hayashi T et al, Diabetes Care.2013). Insulin measurement is very sensible to hemolysis and can advantageously be replaced by C-peptide determination. However, little is known about C-peptide reference values and response to OGTT.Material and Methods: 128 patients were included to evaluate glyceamia (COBASe801® ROCHE Diagnostics, France), insulin and C-peptide (LiaisonXL®, Diasorin, France) responses to OGTT.Results: According to Hayashi classification, 23 (18%) patients of the whole cohort harbored a physiological insulin response corresponding to profile I (peak of insulin during OGTT at 30 min and higher insulin level at 60 vs. 120 min). Others presented 5 pathological profiles: 14 (11%) patients were classified in profile II (peak of insulin at 30 min and lower or equal insulin level at 60 vs. 120 min), 56 (44%) in profile III (peak of insulin at 60 min), 26 (20%) in profile IV (peak of insulin at 120 min and lower insulin level at 30 vs. 60 min), and finally 9 (7%) in profile V (peak of insulin at 120 min and higher or equal insulin level at 30 vs. 60 min). Only 4 different mean C-peptide profiles emerged from the subgroups previously defined by insulin profile, mean C-peptide profile being substantially similar to mean insulin profile. The only major difference relied on a similar C-peptide profile corresponding to a growing curve from T0 to T120 in both patients with insulin profile IV and V. Mean and 95% confidence interval of C-peptide value at the different times of OGTT were also calculated in the subgroup of patients with both normal glycemic and insulin (pattern I) responses to propose reference values: respectively T0: 0.53 (0.26-0.77); T30: 2.2 (1.24-3.29); T60: 2.26 (1.36-3.68); T120: 1.88 (0.84-2.62) nmol/L. Conclusion: C-peptide response to OGTT profile seems to give globally the same information as insulin profile and should therefore also be predictive of the risk type 2 diabetes in case of hemolyzed samples. The slight differences observed between insulin and C-peptide profiles can be explained by their different metabolic pathways, insulin being quickly degraded in the liver and C-peptide undergoing a longer renal elimination. This work also allows us to propose for the first-time reference values for C-peptide at the different times of OGTT using Liaison XL®.

Basal-Bolus Insulin Therapy with Gla-300 During Hospitalization Reduces Nocturnal Hypoglycemia in Patients with Type 2 Diabetes Mellitus: A Randomized Controlled Study.

IntroductionAlthough reduction in the incidence of nocturnal hypoglycemia, as estimated by symptom or self-monitored plasma glucose, was shown to be more pronounced with 300 units/mL insulin glargine (Gla-300) than with 100 units/mL insulin glargine (Gla-100) in type 2 diabetes patients, the exact frequency of nocturnal hypoglycemia estimated with continuous glucose monitoring (CGM) has not been reported.MethodsForty patients with type 2 diabetes who were admitted for glycemic control with basal–bolus insulin therapy (BBT) were randomized into the Gla-100 and Gla-300 groups. Insulin doses were adjusted to maintain blood glucose levels within 100–120 mg/dL at each meal. Plasma glucose and C-peptide profiles were estimated serially after admission and before discharge. Daily CGM was also performed before discharge.ResultsIn the Gla-100 and Gla-300 groups, the mean duration of hospitalization was 15 ± 2 and 15 ± 1 days, respectively, and the mean basal insulin dose before discharge was 13 ± 7 and 15 ± 10 units, respectively. The dose of meal-time insulin was not different between the two groups. Compared with the Gla-300 group, the Gla-100 group had significantly lower nocturnal profiles of plasma glucose and C-peptide, but significantly higher frequency of CGM-estimated nocturnal hypoglycemia (10.7% ± 18.4% versus 1.2% ± 3.6%, P = 0.033).ConclusionIn type 2 diabetic patients, reduction in the incidence of CGM-estimated nocturnal hypoglycemia by BBT under tightly controlled diet therapy was higher with Gla-300 than with Gla-100.Trial RegistrationUMIN clinical trials registry (UMIN000023360).

Hepatic and Extrahepatic Insulin Clearance Are Differentially Regulated: Results From a Novel Model-Based Analysis of Intravenous Glucose Tolerance Data.

Insulin clearance is a highly variable and important factor that affects circulating insulin concentrations. We developed a novel model-based method to estimate both hepatic and extrahepatic insulin clearance using plasma insulin and C-peptide profiles obtained from the insulin-modified frequently sampled intravenous glucose tolerance test. Data from 100 African immigrants without diabetes (mean age 38 years, body weight 81.7 kg, fasting plasma glucose concentration 83 mg/dL, and fasting insulin concentration 37 pmol/L) were used. Endogenous insulin secretion (calculated by C-peptide deconvolution) and insulin infusion rates were used as inputs to a new two-compartment model of insulin kinetics and hepatic and extrahepatic clearance parameters were estimated. Good agreement between modeled and measured plasma insulin profiles was observed (mean normalized root mean square error 6.8%), and considerable intersubject variability in parameters of insulin clearance among individuals was identified (the mean [interquartile range] for hepatic extraction was 25.8% [32.7%], and for extrahepatic insulin clearance was 20.7 mL/kg/min [11.7 mL/kg/min]). Parameters of insulin clearance were correlated with measures of insulin sensitivity and acute insulin response to glucose. The method described appears promising for future research aimed at characterizing variability in insulin clearance and the mechanisms involved in the regulation of insulin clearance.

Niacin increased glucose, insulin, and C-peptide levels in sedentary nondiabetic postmenopausal women.

The current study examined the effects of niacin and a single bout of aerobic exercise on plasma glucose, insulin, and C-peptide in sedentary, nondiabetic postmenopausal women. As a crossover design, 17 participants underwent four different trials: rest during the no-niacin condition (R), exercise during the no-niacin condition (E), rest during the with-niacin condition (RN), and exercise during the with-niacin condition (EN). All participants took 1,000 mg/day of extended-release niacin for 4 weeks during the with-niacin conditions (RN and EN). The exercise treatment consisted of a single bout of treadmill walking at 60% heart rate reserve until 400 kcal were expended. Blood samples were collected at 24 hours after each trial and analyzed for changes in plasma glucose, insulin, and C-peptide. A two by two analysis of variance was used to examine the changes in dependent variables, and the Bonferroni adjustment was employed as the post hoc test. The level of statistical significance was set at P<0.05. There was no significant interaction between exercise and niacin, nor was there a main effect of exercise for changes in glucose, insulin, or C-peptide. However, there was a significant main effect for niacin as mean glucose, insulin, and C-peptide values significantly increased with niacin; glucose increased 10.6% (P=0.001), from 95.03±10.67 mg/dL to 105.07±13.56 mg/dL; insulin increased 61.8% (P=0.001), from 16.98±12.49 μU/mL to 27.48±14.84 μU/mL; and C-peptide increased 46.1% (P=0.001), from 1.65±0.75 ng/mL to 2.41±0.97 ng/mL. Although niacin was generally well tolerated, given its adverse effects on glucose, insulin, and C-peptide profiles, the use of niacin should be done so with caution and under medical supervision.

Effect of canagliflozin, a sodium glucose co-transporter 2 inhibitor, on C-peptide kinetics.

Canagliflozin, a sodium glucose co-transporter 2 inhibitor, improves indices of β-cell function estimated based on circulating C-peptide and glucose concentrations (e.g., Homeostasis Model Assessment [HOMA2-%B], meal tolerance test-based indices). However, use of these β-cell function indices assumes C-peptide kinetics are not altered by canagliflozin. This 2-period crossover study assessed the effect of a single canagliflozin 300-mg dose on C-peptide kinetics in 10 healthy participants. Two hours after receiving canagliflozin or placebo, participants received intravenous somatostatin infusion to suppress endogenous C-peptide secretion and 1 hour later received a bolus injection of synthetic human C-peptide 150 µg. Serum C-peptide was measured over 3 hours and urinary glucose and C-peptide excretion were measured. C-peptide kinetic parameters, including total clearance (CLtotal ) and renal clearance (CLrenal ), were calculated. Serum C-peptide profiles were similar following canagliflozin or placebo treatment. C-peptide CLtotal was slightly lower with canagliflozin versus placebo (mean (SD) of 190 (37) vs. 197 (30) mL/min; canagliflozin/placebo ratio [90% CI] = 96.1% [93.0%; 99.3%]). Other kinetic parameters, including CLrenal , were generally similar between treatments. Results indicate canagliflozin 300 mg does not meaningfully alter C-peptide clearance or other kinetic parameters; therefore, C-peptide-based measurements of insulin secretion are appropriate for assessing β-cell function in canagliflozin-treated participants.

Proinsulin level as a predictor of metabolic syndrome in the romanian population

Abstract Background and Aims: The aim of the present study was to determine discriminating values of proinsulin (FPP), proinsulin to insulin ratio (PIR), proinsulin to C-peptide ratio (PCPR) and Homeostasis model of assessment of insulin resistance (HOMA-IR) for the metabolic syndrome (MetS) as well as discovering sex-specific cutoff points of these parameters in the Romanian population. Material and Methods: We analyzed data from 224 patients. Circulating levels of fasting plasma glucose (FPG), fasting plasma insulin (FPI), FPP, fasting plasma C-peptide, HbA1c, and lipid profile were measured. Results: Among the 224 patients (87 males) MetS was diagnosed in 97 patients (43.3%) according to International Diabetes Federation (IDF) criteria. After stratification by gender, 43 men (49.4%) and 54 women (39.4%) had MetS. There were statistically significant differences between sexes for body mass index (BMI), % body fat, FPG, FPP, PIR, PCPR (all p&lt;0.05). On multivariate logistic regression analysis, only age, BMI, FPP, and HOMA-IR were the independent factors associated with the presence of MetS. Conclusions: The present study showed that FPP and HOMA-IR were the best predictors for MetS in this sample of the Romanian population. Our results suggest that, regardless of gender, HOMA-IR and FPP could be the preferred parameters for predicting MetS.

The energetics of lactation and the return to fecundity in wild chimpanzees

Parental provisioning of offspring is an intensive energetic investment that is expected to compromise future offspring production. This trade-off is particularly salient for mammals in which mothers bear the exclusive burden of lactation and draw from their own energy reserves to provision offspring. The degree to which lactation impacts future reproductive ability should vary not only by the absolute cost of milk production but also by the ability of individual mothers to afford it. Few studies have been able to quantify the costs of lactation or how they affect reproductive rates. Here, we examine the metabolic load of lactation in chimpanzees, a species with intensive parental investment and extremely slow reproductive rates. We used urinary C-peptide of insulin to trace changes in energetic condition in 17 wild, unprovisioned chimpanzee mothers in Kibale National Park, Uganda. C-peptide levels of nursing mothers were depressed for six months postpartum, thereafter showing a net increase through the second year. These changes are consistent with milestones of infant physical and behavioral development. Mothers inhabiting lower quality foraging areas experienced a higher metabolic load of lactation, as indicated by lower C-peptide profiles than mothers in food-rich areas. Ovarian activity was closely correlated with energetic condition. Cycling resumed only after a sustained period of energy gain, suggesting that the slow reproductive pattern in wild chimpanzees results not only from the direct expense of milk production but also from the long period that mothers require to recover their physical condition in a food-limited environment. Key wor ds: C-peptide of insulin, energy balance, interbirth inter vals, lactation, reproduction, weaning. [Behav Ecol]

Identification of insulin secretory defects and insulin resistance during oral glucose tolerance test in a cohort of cystic fibrosis patients

Cystic fibrosis (CF)-related diabetes is a leading complication of CF and is associated with pulmonary and nutritional deterioration, years before an evident hyperglycemia, possibly because of insulin deficiency and resistance. To evaluate glucose tolerance, insulin secretion, and insulin sensitivity by a widely applicable method suitable for accurate and prospective measurements in a CF population. A total of 165 CF subjects (80 females) aged 17±5 years and 18 age- and sex-matched healthy controls (CON) received an oral glucose tolerance test with glucose, insulin and C-peptide determinations. Insulin sensitivity was defined on the basis of glucose and insulin concentrations using the oral glucose insulin sensitivity index, whereas β-cell function was determined on the basis of a model relating insulin secretion (C-peptide profile) to glucose concentration. Fifteen percent of CF patients had glucose intolerance and 6% had diabetes without fasting hyperglycemia and 3% had diabetes with fasting hyperglycemia. β-cell function was reduced in CF patients compared with CON (70.0±4.1 vs 117.9±11.6 pmol/min per m(2) per mM, P<0.001) and decreased significantly with age by -2.7 pmol/min per m(2) per mM per year (confidence interval (CI) -4.5 to -0.82), i.e. almost 4% yearly. The early insulin secretion index was also reduced. Insulin sensitivity was similar to CON. CF patients who attained glucose tolerance comparable to CON had lower β-cell function and higher insulin sensitivity. The major alteration in insulin secretion and insulin sensitivity of CF patients is slowly declining β-cell function, consisting of delayed and reduced responsiveness to hyperglycemia, that in CF patients with normal glucose tolerance may be compensated by an increased insulin sensitivity.

Effects Of Niacin And Aerobic Exercise On Glucose, Insulin, And C-peptide Profiles In Postmenopausal Women

The effects of niacin and exercise on glucose metabolism are well documented in men and premenopausal women; however, no studies have been conducted with postmenopausal women. PURPOSE: To determine the effects of niacin and a single bout of aerobic exercise on glucose, insulin, and C-peptide profiles in sedentary, postmenopausal women. METHODS: Seventeen sedentary, postmenopausal women (mean ± SD; 57 ± 7.5 years; 160.1 ± 7 cm; 77.2 ± 14.8 kg, 47.0 ± 6.2 % body fat) served as participants. All participants were randomly assigned to the resting or exercise trial without niacin followed by the with-niacin trial (1000 mg/day of extended release niacin for 4 weeks). The exercise trial consisted of treadmill walking at 60% heart rate reserve until 400 kcal were expended. Blood samples collected 24 hr post rest and exercise trials were analyzed for changes in glucose, insulin, and C-peptide. Data were analyzed using a 2 × 2 repeated measures analysis of variance (ANOVA) and the Bonferroni adjustment served as the post hoc test. The level of statistical significance was set at p <.05. RESULTS: There was no significant interaction of exercise with niacin for glucose, insulin, and C-peptide, nor was there a main effect of exercise. There was a significant main effect for niacin as mean glucose, insulin, and C-peptide values all significantly increased with niacin use; glucose increased 10.6%, from 95.03 ± 10.67 mg/dL to 105.07 ± 13.56 mg/dL; insulin increased 61.8%, from 16.98 ± 12.49 μU/mL to 27.48 ± 14.84 μU/mL; and C-peptide increased 46.1%, from 1.65 ± 0.75 ng/mL to 2.41 ± 0.97 ng/mL. CONCLUSION: Although niacin was generally well tolerated by the participants, given its adverse effects on glucose, insulin, and C-peptide profiles, the use of niacin in sedentary, postmenopausal women should be done so with caution and under medical supervision until more comprehensive investigations consisting of niacin alone or with aerobic exercise are conducted.

Major influence of liver function itself but not of immunosuppression determines glucose tolerance after living-donor liver transplantation

Controversial data exists concerning the impact of immunosuppressive therapy on the development of post-transplantation diabetes mellitus (PTDM). Therefore, we investigated glucose metabolism in healthy donors and in recipients of living-donor liver transplants (LD-LTX, n=18) without pre-existing diabetes mellitus before, on day 10, month 6, and month 12 after intervention. The computer-assisted analysis of glucose, insulin, and C-peptide profiles obtained from frequently sampled intravenous glucose tolerance tests allows to achieve an integrated view of factors controlling glucose tolerance, i.e., insulin sensitivity (SI), first and second phase insulin secretion (phi1 and phi2). SI of donors declined by day 10 after operation (SI 2.65 +/- 0.41 vs. 4.90 +/- 0.50 10(-4) minute(-1) microU ml(-1), P < 0.01) but returned to values as before after 6 months. Phi1 did not change. Phi(2), however, significantly increased by day 10 (8.57 +/- 0.82 10(9) minute(-1) to 13.77 +/- 1.53 10(9) minute(-1), P < 0.01) but was in the same range as before after 6 months. In parallel to donors SI of recipients progressively increased after LD-LTX. Phi1 did not alter in recipients. Phi2 continuously decreased and was not different from donors by month 12. The extent of liver injury assessed by liver enzyme concentrations and liver function represented by cholinesterase activity, albumin, and INR were closely related with changes of SI in donors and recipients during the first year after intervention. In conclusion, the extent of liver damage plays a predominant role in regulating glucose tolerance. No impact of immunosuppressive therapy on SI, phi1 and phi2 was detected.

Relationship between calpain-10 gene polymorphism and insulin resistance phenotypes in Chinese.

In order to determine whether the variations in the calpain-10 gene constitutes risk of type 2 diabetes (T2DM) in Chinese, the frequency of UCSNP-43, 44 in 268 adults newly diagnosed with T2DM (according to the 1999 ADA criteria) and 153 non-diabetic control subjects was investigated. For all subjects, the height, weight, waist-to-hip ratio (W/H) and blood pressure, as well as following parameters were measured: (1) 75-g oral glucose tolerance test with insulin, C-peptide, HbA1c and blood lipid profiles; (2) Genomic DNA extracted from peripheral blood lymphocytes was genotyped for UCSNP-43 (calpain-10-g. 4852 G/A) and UCSNP-44 (calpain-10-g. 4841 T/C) by sequencing a polymerase chain reaction (PCR)-amplified fragment. PCR product was selected by single strand conformation polymorphism (SSCP) and then sequenced. The results showed that there was significant difference between T2DM group and normal control group in allele frequencies, haplotype frequencies, or haplotype combinations of UCSNP-43 and -44 either. But in newly diagnosed T2DM group, it was found that the individuals with the genotype UCSNP-44 T/C + C/C had significantly increased fasting and post-challenge insulin levels (Fins and P2hIns), consistent with reduced insulin sensitivity. In the BMI> 25 subgroup, the differences were even more significant. It was demonstrated that the Calpain-10 gene polymorphism UCSNP-44 was associated with insulin sensitivity and Fins and P2hIns in newly diagnosed T2DM, although Calpain-10 doesn't appear as a major diabetes susceptible gene in this population.

Prediction of the long-term metabolic success of the pancreatic graft function.

Strategies to prevent the return to the diabetic state for graft loss or failure or any other cause after pancreas transplantation require the identification of the subjects at risk. This study evaluated whether daily glucose, insulin, and c-peptide profiles and studies of insulin sensitivity and secretion after transplantation predict pancreatic graft failure. Fifty-three subjects with type 1 diabetes with end-stage renal failure who received a combined pancreas and kidney transplant underwent the following procedures 1 year after transplantation: 1-day metabolic profiles, sampling every 2 hours for plasma glucose, serum insulin, and c-peptide (n=51); an intravenous glucose tolerance test (IVGTT) to evaluate insulin secretion (n=48); and an euglycemic insulin clamp to evaluate insulin sensitivity (M value, n=14). The recipients were then followed up to 8 years (mean follow-up 4.8+/-0.3 years) to evaluate the return to the diabetic state. Survival analysis showed that plasma glucose in the profiles and insulin secretion in IVGTT were strongly related to the risk of returning to the diabetic state. A cutoff value of mean daily plasma glucose >127 mg/dL, corresponding to the top quartile of the mean plasma glucose distribution in the profiles, predicted the return to the diabetic state within 4 years from transplantation with a 93% specificity and a 100% sensitivity. A cutoff value of insulin delta peak <32 microU/ml in the IVGTT predicted the return to the diabetic state within 4 years from transplantation with a 75% specificity and a 75% sensitivity. In contrast, the M value in the clamp was devoid of predictive value. This study indicates that the mean 24-h plasma glucose 1 year after transplantation is the strongest predictor of the return to the diabetic state. The risk is related to defects in insulin secretion and not to insulin resistance. Metabolic profiles can be used to screen the subjects at risk to strictly monitor the graft function and to investigate early determinants of graft failure.

Circulating fatty acids are essential for efficient glucose-stimulated insulin secretion after prolonged fasting in humans.

In the fasted rat, efficient glucose-stimulated insulin secretion (GSIS) is absolutely dependent on an elevated level of circulating free fatty acids (FFAs). To determine if this is also true in humans, nonobese volunteers were fasted for 24 h (n = 5) or 48 h (n = 5), after which they received an infusion of either saline or nicotinic acid (NA) to deplete their plasma FFA pool, followed by an intravenous bolus of glucose. NA treatment resulted in a fall in basal insulin concentrations of 35 and 45% and in the area under the insulin response curve (area under the curve [AUC]) to glucose of 47 and 42% in the 24- and 48-h fasted individuals, respectively. The 48-h fasted subjects underwent the same procedure with the addition of a coinfusion of Intralipid plus heparin (together with NA) to maintain a high concentration of plasma FFAs throughout the study. The basal level and AUC for insulin were now completely normalized (C-peptide profiles paralleled those for insulin). To assess the effect of an overnight fast, nonobese (n = 6) and obese (n = 6) subjects received an infusion of either saline or NA, followed by a hyperglycemic clamp (200 mg/dl). The insulin AUC in response to glucose was unaffected by lowering of the FFA level in nonobese subjects, but fell by 29% in the obese group. The data clearly demonstrate that in humans, the rise in circulating FFA levels after 24 and 48 h of food deprivation is critically important for pancreatic beta-cell function both basally and during subsequent glucose loading. They also suggest that the enhancement of GSIS by FFAs in obese individuals is more prominent than that seen in their nonobese counterparts.

Sequential metabolic studies of pancreas allograft function in type 1 diabetic recipients.

We have previously shown that the loss of acute first phase insulin secretion precedes pancreas allograft rejection and development of glucose intolerance in Type 1 diabetic patients. In order to examine whether there is a progressive loss of phases of insulin secretion and beta-cell function in technically successful pancreas transplants during the first year, we measured glucose, insulin, and C-peptide responses to physiological (mixed meal) and pharmacological (IV glucose and IV glucagon) stimulation in 27 glucose-tolerant, insulin-independent allograft recipients at 3, 6, and 12 months. Mean +/- SE fasting serum glucose levels were normalized throughout the study period. Postprandial serum glucose profiles tended to increase by 12 months compared to 3 and 6 months, although peak glucose levels were not statistically different. Following pancreas transplantation, basal serum insulin levels were high at 3 months (163 +/- 17 pM), 6 months (165 +/- 22 pM), and 12 months (248 +/- 54 pM, p = NS) in the Type 1 diabetic pancreas allograft recipients when compared to normal (25 +/- 3 pM). We observed slight elevations in postprandial insulin and C-peptide profiles at 12 months compared to 3 and 6 months. Following IV glucose and glucagon stimulation, serum insulin and C-peptide levels as well as phases of insulin release did not differ over the 12-month study period. Similarly, the glucose decay constant (KG) was nearly identical at 3, 6, and 12 months. In summary, 1 year following successful whole cadaveric, heterotopic pancreas transplantation in Type 1 diabetic recipients, fasting serum glucose remains normalized, while postprandial glucose tends to rise.(ABSTRACT TRUNCATED AT 250 WORDS)

Partial recovery of insulin secretion and action after combined insulin-sulfonylurea treatment in Type 2 (non-insulin-dependent) diabetic patients with secondary failure to oral agents

Metabolic control, insulin secretion and insulin action were evaluated in seven Type 2 (non-insulin-dependent) diabetic patients with secondary failure to oral antidiabetic agents before and after two months of combined therapy with supper-time insulin (Ultratard: 0.4 U/kg body weight/day) plus premeal glibenclamide (15 mg/day). Metabolic control was assessed by 24 h plasma glucose, NEFA, and substrate (lactate, alanine, glycerol, ketone bodies) profile. Insulin secretion was evaluated by glucagon stimulation of C-peptide secretion, hyperglycaemic clamp (+ 7 mmol/l) and 24 h free-insulin and C-peptide profiles. The repeat studies, after two months of combined therapy, were performed at least 72 h after supper-time insulin withdrawal. Combining insulin and sulfonylurea agents resulted in a reduction in fasting plasma glucose (12.9 +/- 7 vs 10.4 +/- 1.2 mmol/l; p less than 0.05) and hepatic glucose production (13.9 +/- 1.1 vs 11.1 +/- 1.1 mumol.kg-1.min-1; p less than 0.05). Mean 24 h plasma glucose was also lower (13.7 +/- 1.2 vs 11.1 +/- 1.4 mmol/l; p less than 0.05). Decrements in fasting plasma glucose and mean 24 h profile were correlated (r = 0.90; p less than 0.01). HbA1c also improved (11.8 +/- 0.8 vs 8.9 +/- 0.5%; p less than 0.05). Twenty-four hour profile for NEFA, glycerol, and ketone bodies was lower after treatment, while no difference occurred in the blood lactate and alanine profile. Insulin secretion in response to glucagon (C-peptide = +0.53 +/- 0.07 vs +0.43 +/- 0.07 pmol/ml) and hyperglycaemia (freeinsulin = 13.1 +/- 2.0 vs 12.3 +/- 2.2 mU/l) did not change.(ABSTRACT TRUNCATED AT 250 WORDS)

Nutritional Assessment in Humans and Rats of Leucrose [D-glucopyranosyl-α(1 → 5)-D-fructopyranose] as a Sugar Substitute

Leucrose [D-glucosyl-alpha(1----5)-D-fructopyranose], prepared by an enzyme-catalyzed transglycosidation from sucrose with greater than 99% purity, has previously been shown to be noncariogenic and was found in the present study to be apparently easily digestible when given to humans as a single oral dose of 100 g, or when fed to rats at a level of 35 g/kg body wt daily. Weanling rats fed a 25% leucrose diet grew as well as rats fed a diet containing 25% sucrose or corn starch. When 1 g of leucrose was given intravenously to adult rats, 70% of this disaccharide was excreted in the urine within 24 h, and feeding and drinking behavior of the rats was not altered. No adverse effects on their general health were observed. The substrate properties of leucrose for alpha-glucosidase from yeast and for carbohydrases from human jejunal mucosa were determined, and these data were then compared with those of maltose and sucrose. The cleavage rate of leucrose in vitro by human digestive carbohydrases was 31% that of maltose and 63% that of sucrose. Hydrogenated leucrose (leucritol) was cleaved 10 times slower, with a Michaelis constant close to that of leucrose. Blood glucose and fructose profiles in humans given leucrose per os tended to be lower than those in humans given sucrose, while insulin and C-peptide profiles were unaltered.

The effects of long term gliclazide administration on insulin secretion and insulin sensitivity.

Gliclazide (80 mg bd) was administered to nine subjects with type 2 (non insulin dependent) diabetes inadequately controlled on diet only. Twenty-four hour glucose, insulin and c-peptide profiles were obtained before and after one week and four months of therapy. Insulin sensitivity was assessed by euglycemic hyperinsulinemic clamp before and after four months of treatment. Twenty-four hour glucose levels were significantly lowered after one week and four months. Insulin secretion, as assessed by the areas under the insulin and c-peptide curves, was enhanced after one week. The increase was most noted during the day in response to meals. The enhancement was maintained after four months of treatment with the increase in the postabsorptive phase becoming significant. Glucose utilisation rate was significantly increased at four months. It is concluded that both acute and prolonged gliclazide therapy directly or indirectly 1) enhances both meal stimulated and post absorptive insulin secretion and 2) increases insulin sensitivity. The relative contribution of each to improved diabetic control has not been established.