Plasma C-peptide Concentrations Research Articles

1951-P: Prolonged (12-Hour) Glucagon Infusion Leads to Transient Elevation of Plasma Glucose but Sustained Elevation of Hepatic Glucose Production

Recently, novel non-glycemic effects of glucagon have been described. Although short-term glucagon infusion is well known to elevate plasma glucose levels, long-term effect of increased plasma glucagon on glucose and lipid metabolism is unclear. The aim of the present study was to evaluate the effect of 12-hour glucagon infusion on hepatic glucose production and lipid metabolism in healthy NGT individuals. 8 NGT subjects (5M/3F, age=35± 5 years, BMI = 24 ± 1 kg/m2, HbA1c 5.2± 0.1%) received an 2-hour (75gram) OGTT. On a different day subjects received a 12-hour (6PM to 6 AM) glucagon infusion (3ng/kg/minutes) with the measurement of hepatic glucose production (HGP) with 3-3H-glucose on the following morning from 6-10 AM. HGP in glucagon infused subjects was compared to values in 20 age/gender/weight matched NGT subjects studied after an overnight fast from 6-10 AM. Plasma glucose, insulin, C-peptide, glucagon, and FFA concentrations were obtained every 15 minutes during OGTT. Plasma glucagon concentrations increased from 40 ± 4 to 120 ± 34 pg/ml at 6 AM. Plasma glucose increased 2 hours after the start of infusion from 95 ± 6 to 111 ± 6 mg/dl (p<0.005); after 12 hours of glucagon infusion the plasma glucose concentration declined to the mean baseline levels. After 12-hour glucagon infusion (6 AM), plasma insulin and C-peptide were not significantly changed. Basal hepatic glucose production was significantly higher following prolonged (12-hour) glucagon infusion compared to NGT control subjects following 12-hour overnight fast (3.1 ± 0.1 vs. 2.2 ± 0.2 mg/kg/minutes, p<0.05). Plasma FFA concentrations did not change following 12-hour glucagon infusion (0.629±0.1 vs. 0.670±0.2mml/l, p=ns). Thus 12-hour glucagon infusion led to higher basal rate of HGP, but unchanged plasma FFA levels. These results demonstrate that prolonged physiologic hyperglucagonemia results in a transient elevation of plasma glucose concentration but sustained increase in hepatic glucose production. Disclosure X. Chen: None. A. Merovci: None. E. Case: None. R.A. DeFronzo: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Elcelyx Therapeutics, Inc., Intarcia Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Novo Nordisk Inc. Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Merck & Co., Inc. Speaker's Bureau; Self; AstraZeneca, Novo Nordisk Inc. D. Tripathy: None.

1967-P: Mild Physiologic Hyperglycemia Impairs Insulin-Mediated Suppression of Plasma Glucagon in Healthy Normal Glucose Tolerant Subjects

Hyperglycemia adversely affects skeletal muscle and hepatic insulin sensitivity (glucotoxicity). However, the effect of prolonged hyperglycemia on glucose and insulin-mediated suppression of glucagon is not known. The aim of the present study was to evaluate effect of a chronic (72 hours) physiologic increase (+45 mg/dl) in plasma glucose concentration on the suppression of plasma glucagon concentration in healthy NGT individuals: 12 without family history of T2DM (FH-) (9M/3F, age = 50± 4 years, BMI = 27 ± 1 kg/m2) and 8 with FH of T2DM (FH+) (4M/4F, age = 48±2, BMI = 26±1 kg/m2). Subjects received an OGTT and 2-step hyperglycemic (+125 and +300 mg/dl) clamp (duration of each step = 80 minutes) before and after 72-hour glucose infusion. Plasma insulin and C-peptide concentrations were obtained every 2-5 minutes during each hyperglycemic clamp step and plasma glucagon concentrations were measured every 10 minutes. The ratio of insulin/glucagon was measured and used as an index of insulin-medicated suppression of plasma glucagon. FPG concentration increased from 97±4 to 140±4 mg/dl during the 72-hour glucose infusion. Following chronic glucose infusion, plasma insulin levels were significantly higher during the basal state and during each hyperglycemic clamp step (by 59% and 78%) during the 0-80 and 80-160 min time periods, respectively. There was no difference in plasma glucagon levels following chronic glucose infusion. However, the plasma insulin/glucagon ratio was significantly higher during the fasting state (by 76%) and during the first (by 128%) and second (by 178%) hyperglycemic clamp steps. There was no difference in the effect of chronic glucose infusion on glucagon secretion between FH+ and FH-subjects. These results demonstrate that sustained physiologic hyperglycemia for 72 hours (i.e., glucotoxicity) impairs insulin-mediated suppression of glucagon, and could contribute to fasting and post-prandial hyperglycemia in T2DM patients. Disclosure A. Merovci: None. X. Chen: None. R.A. DeFronzo: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Elcelyx Therapeutics, Inc., Intarcia Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Novo Nordisk Inc. Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Merck & Co., Inc. Speaker's Bureau; Self; AstraZeneca, Novo Nordisk Inc. D. Tripathy: None. Funding National Institutes of Health

224-OR: Diurnal Pattern of Insulin Action and Beta-Cell Function in Health and Type 2 Diabetes

We have previously reported differences in insulin sensitivity (SI) between T1D and nondiabetic (ND) subjects throughout the day. To explore differences in the diurnal pattern of SI, beta-cell responsivity to glucose (Φ) and disposition index (DI) between type 2 diabetes (T2D) and ND subjects, we present novel preliminary data from 5 ND (BMI 26.6±1.8 kg/m2, age 62.6±4.8 years, Mean±SE) and 5 T2D subjects (BMI 33.6±2.4 kg/m2, age 60.0±6.0 years, HbA1c 55±11 mmol/mol). Studies were conducted in the Clinical Research Unit. Subjects ingested identical mixed meals (75 g carbs, 55% carbohydrate, 15% protein, 30% fat) at either breakfast (B), lunch (L) or dinner (D) in randomized Latin Square order on three consecutive days. Plasma glucose (G), insulin (I) and C-peptide (C) concentrations were frequently sampled. Oral glucose and C-peptide minimal models were applied to estimate SI, Φ and DI. Differences among B, L and D and between ND and T2D were assessed by two-way ANOVA (a p-value <0.05 was considered statistically significant). The emerging patterns suggest that SI, Φ and DI were lower in T2D than ND (Figure 1) subjects throughout the day. While SI steadily decreased in T2D, it was variable in ND subjects as the day progressed. DI was significantly lower in T2D at dinner than at Breakfast. The data to date indicate that the diurnal patterns of insulin action and beta cell function differ between ND and T2D subjects through the day. Disclosure D. Romeres: None. M. Schiavon: None. C. Cobelli: None. C. Dalla Man: None. A. Basu: Research Support; Spouse/Partner; AstraZeneca. R. Basu: Other Relationship; Self; AstraZeneca. Funding National Institutes of Health (R01029953)

Assessment of pulsatile insulin secretion derived from peripheral plasma C-peptide concentrations by nonparametric stochastic deconvolution.

The characteristics of pulsatile insulin secretion are important determinants of type 2 diabetes pathophysiology, but they are understudied due to the difficulties in measuring pulsatile insulin secretion noninvasively. Deconvolution of either peripheral C-peptide or insulin concentrations offers an appealing alternative to hepatic vein catheterization. However, to do so, there are a series of methodological challenges to overcome. C-peptide has a relatively long half-life and accumulates in the circulation. On the other hand, peripheral insulin concentrations reflect relatively fast clearance and hepatic extraction as it leaves the portal circulation to enter the systemic circulation. We propose a method based on nonparametric stochastic deconvolution of C-peptide concentrations, using individually determined C-peptide kinetics, to overcome these limitations. The use of C-peptide (instead of insulin) concentrations allows estimation of portal (and not post-hepatic) insulin pulses, whereas nonparametric stochastic deconvolution allows evaluation of pulsatile signals without any a priori assumptions of pulse shape and occurrence. The only assumption required is the degree of smoothness of the (unknown) secretion rate. We tested this method first on simulated data and then on 29 nondiabetic subjects studied during euglycemia and hyperglycemia and compared our estimates with the profiles obtained from hepatic vein insulin concentrations. This method produced satisfactory results both in the ability to fit the data and in providing reliable estimates of pulsatile secretion, in agreement with hepatic vein measurements. In conclusion, the proposed method enables reliable and noninvasive measurement of pulsatile insulin secretion. Future studies will be needed to validate this method in people with type 2 diabetes.

Postprandial Duration Influences the Association of Insulin-Related Dietary Indexes and Plasma C-peptide Concentrations in Adult Men and Women

The dietary insulin index (II) directly quantifies dietary effects on postprandial insulin secretion, whereas the empirical dietary index for hyperinsulinemia (EDIH), based on fasting C-peptide concentrations, is primarily reflective of insulin resistance. How these scores are related to nonfasting C-peptide in cohort studies has not been examined. We investigated the extent to which EDIH and II scores predict plasma C-peptide concentrations, in cross-sectional analyses by postprandial duration at blood collection from 1 to ≥15 h. Both EDIH and II scores were calculated from food-frequency questionnaire data reported by 3964 men in the Health Professionals Follow-up Study (1993-1995) and 6215 women in the Nurses' Health Study (1989-1990) who were not diabetic. We constructed 12 multivariable-adjusted linear regression models separately in men and women, by postprandial duration, to calculate relative differences and absolute values of plasma C-peptide concentrations in dietary index quintiles. In both men and women, C-peptide concentrations were elevated 1-2 h after eating and declined with increasing postprandial duration. In men, percent differences in C-peptide concentration in the highest compared with lowest dietary index quintile were: EDIH: 0-1 h: 50%; 2 h: 22%; 14 h: 14%; ≥15 h: 30% (all P-trend<0.05). II: 0-1 h: 19% (P-trend=0.09); 2 h: 3% (P-trend=0.09); 14 h: -6% (P-trend=0.17); ≥15 h: -15% (P-trend=0.02). Corresponding results among women were: EDIH: 0-1 h: 29% (P-trend=0.002); 2 h: 33% (P-trend=0.009); 14 h: 44% (P-trend<0.0001); ≥15h: 40% (P-trend<0.0001). II: 0-1 h: -12% (P-trend=0.09); 2 h: 17% (P-trend=0.09); 14 h: -14% (P-trend=0.009); ≥15 h: -3% (P-trend=0.37). The EDIH was superior to the II in predicting both fasting and nonfasting C-peptide concentrations, suggesting that the EDIH may be better in assessing dietary effects of hyperinsulinemia on disease risk in adult men and women.

Preoperative High-Dose Methylprednisolone and Glycemic Control Early After Total Hip and Knee Arthroplasty: A Randomized, Double-Blind, Placebo-Controlled Trial.

To evaluate the effect of a single preoperative dose of 125 mg methylprednisolone (MP) on glycemic homeostasis early after fast-track total hip and knee arthroplasty. One-hundred thirty-four patients undergoing elective unilateral total hip arthroplasty and total knee arthroplasty were randomized (1:1) to preoperative intravenous MP 125 mg (group MP) or isotonic saline intravenous (group C). All procedures were performed under spinal anesthesia, using a standardized multimodal analgesic regime. The primary outcome was the change in plasma glucose 2 hours postoperatively, and secondary outcomes included plasma C-peptide concentrations, homeostatic model assessment (HOMA), HOMA-IR (insulin resistance), and HOMA-B (β-cell function). Fasting blood samples were collected at baseline and 2, 6 (nonfasting), 24, and 48 hours after surgery with complete samples from 122 patients (group MP = 62, group C = 60) for analyses. MP patients had increased plasma glucose levels at 2 hours (adjusted mean [95% CI], 7.4 mmol·L [7.2-7.5] vs 6.0 mmol·L [5.9-6.2]; P = .023) and 6 hours (13.9 mmol·L [13.3-14.5] vs 8.4 mmol·L [7.8-9.0]; P < .001), and in plasma C-peptide 24 hours postoperatively (1675 pmol·L [1573-1778] vs 1248 pmol·L [1145-1351]; P < .001). An impaired insulin response was also observed in group MP as reflected by HOMA-B (P < .001). Additionally, HOMA-IR increased 24 hours postoperatively in group MP compared to group C (P < .001). Parameters were normalized 48 hours postoperatively. Preoperative administration of MP 125 mg resulted in a transient postoperative increase in plasma glucose and insulin resistance and impaired insulin secretion in response to hyperglycemia.

Refractory spontaneous hypoglycaemia: a diagnostic conundrum

SummaryA frail 79-year-old lady with dementia presented with a 2-year history of frequent falls. Recurrent hypoglycaemic episodes were diagnosed and treated with continuous glucose infusion in multiple hospital admissions. Hypoadrenalism and hypothyroidism were ruled out. Whilst hypoglycaemic (blood glucose 1.6 mmol/L), both plasma C-peptide and proinsulin concentrations, were inappropriately elevated at 4210 pmol/L (174–960) and >200 pmol/L (0–7) respectively with plasma insulin suppressed at 12 pmol/L (0–180). Whilst reported cases of proinsulinoma are typically pancreatic in origin, radiological investigations of the pancreas in this patient did not identify abnormalities. Unexpectedly contrast CT identified a heterogeneously enhancing mass (6.6 cm) at the lower pole of the left kidney consistent with renal cell carcinoma. Non-islet cell tumour-induced hypoglycaemia has been associated with renal malignancy; however, a serum IGF2:IGF1 ratio measured at <10 effectively excludes this diagnosis. Concomitantly on the CT, extensive peripherally enhancing heterogeneous mass lesions in the liver were identified, the largest measuring 12 cm. A palliative approach was taken due to multiple comorbidities. On post-mortem, the kidney lesion was confirmed as clear cell renal carcinoma, whilst the liver lesions were identified as proinsulin-secreting neuroendocrine tumours. In conclusion, the diagnosis of proinsulinoma can be missed if plasma proinsulin concentration is not measured at the time of hypoglycaemia. In this case, the plasma insulin:C-peptide ratio was too high to be accounted for by the faster relative clearance of insulin and was due to proinsulin cross-reactivity in the C-peptide assay. In addition, the concomitant malignancy proved to be a challenging red herring.Learning points:Even in non-diabetics, hypoglycaemia needs to be excluded in a setting of frequent falls. Insulin- or proinsulin-secreting tumours are potentially curable causes.Whilst investigating spontaneous hypoglycaemia, if plasma insulin concentration is appropriate for the hypoglycaemia, it is prudent to check proinsulin concentrations during the hypoglycaemic episode.Proinsulin cross-reacts variably with C-peptide and insulin assays; the effect is method dependent. In this case, the discrepancy between the insulin and C-peptide concentrations was too great to be accounted for by the faster relative clearance of insulin, raising the suspicion of assay interference. The C-peptide assay in question (Diasorin liaison) has been shown to be 100% cross reactive with proinsulin based on spiking studies with a proinsulin reference preparation.Whilst reported cases of proinsulinoma and 99% of insulinomas are of pancreatic origin, conventional imaging studies (CT, MRI or ultrasound) fail to detect neuroendocrine tumours <1 cm in 50% of cases.The concomitant renal mass identified radiologically proved to be a red herring. In view of the rarity of proinsulinoma, no conclusive association with renal cell carcinoma can be established.

The association between plasma C-peptide concentration and the risk of prostate cancer: a nested case-control study within a Japanese population-based prospective study.

The association between plasma C-peptide concentration and prostate cancer is unclear. Inconsistency of results from previous studies motivates this study. Using the Japan Public Health Center-based Prospective study, 201 prostate cancer cases and 402 controls were matched by age, public health center area, residence, date and time of blood collection, and fasting duration before blood collection. Odds ratios (OR) and 95% confidence intervals (CIs) were estimated by conditional logistic regression models. Out of 201 cases, 144 were localized and 48 were advanced. The overall association between median plasma C-peptide concentration and prostate cancer was not significant (OR for the highest tertile=0.81, 95% CI: 0.43-1.56, P-trend=0.54). Although stratification of prostate cancer by stage indicated different effects of plasma C-peptide on localized and advanced cases, there was no association between plasma C-peptide concentration and advanced prostate cancer (OR=2.82, 95% CI: 0.30-26.36 for the highest category, P-trend=0.37) and localized cases (OR=0.49, 95% CI: 0.23-1.04 for the highest category, P-trend=0.06) for patients fasting at the time of blood collection. The association between plasma C-peptide concentration and prostate cancer risk differed by cancer stage. Differentiation of localized and advanced prostate cancer cases is crucial when investigating the association between plasma C-peptide concentration and the risk of prostate cancer.

Beta cell function in type 1 diabetes determined from clinical and fasting biochemical variables.

Beta cell function in type 1 diabetes is commonly assessed as the average plasma C-peptide concentration over 2h following a mixed-meal test (CPAVE). Monitoring of disease progression and response to disease-modifying therapy would benefit from a simpler, more convenient and less costly measure. Therefore, we determined whether CPAVE could be reliably estimated from routine clinical variables. Clinical and fasting biochemical data from eight randomised therapy trials involving participants with recently diagnosed type 1 diabetes were used to develop and validate linear models to estimate CPAVE and to test their accuracy in estimating loss of beta cell function and response to immune therapy. A model based on disease duration, BMI, insulin dose, HbA1c, fasting plasma C-peptide and fasting plasma glucose most accurately estimated loss of beta cell function (area under the receiver operating characteristic curve [AUROC] 0.89 [95% CI 0.87, 0.92]) and was superior to the commonly used insulin-dose-adjusted HbA1c (IDAA1c) measure (AUROC 0.72 [95% CI 0.68, 0.76]). Model-estimated CPAVE (CPEST) reliably identified treatment effects in randomised trials. CPEST, compared with CPAVE, required only a modest (up to 17%) increase in sample size for equivalent statistical power. CPEST, approximated from six variables at a single time point, accurately identifies loss of beta cell function in type 1 diabetes and is comparable to CPAVE for identifying treatment effects. CPEST could serve as a convenient and economical measure of beta cell function in the clinic and as a primary outcome measure in trials of disease-modifying therapy in type 1 diabetes.

Trajectories of body fatness from age 5 to 60 y and plasma biomarker concentrations of the insulin–insulin-like growth factor system

A major pathway through which obesity increases the risk of cardiometabolic diseases and cancer is by inducing hormonal and metabolic abnormalities, including hyperinsulinemia and altered insulin-like growth factor (IGF) signaling. However, little is known about the influence of lifetime adiposity on the relevant biomarkers. The aim of this study was to examine associations of trajectories of body fatness with plasma biomarker concentrations of the insulin-IGF system in 2 large prospective cohorts of US men and women. Associations between trajectories of body fatness and concentrations of plasma C-peptide, IGF-I, IGF-binding protein (IGFBP) 1, IGFBP-3, and the IGF-I-to-IGFBP-3 molar ratio was examined in 9386 women of the Nurses' Health Study and 3941 men of the Health Professionals Follow-Up Study. Group-based trajectory modeling was used to create trajectory groups on the basis of self-reported somatotype data at ages 5, 10, 20, 30, and 40 y and body mass index (BMI) at ages 45, 50, 55, and 60 y. We used multivariate linear regression models to examine the associations of trajectories with biomarker concentrations. Five trajectories of body fatness were identified: "lean-stable," "lean-moderate increase," "lean-marked increase," "medium-stable/increase," and "medium-marked increase." Compared with the lean-stable group, the lean-marked increase and medium-marked increase groups had significantly higher concentrations of C-peptide (percentage difference-women: 44% and 73%; men: 27% and 51%) and lower concentrations of IGFBP-1 (women: -61% and -78%; men: -47% and -65%). Adjustment for current BMI attenuated the association to null for the medium-marked increase group, but the lean-marked increase group still had modestly higher concentrations of C-peptide (women: 10%; men: 6%) and lower concentrations of IGFBP-1 (women: -18%; men: -21%) than the lean-stable group. Adiposity across the life span was associated with higher C-peptide and lower IGFBP-1 concentrations in adulthood. The associations were largely driven by attained adiposity and, to a lesser extent, weight gain in early-middle adulthood. This trial was registered at www.clinicaltrials.gov as NCT03419455.

Paradigm Shifts in Nocturnal Glucose Control in Type 2 Diabetes.

A better understanding of nocturnal regulation of glucose homeostasis will provide the framework for designing rational therapeutic strategies to improve the management of overnight glucose in patients with type 2 diabetes (T2D). To establish the nocturnal pattern and regulation of glucose production (EGP) in humans and to determine whether the pattern is dysregulated in people with T2D. Subjects were infused with [3-3H] glucose overnight. Arterial blood samples were drawn for hormones and analytes to estimate EGP throughout the night. Deuterium-labeled water was provided to measure gluconeogenesis (GNG) using the hexamethylenetetramine method of Landau. Mayo Clinic Clinical Research Trials Unit, Rochester, MN, USA. A total of 43 subjects [23 subjects with T2D and 20 nondiabetic (ND) subjects comparable for age and body mass index] were included in this study. Glucose and EGP. Plasma glucose, C-peptide, and glucagon concentrations were higher throughout the night, whereas insulin concentrations were higher in subjects with T2D vs ND subjects at 1:00 and 4:00 am but similar at 7:00 am. EGP was higher in the subjects with T2D than in the ND subjects throughout the night (P < 0.001). Glycogenolysis (GGL) fell and GNG rose, resulting in significantly higher (P < 0.001) rates of GNG at 4:00 and 7:00 am and significantly (P < 0.001) higher rates of GGL at 1:00, 4:00, and 7:00 am in T2D as compared with ND. These data imply that optimal therapies for T2D for nocturnal/fasting glucose control should target not only the absolute rates of EGP but also the contributing pathways of GGL and GNG sequentially.

Novel Use of Agent 11C-PHNO for Pet CT Imaging of Pancreatic Beta-Cell Mass

There is growing interest in developing a method to measure pancreatic beta-cell mass (BCM) so as to: 1) monitor progression of beta cell changes in type 1 and type 2 diabetes; 2) identify therapies to preserve, restore or regenerate beta cells; and 3) monitor viability of islets after transplantation therapy. Given that beta cells and neurons have functional similarities, we tested the hypothesis that receptors, transporters, or proteins essential for signal detection and propagation, may be common to both cell types. Hence, we assessed if Positron Emission Tomography (PET) imaging ligands originally developed for neuroimaging may provide a means for imaging BCM as well. Previous studies have shown higher uptake of 11C-(+)-4-propyl-9-hydroxynaphthoxazine (PHNO), a dopamine D2/D3 agonist radioligand (D3-preferring), in the pancreatic tissue of healthy controls vs. T1DM in humans. In this study, we sought to determine whether 11C-PHNO, would be useful for measuring BCM. Eleven subjects (6 with T1DM, 4 males and 2 females, age 30.8 ± 11.4 years, BMI 24.4 ± 2.0, and 5 matched healthy controls, 3 males and 2 females, age 32.2 ± 11.4 years, BMI 26.4 ± 2.1) underwent abdominal PET/CT imaging using 11C-PHNO. Regions-of-interest (ROIs) were applied to the pancreas, liver, spleen, and kidney and time-activity curves (TACs) were produced and converted to standard uptake value (SUV) units. The distribution of activity between the head, body, and tail of the pancreas was also assessed. We observed that there was a 41% reduction in 11C-PHNO SUV in T1DM patients as compared to the healthy control group (p = 0.026). Moreover, there was a positive correlation between plasma c-peptide concentrations and 11C-PHNO SUV in the pancreas (r = 0.78), although this relationship did not reach statistical significance (p = 0.1), most likely due to the small sample size. These data suggest that dopamine D3 expression in pancreatic tissue might serve as a useful biomarker for assessing beta cell mass in diabetic humans. Disclosure E. Sanchez Rangel: None. J. Bini: None. N.B. Nabulsi: None. Y. Huang: None. K.C. Herold: None. R. Sherwin: Other Relationship; Self; QuintilesIMS, MannKind Corporation. Research Support; Self; Regeneron Pharmaceuticals, Inc.. Other Relationship; Self; ICON plc. R.E. Carson: Research Support; Self; Pfizer Inc., Bristol-Myers Squibb Company, Eli Lilly and Company, UCB, Inc., Siemens. G. Cline: None.

Lean Subjects with Fatty Liver Show Decreased GLP-1 and GIP Response during OGTT

Subjects with nonalcoholic fatty liver disease (NAFLD) are at high risk of type 2 diabetes even if they are not obese and recent studies have indicated that liver fat (LF)&amp;gt;2.5% was already associated with alteration in glucose and insulin metabolism. Our aim was to investigate if having LF as low as 2.5% was associated to impairment in insulin sensitivity, secretion (ISR) and/or incretin hormones glucagon-like peptide (GLP) 1 and glucose-dependent insulinotropic peptide (GIP) released during an oral glucose tolerance test (OGTT). We studied 49 nondiabetic non-obese subjects (age 52±4; BMI 24.2±0.4 kg/m2). All subjects underwent a 2 h OGTT with plasma insulin, C-peptide, GLP-1, and GIP concentrations were measured every 15-30 min and ISR was quantitated by C-peptide deconvolution. Insulin sensitivity was quantified by HOMA and Matsuda index. Liver fat (LF) accumulation was quantified by magnetic resonance spectroscopy (MRS). In this group of non-obese subjects the great majority were non-NAFLD (31 had LF&amp;lt;2.5%), while 18 had NAFLD (9 had LF 2.5-5% and 9 had LF&amp;gt;5%). Age, BMI, HOMA (1.4±0.2 vs. 1.1±0.2), Matsuda index (7.3±0.7 vs. 10.6±1.3), fasting glucose (5.2±0.1 vs. 5.2±0.1 mmol/l), insulin (6.1±0.7 vs. 4.7±0.7 mU/l), ALT (20±1 vs. 19±1 U/l) and TG (96±22 vs. 88±6 mg/dl) were similar in NAFLD and non-NAFLD. Subjects with LF&amp;gt;2.5% had lower GLP-1 [GLP-1_AUC0-120 was 2.8±0.3 vs. 3.7±0.3, p=0.03], insulin secretion [ISR_AUC60-120 was 61±5 vs. 78±5 nmol, p=0.03] and insulin clearance [MCRI0-120 69±6 vs. 91±7 ml/kg/min, p=0.01] but not GIP [GIP_AUC0-120 was 4.6±0.3 vs. 5.3±0.3, p=ns] response compared to NAFLD; glucose and insulin concentrations during OGTT were similar [Glu0-120 6.7±0.3 vs. 7.3±0.3 mmol/l; Ins0-120 39.9±3.7 vs. 37.5±3.3 mU/l]. Conclusions: Liver fat accumulation (LF&amp;gt;2.5%) is associated with reduced GLP-1, ISR and MCRI; this can help to explain the increased risk of T2D of subjects with NAFLD. Disclosure A. Gastaldelli: Advisory Panel; Self; Gilead Sciences, Inc.. Other Relationship; Self; European Foundation for the Study of Diabetes. Consultant; Self; INVENTIVA SA. J. Garduno-Garcia: Speaker's Bureau; Self; Sanofi-Aventis, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Novo Nordisk Inc., AstraZeneca. R.A. DeFronzo: Speaker's Bureau; Self; AstraZeneca, Novo Nordisk Inc.. Advisory Panel; Self; AstraZeneca, Novo Nordisk Inc., Janssen Pharmaceuticals, Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Elcelyx Therapeutics, Inc., Intarcia Therapeutics, Inc.. Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Takeda Pharmaceuticals U.S.A., Inc. J.J. Holst: Advisory Panel; Self; Novo Nordisk A/S. Board Member; Self; Zealand Pharma A/S. Speaker's Bureau; Self; Merck Sharp &amp; Dohme Corp., AstraZeneca. Research Support; Self; Danish Diabetes Academy, Novo Nordisk Foundation. Other Relationship; Self; Antag Therapeutics. Other Relationship; Spouse/Partner; Antag Therapeutics. N. Musi: None.

TCF7L2 correlation in both insulin secretion and postprandial insulin sensitivity

BackgroundThe TCF7L2 rs7903146 variant is strongly associated with type 2 diabetes mellitus (T2DM). However, the mechanisms involved in this association remain unknown and may include extrapancreatic effects. The aim of this study was to perform a metabolic characterization of T2DM patients with and without the TCF7L2 rs7903146 risk T allele and analyze some influences of the TCF7L2 genotype on glucose metabolism.MethodsPatients with T2DM (n = 162) were genotyped for the TCF7L2 rs7903146 single nucleotide polymorphism. Individuals with CT/TT and CC genotypes were compared regarding basal serum levels of glucose, glycosylated hemoglobin A1C, HDL, uric acid, insulin, and C-peptide. A subset of 56 individuals was evaluated during a 500-calorie mixed-meal test with measurements of glucose, insulin, proinsulin, C-peptide and glucagon. Additional secondary assessments included determination of insulinogenic index (IGI30), and insulin sensitivity (%S) and resistance (IR) by Homeostatic model assessment (HOMA).ResultsPatients with the CT/TT genotype showed lower baseline plasma concentrations of C-peptide when compared with those with the CC genotype. Of the 56 individuals who participated in the mixed-meal test, 26 and 30 had the CC and CT/TT genotypes, respectively. CT/TT subjects, compared with CC individuals, had higher post prandial plasma levels of insulin and C-peptide at 30–120 min (p < 0.05) and proinsulin at 45–240 min (p < 0.05). Interestingly CT/TT individuals presented at baseline higher %S (p = 0.021), and lower IR (p = 0.020) than CC individuals. No significant differences in IGI30 values were observed between groups.ConclusionsThe T2DM individuals carrying the rs7903146 T allele of the TCF7L2 gene presented higher IR pattern in response to a mix-meal test, different of beta cell function at baseline assessed by C-peptide levels which was lower, and Homa-IR was lower when comparing with non-carriers.

Insulin secretion predicts the response to therapy with exenatide plus pioglitazone, but not to basal/bolus insulin in poorly controlled T2DM patients: Results from the Qatar study.

The present study aims to identify predictors for response to combination therapy with pioglitazone plus exenatide vs basal/bolus insulin therapy in T2DM patients who are poorly controlled with maximum/near-maximum doses of metformin plus a sulfonylurea. Participants in the Qatar study received a 75-g OGTT with measurement of plasma glucose, insulin and C-peptide concentration at baseline and were then randomized to receive either treatment with pioglitazone plus exenatide or basal/bolus insulin therapy for one year. Insulin secretion measured with plasma C-peptide concentration during the OGTT was the strongest predictor of response to combination therapy (HbA1c ≤ 7.0%) with pioglitazone plus exenatide. A 54% increase in 2-hour plasma C-peptide concentration above the fasting level identified subjects who achieved the glycaemic goal (HbA1c < 7.0%) with 82% sensitivity and 79% specificity. Only baseline HbA1c was a predictor of response to basal/bolus insulin therapy. Thus, the increment in 2-hour plasma C-peptide concentration above the fasting level provides a useful tool to identify poorly controlled T2DM patients who can achieve glycaemic control without insulin therapy, and thereby, can be used to individualize antihyperglycaemic therapy in poorly controlled T2DM patients.

Sodium-glucose co-transport 2 inhibitor decreases fasting plasma glucose level in impaired fasting glucose but not in normal glucose tolerance subjects

Renal sodium-glucose co-transport 2 inhibitor (SGLT2i) can reduce fasting plasma glucose (FPG) in patients with type 2 diabetes mellitus, but its effect on FPG and β-cell function in impaired fasting glucose (IFG) is unclear. The current article is the Chinses translation of an article entitled as Inhibition of Renal Sodium-Glucose Co-Transport with Empagliflozin Lowers Fasting Plasma and Improves Beta Cell Function in Subjects With Impaired Fasting Glucose , which was published in Diabetes in September [Diabetes, 2017, 66: 2495-2502], with the consent of Diabetes . Eight subjects with IFG and eight subjects with normal FPG (NFG) were included in the study. 9-stage high glucose clamp test was done before and 48 hours, 14 days after taking empagliflozin to quantitatively evaluate the effect of FPG reduction on islet β-cell function. The results showed that FPG concentration decreased only in IFG subjects from (110±2) to (103±3) mg/dl (P<0.01) after taking empagliflozin for 14 days, but the FPG remained unchanged [(95±2) to (94±2) mg/dl] in NFG subjects. The incremental area under the plasma C-peptide concentration curve during the hyperglycemic clamp increased by 22%±4% and 23%±4% in IFG subjects after 48 hours and 14 days, respectively (P<0.01); the plasma C-peptide response remained unchanged in NFG subjects. The insulin secretion/insulin sensitivity (disposition) index increased significantly in IFG, but not in NFG subjects. In conclusion, empagliflozin only reduces the FPG concentration and improves β-cell function in IFG. (Chin J Endocrinol Metab, 2017, 33: 874-879) Key words: Sodium-glucose co-transport 2 inhibitor; Empagliflozin; Fasting plasma glucose; β-cell function; Impaired fasting glucose.

Plasma C-Peptide Concentration and Risk of Hypoglycemia in People with T2DM treated with Insulin Glagine 300 U/mL (Gla-300) or Insulin Glargine 100 U/mL (Gla-100)

Risk of hypoglycaemia on insulin treatment increases as B-cell function progressively deteriorates in Type 2 diabetes. Using data from the EDITION 1, 2 and 3 treat-to-target trials in T2DM, we analyzed baseline fasting plasma C-peptide concentration and hypoglycemia during 6 months treatment with Gla-300 vs Gla-100 to explore if C-peptide was associated with hypoglycemia risk. C-peptide levels <0.4 nmol/L were more frequent in previously insulin-treated participants in EDITION 1and 2 trials (54%) compared with the insulin-naïve in EDITION 3 (12.5%). Comparable numbers of participants treated with Gla-300 or Gla-100 had lower C-peptide (EDITION 1, 221 vs 209; EDITION 2, 207 vs 216; EDITION 3, 52 vs 43).

Hyperglycaemic preterm neonates exhibit insulin resistance and low insulin production

ObjectivesTo explore and compare the relationships between postmenstrual age (PMA), insulin, C-peptide and blood glucose concentrations (BGC) in hyperglycaemic and euglycaemic preterm neonates (PMA <30 weeks).DesignObservational.SettingDunedin Hospital Neonatal Intensive Care...

Inhibition of Renal Sodium-Glucose Cotransport With Empagliflozin Lowers Fasting Plasma Glucose and Improves β-Cell Function in Subjects With Impaired Fasting Glucose.

The objective of this study was to examine the effect of renal sodium-glucose cotransporter inhibition with empagliflozin on the fasting plasma glucose (FPG) concentration and β-cell function in subjects with impaired fasting glucose (IFG). Eight subjects with normal fasting glucose (NFG) and eight subjects with IFG received empagliflozin (25 mg/day) for 2 weeks. FPG concentration and β-cell function was measured with a nine-step hyperglycemic clamp before and 48 h and 14 days after the start of empagliflozin. Empagliflozin caused 50 ± 4 and 45 ± 4 g glucosuria on day 2 in subjects with IFG and NFG, respectively, and the glucosuria was maintained for 2 weeks in both groups. The FPG concentration decreased only in subjects with IFG from 110 ± 2 to 103 ± 3 mg/dL (P < 0.01) after 14 days. The FPG concentration remained unchanged (95 ± 2 to 94 ± 2 mg/dL) in subjects with NFG. Empagliflozin enhanced β-cell function only in subjects with IFG. The incremental area under the plasma C-peptide concentration curve during the hyperglycemic clamp increased by 22 ± 4 and 23 ± 4% after 48 h and 14 days, respectively (P < 0.01); the plasma C-peptide response remained unchanged in subjects with NFG. Insulin sensitivity during the hyperglycemic clamp was not affected by empagliflozin in either IFG or NFG. Thus, β-cell function measured with the insulin secretion/insulin sensitivity (disposition) index increased significantly in IFG, but not in subjects with normal glucose tolerance. Inhibition of renal sodium-glucose cotransport with empagliflozin in subjects with IFG and NFG produces comparable glucosuria but lowers the plasma glucose concentration and improves β-cell function only in subjects with IFG.

Reduced circulating stem cells associate with excess fasting and post-load NEFA exposure in healthy adults with normal glucose tolerance

Background and aimsReduced levels of circulating stem cells (CSCs) predict cardiovascular events and death, but the factors underlying variability of CSCs in healthy adults are mostly unknown. Previous studies detected associations of CSCs with glucose tolerance or insulin resistance, while the role of fatty acids has been overlooked. We herein aimed to describe in better detail the metabolic abnormalities associated with a reduced CSC level. MethodsThis was a cross-sectional study on 94 healthy male and female individuals with normal glucose tolerance, aged 18–65 years. All participants underwent an oral glucose tolerance test (OGTT) with blood samples collected at 0, 10, 20, 30, 60, 90 and 120 min. Mathematical models were applied to plasma glucose, insulin, C-peptide and non-esterified fatty acids (NEFA) concentrations. CSCs were defined as CD34+ or CD133+. ResultsParticipants (mean ± SEM age 43.8 ± 0.7; 41% males) were divided according to CSC levels below (low) or above (high) the median value and metabolic parameters were compared. There was no significant baseline difference between groups except for higher concentrations of fasting NEFA in subjects with low CSCs. Upon OGTT, individuals with low CSCs had higher area under curve (AUC) of NEFA (p < 0.001) and no significant differences in glucose, insulin and C-peptide. Several insulin sensitivity and beta cell function indexes were not significantly different, except for a decrease in the disposition index (DI) in subjects with low CSCs. CSCs were associated with excess NEFA levels independently from age and DI. ConclusionsWe show for the first time that, in healthy adults with normal glucose tolerance, low CSCs are strongly associated with excess NEFA exposure. The pathophysiological consequence of this association needs to be interpreted in view of the prognostic role of CSCs. Future studies should explore whether excess NEFA and low CSCs and are causally interconnected.