OBJECTIVE

To evaluate the glucose dependency of glucose-dependent insulinotropic polypeptide (GIP) effects on insulin and glucagon release in 10 healthy male subjects ([means ± SEM] aged 23 ± 1 years, BMI 23 ± 1 kg/m2, and HbA1c 5.5 ± 0.1%).

RESEARCH DESIGN AND METHODS

Saline or physiological doses of GIP were administered intravenously (randomized and double blinded) during 90 min of insulin-induced hypoglycemia, euglycemia, or hyperglycemia.

RESULTS

During hypoglycemia, GIP infusion caused greater glucagon responses during the first 30 min compared with saline (76 ± 17 vs. 28 ± 16 pmol/L per 30 min, P < 0.008), with similar peak levels of glucagon reached after 60 min. During euglycemia, GIP infusion elicited larger glucagon responses (62 ± 18 vs. −11 ± 8 pmol/L per 90 min, P < 0.005). During hyperglycemia, comparable suppression of plasma glucagon (−461 ± 81 vs. −371 ± 50 pmol/L per 90 min, P = 0.26) was observed with GIP and saline infusions. In addition, during hyperglycemia, GIP more than doubled the insulin secretion rate (P < 0.0001).

CONCLUSIONS

In healthy subjects, GIP has no effect on glucagon responses during hyperglycemia while strongly potentiating insulin secretion. In contrast, GIP increases glucagon levels during fasting and hypoglycemic conditions, where it has little or no effect on insulin secretion. Thus, GIP seems to be a physiological bifunctional blood glucose stabilizer with diverging glucose-dependent effects on the two main pancreatic glucoregulatory hormones.

OBJECTIVE

Glucagon-like peptide 1 (GLP-1) exerts beneficial antidiabetic actions via effects on pancreatic β- and α-cells. Previous studies have focused on the improvements in β-cell function, while the inhibition of α-cell secretion has received less attention. The aim of this research was to quantify the glucagonostatic contribution to the glucose-lowering effect of GLP-1 infusions in patients with type 2 diabetes.

RESEARCH DESIGN AND METHODS

Ten male patients with well-regulated type 2 diabetes (A1C 6.9 ± 0.8%, age 56 ± 10 years, BMI 31 ± 3 kg/m2 [means ± SD]) were subjected to five 120-min glucose clamps at fasting plasma glucose (FPG) levels. On day 1, GLP-1 was infused to stimulate endogenous insulin release and suppress endogenous glucagon. On days 2–5, pancreatic endocrine clamps were performed using somatostatin infusions of somatostatin and/or selective replacement of insulin and glucagon; day 2, GLP-1 plus basal insulin and glucagon (no glucagon suppression or insulin stimulation); day 3, basal insulin only (glucagon deficiency); day 4, basal glucagon and stimulated insulin; and day 5, stimulated insulin. The basal plasma glucagon levels were chosen to simulate portal glucagon levels.

RESULTS

Peptide infusions produced the desired hormone levels. The amount of glucose required to clamp FPG was 24.5 ± 4.1 (day 1), 0.3 ± 0.2 (day 2), 10.6 ± 1.1 (day 3), 11.5 ± 2.7 (day 4), and 24.5 ± 2.6 g (day 5) (day 2 was lower than days 3 and 4, which were both similar and lower than days 1 and 5).

CONCLUSIONS

We concluded that insulin stimulation (day 4) and glucagon inhibition (day 3) contribute equally to the effect of GLP-1 on glucose turnover in patients with type 2 diabetes, and these changes explain the glucose-lowering effect of GLP-1 (day 5 vs. day 1).

Background

Dairy proteins, in particular the whey fraction, exert insulinogenic properties and facilitate glycemic regulation through a mechanism involving elevation of certain plasma amino acids, and stimulation of incretins. Human milk is rich in whey protein and has not been investigated in this respect.

Method

Nine healthy volunteers were served test meals consisting of human milk, bovine milk, reconstituted bovine whey- or casein protein in random order. All test meals contributed with 25g intrinsic or added lactose, and a white wheat bread (WWB) meal was used as reference, providing 25g starch. Post-prandial levels in plasma of glucose, insulin, incretins and amino acids were investigated at time intervals for up to 2 h.

Results

All test meals elicited lower postprandial blood glucose responses, expressed as iAUC 0–120 min compared with the WWB (P < 0.05). The insulin response was increased following all test meals, although only significantly higher after whey. Plasma amino acids were correlated to insulin and incretin secretion (iAUC 0–60 min) (P ≤ 0.05). The lowered glycemia with the test meals (iAUC 0–90 min) was inversely correlated to GLP-1 (iAUC 0–30 min) (P ≤ 0.05).

Conclusion

This study shows that the glycemic response was significantly lower following all milk/milk protein based test meals, in comparison with WWB. The effect appears to originate from the protein fraction and early phase plasma amino acids and incretins were involved in the insulin secretion. Despite its lower protein content, the human milk was a potent GLP-1 secretagogue and showed insulinogenic properties similar to that seen with reconstituted bovine whey-protein, possibly due to the comparatively high proportion of whey in human milk.

Background

Whey proteins have insulinogenic properties and the effect appears to originate from a specific postprandial plasma amino acid pattern. The insulinogenic effect can be mimicked by a specific mixture of the five amino acids iso, leu, lys, thr and val.

Objective

The objective was to evaluate the efficacy of pre-meal boluses of whey or soy protein with or without added amino acids on glycaemia, insulinemia as well as on plasma responses of incretins and amino acids at a subsequent composite meal. Additionally, plasma ghrelin and subjective appetite responses were studied.

Design

In randomized order, fourteen healthy volunteers were served a standardized composite ham sandwich meal with either water provided (250 ml) during the time course of the meal, or different pre-meal protein drinks (PMPD) (100 ml provided as a bolus) with additional water (150 ml) served to the meal. The PMPDs contained 9 g protein and were based on either whey or soy protein isolates, with or without addition of the five amino acids (iso, leu, lys, thr and val) or the five amino acids + arg.

Results

All PMPD meals significantly reduced incremental area for plasma glucose response (iAUC) during the first 60 min. All whey based PMPD meals displayed lower glycemic indices compared to the reference meal. There were no significant differences for the insulinemic indices. The early insulin response (iAUC 0–15 min) correlated positively to plasma amino acids, GIP and GLP-1 as well as to the glycemic profile. Additionally, inverse correlations were found between insulin iAUC 0–15 min and the glucose peak.

Conclusion

The data suggests that a pre-meal drink containing specific proteins/amino acids significantly reduces postprandial glycemia following a composite meal, in absence of elevated insulinemic excursions. An early phase insulinemic response induced by plasma amino acids and incretins appears to mediate the effect.

Trial Registration

ClinicalTrials.gov NCT01586780

Introduction

Linagliptin is a xanthine-based dipeptidyl peptidase (DPP)-4 inhibitor that is now available in numerous countries worldwide for the treatment of type 2 diabetes mellitus (T2DM). The aim of this study was to evaluate further the mechanisms underlying the improvements in glycemic control observed with linagliptin. The effects of linagliptin on DPP-4, pharmacodynamic parameters, and glycemic control versus placebo were assessed in patients with inadequately controlled T2DM.

Methods

Patients in this phase 2a, multicenter, randomized, double-blind, placebo-controlled study received placebo (n = 40) or linagliptin 5 mg (n = 40). Sitagliptin 100 mg (n = 41) once daily for 4 weeks was included for exploratory purposes. Primary endpoints for linagliptin versus placebo: change from baseline to day 28 in 24-h weighted mean glucose (WMG) and intact glucagon-like peptide (GLP)-1 area under the time–effect curve between 0 and 2 h (AUEC0–2h) following meal tolerance test on day 28.

Results

Linagliptin increased intact GLP-1 AUEC0–2h (+18.1 pmol/h/L) and lowered 24-h WMG (−1.1 mmol/L) versus placebo (both P < 0.0001) after 28 days. Intact glucose-dependent insulinotropic polypeptide increased in line with GLP-1 (+91.4 pmol/h/L increase vs. placebo; P < 0.0001). Glycated hemoglobin (−0.22%; P = 0.0021), fasting plasma glucose (−0.6 mmol/L; P = 0.0283), and glucose (AUEC0–3h) (−5.9 mmol/h/L; P < 0.0001) improved significantly with linagliptin versus placebo. Most adverse events were mild; hypoglycemia or serious adverse events were not reported. Sustained DPP-4 inhibition (≥80%) throughout the treatment period was accompanied by significant reductions in glucagon starting at day 1 of linagliptin administration.

Conclusion

Linagliptin was well tolerated and effectively inhibited plasma DPP-4 activity in patients with T2DM, producing immediate improvements in incretin levels, glucagon suppression, and glycemic control that were maintained throughout the study period.

OBJECTIVE

In patients with type 2 diabetes, glucagon levels are often increased. Furthermore, pulsatile secretion of insulin is disturbed in such patients. Whether pulsatile glucagon secretion is altered in type 2 diabetes is not known.

RESEARCH DESIGN AND METHODS

Twelve patients with type 2 diabetes and 13 nondiabetic individuals were examined in the fasting state and after mixed meal ingestion. Deconvolution analyses were performed on insulin and glucagon concentration time series sampled at 1-min intervals.

RESULTS

Both insulin and glucagon were secreted in distinct pulses, occurring at ∼5-min intervals. In patients with diabetes, postprandial insulin pulse mass was reduced by 74% (P < 0.001). Glucagon concentrations were increased in the patients during fasting and after meal ingestion (P < 0.05), specifically through an increased glucagon pulse mass (P < 0.01). In healthy subjects, the increase in postprandial insulin levels was inversely related to respective glucagon levels (P < 0.05). This relationship was absent in the fasting state and in patients with diabetes.

CONCLUSIONS

Glucagon and insulin are secreted in a coordinated, pulsatile manner. A plausible model is that the postprandial increase in insulin burst mass represses the corresponding glucagon pulses. Disruption of the insulin–glucagon interaction in patients with type 2 diabetes could potentially contribute to hyperglucagonemia.

Background

Glucagon-like peptide-2(GLP-2) induces small intestine mucosal epithelial cell (EC) proliferation; and may have benefit for patients suffering from short bowel syndrome (SBS). However, GLP-2 is rapidly inactivated in vivo by dipeptidyl peptidase IV (DPPIV). Therefore, we hypothesized that selectively inhibiting DPPIV would prolong the circulating life of GLP-2 and lead to increased intestinal adaptation after development of SBS.

Methods

8-week old C57BL/6J mice underwent a 50% proximal small bowel resection and were treated with either sitagliptin, a DPPIV-inhibitor (DPPIV-I), starting 1 day before surgery versus placebo. DPPIV-I efficacy was assessed 3 days after resection, including intestinal morphology, EC apoptosis and EC proliferation. Adaptive mechanisms were assessed with quantitative real-time PCR, and plasma bioactive GLP-2 was measured by radioimmunoassay.

RESULT

Body weight loss and peripheral blood glucose levels did not change compared to SBS controls. DPPIV-I treatment led to significant increases in villus height and crypt depth. DPPIV-I treatment did not significantly change EC apoptosis rates, but significantly increased crypt EC proliferation versus placebo-SBS controls. DPPIV-I treatment markedly increased mRNA expression of β-catenin and c-myc in ileal mucosa. Plasma GLP-2 levels significantly increased(~40.9%) in DPPIV-I-SBS mice.

Conclusions

DPPIV- I treatment increased SBS adaptation, and may potentially be useful for SBS patients.

Background

Whey protein increases postprandial serum insulin levels. This has been associated with increased serum levels of leucine, isoleucine, valine, lysine, threonine and the incretin hormone glucose-dependent insulinotropic polypeptide (GIP). We have examined the effects of these putative mediators of whey’s action on insulin secretion from isolated mouse Langerhans islets.

Methods

Mouse pancreatic islets were incubated with serum drawn from healthy individuals after ingestion of carbohydrate equivalent meals of whey protein (whey serum), or white wheat bread (control serum). In addition the effect of individual amino acid combinations on insulin secretion was also tested. Furthermore, the stimulatory effects of whey serum on insulin secretion was tested in vitro in the absence and presence of a GIP receptor antagonist ((Pro(3))GIP[mPEG]).

Results

Postprandial amino acids, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) responses were higher after whey compared to white wheat bread. A stimulatory effect on insulin release from isolated islets was observed with serum after whey obtained at 15 min (+87%, P < 0.05) and 30 min (+139%, P < 0.05) postprandially, compared with control serum. The combination of isoleucine, leucine, valine, lysine and threonine exerted strong stimulatory effect on insulin secretion (+270%, P < 0.05), which was further augmented by GIP (+558% compared to that produced by glucose, P < 0.05). The stimulatory action of whey on insulin secretion was reduced by the GIP-receptor antagonist (Pro(3))GIP[mPEG]) at both 15 and 30 min (−56% and −59%, P < 0.05).

Conclusions

Compared with white wheat bread meal, whey causes an increase of postprandial insulin, plasma amino acids, GIP and GLP-1 responses. The in vitro data suggest that whey protein exerts its insulinogenic effect by preferential elevation of the plasma concentrations of certain amino acids, GIP and GLP-1.

OBJECTIVE

Glucagon-like peptide (GLP)-1 lowers postprandial glycemia primarily through inhibition of gastric emptying. We addressed whether the GLP-1–induced deceleration of gastric emptying is subject to rapid tachyphylaxis and if so, how this would alter postprandial glucose control.

RESEARCH DESIGN AND METHODS

Nine healthy volunteers (25 ± 4 years old, BMI: 24.6 ± 4.7 kg/m2) were examined with intravenous infusion of GLP-1 (0.8 pmol · kg−1 . min−1) or placebo over 8.5 h. Two liquid mixed meals were administered at a 4-h interval. Gastric emptying was determined, and blood samples were drawn frequently.

RESULTS

GLP-1 decelerated gastric emptying significantly more after the first meal compared with the second meal (P = 0.01). This was associated with reductions in pancreatic polypeptide levels (marker of vagal activation) after the first but not the second meal (P < 0.05). With GLP-1, glucose concentrations declined after the first meal but increased after the second meal (P < 0.05). The GLP-1–induced reductions in postprandial insulin and C-peptide levels were stronger during the first meal course (P < 0.05). Likewise, glucagon levels were lowered by GLP-1 after the first meal but increased after the second test meal (P < 0.05).

CONCLUSIONS

The GLP-1–induced delay in gastric emptying is subject to rapid tachyphylaxis at the level of vagal nervous activation. As a consequence, postprandial glucose control by GLP-1 is attenuated after its chronic administration.

OBJECTIVE

To investigate the effect of exogenous as well as endogenous glucagon-like peptide 1 (GLP-1) on postprandial glucose excursions and to characterize the secretion of incretin hormones in type 1 diabetic patients with and without residual β-cell function.

RESEARCH DESIGN AND METHODS

Eight type 1 diabetic patients with (T1D+), eight without (T1D−) residual β-cell function, and eight healthy matched control subjects were studied during a mixed meal with concomitant infusion of GLP-1 (1.2 pmol/kg/min), saline, or exendin 9-39 (300 pmol/kg/min). Before the meal, half dose of usual fast-acting insulin was injected. Plasma glucose (PG), glucagon, C-peptide, total GLP-1, intact glucose-dependent insulinotropic polypeptide (GIP), free fatty acids, triglycerides, and gastric emptying rate (GE) by plasma acetaminophen were measured.

RESULTS

Incretin responses did not differ between patients and control subjects. Infusion of GLP-1 decreased peak PG by 45% in both groups of type 1 diabetic patients. In T1D+ patients, postprandial PG decreased below fasting levels and was indistinguishable from control subjects infused with saline. In T1D− patients, postprandial PG remained at fasting levels. GLP-1 infusion reduced GE and glucagon levels in all groups and increased fasting C-peptide in T1D+ patients and control subjects. Blocking endogenous GLP-1 receptor action increased endogenous GLP-1 secretion in all groups and increased postprandial glucose, glucagon, and GE in T1D+ and T1D− patients. The insulinogenic index (the ratio of insulin to glucose) decreased in T1D+ patients during blockade of endogenous GLP-1 receptor action.

CONCLUSIONS

Type 1 diabetic patients have normal incretin responses to meals. In type 1 diabetic patients, exogenous GLP-1 decreases peak postprandial glucose by 45% regardless of residual β-cell function. Endogenous GLP-1 regulates postprandial glucose excursions by modulating glucagon levels, GE, and β-cell responsiveness to glucose. Long-term effects of GLP-1 in type 1 diabetic patients should be investigated in future clinical trials.

OBJECTIVE

The incretin glucagon-like peptide 1 (GLP-1) exerts insulinotropic activity in type 2 diabetic patients, whereas glucose-dependent insulinotropic polypeptide (GIP) no longer does. We studied whether GIP can alter the insulinotropic or glucagonostatic activity of GLP-1 in type 2 diabetic patients.

RESEARCH DESIGN AND METHODS

Twelve patients with type 2 diabetes (nine men and three women; 61 ± 10 years; BMI 30.0 ± 3.7 kg/m2; HbA1c 7.3 ± 1.5%) were studied. In randomized order, intravenous infusions of GLP-1(7-36)-amide (1.2 pmol · kg−1 · min−1), GIP (4 pmol · kg−1 · min−1), GLP-1 plus GIP, and placebo were administered over 360 min after an overnight fast (≥1 day wash-out period between experiments). Capillary blood glucose, plasma insulin, C-peptide, glucagon, GIP, GLP-1, and free fatty acids (FFA) were determined.

RESULTS

Exogenous GLP-1 alone reduced glycemia from 10.3 to 5.1 ± 0.2 mmol/L. Insulin secretion was stimulated (insulin, C-peptide, P < 0.0001), and glucagon was suppressed (P = 0.009). With GIP alone, glucose was lowered slightly (P = 0.0021); insulin and C-peptide were stimulated to a lesser degree than with GLP-1 (P < 0.001). Adding GIP to GLP-1 did not further enhance the insulinotropic activity of GLP-1 (insulin, P = 0.90; C-peptide, P = 0.85). Rather, the suppression of glucagon elicited by GLP-1 was antagonized by the addition of GIP (P = 0.008). FFA were suppressed by GLP-1 (P < 0.0001) and hardly affected by GIP (P = 0.07).

CONCLUSIONS

GIP is unable to further amplify the insulinotropic and glucose-lowering effects of GLP-1 in type 2 diabetes. Rather, the suppression of glucagon by GLP-1 is antagonized by GIP.

Objective

Low Glucagon-like Peptide-1 (GLP-1) concentrations have been observed in impaired fasting glucose (IFG). It is uncertain if these abnormalities contribute directly to the pathogenesis of IFG and impaired glucose tolerance. Dipeptidyl peptidase-4 (DPP-4) inhibitors raise incretin hormone concentrations enabling an examination of their effects on glucose turnover in IFG.

Research Design and Methods

We studied 22 subjects with IFG using a double blind, placebo-controlled parallel group design. At the time of enrollment, subjects ate a standardized meal labeled with [1-13C]-glucose. Infused [6-3H] glucose enabled measurement of systemic meal appearance (MRa). Infused [6,6-2H2] glucose enabled measurement of endogenous glucose production (EGP) and glucose disappearance (Rd). Subsequently, subjects were randomized to100mg of sitagliptin daily or placebo. After an 8-week treatment period, the mixed meal was repeated.

Results

As expected, subjects with IFG who received placebo did not experience any change in glucose concentrations. Despite raising intact GLP-1 concentrations, treatment with sitagliptin did not alter either fasting or postprandial glucose, insulin or C-peptide concentrations. Postprandial EGP (18.1±0.7 vs. 17.6±0.8 µmol/kg/min, p = 0.53), Rd (55.6±4.3 vs. 58.9±3.3 µmol/kg/min, p = 0.47) and MRa (6639±377 vs. 6581±316 µmol/kg per 6h, p = 0.85) were unchanged. Sitagliptin was associated with decreased total GLP-1 implying decreased incretin secretion.

Conclusions

DPP-4 inhibition did not alter fasting or postprandial glucose turnover in people with IFG. Low incretin concentrations are unlikely to be involved in the pathogenesis of IFG.

OBJECTIVE

To evaluate metabolic effects of sex steroids in nonfasting and fasting conditions, independent from changes in body composition.

RESEARCH DESIGN AND METHODS

A randomized clinical trial was performed to create contrasting sex steroid levels in healthy young men: by letrozole (aromatase inhibitor) to lower estradiol (E2) and increase testosterone (group T, n = 10) versus letrozole plus E2 patches to lower T and raise E2 (group E, n = 10). Mixed meals and hyperinsulinemic-euglycemic clamps were performed before and after a 1-week treatment period.

RESULTS

Following intervention, the postprandial triglyceride response displayed a diverging response with a decline in group T and an increase in group E; the postprandial glucose-dependent insulinotropic polypeptide (GIP) response increased in group T. Insulin sensitivity increased in group T but remained unaltered in group E.

CONCLUSIONS

In healthy young men, short-term changes in sex steroids affect postprandial triglyceride and GIP response and insulin sensitivity.

OBJECTIVE

The aim of this study was to determine whether the type 2 diabetes–associated T-allele of transcription factor 7-like 2 (TCF7L2) rs7903146 associates with impaired insulin secretion to compensate for insulin resistance induced by bed rest.

RESEARCH DESIGN AND METHODS

A total of 38 healthy young Caucasian men were studied before and after bed rest using the hyperinsulinemic-euglycemic clamp technique combined with indirect calorimetry preceded by an intravenous glucose tolerance test. The TCF7L2 rs7903146 was genotyped using allelic discrimination performed with an ABI 7900 system. The genetic analyses were done assuming a dominant model of inheritance.

RESULTS

The first-phase insulin response (FPIR) was significantly lower in carriers of the T-allele compared with carriers of the CC genotype before bed rest, with and without correction for insulin resistance. The incremental rise of FPIR in response to insulin resistance induced by bed rest was lower in carriers of the T-allele (P < 0.001). Fasting plasma glucagon levels were significantly lower in carriers of the T-allele before and after bed rest. While carriers of the CC genotype developed increased hepatic insulin resistance, the TCF7L2 rs7903146 did not influence peripheral insulin action or the rate of lipolysis before or after bed rest.

CONCLUSIONS

Healthy carriers of the T-allele of TCF7L2 rs7903146 exhibit a diminished increase of insulin secretion in response to intravenous glucose to compensate for insulin resistance as induced by bed rest. Reduced paracrine glucagon stimulation may contribute to the impairment of β-cell function in the carriers TCF7L2 rs7903146 T-allele associated with increased risk of type 2 diabetes.

Background

To investigate glucose homeostasis in detail in Turner syndrome (TS), where impaired glucose tolerance (IGT) and type 2 diabetes are frequent.

Methods

Cross sectional study of women with Turner syndrome (TS)(n = 13) and age and body mass index matched controls (C) (n = 13), evaluated by glucose tolerance (oral and intravenous glucose tolerance test (OGTT and IVGTT)), insulin sensitivity (hyperinsulinemic, euglycemic clamp), beta-cell function (hyperglycaemic clamp, arginine and GLP-1 stimulation) and insulin pulsatility.

Results

Fasting glucose and insulin levels were similar. Higher glucose responses was seen in TS during OGTT and IVGTT, persisting after correction for body weight or muscle mass, while insulin responses were similar in TS and C, despite the higher glucose level in TS, leading to an insufficient increase in insulin response during dynamic testing. Insulin sensitivity was comparable in the two groups (TS vs. control: 8.6 ± 1.8 vs. 8.9 ± 1.8 mg/kg*30 min; p = 0.6), and the insulin responses to dynamic β-cell function tests were similar. Insulin secretion patterns examined by deconvolution analysis, approximate entropy, spectral analysis and autocorrelation analysis were similar. In addition we found low IGF-I, higher levels of cortisol and norepinephrine and an increased waist-hip ratio in TS.

Conclusions

Young normal weight TS women show significant glucose intolerance in spite of normal insulin secretion during hyperglycaemic clamping and normal insulin sensitivity. We recommend regularly testing for diabetes in TS.

Trial Registration

Registered with http://clinicaltrials.com, ID nr: NCT00419107

OBJECTIVE

To examine after gastric bypass the effect of peroral versus gastroduodenal feeding on glucose metabolism.

RESEARCH DESIGN AND METHODS

A type 2 diabetic patient was examined on 2 consecutive days 5 weeks after gastric bypass. A standard liquid meal was given on the first day into the bypassed gastric remnant and on the second day perorally. Plasma glucose, insulin, C-peptide, glucagon, incretin hormones, peptide YY, and free fatty acids were measured.

RESULTS

Peroral feeding reduced 2-h postprandial plasma glucose (7.8 vs. 11.1 mmol/l) and incremental area under the glucose curve (iAUC) (0.33 vs. 0.49 mmol · l−1 · min−1) compared with gastroduodenal feeding. β-Cell function (iAUCCpeptide/Glu) was more than twofold improved during peroral feeding, and the glucagon-like peptide (GLP)-1 response increased nearly fivefold.

CONCLUSIONS

Improvement in postprandial glucose metabolism after gastric bypass is an immediate and direct consequence of the gastrointestinal rearrangement, associated with exaggerated GLP-1 release and independent of changes in insulin sensitivity, weight loss, and caloric restriction.

OBJECTIVE

KCNQ1 gene polymorphisms are associated with type 2 diabetes. This linkage appears to be mediated by altered β-cell function. In an attempt to study underlying mechanisms, we examined the effect of four KCNQ1 single nucleotide polymorphisms (SNPs) on insulin secretion upon different stimuli.

RESEARCH DESIGN AND METHODS

We genotyped 1,578 nondiabetic subjects at increased risk of type 2 diabetes for rs151290, rs2237892, rs2237895, and rs2237897. All participants underwent an oral glucose tolerance test (OGTT); glucagon-like peptide (GLP)-1 and gastric inhibitory peptide secretion was measured in 170 participants. In 519 participants, a hyperinsulinemic-euglycemic clamp was performed, in 314 participants an intravenous glucose tolerance test (IVGTT), and in 102 subjects a hyperglycemic clamp combined with GLP-1 and arginine stimuli.

RESULTS

rs151290 was nominally associated with 30-min C-peptide levels during OGTT, first-phase insulin secretion, and insulinogenic index after adjustment in the dominant model (all P ≤ 0.01). rs2237892, rs2237895, and rs2237897 were nominally associated with OGTT-derived insulin secretion indexes (all P < 0.05). No SNPs were associated with β-cell function during intravenous glucose or GLP-1 administration. However, rs151290 was associated with glucose-stimulated gastric inhibitory polypeptide and GLP-1 increase after adjustment in the dominant model (P = 0.0042 and P = 0.0198, respectively). No associations were detected between the other SNPs and basal or stimulated incretin levels (all P ≥ 0.05).

CONCLUSIONS

Common genetic variation in KCNQ1 is associated with insulin secretion upon oral glucose load in a German population at increased risk of type 2 diabetes. The discrepancy between orally and intravenously administered glucose seems to be explained not by altered incretin signaling but most likely by changes in incretin secretion.

OBJECTIVE—The aim of this study was to describe the natural history of insulin secretion and insulin sensitivity in the development of isolated impaired fasting glycemia (i-IFG), isolated impaired glucose tolerance (i-IGT), and combined IFG/IGT.

RESEARCH DESIGN AND METHODS—Baseline and 5-year follow-up data from the Inter99 study were used. Individuals with normal glucose tolerance (NGT) at baseline and i-IFG, i-IGT, combined IFG/IGT, or NGT at the 5-year follow-up were examined with an oral glucose tolerance test (n = 3,145). Insulin sensitivity index (ISI), homeostasis model assessment of insulin sensitivity (HOMA-IS), early-phase insulin release (EPIR), and insulin secretion relative to insulin action (disposition index) were estimated.

RESULTS—Five years before the pre-diabetes diagnoses (i-IFG, i-IGT, and IFG/IGT), ISI, HOMA-IS, EPIR, and disposition index were lower than in individuals who maintained NGT. During the 5-year follow-up, individuals developing i-IFG experienced a significant decline only in HOMA-IS, whereas individuals developing i-IGT experienced significant declines in ISI, EPIR, and disposition index. Individuals with IFG/IGT exhibited pronounced declines in ISI, HOMA-IS, EPIR, and disposition index during the 5-year follow-up.

CONCLUSIONS—A stationary reduced insulin secretion followed by a decline in primarily hepatic insulin sensitivity characterizes the transition from NGT to i-IFG. In contrast, low whole-body insulin sensitivity with a secondary lack of β-cell compensation is associated with the development of i-IGT. Thereby, i-IFG and i-IGT appear to result from different underlying mechanisms, which may have implications for the prevention and treatment of the diabetes that succeeds them.

The effects of colon-derived butyrate on intestinal cell proliferation are controversial. In vitro studies suggest an inhibitory effect, and in vivo studies suggest the opposite, but neither type of study has been based on a physiologically relevant, intracolonic supply of butyrate. In this study, piglets (n = 24) were fed sow’s milk replacement formula and randomized into 4 equal groups: 1) control; 2) cecal butyrate infusion at a rate equal to that produced in the colon; 3) inulin supplementation at a concentration previously found to lower cecal cell proliferation; and 4) butyrate infusion plus inulin supplementation. After 6 d of oral feeding, cecal butyrate infusions were initiated for a period of 4 d. Cecal, distal colonic, jejunal, and ileal cell proliferation, apoptosis, and morphology were evaluated and serum concentration of glucagon-like peptide-2 (GLP-2) was measured. Butyrate or inulin did not affect GLP-2, weight gain, apoptosis, intestinal injury scores, cecal or colon crypt depth, and jejunal or ileal villus height. For cell proliferation, there was a significant interaction between inulin, butyrate, and tissue (P = 0.007). Inulin modified the effect of butyrate (butyrate × inulin interaction in cecum, P = 0.001; in distal colon, P = 0.018; in ileum, P = 0.001; and in jejunum, P = 0.003). In the absence of inulin, butyrate caused a 78–119% increase in cell proliferation in the ileum, distal colon, jejunum, and cecum (P ≤ 0.002). Thus, at an entry rate into the colon within the physiological range, butyrate caused increased intestinal cell proliferation, but inulin tended to block this effect. Thus, intracolonic butyrate may enhance intestinal growth during infancy.

We have previously described the only reported case of human proprotein convertase 1 (PC1) deficiency, in a female (Subject A) with obesity, hypogonadism, hypoadrenalism, and reactive hypoglycemia. We now report the second case of human PC1 deficiency (Subject B), also due to compound heterozygosity for novel missense and nonsense mutations. While both subjects shared the phenotypes of obesity, hypoadrenalism, reactive hypoglycemia, and elevated circulating levels of certain prohormones, the clinical presentation of Subject B was dominated by severe refractory neonatal diarrhea, malabsorptive in type. Subsequent investigation of Subject A revealed marked small-intestinal absorptive dysfunction, which was not previously clinically suspected. We postulate that PC1, presumably in the enteroendocrine cells, is essential for the normal absorptive function of the human small intestine. The differences in the nature and severity of presentation between the two cases cannot readily be explained on the basis of allelic heterogeneity, as the nonsense and missense mutations from both subjects had comparably severe effects on the catalytic activity of PC1. Despite Subject A’s negligible PC1 activity, some mature ACTH and glucagon-like peptide 17-36amide were detectable in her plasma, suggesting that the production of these hormones, at least in humans, does not have an absolute dependence on PC1. The presence of severe obesity and the absence of growth retardation in both subjects contrast markedly with the phenotype of mice lacking PC1 and suggest that the precise physiological repertoire of this enzyme may vary between mammalian species.

GLP-1 is an insulinotropic hormone that synergistically with glucose gives rise to an increased insulin response. Its secretion is increased following a meal and it is thus of interest to describe the secretion of this hormone following an oral glucose tolerance test (OGTT). The aim of this study was to build a mechanism-based population model that describes the time course of total GLP-1 and provides indices for capability of secretion in each subject. The goal was thus to model the secretion of GLP-1, and not its effect on insulin production. Single 75 g doses of glucose were administered orally to a mixed group of subjects ranging from healthy volunteers to patients with type 2 diabetes (T2D). Glucose, insulin, and total GLP-1 concentrations were measured. Prior population data analysis on measurements of glucose and insulin were performed in order to estimate the glucose absorption rate. The individual estimates of absorption rate constants were used in the model for GLP-1 secretion. Estimation of parameters was performed using the FOCE method with interaction implemented in NONMEM VI. The final transit/indirect-response model obtained for GLP-1 production following an OGTT included two stimulation components (fast, slow) for the zero-order production rate. The fast stimulation was estimated to be faster than the glucose absorption rate, supporting the presence of a proximal–distal loop for fast secretion from L-cells. The fast component (st3 = 8.64·10−5 [mg−1]) was estimated to peak around 25 min after glucose ingestion, whereas the slower component (st4 = 26.2·10−5 [mg−1]) was estimated to peak around 100 min. Elimination of total GLP-1 was characterised by a first-order loss. The individual values of the early phase GLP-1 secretion parameter (st3) were correlated (r = 0.52) with the AUC(0–60 min.) for GLP-1. A mechanistic population model was successfully developed to describe total GLP-1 concentrations over time observed after an OGTT. The model provides indices related to different mechanisms of subject abilities to secrete GLP-1. The model provides a good basis to study influence of different demographic factors on these components, presented mainly by indices of the fast- and slow phases of GLP-1 response.

Background

We aimed to evaluate the effects of the G-allele of rs6232 and the C-allele of rs6235 within PCSK1 on measures of body fat and glucose homeostasis in Danish individuals and to assess interactions of genotypes with age, sex and glucose tolerance status. Data were included in meta-analyses of additional Europeans.

Methodology/Principal Findings

Rs6232 and rs6235 were genotyped in 6,164 Danes from the Inter99 study of middle-aged people. Results from these analyses were combined with previously published studies in meta-analyses of a total of 27,786 individuals. The impact of the variants was also investigated in a subset of 62 glucose-tolerant men during a meal challenge including measures of serum incretins. In men we found an effect on body composition in sex-stratified analyses where the rs6235 C-allele conferred an increased waist circumference of 0.8 cm per allele (0.2–1.5, p = 0.008) and increased waist-to-hip ratio of 0.004 (0.0005–0.008, p = 0.027). In the meta-analyses where men and women were combined, the rs6232 G-allele associated with increased waist-to-hip ratio (p = 0.02) and the rs6235 C-allele associated with increased waist circumference (p = 0.01). Furthermore, the rs6235 C-allele was associated nominally with a 0.6% (0.1–1%, p = 0.01) reduction in fasting glucose, it interacted with glucose tolerance status for traits related to glucose metabolism and analysis among individuals having abnormal glucose tolerance revealed a 5% (−0.7–9%, p = 0.02) elevated level of acute insulin response for this variant. Finally, we found that the rs6232 G-allele associated with higher levels of GLP-1, GLP-2 and glucagon and that the rs6235 C-allele associated with higher levels of GIP and glucagon during a meal-test.

Conclusions/Significance

PCSK1 rs6232 G-allele and rs6235 C-allele have an effect on body composition which may be modified by sex, whereas the effect of rs6235 C-allele on fasting and stimulated circulating plasma glucose and hormone levels may be influenced by glucose tolerance status.