Anticipated Preferred Drug List (PDL) - January 1, 2011 Drug classes not included on this list are not managed through a Preferred Drug List (PDL). HOWEVER, THIS EXCLUSION IS NOT A GUARANTEE OF PAYMENT OR COVERAGE. Dosage limits and other requirements may apply. Please refer to the Additional Therapeutic Criteria Chart, Dosage Limitation List, Epocrates, and the Wyoming EqualityCare Provider Manual at http://wyequalitycare.org for
Nfdx.smu.edu.cnSecretion of glucagon-like peptide-1 (GLP-1) in type 2diabetes: what is up, what is down? M. A. Nauck & I. Vardarli & C. F. Deacon & J. J. Holst &J. J. Meier Received: 3 April 2010 / Accepted: 30 July 2010 # Springer-Verlag 2010 Abstract The incretin hormones gastric inhibitory poly- the variations in published findings of group differences in peptide and especially glucagon-like peptide (GLP) have an GLP-1 responses to nutrient intake.
important physiological function in augmenting post-prandial insulin secretion. Since GLP-1 may play a role in Keywords Glucagon-like peptide-1 . Gut hormones .
the pathophysiology and treatment of type 2 diabetes, Incretin hormones . L-cell . Meta-analysis .
assessment of meal-related GLP-1 secretory responses in Pathophysiology . Review type 2 diabetic patients vs healthy individuals is of greatinterest. A common view states that GLP-1 secretion in patients with type 2 diabetes is deficient and that this Dipeptidyl peptidase applies to a lesser degree in individuals with impaired Gastric inhibitory polypeptide glucose tolerance. Such a deficiency is the rationale for Glucagon-like peptide replacing endogenous incretins with GLP-1 receptor agonists or re-normalising active GLP-1 concentrations with dipep-tidyl peptidase-4 inhibitors. This review summarises theliterature on this topic, including a meta-analysis of published studies on GLP-1 secretion in individuals with and withoutdiabetes after oral glucose and mixed meals. Our analysis Incretins are gut-derived hormones that can stimulate insulin does not support the contention of a generalised defect in secretion and make a significant contribution to overall nutrient-related GLP-1 secretory responses in type 2 diabetes postprandial insulin release One of them, glucagon- patients. Rather, factors are identified that may determine like peptide (GLP)-1, has glucose-lowering properties [ individual incretin secretory responses and explain some of and has been the basis of two novel classes of glucose-lowering agents, incretin mimetics (i.e. GLP-1 receptoragonists) and inhibitors of protease dipeptidyl peptidase M. A. Nauck (*) I. Vardarli (DPP)-4 (incretin enhancers) . Since the latter are Diabeteszentrum Bad Lauterberg, thought to exert their glucose-lowering activity by prevent- ing the degradation and inactivation (with regard to 37431 Bad Lauterberg im Harz, Germanye-mail: M.Nauck@diabeteszentrum.de insulinotropic effects) of endogenously released intact,biologically active GLP-1 , their pharmacological action C. F. Deacon : J. J. Holst should critically depend on availability of the major Department of Medical Physiology, Panum Institute, substrate, GLP-1. Against this background, reports that University of Copenhagen,Copenhagen, Denmark GLP-1 secretion from L-cells is reduced in patients withtype 2 diabetes  have prompted several hypotheses about how this affects the estimated clinical effectiveness of Medizinische Klinik I, St Josef-Hospital Bochum, these novel drugs. They have mainly been based on a study Ruhr-University Bochum,Bochum, Germany by Toft-Nielsen et al. [which reported an increase in ‘total' GLP-1 (all forms including intact GLP-1 [7-36 The main meal components that act as potent stimulants of amide] and the DPP-4-degraded, non-insulinotropic form GLP-1 secretion are glucose [and triacylglycerol [ GLP-1 [9-36 amide]) from basal levels of around 5 pmol/l but fructose and some proteins are also effective. Oral to mean values of about 16 to 17 pmol/l in 33 healthy glucose is a good stimulus for the release of GLP-1, participants and 13 to 14 pmol/l in 54 type 2 diabetic whereas plasma GLP-1 concentrations do not change when patients, both after 60 min. In the second hour, peak GLP- glucose is administered intravenously, i.e. by bypassing 1 concentrations were maintained in healthy participants, absorptive processes in the gut , ]. Typically, ‘total' but returned to lower levels in type 2 diabetic patients.
GLP-1 concentrations are between 5 and 15 pmol/l in the Overall, this resulted in a 53% reduction in integrated basal state, rising to between 20 and 60 pmol/l after oral incremental GLP-1 concentrations (AUC above baseline) glucose or meals .
in type 2 diabetic patients relative to healthy controls and a The temporal pattern of nutrient intake-related increments 19% reduction in the total AUC (above 0 pmol/l). These in plasma GLP-1 begins with a rather early rise (starting differences were highly significant. Participants with approximately 10 to 15 min after eating , peaks during impaired oral glucose tolerance ranked between healthy the second hour and then slowly declines to baseline over volunteers and type 2 diabetic patients and thus had an several hours. Some studies suggest a biphasic pattern, with intermediate GLP-1 response. Based on this largest an early peak followed by a nadir and a second rise in GLP-1 available cross-sectional study comparing GLP-1 release concentrations but other studies in humans tend to in type 2 diabetic patients and healthy controls, it has describe monophasic secretory responses , ].
specifically been pointed out that: The intracellular events leading to L-cell secretion have been reviewed in detail ]. Novel components of L-cells 1. Slightly reduced GLP-1 concentrations after a meal in that are involved in nutrient sensing are sweet taste participants with impaired oral glucose tolerance and receptors and the G-protein gustducin [as well as more severely impaired GLP-1 secretion in type 2 NEFA receptors or their modifications such as G-protein- diabetic patients, as demonstrated in cross-sectional coupled receptor (GPR) 119 [GPR 120 [and analyses, may translate into a progressive loss of the perhaps GPR 40 [GPR 119 and 120 are rather specific ability to secrete GLP-1 with advancing type 2 diabetes for long-chain monounsaturated NEFA such as α-linolenic as part of the process of disease progression.
acid. It is not known whether GPR 119 and/or 120 are 2. This loss of GLP-1 secretion is part of the pathophysio- located to the luminal (brush border) membrane, which is logical explanation for a lost incretin effect , a primarily involved in sensing NEFA in chymus, or to the phenomenon typically observed in patients with type 2 baso-lateral membrane, where they would be exposed to interstitial fluid more similar in composition to plasma 3. The above point (2) provides evidence that loss of GLP-1 secretion with immediate pathophysiological consequen-ces (reduced incretin effect as part of impaired postpran-dial beta cell function) calls for a replacement therapy Where in the gut is GLP-1 released? with incretin-based glucose-lowering medications 4. Based on such reasoning, DPP-4 inhibitors cannot be Especially the predominant location of L-cells in the distal expected [, ] to lower blood glucose in later stages of parts of the gut [has prompted hypotheses about the type 2 diabetes (because of lost ability to secrete GLP-1).
early increase in GLP-1 concentrations immediately after This review aims to put these hypotheses into perspective starting a meal [, ]. It has been difficult to with the available data on GLP-1 release in healthy and type understand how L-cells in the distal ileum can be exposed 2 diabetic participants, and to address common differences of to nutrients minutes after their ingestion [Measurement opinion and some potential misconceptions in the inter- of plasma concentration profiles after nutrient ingestion (e.g.
pretation of commonly quoted landmark publications.
Fig. with the early phase being the consequence ofpotential indirect mechanisms, followed by a later phase ofdirect stimulation, when gut contents have travelled to Mechanisms of L-cell GLP-1 secretion distal parts of the intestines) have not accumulated muchevidence in favour of a biphasic GLP-1 response in human Physiologically, L-cells, which are most common in the participants. Nevertheless, some indirect mechanisms have distal parts of the intestines ], are stimulated to secrete been proposed. These potential pathways include ‘upper- all their secretory products (GLP-1, GLP-2, gut-derived gut signals', i.e. stimulation of the autonomous nervous glucagon [also called glicentin], peptide tyrosine tyrosine, system –as well as endocrine transmission through oxyntomodulin) in response to nutrient ingestion .
gastrointestinal hormones , ], both of which may
Fig. 1 The L-cell with compo- nents that may be involved intriggering or modulating GLP-1secretion. The primary process leading to release of preformedsecretory granules may start with the absorption of glucose neuropeptides (e.g. GRP) through glucose transporters inmicrovilli of the luminal (brush border) membrane.
Additional signals are sweet taste receptors, receptors forNEFA, neurotransmitters peptide, others), gastrointestinalhormones (GIP) and glucagon.
GPR 120 (GPR 119, GPR 40; For details, see text. Glc, glucose Long-chain unsaturated NEFA(e.g. α-linolenic acid) Sweet taste receptor Glc (binding?) Na+ Glc be activated when appropriate nutrients enter the duodenum a rise in GLP-1 concentrations in human participants with or upper jejunum. Along these lines, gastric inhibitory ] and without  type 2 diabetes. Neurotransmitters polypeptide (GIP) triggers release of GLP-1 from cell lines such as acetylcholine , and gastrin-releasing resembling L-cells and in animal experiments (rodents) ].
peptide ] also trigger GLP-1 release, suggesting the However, even high doses of exogenous GIP do not lead to intramural enteric nervous system is involved in mediating the 85 104 189 Type 2 diabetes Integrated incremental GLP-1 -60 134 83 217 Healthy controls              Studies [reference number] Fig. 2 Integrated responses of ‘total' GLP to oral glucose or mixed tolerance test (75 g) and/or after a standardised mixed meal. Two meals based on individual studies (a) reporting integrated incremental independent authors (M. Nauck and I. Vardarli) examined the studies ‘total' GLP-1 responses in patients with type 2 diabetes and an and extracted data. We included nine studies with 13 datasets and 406 appropriate control group (weight-matched, non-diabetic participants) participants (189 patients with type 2 diabetes, 217 healthy controls) in and using non-specific assays that measured intact and DPP-4-degraded the meta-analysis. Data from studies using early, non-specific assays forms of GLP-1. The response in type 2 diabetic patients (mean ± SEM) that would cross-react with the major proglucagon fragment ] is expressed as percentage of the mean value in the control group.
were excluded. As effect size, we used the mean difference. Pooled *p<0.05 vs control. Numbers in bars indicate number of type 2 diabetic estimates were obtained using the DerSimonian and Laird random patients (upper row) and control participants (lower row) studied.
effects model. The pooled estimates of the mean difference of integrated Studies are indicated by reference number, i.e. , , incremental plasma concentrations of GLP-1 between patients with type 72]. a0–20 min, b20–120 min, c0–30 min, d30–180 min. b For 2 diabetes and healthy controls are shown. After an oral glucose the meta-analysis, electronic databases (PubMed and EMBASE) were challenge as well as after a mixed meal test, the integrated incremental searched (until 28 February 2010) for studies dealing with the secretion plasma concentrations of GLP-1 were not significantly different and providing integrated incremental responses of GLP-1 in healthy between patients with type 2 diabetes and controls (p=0.44). Light participants and patients with type 2 diabetes after an oral glucose blue, oral glucose; dark blue, mixed meal ‘upper gut signal'. In a recent study, GLP-1 release triggered probably related to the use of side-viewing antibodies, by oleate was attenuated by a cholecystokinin type 1 receptor which also detect the major proglucagon fragment [ More recent studies have described either no abnormalities However, gut resections at any level of the small or large at all in oral glucose-induced GLP-1 secretion or GLP-1 intestines do not typically lead to reduced GLP-1 secretion hyposecretion (Fig. Meal-induced GLP-1 responses ]. This may indicate that the release of GLP-1 occurs were significantly reduced in the above-mentioned largest primarily from L-cells immediately exposed to ingested cross-sectional study [by Toft-Nielsen et al. and more nutrients (i.e. L-cells in the upper parts of the small intestine), similar to those found in healthy participants in some other, rather than from those parts of the gut where the majority of smaller studies (Fig. ). The second-largest recent study, by L-cells are located (i.e. the ileum and large intestine) Vollmer et al. ], found no impairment in mixed meal- In fact, L-cells have also been identified in the duodenum induced GLP-1 secretion. The bottom line suggests that there and certainly in the jejunum with the respective is some variation in GLP-1 secretion and that in some cohorts, numbers increasing aborally towards the ileum and colon/ on balance, the GLP-1 response is somewhat reduced, whereas rectum . It has been estimated that the amount of GLP-1 in other studies such differences are not as apparent (Fig. ).
secreted after ingestion of a single nutrient load (calculated Since in some of the studies analysed type 2 diabetic as integrated incremental response multiplied by the known patients were treated with metformin, which has been metabolic clearance rate for GLP-1) accounts for about 10 % shown to enhance GLP-1 responses [any potential of the GLP-1 content of jejunal L-cells [A second difference in GLP-1 secretory responses between type 2 argument in favour of direct stimulation of upper-gut L-cells diabetic patients and healthy participants may have been is the observation that the release of GIP is closely related to modified by this mechanism.
that of GLP-1, even at an intra-individual level, indicating In the absence of a more general difference in GLP-1 that some individuals have a poor response of GIP and secretory responses between type 2 diabetic patients and GLP-1, and others have average or higher release of both healthy participants, we have attempted to identify participant/ incretin hormones Consistent with this observation, a patient characteristics that would determine individual GLP-1 subset of entero-endocrine cells has been shown to co- responses: Fig. shows univariate regression analysis for express GIP and the proglucagon gene, suggesting concom- GLP-1 secretory responses after oral glucose ingestion, from itant secretion of both incretin hormones from such cells .
which responses appear to be predicted by baseline Further evidence for immediate secretion of GLP-1 from characteristics such as age, body weight (obesity), fasting L-cells in the proximal gut comes from work by Schirra et NEFA concentrations and fasting glucagon concentrations.
al. [in which GIP and GLP-1 secretion was determined Similar relationships can be found for mixed meal-induced in relation to the gastro-duodenal transit of nutrients. These GLP-1 secretory responses and for GIP secretion (details studies revealed a rapid onset of GIP and GLP-1 secretion not shown) in relation to baseline characteristics. As shown after ingestion of oral glucose, along with high rates of in Table , most of the individual factors found to be nutrients passing into the duodenum. Interestingly, the significantly related to GLP-1 secretory responses in uni- nutrient flow rates required to sustain stimulated secretion variate analyses remained significant in a multivariate of incretin hormones were far higher for GLP-1 (6 kJ/min) analysis, with similar results for GLP-1 responses induced than for GIP (<1 kJ/min) [This suggests that the by oral glucose or mixed meal ingestion. Some relationship velocity of transpyloric gastric content movement required between obesity and GLP-1 secretion has been noted before to stimulate K-cells in the duodenum is lower than that , Exogenous glucagon has been found to be required to stimulate L-cells at a more distal location (i.e. at associated with suppressed GLP-1 secretion although least the proximal jejunum or further down), where in the isolated, perfused gut no such interaction was apparent significant numbers of L-cells can be found ]. On the The fact that variables related to obesity no longer basis of the evidence available, we hypothesise that direct showed a strongly significant correlation in the multivariate stimulation of the more proximal L-cells is the predominant analysis (Table may be related to the influence of mechanism. However, the relative contributions of direct associated factors, e.g. elevated NEFA concentrations.
and indirect mechanisms prompting secretion of GLP-1 in Certainly, hyperglycaemia (or oral glucose tolerance) did humans remain to be fully elucidated.
not turn out to be a strong predictor of GLP-1 secretion,suggesting that other characteristics of type 2 diabeticpatients not represented by elevated glucose concentrations GLP-1 secretion in patients with type 2 diabetes in the fasting or postprandial state may determine GLP-1secretion, although opinions differ ]; insulin resistance, GLP-1 hypersecretion was described in some early studies moreover, has also been described as a factor impairing , ] in response to the ingestion of oral glucose,
Fig. 3 Univariate correlation of BMI (a), age (b), fasting glucagon (c) and NEFA (d) to integrated incremental responses of GLP-1 following ingestion of a mixed meal in participants with normal oral glucosetolerance (green symbols, n=14), impaired oral glucose tolerance (blue symbols, n=17) and type 2 diabetes (red symbols, n=17). Data were re-analysed from Vollmer et al.
Integrated incremental GLP-1 Integrated incremental GLP-1 . a r2=0.037, p=0.19; b r2=0.066, p=0.079; c r2= 0.142, p=0.0082; d r2=0.081, Integrated incremental GLP-1 Integrated incremental GLP-1 Fasting glucagon (pmol/l) Fasting NEFA (mmol/l) Factors that determine GLP-1 secretion give an indication described by multivariate regression analysis (Table why some studies found differences in GLP-1 secretory These associations, however, may only be valid in relatively responses between type 2 diabetic patients and healthy well controlled patients with type 2 diabetes, in whom controls, while others did not. These interdependences are glucose-lowering treatment is administered as usual when illustrated in Table Type 2 diabetic cohorts, especially if the nutrient stimulation to trigger GLP-1 release is performed.
not perfectly matched to healthy participants, will tend to be The mechanism driving glucagon-induced suppression older, more obese and exhibit hyperglucagonaemia as well of GLP-1 secretion has yet to be determined. Since GLP-1 as elevated fasting NEFA levels. Some of these factors is known to reduce glucagon [a reverse association predict lower GLP-1 responses (higher weight or BMI, and may apply. Alternatively, a third, unknown factor may high glucagon concentrations), while others are determi- influence GLP-1 secretion and glucagon, explaining this nants of enhanced GLP-1 secretion (older age, higher association. A link between glucagon and GLP-1 secretion fasting NEFA concentrations). Therefore, the ability to has recently been confirmed . Nevertheless, open predict ‘normal' or impaired GLP-1 response in patients questions remain. Can, for example, a direct effect be with type 2 diabetes will depend on the individual balance mediated by glucagon receptors on L-cells? Do motility of these factors as well as the rate of gastric emptying. The effects contribute to a reduction of GLP-1 secretion, e.g. by same reasoning can be applied to reported studies. Thus slowing antro-duodenal transit of nutrients? Since approx- Toft-Nielsen et al. [studied healthy and type 2 diabetic imately 40% of type 2 diabetic patients can be expected to participants with similar fasting NEFA concentrations, but have delayed gastric emptying, how does this affect GLP-1 differences in glucagon levels. Otherwise (age, BMI) their secretion? Does autonomous neuropathy ] play a role in participants were well matched, meaning that the overall this context? Is the influence of NEFA or similar ligands balance was shifted towards reduced GLP-1 secretion. In mediated by GPR 119, 120 or 40? Does this indicate that our recent study, type 2 diabetic patients had high NEFA these receptors are located on the basolateral membrane, concentrations as well as hyperglucagonaemia, the influen- thereby being accessible and responsive to changes in ces of which may have balanced each other out, resulting in circulating concentrations of NEFA? Are the NEFA that no net difference in GLP-1 secretory responses ]. These activate GPR 120 receptors the same ones that stimulate analyses further strengthen the credibility of the associations GLP-1 secretion, e.g. long-chain monounsaturated NEFA? Table 1 Multiple regression analysis of potential determinants of inhibitors to prevent rapid digestion of starch and complex GLP-1 secretion after oral glucose loads or mixed meals carbohydrates, thereby moving intestinal contents downwards and resulting in preferential digestion and absorption in the lower jejunum or ileum, where L-cells are most prevalent. Inhealthy participants receiving test meals composed of sucrose GLP-1 after oral glucosea and acarbose or voglibose, this approach was highly effective, Glucose toleranceb whereas in studies more realistically copying the ingestion of meals in patients with type 2 diabetes, the effects were rather small or completely negligible [This may be Glucagon (pmol/l) different with second-generation α-glucosidase inhibitors such as voglibose and miglitol ].
Recently, metformin was seen to lead to higher meal- GLP-1 after a mixed mealc related increments in total and intact GLP-1, indicating a Glucose tolerancea stimulation of GLP-1 secretion. Moreover, when metformin was combined with a DPP-4 inhibitor, concentrations of intact GLP-1 were increased beyond those observed with Glucagon (pmol/l) the DPP-4 inhibitor alone ]. The effects of metformin are compatible with previous results from animal studies with metformin and other biguanide drugs Themechanism by which metformin augments GLP-1 res- Integrated incremental GLP-1 responses were determined using methods ponses is not entirely clear.
for determining ‘total' GLP-1 concentrations (including DPP-4 break-down products) Certainly, there still is a lack of strategies to augment secretion of endogenous GLP-1 through dietary measures B and ß are the non-standardised and standardised regressioncoefficients, respectively, both displayed with their respective standard or with drugs specifically designed to stimulate L-cell error (SE); data were re-analysed from Vollmer et al.  secretion. We expect this to be an active area of research in Calculations: Statistica 5.0, StatSoft, Hamburg, Germany the near future.
a For the analysis of GLP-1 after oral glucose, the correlation coefficientsquared (R2) was 0.784, the corrected R2 was 0.753 and the F value with6 and 42 degrees of freedom was 25.4, for a p value <0.0001b Glucose tolerance was entered as the continuous variable glucose concentration 120 min after 75 g oral glucosec First, it is too early to conclude that advancing type 2 For the analysis of GLP-1 after oral glucose, the correlation coefficient squared (R2) was 0.767, the corrected R2 was 0.734 and the F value with diabetes is characterised by a progressive loss of the 6 and 42 degrees of freedom was 23.1, for a p value <0.0001 potential to secrete GLP-1 as part of the process of diseaseprogression. To draw such a conclusion, we need studies Can dietary manipulations be derived from such knowledge that longitudinally assess GLP-1 secretion in cohorts of that would help sustain meal-related endogenous release of prediabetic participants followed until diagnosis of type 2 GLP-1, especially in patients treated with DPP-4 inhibitors? Table 2 Typical characteristics in type 2 diabetic patients and theirconsequences for GLP-1 secretion based on univariate and multivar- Augmenting L-cell GLP-1 secretion iate regression analysis of factors determining GLP-1 responsesassessed from previously reported dataa By doubling meal-related responses of intact, biologically Typical consequences active GLP-1, DPP-4 inhibitors exert profound effects onglycaemic control in patients with type 2 diabetes; indeed, In type 2 diabetes For GLP-1 secretion any augmentation of GLP-1 responses would probably be welcome and could help control glycaemia in patients with type 2 diabetes.
Single dietary interventions have met with partial success.
For example, protein preloads ] or large quantities of Overall individual balance ≈ or ↓ or ↑ single amino acids (glutamine) ] have been used to elicithigher GLP-1 responses by enhancing GLP-1 secretion.
a Vollmer et al.  The fact that the majority of L-cells are located distally in b Influence of body weight was significant upon univariate (Fig. ), the small intestine has prompted attempts to use α-glucosidase but not multiple regression analysis (Table diabetes and through progression over the following years.
4. Meier JJ, Nauck MA (2004) The potential role of glucagon-like peptide 1 in diabetes. Curr Opin Investig Drugs 5:402–410 Current data allow hypotheses, but not predictions of the 5. Nauck MA, Meier JJ, Creutzfeldt W (2003) Incretins and their results of such a study.
analogues as new antidiabetic agents. Drug News Perspect Second, small differences in GLP-1 concentrations within physiological limits are not sufficient to affect 6. Nauck MA, Meier JJ (2005) Glucagon-like peptide 1 (GLP-1) and its derivatives in the treatment of diabetes. Regul Pept 124 insulin secretion. Physiological replacement of GLP-1 by exogenous administration had little effect, but this may 7. Deacon CF, Holst JJ (2006) Dipeptidyl peptidase IV inhibitors: a underestimate the role of endogenous GLP-1 for insulin promising new therapeutic approach for the management of type 2 secretion, because intravenous administration bypasses diabetes. Int J Biochem Cell Biol 38:831–844 important hepato-portal sensors for GLP-1 [Certainly, 8. Åhren B (2007) DPP-4 inhibitors. Best Pract Res Clin Endocrinol Metab 21:517–533 differences during the second and third hour after meal 9. Holst JJ, Deacon CF (2005) Glucagon-like peptide-1 mediates the stimulation as reported by Toft-Nielsen et al. ] do not therapeutic actions of DPP-IV inhibitors. Diabetologia 48:612– help to explain any of the important differences in early- phase insulin secretion that are typical of type 2 diabetes 10. Toft-Nielsen MB, Madsbad S, Holst JJ (2001) Determinants of the effectiveness of glucagon-like peptide-1 in type 2 diabetes. J Clin (and are found in the first 30 to 60 min after meal ingestion Endocrinol Metab 86:3853–3860 begins). The reduced incretin effect in type 2 diabetic 11. Lugari R, Dei Cas A, Ugolotti D et al (2002) Evidence for early patients is much more closely related to the losses in impairment of glucagon-like peptide 1-induced insulin secretion in insulinotropic activity of GIP, which are typical of this human type 2 (non insulin-dependent) diabetes. Horm Metab Res34:150–154 condition, and less so to those related to GLP-1 ].
12. Toft-Nielsen MB, Damholt MB, Madsbad S et al (2001) Third, and for the same reason(s), any observed deficit in Determinants of the impaired secretion of glucagon-like peptide- GLP-1 responses after meals does not simply call for a 1 in type 2 diabetic patients. J Clin Endocrinol Metab 86:3717– ‘true' replacement therapy with incretin-based glucose- 13. Nauck M, Stöckmann F, Ebert R, Creutzfeldt W (1986) Reduced lowering medications. Incretin mimetics provide a pharma- incretin effect in type 2 (non-insulin-dependent) diabetes. Diabetologia cological stimulus to insulin secretion and elicit other GLP- 1-receptor-mediated activity as drugs, but are typically 14. Knop FK, Vilsbøll T, Højberg PV et al (2007) Reduced incretin introduced at much higher concentrations compared with effect in type 2 diabetes: cause or consequence of the diabeticstate? Diabetes 56:1951–1959 physiological levels of GLP-1 , 15. Eissele R, Göke R, Willemer S et al (1992) Glucagon-like Finally, and as a consequence of the above, DPP-4 peptide-1 cells in the gastrointestinal tract and pancreas of rat, inhibitors can exert their clinical effects even in advanced pig and man. Eur J Clin Invest 22:283–291 stages of type 2 diabetes. This condition is not in itself 16. Kreymann B, Williams G, Ghatei MA, Bloom SR (1987) Glucagon-like peptide-1 [7-36]: a physiological incretin in man.
characterised by reduced meal-induced GLP-1 concentra- Lancet 2:1300–1304 tions that are too low to be effective, as supported by recent 17. Ørskov C, Knuhtsen S, Baldissera FG, Poulsen SS, Nielsen OV, Holst JJ (1986) Glucagon-like peptides GLP-1 and GLP-2, In conclusion, while reduced GLP-1 levels have been predicted products of the glucagon gene, are secreted separatelyfrom pig small intestine but not pancreas. Endocrinology described individually in some participants as well as in groups with type 2 diabetes mellitus, this does not seem to be 18. Ørskov C, Jeppesen J, Madsbad S, Holst JJ (1991) Proglucagon a universal characteristic that is representative of all patients.
products in plasma of noninsulin-dependent diabetics and non-diabetic controls in the fasting state and after oral glucose andintravenous arginine. J Clin Invest 87:415–423 We thank K. Vollmer, Ruhr-University 19. D'Alessio D, Thirlby R, Laschansky E, Zebroski H, Ensinck J Bochum, Germany, for providing original data from her study (1993) Response of tGLP-1 to nutrients in humans. Digestion (Vollmer et al. ) for further analysis.
20. Nauck MA, El-Ouaghlidi A, Gabrys B et al (2004) Secretion of Duality of interest The authors declare that there is no duality of incretin hormones (GIP and GLP-1) and incretin effect after oral interest associated with this manuscript.
glucose in first-degree relatives of patients with type 2 diabetes.
Regul Pept 122:209–217 21. Ørskov C, Rabenhøj L, Wettergren A, Kofod H, Holst JJ (1994) Tissue and plasma concentrations of amidated and glycine- extended glucagon-like peptide 1 in humans. Diabetes 43:535–539 1. Creutzfeldt W, Nauck M (1992) Gut hormones and diabetes 22. Åhren B, Holst JJ (2001) The cephalic insulin response to meal mellitus. Diabetes/Metab Rev 8:149–177 ingestion in humans is dependent on both cholinergic and 2. Holst JJ, Ørskov C (2001) Incretin hormones—an update. Scand J noncholinergic mechanisms and is important for postprandial Clin Lab Invest 234(suppl):75–85 glycemia. Diabetes 50:1030–1038 3. Drucker DJ, Nauck MA (2006) The incretin system: glucagon-like 23. Rask E, Olsson T, Soderberg S et al (2001) Impaired incretin peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors response after a mixed meal is associated with insulin resistance in in type 2 diabetes. Lancet 368:1696–1705 nondiabetic men. Diabetes Care 24:1640–1645 24. Vilsbøll T, Krarup T, Deacon CF, Madsbad S, Holst JJ (2001) GLP-1 and GIP. Am J Physiol (Endocrinol Metab) 290:E 550– Reduced postprandial concentrations of intact biologically active glucagon-like peptide 1 in type 2 diabetic patients. Diabetes 45. Mortensen K, Petersen LL, Orskov C (2000) Colocalization of GLP-1 and GIP in human and porcine intestine. Ann N Y Acad 25. Vollmer K, Holst JJ, Baller B et al (2008) Predictors of incretin Sci 921:469–472 concentrations in subjects with normal, impaired, and diabetic 46. Nauck MA, Holst JJ, Willms B, Schmiegel W (1997) Glucagon- glucose tolerance. Diabetes 57:678–687 like peptide 1 (GLP-1) as a new therapeutic approach for type 2- 26. Reimann F (2006) GLP-1. Diabetes 5(suppl 1):S 78–85 diabetes. Exp Clin Endocrinol Diabetes 105:187–195 27. Jang HJ, Kokrashvili Z, Theodorakis MJ et al (2007) Gut-expressed 47. Schirra J, Katschinski M, Weidmann C et al (1996) Gastric gustducin and taste receptors regulate secretion of glucagon-like emptying and release of incretin hormones after glucose ingestion peptide-1. Proc Natl Acad Sci USA 104:15069–15074 in humans. J Clin Invest 97:92–103 28. Lauffer LM, Iakoubov R, Brubaker PL (2009) GPR119 is essential 48. Miholic J, Ørskov C, Holst JJ, Kotzerke J, Meyer HJ (1991) for oleoylethanolamide-induced glucagon-like peptide-1 secretion Emptying of the gastric substitute, glucagon-like peptide-1 (GLP-1), from the intestinal enteroendocrine L-cell. Diabetes 58:1058–1066 and reactive hypoglycemia after total gastrectomy. Dig Dis Sci 29. Hirasawa A, Tsumaya K, Awaji T et al (2005) Free fatty acids regulate gut incretin glucagon-like peptide-1 secretion through 49. Fukase N, Takahashi H, Manaka H et al (1992) Differences in GPR120. Nat Med 11:90–94 glucagon-like peptide-1 and GIP responses following sucrose 30. Zhao X, Cui YM, Zhou Y et al (2008) Exenatide pharmacokinetics ingestion. Diabetes Res Clin Pract 15:187–195 in healthy Chinese subjects. Int J Clin Pharmacol Ther 46:459–465 50. Patzelt C, Schiltz E (1984) Conversion of proglucagon in 31. Gray GM (1970) Carbohydrate digestion and absorption. Gastro- pancreatic alpha cells: the major endproducts are glucagon and a enterol 58:96–107 single peptide, the major proglucagon fragment, that contains two 32. Herrmann-Rinke C, Vöge A, Hess M, Göke B (1995) Regulation glucagon-like sequences. Proc Natl Acad Sci USA 81:5007–5011 of glucagon-like peptide-1 secretion from rat ileum by neuro- 51. Migoya E, Miller J, Luo W-L et al (2010) Sitagliptin and metformin transmitters and peptides. J Endocrinol 147:25–31 increase active GLP-1 by complementary mechanisms in treatment- 33. Brubaker PL (1991) Regulation of intestinal proglucagon-derived naïve patients with type 2 diabetes. Diabetes 59(suppl 1):A 156 peptide secretion by intestinal regulatory peptides. Endocrinol 52. Ranganath LR, Beety LM, Morgan LM, Wright JW, Howland R, Marks V (1996) Attenuated GLP-1 secretion in obesity: cause or 34. Rocca AS, Brubaker PL (1999) Role of the vagus nerve in consequence? Gut 38:916–919 mediating proximal nutrient-induced glucagon-like peptide-1 53. Hansen L, Hartmann B, Mineo H, Holst JJ (2004) Glucagon-like secretion. Endocrinology 140:1687–1694 peptide-1 secretion is influenced by perfusate glucose concentra- 35. Anini Y, Brubaker PL (2003) Muscarinic receptors control tion and by a feedback mechanism involving somatostatin in glucagon-like peptide 1 secretion by human endocrine L cells.
isolated perfused porcine ileum. Regul Pept 118:11–18 54. Muscelli E, Mari A, Casolaro A et al (2008) Separate impact of 36. Roberge JN, Brubaker PL (1993) Regulation of intestinal obesity and glucose tolerance on the incretin effect in normal proglucagon-derived peptide secretion by glucose-dependent subjects and type 2 diabetic patients. Diabetes 57:1340–1348 insulinotropic peptide in a novel enteroendocrine loop. Endocri- 55. Nauck MA, Kleine N, Ørskov C, Holst JJ, Willms B, Creutzfeldt W nology 133:233–240 (1993) Normalization of fasting hyperglycaemia by exogenous 37. Roberge JN, Gronau KA, Brubaker PL (1996) Gastrin-releasing glucagon-like peptide 1 (7-36 amide) in type 2 (non-insulin- peptide is a novel mediator of proximal nutrient-induced proglucagon- dependent) diabetic patients. Diabetologia 36:741–744 derived peptide secretion from the distal gut. Endocrinology 137: 56. Meier JJ, Ritter PR, Jacob A et al (2010) Impact of exogenous hyperglucagonemia on postprandial concentrations of gastric 38. Nauck MA, Heimesaat MM, Ørskov C, Holst JJ, Ebert R, inhibitory polypeptide and glucagon-like peptide-1 in humans.
Creutzfeldt W (1993) Preserved incretin activity of glucagon- J Clin Endocrinol Metab 95:4061–4065 like peptide 1 [7-36 amide] but not of synthetic human gastric 57. Ma J, Stevens JE, Cukier K et al (2009) Effects of a protein inhibitory polypeptide in patients with type-2 diabetes mellitus.
preload on gastric emptying, glycemia, and gut hormones after a J Clin Invest 91:301–307 carbohydrate meal in diet-controlled type 2 diabetes. Diabetes 39. Fieseler P, Bridenbaugh S, Nustede R et al (1995) Physiological Care 32:1600–1602 augmentation of amino acid-induced insulin secretion by GIP and 58. Greenfield JR, Farooqi IS, Keogh JM et al (2009) Oral glutamine GLP-I but not by CCK-8. Am J Physiol (Endocrinol Metab) 268: increases circulating glucagon-like peptide 1, glucagon, and insulin concentrations in lean, obese, and type 2 diabetic subjects.
40. Balks HJ, Holst JJ, von zur Mühlen A, Brabant G (1997) Rapid Am J Clin Nutr 89:106–113 oscillations in plasma glucagon-like peptide-1 (GLP-1) in 59. Seifarth C, Bergmann J, Holst JJ, Ritzel R, Schmiegel W, Nauck MA humans: cholinergic control of GLP-1 secretion via muscarinic (1998) Prolonged and enhanced secretion of glucagon-like peptide 1 receptors. J Clin Endocrinol Metab 82:786–790 (7-36 amide) after oral sucrose due to alpha-glucosidase inhibi- 41. Beglinger S, Drewe J, Schirra J, Göke B, D'Amato M, Beglinger C tion (acarbose) in type 2 diabetic patients. Diabet Med 15:485– (2010) Role of fat hydrolysis in regulating glucagon-like peptide-1 secretion. J Clin Endocrinol Metab 95:879–886 60. Göke B, Fuder H, Wieckhorst G et al (1995) Voglibose (AO-128) 42. Nauck MA, Siemsglüß J, Ørskov C, Holst JJ (1996) Release of is an efficient alpha-glucosidase inhibitor and mobilizes the glucagon-like peptide 1 (GLP-1 [7-36 amide]), gastric inhibitory endogenous GLP-1 reserve. Digestion 56:493–501 polypeptide (GIP) and insulin in response to oral glucose after 61. Lee A, Patrick P, Wishart J, Horowitz M, Morley JE (2002) The upper and lower intestinal resections. Z Gastroenterol 34:159–166 effects of miglitol on glucagon-like peptide-1 secretion and 43. Hansen L, Lampert S, Mineo H, Holst JJ (2004) Neural regulation appetite sensations in obese type 2 diabetics. Diabetes Obes of glucagon-like peptide-1 secretion in pigs. Am J Physiol Metab 4:329–335 (Endocrinol Metab) 287:E 939–947 62. Yasuda N, Inoue T, Nagakura T et al (2002) Enhanced secretion of 44. Theodorakis MJ, Carlson O, Michopoulos S et al (2006) Human glucagon-like peptide 1 by biguanide compounds. Biochem duodenal enteroendocrine cells: source of both incretin peptides, Biophys Res Commun 298:779–784 63. Burcelin R, Da Costa A, Drucker D, Thorens B (2001) Glucose vildagliptin added to insulin in patients with type 2 diabetes competence of the hepatoportal vein sensor requires the presence mellitus. Horm Metab Res 40:427–430 of an activated glucagon-like peptide-1 receptor. Diabetes 68. Vilsbøll T, Krarup T, Sonne J et al (2003) Incretin secretion in relation to meal size and body weight in healthy subjects and 64. Kjems LL, Holst JJ, Vølund A, Madsbad S (2003) The influence people with type 1 and type 2 diabetes mellitus. J Clin Endocrinol of GLP-1 on glucose-stimulated insulin secretion: effects on beta- Metab 88:2706–2713 cell sensitivity in type 2 and nondiabetic subjects. Diabetes 69. Ryskjaer J, Deacon CF, Carr RD et al (2006) Plasma dipeptidyl peptidase-IV activity in patients with type-2 diabetes mellitus 65. Kolterman OG, Kim DD, Shen L et al (2005) Pharmacoki- correlates positively with HbA1c levels, but is not acutely affected netics, pharmacodynamics, and safety of exenatide in patients by food intake. Eur J Endocrinol 155:485–493 with type 2 diabetes mellitus. Am Health Syst Pharm 62:173– 70. Salinari S, Bertuzzi A, Asnaghi S, Guidone C, Manco M, Mingrone G (2009) First-phase insulin secretion restoration and 66. Elbrønd B, Jakobsen G, Larsen S et al (2002) Pharmacokinetics, differential response to glucose load depending on the route of pharmacodynamics, safety, and tolerability of a single-dose of administration in type 2 diabetic subjects after bariatric surgery.
NN2211, a long-acting glucagon-like peptide 1 derivative, in Diabetes Care 32:375–380 healthy male subjects. Diabetes Care 25:1398–1404 71. Fukase N, Igarashi M, Takahashi H et al (1993) Hypersecretion of 67. Fonseca V, Baron M, Shao Q, Dejager S (2008) Sustained efficacy truncated glucagon-like peptide-1 and gastric inhibitory polypep- and reduced hypoglycemia during one year of treatment with tide in obese patients. Diabet Med 10:44–49
Sankt Marien-Hospital Buer Liebe Patientin, lieber Patient Wichtiger Hinweis zu Medikamenten Kleidung, die nutzt Sie haben eine ausgeprägte Arthrose, das heißt einen Lesen Sie bitte den dieser Information beigefügten Bitte bringen Sie zur stationären Aufnahme festes starken Gelenkverschleiß! Auch nach Ausschöp-