The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes

I read this book the same weekend that the Packers took on the Rams, and the experience of the latter event, obviously, colored my judgment. Although I abhor anything that smacks of being a handbook (like, \"How to Earn a Merit Badge in Neurosurgery\") because too many volumes in biomedical science already evince a boyscout-like approach, I must confess that parts of this volume are fast, scholarly, and significant, with certain reservations. I like parts of this well-illustrated book because Dr. Sj6strand, without so stating, develops certain subjects on technique in relation to the acquisition of judgment and sophistication. And this is important! So, given that the author (like all of us) is somewhat deficient in some areas, and biased in others, the book is still valuable if the uninitiated reader swallows it in a general fashion, realizing full well that what will be required from the reader is a modulation to fit his vision, propreception, adaptation and response, and the kind of problem he is undertaking. A major deficiency of this book is revealed by comparison of its use of physics and of chemistry to provide understanding and background for the application of high resolution electron microscopy to problems in biology. Since the volume is keyed to high resolution electron microscopy, which is a sophisticated form of structural analysis, but really morphology in a modern guise, the physical and mechanical background of The instrument and its ancillary tools are simply and well presented. The potential use of chemical or cytochemical information as it relates to biological fine structure , however, is quite deficient. I wonder when even sophisticated morphol-ogists will consider fixation a reaction and not a technique; only then will the fundamentals become self-evident and predictable and this sine qua flon will become less mystical. Staining reactions (the most inadequate chapter) ought to be something more than a technique to selectively enhance contrast of morphological elements; it ought to give the structural addresses of some of the chemical residents of cell components. Is it pertinent that auto-radiography gets singled out for more complete coverage than other significant aspects of cytochemistry by a high resolution microscopist, when it has a built-in minimal error of 1,000 A in standard practice? I don't mean to blind-side (in strict football terminology) Dr. Sj6strand's efforts for what is \"routinely used in our laboratory\"; what is done is usually well done. It's just that …

Methods in Enzymology.

Biology of Incretins: GLP-1 and GIP

Glucagon-like peptide 1 (GLP-1) is a 30-amino acid peptide hormone produced in the intestinal epithelial endocrine L-cells by differential processing of proglucagon, the gene which is expressed in ...

The Physiology of Glucagon-like Peptide 1

were frequent in conjunction with small intestinal (29.0%), gastric (20.5%), colonic (20.0%), and appendiceal (18.2%) carcinoids. The highest percentages of nonlocalized lesions were noted for cecal (81.5‐ 83.2%) and pancreatic (71.9 ‐ 81.3%) carcinoids, whereas the highest percentage of localized disease was found among rectal (81.7%), gastric (67.5%), and bronchopulmonary (65.4%) carcinoids. The best 5-year survival rates were recorded for patients with rectal (88.3%), bronchopulmonary (73.5%), and appendiceal (71.0%) carcinoids; these tumors exhibited invasive growth or metastatic spread in 3.9%, 27.5%, and 38.8% of patients, respectively. CONCLUSIONS. Carcinoids appear to have increased in overall incidence over the past 30 years; for some sites, this trend has been evident for nearly half a century. Recent marked increases in gastric and rectal carcinoids and a concomitant decrease in appendiceal carcinoid incidence may be due in part to varying rules of registration among the compiled databases examined in this report or to improvements in diagnostic technology; increased awareness of and about carcinoid tumors also may play a significant role. In 12.9% of all patients with carcinoid, distant metastases already were evident at the time of diagnosis; the overall 5-year survival rate for all carcinoid tumors, regardless of site, was 67.2%. These findings bring into question the widely promulgated relative benignity of carcinoid disease. Certain carcinoid tumors, such as those of the rectum, appear to be over-represented among the black and Asian populations within the United States, suggesting the role of genetics in the development of this intriguing disease. Cancer 2003;97: 934 –59. © 2003 American Cancer Society. DOI 10.1002/cncr.11105

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A 5‐decade analysis of 13,715 carcinoid tumors

In type-2 diabetes, the overall incretin effect is reduced. The present investigation was designed to compare insulinotropic actions of exogenous incretin hormones (gastric inhibitory peptide [GIP] and glucagon-like peptide 1 [GLP-1] [7-36 amide]) in nine type-2 diabetic patients (fasting plasma glucose 7.8 mmol/liter; hemoglobin A1c 6.3 +/- 0.6%) and in nine age- and weight-matched normal subjects. Synthetic human GIP (0.8 and 2.4 pmol/kg.min over 1 h each), GLP-1 [7-36 amide] (0.4 and 1.2 pmol/kg.min over 1 h each), and placebo were administered under hyperglycemic clamp conditions (8.75 mmol/liter) in separate experiments. Plasma GIP and GLP-1 [7-36 amide] concentrations (radioimmunoassay) were comparable to those after oral glucose with the low, and clearly supraphysiological with the high infusion rates. Both GIP and GLP-1 [7-36 amide] dose-dependently augmented insulin secretion (insulin, C-peptide) in both groups (P < 0.05). With GIP, the maximum effect in type-2 diabetic patients was significantly lower (by 54%; P < 0.05) than in normal subjects. With GLP-1 [7-36 amide] type-2 diabetic patients reached 71% of the increments in C-peptide of normal subjects (difference not significant). Glucagon was lowered during hyperglycemic clamps in normal subjects, but not in type-2 diabetic patients, and further by GLP-1 [7-36 amide] in both groups (P < 0.05), but not by GIP. In conclusion, in mild type-2 diabetes, GLP-1 [7-36 amide], in contrast to GIP, retains much of its insulinotropic activity. It also lowers glucagon concentrations.

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Preserved incretin activity of glucagon-like peptide 1 [7-36 amide] but not of synthetic human gastric inhibitory polypeptide in patients with type-2 diabetes mellitus.

Integrated incremental immunoreactive insulin and connecting peptide responses to an oral glucose load of 50 g and an "isoglycaemic" intravenous glucose infusion, respectively, were measured in 14 Type 2 (non-insulin-dependent) diabetic patients and 8 age- and weight-matched metabolically healthy control subjects. Differences between responses to oral and intravenous glucose administration are attributed to factors other than glucose itself (incretin effect). Despite higher glucose increases, immunoreactive insulin and connecting peptide responses after oral glucose were delayed in diabetic patients. Integrated responses were not significantly different between both groups. However, during "isoglycaemic" intravenous infusion, insulin and connecting peptide responses were greater in diabetic patients than in control subjects as a consequence of the higher glycaemic stimulus. The contribution of incretin factors to total insulin responses was 72.8 +/- 6.9% (100% = response to oral load) in control subjects and 36.0 +/- 8.8% in diabetic patients (p less than or equal to 0.05). The contribution to connecting peptide responses was 58.4 +/- 7.6% in control subjects and 7.6 +/- 14.5% (p less than or equal to 0.05) in diabetic patients. Ratios of integrated insulin to connecting peptide responses suggest a reduced (hepatic) insulin extraction in control subjects after oral as compared to intravenous glucose. This was not the case in diabetic patients. Immunoreactive gastric inhibitory polypeptide responses were not different between control subjects and diabetic patients.(ABSTRACT TRUNCATED AT 250 WORDS)

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Reduced incretin effect in type 2 (non-insulin-dependent) diabetes.

Glucagon-like peptide 1 (GLP-1) (7-36 amide) is a physiological incretin hormone that is released after nutrient intake from the lower gut and stimulates insulin secretion at elevated plasma glucose concentrations. Previous work has shown that even in Type 2 (non-insulin-dependent) diabetic patients GLP-1 (7-36 amide) retains much of its insulinotropic action. However, it is not known whether the magnitude of this response is sufficient to normalize plasma glucose in Type 2 diabetic patients with poor metabolic control. Therefore, in 10 Type 2 diabetic patients with unsatisfactory metabolic control (HbA1c 11.6 +/- 1.7%) on diet and sulphonylurea therapy (in some patients supplemented by metformin or acarbose), 1.2 pmol x kg-1 x min-1 GLP-1 (7-36 amide) or placebo was infused intravenously in the fasting state (plasma glucose 13.1 +/- 0.6 mmol/l). In all patients, insulin (by 17.4 +/- 4.7 nmol x 1-1 x min; p = 0.0157) and C-peptide (by 228.0 +/- 39.1 nmol x 1-1 x min; p = 0.0019) increased significantly over basal levels, glucagon was reduced (by -1418 +/- 308 pmol x 1-1 x min) and plasma glucose reached normal fasting concentrations (4.9 +/- 0.3 mmol/l) within 4 h of GLP-1 (7-36 amide) administration, but not with placebo. When normal fasting plasma glucose concentrations were reached insulin returned towards basal levels and plasma glucose concentrations remained stable despite the ongoing infusion of GLP-1 (7-36 amide). Therefore, exogenous GLP-1 (7-36 amide) is an effective means of normalizing fasting plasma glucose concentrations in poorly-controlled Type 2 diabetic patients.(ABSTRACT TRUNCATED AT 250 WORDS)

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Normalization of fasting hyperglycaemia by exogenous glucagon-like peptide 1 (7-36 amide) in type 2 (non-insulin-dependent) diabetic patients.

Normalization of fasting hyperglycaemia by exogenous glucagon-like peptide 1(7-36)amide in type 2 (non-insulin-dependent) diabetic patients

Integrated insulin secretion rates calculated from peripheral venous C-peptide measurements by two-compartment kinetic analysis were measured in six young normal subjects after increasing oral glucose loads of 25, 50, and 100 g and respective isoglycemic glucose infusions. The differences in B-cell secretory responses between oral and iv glucose challenges were attributed to factors other than glycemia itself (incretin effect). Both insulin and C-peptide concentrations as well as calculated integrated insulin secretion rates increased with increasing oral glucose loads. Due to the similarity in the glucose profiles after all oral loads, almost identical amounts of iv glucose (approximately 20 g) were infused in all "isoglycemic" infusion experiments, with resulting similar hormone profiles and insulin secretion rates. The percent contribution of incretin factors to total immunoreactive insulin responses after 25, 50, and 100 g glucose (85.6%, 74.9%, and 93.0%; response to oral load, 100%) was significantly higher than their contribution to integrated C-peptide responses (27.6-62.9%) or calculated integrated insulin secretion rates (19.2-61.0%). These findings indicate that the degree of incretin stimulation of insulin secretion depends on the amount of glucose ingested. A discrepancy between the estimates of the incretin effect derived from peripheral venous insulin responses, on the one hand, and C-peptide responses or calculated insulin secretion rates, on the other hand, exists. Inasmuch as peripheral insulin values reflect both insulin secretion and hepatic insulin removal, this discrepancy suggests that elimination kinetics of insulin differ between oral and iv glucose administration. This difference can be related to a significantly reduced fractional hepatic insulin extraction after oral (46.9-54.6%) compared to iv (63.4-76.5%) glucose administration when calculated by a three-compartment kinetic model. This reduction in fractional hepatic insulin extraction could be caused by gastrointestinal factors (hormones or nerves) stimulated in the course of glucose ingestion.

Werner Creutzfeldt

Papers

Preserved incretin activity of glucagon-like peptide 1 [7-36 amide] but not of synthetic human gastric inhibitory polypeptide in patients with type-2 diabetes mellitus.

Reduced incretin effect in type 2 (non-insulin-dependent) diabetes.

Normalization of fasting hyperglycaemia by exogenous glucagon-like peptide 1 (7-36 amide) in type 2 (non-insulin-dependent) diabetic patients.

Normalization of fasting hyperglycaemia by exogenous glucagon-like peptide 1(7-36)amide in type 2 (non-insulin-dependent) diabetic patients

Incretin effects of increasing glucose loads in man calculated from venous insulin and C-peptide responses