The Insulin Response to Oral Glucose in GIP and GLP-1 Receptor Knockout Mice: Review of the Literature and Stepwise Glucose Dose Response Studies in Female Mice

A key factor for the insulin response to oral glucose is the pro-glucagon derived incretin hormone glucagon-like peptide-1 (GLP-1), together with the companion incretin hormone, glucose-dependent insulinotropic polypeptide (GIP). Studies in GIP and GLP-1 receptor knockout (KO) mice have been undertaken in several studies to examine this role of the incretin hormones. In the present study, we reviewed the literature on glucose and insulin responses to oral glucose in these mice. We found six publications with such studies reporting results of thirteen separate study arms. The results were not straightforward, since glucose intolerance in GIP or GLP-1 receptor KO mice were reported only in eight of the arms, whereas normal glucose tolerance was reported in five arms. A general potential weakness of the published study is that each of them have examined effects of only one single dose of glucose. In a previous study in mice with genetic deletion of both GLP-1 and GIP receptors we showed that these mice have impaired insulin response to oral glucose after large but not small glucose loads, suggesting that the relevance of the incretin hormones may be dependent on the glucose load. To further test this hypothesis, we have now performed a stepwise glucose administration through a gastric tube (from zero to 125mg) in model experiments in anesthetized female wildtype, GLP-1 receptor KO and GIP receptor KO mice. We show that GIP receptor KO mice exhibit glucose intolerance in the presence of impaired insulin response after 100 and 125 mg glucose, but not after lower doses of glucose. In contrast, GLP-1 receptor KO mice have normal glucose tolerance after all glucose loads, in the presence of a compensatory increase in the insulin response. Therefore, based on these results and the literature survey, we suggest that GIP and GLP-1 receptor KO mice retain normal glucose tolerance after oral glucose, except after large glucose loads in GIP receptor KO mice, and we also show an adaptive mechanism in GLP-1 receptor KO mice, which needs to be further examined.

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Further support for heterogeneity of insulin response and insulin sensitivity in non-obese subjects with glucose intolerance

Acta Endocrinologica ◽

10.1530/acta.0.1020410 ◽

1983 ◽

Vol 102 (3) ◽

pp. 410-415 ◽

Cited By ~ 2

Author(s):

K. P. Ratzmann ◽

S. Witt ◽

B. Schulz

Keyword(s):

Insulin Sensitivity ◽

Glucose Tolerance ◽

Glucose Intolerance ◽

Insulin Response ◽

Normal Glucose Tolerance ◽

Oral Glucose ◽

Insulin Deficiency ◽

Normal Glucose ◽

Obese Subjects ◽

Insulin Responses

Abstract. The relationship of insulin secretion and insulin sensitivity was studied in 67 age- and body weight-matched non-obese subjects, classified as having a normal glucose tolerance or glucose intolerance (50 g oral glucose load). Insulin response was studied by means of a 2 h glucose infusion. For the determination of insulin sensitivity a 1 h priming dose-constant insulin infusion technique was used. The per cent decrease of plasma glucose level at comparable steady-state insulin levels served as a measure of body sensitivity to exogenous insulin. In patients with glucose intolerance the early (ΔIRI area 0–5 min) and late (ΔIRI area 30–120 min) insulin responses to iv glucose were significantly reduced in comparison to controls. Controls and subjects with glucose intolerance showed considerable heterogeneity of insulin responses. Patients with glucose intolerance and relative insulin deficiency were not less responsive to insulin than subjects with normal glucose tolerance. There was, however, a wide variation of insulin sensitivity within the two groups. There was a weak significant inverse correlation between insulin response to glucose and insulin sensitivity for the two groups combined and for controls and subjects with glucose intolerance separately. The results demonstrate that the majority of non-obese patients with glucose intolerance and relative insulin deficiency does not exhibit a reduced responsiveness to insulin and therefore hypoinsulinaemia but not insulin resistance is the primary defect for an abnormal glucose tolerance in these group of subjects.

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Effects of exercise and lack of exercise on glucose tolerance and insulin sensitivity

Journal of Applied Physiology ◽

10.1152/jappl.1983.55.2.512 ◽

1983 ◽

Vol 55 (2) ◽

pp. 512-517 ◽

Cited By ~ 195

Author(s):

G. W. Heath ◽

J. R. Gavin ◽

J. M. Hinderliter ◽

J. M. Hagberg ◽

S. A. Bloomfield ◽

...

Keyword(s):

Glucose Tolerance ◽

Insulin Response ◽

Insulin Binding ◽

Normal Glucose Tolerance ◽

Residual Effects ◽

Oral Glucose ◽

Glucose Load ◽

Plasma Insulin Concentration ◽

Normal Glucose ◽

Blood Glucose Concentrations

Physically trained individuals have a markedly blunted insulin response to a glucose load and yet have normal glucose tolerance. This phenomenon has generally been ascribed to long-term adaptations to training which correlate with maximal oxygen uptake (VO2max) and reduced adiposity. Our study was undertaken to test the hypothesis that residual effects of the last bouts of exercise play an important role in this phenomenon. Eight well-trained subjects stopped training for 10 days. There were no significant changes in VO2max (58.6 +/- 2.2 vs. 57.6 +/- 2.1 ml/kg), estimated percent body fat (12.5 +/- 0.7 vs. 12.5 +/- 0.8%), or body weight. The maximum rise in plasma insulin concentration in response to a 100-g oral glucose load was 100% higher after 10 days without exercise than when the subjects were exercising regularly. Despite the increased insulin levels, blood glucose concentrations were higher after 10 days without exercise. Insulin binding to monocytes also decreased with physical inactivity. One bout of exercise after 11 days without exercise returned insulin binding and the insulin and glucose responses to an oral 100-g glucose load almost to the initial “trained” value. These results support our hypothesis.

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PLASMA CORTICOSTEROID, PLASMA INSULIN AND BLOOD SUGAR OF NORMAL FASTING AND DIABETIC SUBJECTS WITH OR WITHOUT HYPERCORTICISM

Acta Endocrinologica ◽

10.1530/acta.0.0580643 ◽

1968 ◽

Vol 58 (4) ◽

pp. 643-654 ◽

Cited By ~ 2

Author(s):

Vivian Harding Asfeldt ◽

Kai R. Jørgensen

Keyword(s):

Glucose Tolerance ◽

Blood Sugar ◽

Plasma Insulin ◽

Insulin Response ◽

Tolerance Test ◽

Normal Glucose Tolerance ◽

Oral Glucose ◽

Acth Stimulation ◽

Normal Glucose ◽

Plasma Insulin Response

ABSTRACT Transient, maximum stimulation with β1–24 corticotrophin has been carried out in nine normal fasting subjects, in two fasting diabetics without hypercorticism and in three fasting diabetics with hypercorticism. Fluorimetric determinations of corticosteroids and determinations of immunological detectable insulin in plasma and blood sugar were made during stimulation. No significant variation in the blood sugar or the plasma insulin during transient, maximum ACTH stimulation was found either in normal fasting subjects or in fasting diabetics with or without hypercorticism. Moreover, in two diabetics with hypercorticism the plasma insulin response was measured during an oral glucose tolerance test. After treatment for approximately seven months with glucocorticosteroids, a reduced glucose tolerance and an increased plasma insulin response were found in one of these two patients. Four and a half months after the termination of steroid treatment, normal glucose tolerance and normal insulin responses were observed. In one patient, after several years of hypercorticism, a reduced glucose tolerance and a markedly reduced plasma insulin response were found.

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Insulin Response to Oral Glucose Load is Associated with Coronary Artery Disease in Subjects with Normal Glucose Tolerance

Journal of Atherosclerosis and Thrombosis ◽

10.5551/jat.e515 ◽

2008 ◽

Vol 15 (1) ◽

pp. 6-12 ◽

Cited By ~ 9

Author(s):

Tetsuro Miyazaki ◽

Kazunori Shimada ◽

Yoshitaka Iwama ◽

Atsumi Kume ◽

Katsuhiko Sumiyoshi ◽

...

Keyword(s):

Coronary Artery Disease ◽

Coronary Artery ◽

Glucose Tolerance ◽

Insulin Response ◽

Normal Glucose Tolerance ◽

Oral Glucose ◽

Oral Glucose Load ◽

Glucose Load ◽

Normal Glucose ◽

Artery Disease

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Effect of Different Insulin Response Patterns During Oral Glucose Tolerance Test on Glycemia in Individuals with Normal Glucose Tolerance

Diabetes Technology & Therapeutics ◽

10.1089/dia.2015.0379 ◽

2016 ◽

Vol 18 (5) ◽

pp. 316-326 ◽

Cited By ~ 1

Author(s):

Edavan Pulikkanath Praveen ◽

Sunil Chouhan ◽

Jayaprakash Sahoo ◽

Sudhir K. Goel ◽

Sada Nand Dwivedi ◽

...

Keyword(s):

Glucose Tolerance ◽

Oral Glucose Tolerance Test ◽

Glucose Tolerance Test ◽

Insulin Response ◽

Tolerance Test ◽

Normal Glucose Tolerance ◽

Oral Glucose ◽

Response Patterns ◽

Oral Glucose Tolerance ◽

Normal Glucose

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Abnormal Regulation of Venous Alanine after Glucose Ingestion in Myotonic Dystrophy

Clinical Science ◽

10.1042/cs0680151 ◽

1985 ◽

Vol 68 (2) ◽

pp. 151-157 ◽

Cited By ~ 8

Author(s):

Richard T. Moxley ◽

William Kingston ◽

Robert C. Griggs

Keyword(s):

Amino Acids ◽

Glucose Tolerance ◽

Myotonic Dystrophy ◽

Normal Glucose Tolerance ◽

Oral Glucose ◽

Oral Glucose Tolerance Testing ◽

Glucose Ingestion ◽

Normal Glucose ◽

Normal Males ◽

Slight Rise

1. The concentration of amino acids in whole blood was measured before and during standard 5 h oral glucose tolerance testing in six male patients with myotonic dystrophy and five normal males. The plasma levels of insulin and glucose were also determined. 2. From 90 to 240 min after glucose ingestion there was a striking decline in venous alanine concentration in the patients with myotonic dystrophy in contrast to a slight rise in alanine in the normal group. 3. The patients displayed normal glucose tolerance, and there was a sustained fall in the venous concentration of the insulin-sensitive amino acids comparable with that seen in the normal controls. However, the patients showed a threefold increase of plasma insulin after glucose. 4. These data indicate an abnormal regulation of alanine in myotonic dystrophy which may be the result of an alteration in muscle synthesis of this amino acid. This defect in alanine synthesis may be due to a decreased availability of intracellular pyruvate caused by the insulin resistance that exists in these patients.

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Glucose Tolerance in Patients with Cystic Fibrosis – Results from the German Cystic Fibrosis Registry

Klinische Pädiatrie ◽

10.1055/a-1117-3771 ◽

2020 ◽

Vol 232 (04) ◽

pp. 210-216

Author(s):

Nicole Prinz ◽

Julia Wosniok ◽

Doris Staab ◽

Manfred Ballmann ◽

Christian Dopfer ◽

...

Keyword(s):

Cystic Fibrosis ◽

Glucose Tolerance ◽

Real World ◽

Normal Glucose Tolerance ◽

Oral Glucose ◽

Real World Data ◽

Clinical Registries ◽

Normal Glucose ◽

Multivariable Regression ◽

Adjusted Model

Abstract Background Oral glucose tolerance (OGT) deteriorates progressively in cystic fibrosis (CF). Clinical registries provide a unique basis to study real-world data. Patients & methods OGT tests (OGTTs) documented in the German CF-registry in 2016 were classified according WHO, modified by ADA: normal glucose tolerance (NGT), indeterminate glycaemia (INDET), impaired fasting glucose (IFG), impaired glucose tolerance (IGT), IFG+IGT, diabetes mellitus (DM). To study the association with lung function, multivariable regression adjusted for age, sex, and CFTR mutation was performed. Results Overall, OGTT screening was done in 35% of CF patients ≧10 years. Of the 996 patients (46.4% females; median age (IQR): 19 (14–27) years) with evaluable OGTTs, 56.2% had either NGT or INDET, whereas 34% had a pre-diabetic OGTT (IFG; IGT; IFG+IGT) and 9.8% a diabetic OGTT. 7 patients had glucose tolerance abnormalities <10 years. DM was more common in females or patients with F508del homozygote mutation, whereas IFG was more frequent in males (all p<0.05). Nearly 75% of patients after transplantation and about half with enteral/parental nutrition and/or steroid use had either a pre-diabetic or diabetic glucose tolerance. In the adjusted model, age (p<0.001) and OGTT category (p=0.013) had both a significant impact on %FEV1. Conclusion Our data of the German CF-registry highlights incidence of glucose tolerance abnormalities in second decade of life in CF patients. However, it also underlines the need for improvement of the documentation and/or performance of OGTT screening in real-world CF care.

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A Clinic-based Approach to Diagnosis and Management of Prediabetes in High-risk Children and Adolescents

Journal of the Endocrine Society ◽

10.1210/jendso/bvaa008 ◽

2020 ◽

Vol 4 (4) ◽

Author(s):

Chelsea Lawson ◽

S Naseeruddin Ahmed ◽

Cassandra Brady ◽

Ashley H Shoemaker

Keyword(s):

High Risk ◽

Glucose Tolerance ◽

Best Practice ◽

Fasting Glucose ◽

Retrospective Chart Review ◽

Normal Glucose Tolerance ◽

Oral Glucose ◽

Oral Glucose Tolerance Testing ◽

Normal Glucose

Abstract Background Type 2 diabetes (T2D) in youth is increasing in prevalence. Diabetes screening is recommended for at-risk youth but best-practice strategies for management of pediatric prediabetes are unknown. This study leverages a pediatric prediabetes clinic to assess identification of high-risk patients, the rate of clinic follow-up and progression to T2D in youth over time. Methods Retrospective chart review of children referred to a single center for evaluation of prediabetes over a 3-year period. Measurements included hemoglobin A1c (HbA1C) and oral glucose tolerance testing. Patients were classified as normal glucose tolerance (NGT), impaired glucose tolerance (IGT) or T2D based on 2019 American Diabetes Association criteria. Patients classified as IGT/T2D were prescribed metformin. Results Of the 254 patients included; 25.6% had IGT and 6.7% had T2D. The IGT/T2D groups were older and more obese than the NGT group. There was a moderate correlation between HbA1C and fasting glucose (r = 0.59, P < 0.001); HbA1C and 2-hour glucose (r = 0.63, P < 0.001). Over the 3-year study, 52 of 82 patients with IGT/T2D (63%) returned for follow-up. Four patients regained NGT; 3 of those had isolated impaired fasting glucose (100 to 102 mg/dL). Three patients (4.6%) progressed from IGT to T2D over an average of 13 ± 6.2 months. In those patients, body mass index had increased 1.7 ± 2.3 kg/m2 from baseline. Conclusions A pediatric prediabetes clinic may allow for identification of high-risk youth but lost to follow-up rates are high. Continued weight gain is a risk factor for progression to T2D and effective weight management programs are needed.

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