From the Incretin Concept and the Discovery of GLP-1 to Today's Diabetes Therapy

Researchers have been looking for insulin-stimulating factors for more than 100 years, and in the 1960ties it was definitively proven that the gastrointestinal tract releases important insulinotropic factors upon oral glucose intake, so-called incretin hormones. The first significant factor identified was the duodenal glucose-dependent insulinotropic polypeptide, GIP, which however, turned out not to stimulate insulin secretion in patients with type 2 diabetes. But resection experiments clearly indicated the presence of an additional incretin, and in 1986, an unexpected processing fragment of the recently identified glucagon precursor, proglucagon, namely truncated glucagon-like peptide 1 (GLP-1 7–36 amide), was isolated from the gut and found to both stimulate insulin secretion and inhibit glucagon secretion. The peptide also inhibited appetite and food intake. Unlike GIP, this peptide had preserved effects in patients with type 2 diabetes and it was soon documented to have powerful antidiabetic effects in clinical studies. Its utility was limited, however, because of an extremely short half-life in humans, but this problem had two solutions, both of which gave rise to important antidiabetic drugs: (1) orally active inhibitors of the enzyme dipeptidylpeptidase 4 (DPP-4 inhibitors), which was responsible for the rapid degradation; the inhibitors protect endogenous GLP-1 from degradation and thereby unfold its antidiabetic activity, and (2) long-acting injectable analogs of GLP-1 protected against DPP-4 degradation. Particularly, the latter, the GLP-1 receptor agonists, either alone or in various combinations, are so powerful that treatment allows more than 2/3 of type 2 diabetes patients to reach glycemic targets. In addition, these agents cause a weight loss which, with the most successful compounds, may exceed 10% of body weight. Most recently they have also been shown to be renoprotective and reduce cardiovascular risk and mortality

Pre-Meal Effect of Whey Proteins on Metabolic Parameters in Subjects with and without Type 2 Diabetes:A Randomized, Crossover Trial

Diabetic dyslipidemia with elevated postprandial triglyceride (TG) responses is characteristic in type 2 diabetes (T2D). Diet and meal timing can modify postprandial lipemia (PPL). The impact of a pre-meal of whey proteins (WP) on lipid metabolism is unidentified. We determined whether a WP pre-meal prior to a fat-rich meal influences TG and apolipoprotein B-48 (ApoB-48) responses differentially in patients with and without T2D. Two matched groups of 12 subjects with and without T2D accomplished an acute, randomized, cross-over trial. A pre-meal of WP (20 g) or water (control) was consumed 15 min before a fat-rich meal (supplemented with 20 g WP in case of water pre-meal). Postprandial responses were examined during a 360-min period. A WP pre-meal significantly increased postprandial concentrations of insulin (P < 0.0001), glucagon (P < 0.0001) and glucose-dependent insulinotropic peptide (GIP) (P < 0.0001) in subjects with and without T2D. We detected no effects of the WP pre-meal on TG, ApoB-48, or non-esterified fatty acids (NEFA) responses to the fat-rich meal in either group. Paracetamol absorption i.e. gastric emptying was delayed by the WP pre-meal (P = 0.039). In conclusion, the WP pre-meal induced similar hormone and lipid responses in subjects with and without T2D. Thus, the WP pre-meal enhanced insulin, glucagon and GIP responses but did not influence lipid or glucose responses. In addition, we demonstrated that a WP pre-meal reduced gastric emptying in both groups

Glucagon-like peptide-1: effect on pro-atrial natriuretic peptide in healthy males

The antihypertensive actions of glucagon-like peptide-1 (GLP1) receptor agonists have been linked to the release of atrial natriuretic peptide (ANP) in mice. Whether a GLP1–ANP axis exists in humans is unknown. In this study, we examined 12 healthy young males in a randomized, controlled, double-blinded, single-day, cross-over study to evaluate the effects of a 2-h native GLP1 infusion. Plasma proANP concentrations were measured by an automated mid-region-directed proANP immunoassay and N-terminal pro B-type natriuretic peptide (BNP) on Roche Modular E170. Urine was collected for measurements of sodium excretion. Although GLP1 infusion increased the urinary sodium excretion markedly, there were no significant changes in either proANP or proBNP concentrations. When GLP1 infusion was stopped, sodium excretion declined rapidly. As proANP concentration reflects ANP secretion, our data could not confirm the existence of a GLP1–ANP axis in humans. Especially, the natriuretic effects of GLP1 seem unlikely to be mediated exclusively via ANP

Effect of oral contraceptives and/or metformin on GLP-1 secretion and reactive hypoglycaemia in polycystic ovary syndrome

Context: Insulin resistance in polycystic ovary syndrome (PCOS) may increase the risk of reactive hypoglycaemia (RH) and decrease glucagon-like peptide-1 (GLP-1) secretion. The possible effects of treatment with oral contraceptives (OCP) and/or metformin on GLP-1 secretion and risk of RH in PCOS is undetermined. Setting: Outpatient clinic. Patients and interventions: Randomized, controlled clinical trial. Ninety women with PCOS were randomized to 12-month treatment with OCP (150 mg desogestrel + 30 mg ethinylestradiol), metformin (2 g/day) or metformin + OCP. Five-hour oral glucose tolerance tests (5-h OGTT) measuring fasting and area under the curve (AUC) for GLP-1, glucose, insulin and C-peptide were performed before and after the intervention period. Sixty-five women completed the study and 34 weight-matched healthy women were included as controls. Main outcome measures: Changes in GLP-1, glucose, insulin and C-peptide during 5-h OGTT. Results: Fasting GLP-1 levels increased during metformin + OCP vs OCP treatment, whereas AUC GLP-1 levels were unchanged during medical treatment. The prevalence of reactive hypoglycemia increased from 9/65 to 14/65 after intervention (P < 0.01) and was more common after treatment with metformin + OCP (increase from 3/23 to 6/23, P = 0.01). Reactive hypoglycaemia was associated with higher insulin and C-peptide levels during 5-h OGTT, but was unassociated with BMI and AUC GLP-1. GLP-1 levels were comparable in PCOS vs controls. AUC GLP-1 levels were significantly lower in obese vs lean patients and were inversely associated with BMI. Conclusions: AUC GLP-1 levels were unchanged during treatment. Increased risk of hypoglycemia during metformin + OCP could be associated with increased insulin secretion

Do glucagonomas always produce glucagon?

Pancreatic islet α-cell tumours that overexpress proglucagon are typically associated with the glucagonoma syndrome, a rare disease entity characterised by necrolytic migratory erythema, impaired glucose tolerance, thromboembolic complications and psychiatric disturbances. Paraneoplastic phenomena associated with enteric overexpression of proglucagon-derived peptides are less well recognized and include gastrointestinal dysfunction and hyperinsulinaemic hypoglycaemia. The diverse clinical manifestations associated with glucagon-expressing tumours can be explained, in part, by the repertoire of tumorally secreted peptides liberated through differential post-translational processing of tumour-derived proglucagon. Proglucagon-expressing tumours may be divided into two broad biochemical subtypes defined by either secretion of glucagon or GLP-1, GLP-2 and the glucagon-containing peptides, glicentin and oxyntomodulin, due to an islet α-cell or enteroendocrine L-cell pattern of proglucagon processing, respectively. In the current review we provide an updated overview of the clinical presentation of proglucagon-expressing tumours in relation to known physiological actions of proglucagon-derived peptides and suggest that detailed biochemical characterisation of the peptide repertoire secreted from these tumours may provide new opportunities for diagnosis and clinical management.   

On the role of gallbladder emptying and incretin hormones for nutrient-mediated TSH suppression in patients with type 2 diabetes

Bile acids are possible candidate agents in newly identified pathways through which energy expenditure may be regulated. Preclinical studies suggest that bile acids activate the enzyme type 2 iodothyronine deiodinase, which deiodinates thyroxine (T(4)) to the biologically active triiodothyronine (T(3)). We aimed to evaluate the influence of bile acid exposure and incretin hormones on thyroid function parameters in patients with type 2 diabetes. Thyroid-stimulating hormone (TSH) and thyroid hormones (total T(3) and free T(4)) were measured in plasma from two human studies: i) 75 g-oral glucose tolerance test (OGTT) and three isocaloric (500 kcal) and isovolaemic (350 ml) liquid meals with increasing fat content with concomitant ultrasonographic evaluation of gallbladder emptying in 15 patients with type 2 diabetes and 15 healthy age, gender and BMI-matched controls (meal-study) and ii) 50 g-OGTT and isoglycaemic intravenous glucose infusions (IIGI) alone or in combination with glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide 1 (GLP1) and/or GLP2, in ten patients with type 2 diabetes (IIGI-study). In both studies, TSH levels declined (P<0.01) similarly following all meal and infusion stimuli. T(3) and T(4) concentrations did not change in response to any of the applied stimuli. TSH levels declined independently of the degree of gallbladder emptying (meal-study), route of nutrient administration and infusion of gut hormones. In conclusion, intestinal bile flow and i.v. infusions of the gut hormones, GIP, GLP1 and/or GLP2, do not seem to affect thyroid function parameters. Thus, the presence of a ‘gut–thyroid–pituitary’ axis seems questionable