Thure Krarup

Reduced postprandial concentrations of intact biologically active glucagon-like peptide 1 in type 2 diabetic patients.

Incretin hormones importantly enhance postprandial insulin secretion but are rapidly degraded to inactive metabolites by ubiquitous dipeptidyl peptidase IV. The concentrations of the intact biologically active hormones remain largely unknown. Using newly developed assays for intact glucagon-like peptide (GLP)-1 and glucose-dependent insulinotropic polypeptide (GIP), we measured plasma concentrations after a mixed breakfast meal (566 kcal) in 12 type 2 diabetic patients (age 57 years [range 49-67], BMI 31 kg/m2 [27-38], and HbA1c 9.2% [7.0-12.5]) and 12 matched healthy subjects. The patients had fasting hyperglycemia (10.7 mmol/l [8.0-14.8]) increasing to 14.6 mmol/l (11.5-21.5) 75 min after meal ingestion. Fasting levels of insulin and C-peptide were similar to those of the healthy subjects, but the postprandial responses were reduced and delayed. Fasting levels and meal responses were similar between patients and healthy subjects for total GIP (intact + metabolite) as well as intact GIP, except for a small decrease in the patients at 120 min; integrated areas for intact hormone (area under the curve [AUC]INT) averaged 52 +/- 4% (for patients) versus 56 +/- 3% (for control subjects) of total hormone AUC (AUC(TOT)). AUC(INT) for GLP-1 averaged 48 +/- 2% (for patients) versus 51 +/- 5% (for control subjects) of AUC(TOT). AUC(TOT) for GLP-1 as well as AUC(INT) tended to be reduced in the patients (P = 0.2 and 0.07, respectively); but the profile of the intact GLP-1 response was characterized by a small early rise (30-45 min) and a significantly reduced late phase (75-150 min) (P < 0.02). The measurement of intact incretin hormones revealed that total as well as intact GIP responses were minimally decreased in patients with type 2 diabetes, whereas the late intact GLP-1 response was strongly reduced, supporting the hypothesis that an impaired function of GLP-1 as a transmitter in the enteroinsular axis contributes to the inappropriate insulin secretion in type 2 diabetes.

Reduced Incretin Effect in Type 2 Diabetes Cause or Consequence of the Diabetic State

We aimed to investigate whether the reduced incretin effect observed in patients with type 2 diabetes is a primary event in the pathogenesis of type 2 diabetes or a consequence of the diabetic state. Eight patients with chronic pancreatitis and secondary diabetes (A1C mean [range] of 6.9% [6.2–8.0]), eight patients with chronic pancreatitis and normal glucose tolerance (NGT; 5.3 [4.9–5.7]), eight patients with type 2 diabetes (6.9 [6.2–8.0]); and eight healthy subjects (5.5 [5.1–5.8]) were studied. Blood was sampled over 4 h on 2 separate days after a 50-g oral glucose load and an isoglycemic intravenous glucose infusion, respectively. The incretin effect (100% × [β-cell secretory response to oral glucose tolerance test − intravenous β-cell secretory response]/β-cell secretory response to oral glucose tolerance test) was significantly (P < 0.05) reduced (means ± SE) in patients with chronic pancreatitis and secondary diabetes (31 ± 4%) compared with patients with chronic pancreatitis and NGT (68 ± 3) and healthy subjects (60 ± 4), respectively. In the type 2 diabetes group, the incretin effect amounted to 36 ± 6%, significantly (P < 0.05) lower than in chronic pancreatitis patients with NGT and in healthy subjects, respectively. These results suggest that the reduced incretin effect is not a primary event in the development of type 2 diabetes, but rather a consequence of the diabetic state.

Role of gastrointestinal hormones in postprandial reduction of bone resorption.

Collagen type I fragments, reflecting bone resorption, and release of gut hormones were investigated after a meal. Investigations led to a dose escalation study with glucagon like peptide‐2 (GLP‐2) in postmenopausal women. We found a dose‐dependent effect of GLP‐2 on the reduction of bone resorption.

Dietary carbohydrate restriction as the first approach in diabetes management: Critical review and evidence base

The inability of current recommendations to control the epidemic of diabetes, the specific failure of the prevailing low-fat diets to improve obesity, cardiovascular risk, or general health and the persistent reports of some serious side effects of commonly prescribed diabetic medications, in combination with the continued success of low-carbohydrate diets in the treatment of diabetes and metabolic syndrome without significant side effects, point to the need for a reappraisal of dietary guidelines. The benefits of carbohydrate restriction in diabetes are immediate and well documented. Concerns about the efficacy and safety are long term and conjectural rather than data driven. Dietary carbohydrate restriction reliably reduces high blood glucose, does not require weight loss (although is still best for weight loss), and leads to the reduction or elimination of medication. It has never shown side effects comparable with those seen in many drugs. Here we present 12 points of evidence supporting the use of low-carbohydrate diets as the first approach to treating type 2 diabetes and as the most effective adjunct to pharmacology in type 1. They represent the best-documented, least controversial results. The insistence on long-term randomized controlled trials as the only kind of data that will be accepted is without precedent in science. The seriousness of diabetes requires that we evaluate all of the evidence that is available. The 12 points are sufficiently compelling that we feel that the burden of proof rests with those who are opposed.

Liraglutide, a once‐daily human GLP‐1 analogue, improves pancreatic B‐cell function and arginine‐stimulated insulin secretion during hyperglycaemia in patients with Type 2 diabetes mellitus

Aims  To assess the effect of liraglutide, a once‐daily human glucagon‐like peptide‐1 analogue on pancreatic B‐cell function.

Beneficial effects of once-daily liraglutide, a human glucagon-like peptide-1 analogue, on cardiovascular risk biomarkers in patients with Type 2 diabetes

Liraglutide is a once-daily, human glucagon-like peptide-1 (GLP-1) analogue. Clinical studies have demonstrated blood glucose and weight-reducing effects, improvements in pancreatic B-cell function and a low risk of hypoglycaemic events with liraglutide [1,2]. Type 2 diabetes is associated with an increased risk of cardiovascular events. Recently, studies in patients with Type 2 diabetes have shown that native GLP-1 may also have beneficial effects on the myocardium [3] and on endothelial function [4]. We present here the effect of liraglutide on biomarkers for cardiovascular risk in patients with Type 2 diabetes, as an exploratory endpoint from a broader clinical study. The design and non-cardiovascular biomarker results of this study have been described previously [1]. The trial was carried out in accordance with good clinical practice. Briefly, 165 patients with Type 2 diabetes were randomized to either placebo or 0.65 mg, 1.25 mg or 1.9 mg liraglutide for 14 weeks. Across the four treatment arms, 17–23% of the subjects were previously treated with diet and exercise and the remaining subjects with oral glucose-lowering agents. Subjects had a mean body mass index (BMI) of 28.9–31.2 kg/m2 and mean glycated haemoglobin (HbA1c) at randomization of 8.1–8.5%. The study was powered against the primary endpoint HbA1c, but was not powered at an 80% level for a difference of 20% for the cardiovascular biomarkers discussed here. At randomization and end of study, the following additional parameters were assessed: adiponectin, leptin, high-sensitivity C-reactive protein (hs-CRP), interleukin 6 (IL-6), tumour necrosis factor alpha (TNF-α), plasminogen activator inhibitor 1 (PAI-1) and B-type natriuretic peptide (BNP). The data are presented in Table 1. A significant decrease in PAI-1 and BNP levels were observed following treatment with liraglutide. There was a non-significant, but dose-dependent, reduction in hs-CRP levels. There were no treatment effects on levels of adiponectin, leptin, IL-6 and TNF-α with liraglutide. Table 1 Baseline levels and change from baseline level of cardiovascular risk markers after 14 weeks of treatment This study was part of a larger clinical trial, which showed significantly improved glycaemic control and a reduction in body weight in subjects treated with liraglutide [1]. In addition, systolic blood pressure (reduction of 8 mmHg at 1.90 mg/day vs. placebo) and plasma triglycerides (reduction of 22% at 1.90 mg/day vs. placebo) were significantly reduced [1]. PAI-1 and hs-CRP are inflammatory biomarkers that are associated with an increased risk of cardiovascular disease [5]. Elevated PAI-1 levels may suppress the fibrinolytic process and thereby be associated with the development of atherosclerosis. BNP is a marker of left ventricular dysfunction and elevated levels are risk markers for cardiovascular diseases, in particular for heart failure [6]. The findings suggest that liraglutide, when used to regulate blood glucose levels in patients with Type 2 diabetes, improves certain biomarkers associated with increased cardiovascular risk. Large prospective trials are needed to confirm these results and to assess whether these effects translate into improvements in cardiovascular risk in patients with Type 2 diabetes.

Loss of Incretin Effect Is a Specific, Important, and Early Characteristic of Type 2 Diabetes

Whereas glucose-tolerant individuals are capable of adjusting their insulin secretion to their actual insulin sensitivity, people with type 2 diabetes are incapable of doing so (1). β-Cell failure is therefore the hallmark of this disease, although failure may be precipitated by the development of insulin resistance, typically as a consequence of obesity. In healthy subjects, a considerable part of the postprandial insulin response is due to the actions of the incretin hormones glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Together, the two hormones are responsible for the so-called incretin effect, i.e., the amplification of insulin secretion that is observed when glucose is taken orally as opposed to infused intravenously to provide identical plasma glucose concentrations (2). Although frequently ignored, the effect strongly depends on the dose of glucose (3). A convenient way of describing the effect is to calculate the gastrointestinally mediated glucose disposal (GIGD) (4). Here the amount of glucose required by intravenous infusion to copy the glucose excursions after the oral load is related to the oral load. Thus, if 25 g is required to copy a 75-g oral glucose load, the GIGD amounts to 100 × (75 – 25)/75 = 66%. In other words, mechanisms associated with and activated by the oral ingestion resulted in a disposal of 75 – 25 = 50 g of the ingested glucose. In healthy subjects, most of the GIGD is accounted for by the actions of the incretin hormones, but inhibition of hepatic glucose production by suppression of glucagon secretion, hepatic uptake of glucose from the portal vein, and gut-brain or liver-brain reflex activity may also play a role. GIGD is particularly useful in the study of oral glucose handling in C-peptide–negative patients with type 1 diabetes, where the classical incretin definitions have no meaning (4). In a …

Four Weeks of Treatment With Liraglutide Reduces Insulin Dose Without Loss of Glycemic Control in Type 1 Diabetic Patients With and Without Residual β-Cell Function

OBJECTIVE To investigate the effect of 4 weeks of treatment with liraglutide on insulin dose and glycemic control in type 1 diabetic patients with and without residual β-cell function. RESEARCH DESIGN AND METHODS Ten type 1 diabetic patients with residual β-cell function (C-peptide positive) and 19 without (C-peptide negative) were studied. All C-peptide–positive patients were treated with liraglutide plus insulin, whereas C-peptide–negative patients were randomly assigned to liraglutide plus insulin or insulin monotherapy. Continuous glucose monitoring with identical food intake and physical activity was performed before (week 0) and during (week 4) treatment. Differences in insulin dose; HbA1c; time spent with blood glucose <3.9, >10, and 3.9–9.9 mmol/L; and body weight were evaluated. RESULTS Insulin dose decreased from 0.50 ± 0.06 to 0.31 ± 0.08 units/kg per day (P < 0.001) in C-peptide–positive patients and from 0.72 ± 0.08 to 0.59 ± 0.06 units/kg per day (P < 0.01) in C-peptide–negative patients treated with liraglutide but did not change with insulin monotherapy. HbA1c decreased in both liraglutide-treated groups. The percent reduction in daily insulin dose was positively correlated with β-cell function at baseline, and two patients discontinued insulin treatment. In C-peptide–positive patients, time spent with blood glucose <3.9 mmol/L decreased from 3.0 to 1.0 h (P = 0.03). A total of 18 of 19 patients treated with liraglutide lost weight during treatment (mean [range] −2.3 ± 0.3 kg [−0.5 to −5.1]; P < 0.001). Transient gastrointestinal adverse effects occurred in almost all patients treated with liraglutide. CONCLUSIONS Treatment with liraglutide in type 1 diabetic patients reduces insulin dose with improved or unaltered glycemic control.

Glucagon-like peptide-1, glucose homeostasis and diabetes

Incretins, enhancers of insulin secretion, are essential for glucose tolerance, and a reduction in their function might contribute to poor beta-cell function in patients with type-2 diabetes mellitus. However, at supraphysiological doses, the incretin glucagon-like peptide-1 (GLP-1) protects pancreatic beta cells, and inhibits glucagon secretion, gastric emptying and food intake, leading to weight loss. GLP-1 mimetics, which are stable-peptide-based activators of the GLP-1 receptor, and incretin enhancers, which inhibit the incretin-degrading enzyme dipeptidyl peptidase-4, have emerged as therapies for type-2 diabetes and have recently reached the market. The pathophysiological basis the clinical use of these therapeutics is reviewed here.

Role of residual insulin secretion in protecting against ketoacidosis in insulin-dependent diabetes.

The role of preserved beta-cell function in preventing ketoacidosis in type I insulin-dependent diabetes was assessed in eight patients with and seven patients without residual beta-cell function as determined from C-peptide concentrations. After 12 hours of insulin fatty-acid, and glycerol concentrations were all significantly higher in patients without beta-cell function than in those with residual secretion. Mean blood glucose concentrations reached 17.2 +/- SE of mean 1.3 mmol/l (310 +/- 23 mg/100 ml) in the first group compared with 8.8 +/- 1.4 mmol/l (159 +/- 25 mg/100 ml) in the second (P less than 0.01), while 3-hydroxybutyrate concentrations rose to 5.5 +/- mmol/l (57 +/- 5 mg/100 ml) and 1.4 +/- 0.3 mmol/l (15 +/- 3 mg/100 ml) in the two groups respectively (P less than 0.01). Individual mean C-peptide concentrations showed a significant inverse correlation with the final blood glucose values (r = -0.91; P less than 0.02). These findings strongly suggest that even minimal residual insulin secretion is important for metabolic wellbeing in diabetes and may prevent the development of severe ketoacidosis when insulin delivery is inadequate.