Showing papers by "Filip K. Knop published in 2016"

Benefits and Harms of Sodium-Glucose Co-Transporter 2 Inhibitors in Patients with Type 2 Diabetes: A Systematic Review and Meta-Analysis.

Abstract: Objective Sodium-glucose co-transporter 2 inhibitors (SGLT2-i) are a novel drug class for the treatment of diabetes. We aimed at describing the maximal benefits and risks associated with SGLT2-i for patients with type 2 diabetes.

Evidence of Extrapancreatic Glucagon Secretion in Man

Abstract: Glucagon is believed to be a pancreas-specific hormone, and hyperglucagonemia has been shown to contribute significantly to the hyperglycemic state of patients with diabetes. This hyperglucagonemia has been thought to arise from α-cell insensitivity to suppressive effects of glucose and insulin combined with reduced insulin secretion. We hypothesized that postabsorptive hyperglucagonemia represents a gut-dependent phenomenon and subjected 10 totally pancreatectomized patients and 10 healthy control subjects to a 75-g oral glucose tolerance test and a corresponding isoglycemic intravenous glucose infusion. We applied novel analytical methods of plasma glucagon (sandwich ELISA and mass spectrometry-based proteomics) and show that 29-amino acid glucagon circulates in patients without a pancreas and that glucose stimulation of the gastrointestinal tract elicits significant hyperglucagonemia in these patients. These findings emphasize the existence of extrapancreatic glucagon (perhaps originating from the gut) in man and suggest that it may play a role in diabetes secondary to total pancreatectomy.

GLP-1 and Amylin in the Treatment of Obesity

Abstract: For decades, extensive research has aimed to clarify the role of pancreas and gut-derived peptide hormones in the regulation of glucose homeostasis and feeding behavior. Among these are the beta-cell hormone amylin and the intestinal L cell hormone glucagon-like peptide-1 (GLP-1). They exhibit distinct and yet several similar physiological actions including suppression of food intake, postprandial glucagon secretion, and gastric emptying-altogether lowering plasma glucose and body weight. These actions have been clinically exploited by the development of amylin and GLP-1 hormone analogs now used for treatment of diabetes and obesity. This review will outline the physiology and pharmacological potential of amylin and GLP-1, respectively, and focus on innovative peptide drug development leading to drugs acting on two or more distinct receptors, such as an amylin and GLP-1 peptide hybrid, potentially producing a more effective treatment strategy to combat the rapidly increasing global obesity.

Effect of the EndoBarrier Gastrointestinal Liner on obesity and type 2 diabetes: a systematic review and meta-analysis

Abstract: Compared with bariatric surgery, less invasive and reversible techniques to counteract obesity and type 2 diabetes (T2D) have been developed, including the EndoBarrier Gastrointestinal Liner [duodenal-jejunal bypass sleeve (DJBS)]. We conducted a systematic review and meta-analyses of eligible trials to evaluate the efficacy and safety of the DJBS. Five randomized controlled trials (RCTs; 235 subjects) and 10 observational studies (211 subjects) were included. The risk of bias was evaluated as high in all studies. The mean body mass index ranged from 30 to 49.2 kg/m(2) and 10-100% of the subjects had T2D. Meta-analysis showed that the DJBS was associated with significant mean differences in body weight and excess weight loss of -5.1 kg [95% confidence interval (CI) -7.3, -3.0; four trials; n = 151; I(2) = 37%] and 12.6% (95% CI 9.0, 16.2; four trials; n = 166; I(2) = 24%), respectively, compared with diet modification. The mean differences in glycated haemoglobin (-0.9%; 95% CI -1.8, 0.0) and fasting plasma glucose (-3.7 mM; 95% CI -8.2, 0.8) among subjects with T2D did not reach statistical significance. Adverse events consisted mainly of abdominal pain, nausea and vomiting. No deaths occurred. Future high-quality long-term RCTs are needed to further assess efficacy and safety.

Postprandial Plasma Concentrations of Individual Bile Acids and FGF-19 in Patients With Type 2 Diabetes

Abstract: Context: Bile acids regulate lipid and carbohydrate metabolism by interaction with membrane or intracellular proteins including the nuclear farnesoid X receptor (FXR). Postprandial activation of ileal FXR leads to secretion of fibroblast growth factor 19 (FGF-19), a gut hormone that may be implicated in postprandial glucose metabolism. Objective: To describe postprandial plasma concentrations of 12 individual bile acids and FGF-19 in patients with type 2 diabetes (T2D) and healthy controls. Design and Setting: Descriptive study, performed at the Center for Diabetes Research, Gentofte Hospital, Hellerup, Denmark. Participants: Fifteen patients with T2D and 15 healthy matched controls with normal glucose tolerance. Interventions: A 75-g oral glucose tolerance test and three isocaloric and isovolemic liquid meals with low, medium, and high fat content, respectively. Main Outcome Measures: Bile acid and FGF-19 concentrations. Results: Postprandial total bile acid concentrations increased with increasing meal ...

The biology of glucagon and the consequences of hyperglucagonemia.

Abstract: The proglucagon-derived peptide hormone, glucagon, comprises 29 amino acids. Its secretion from the pancreatic α cells is regulated by several factors. Glucagon increases blood glucose levels through gluconeogenesis and glycogenolysis. Elevated plasma concentrations of glucagon, hyperglucagonemia, may contribute to diabetes. However, hyperglucagonemia is also observed in other clinical conditions than diabetes, including nonalcoholic fatty liver disease, glucagon-producing tumors and after gastric bypass surgery. Here, we review the current literature on hyperglucagonemia in disease with a particular focus on diabetes, and finally speculate that the primary physiological importance of glucagon may not reside in glucose homeostasis but in regulation of amino acid metabolism exerted via a hitherto unrecognized hepato-pancreatic feedback loop.

N‐terminally and C‐terminally truncated forms of glucose‐dependent insulinotropic polypeptide are high‐affinity competitive antagonists of the human GIP receptor

Abstract: Background and Purpose Glucose-dependent insulinotropic polypeptide (GIP) affects lipid, bone and glucose homeostasis. High-affinity ligands for the GIP receptor are needed to elucidate the physiological functions and pharmacological potential of GIP in vivo. GIP(1–30)NH2 is a naturally occurring truncation of GIP(1–42). Here, we have characterized eight N-terminal truncations of human GIP(1–30)NH2. Experimental Approach COS-7 cells were transiently transfected with human GIP receptors and assessed for cAMP accumulation upon ligand stimulation or competition binding with 125I-labelled GIP(1–42), GIP(1–30)NH2, GIP(2–30)NH2 or GIP(3–30)NH2. Key Results GIP(1–30)NH2 displaced 125I-GIP(1–42) as effectively as GIP(1–42) (Ki 0.75 nM), whereas the eight truncations displayed lower affinities (Ki 2.3–347 nM) with highest affinities for GIP(3–30)NH2 and GIP(5–30)NH2 (5–30)NH2. Only GIP(1–30)NH2 (Emax 100% of GIP(1–42)) and GIP(2–30)NH2 (Emax 20%) were agonists. GIP(2- to 9–30)NH2 displayed antagonism (IC50 12–450 nM) and Schild plot analyses identified GIP(3–30)NH2 and GIP(5–30)NH2 as competitive antagonists (Ki 15 nM). GIP(3–30) NH2 was a 26-fold more potent antagonist than GIP(3–42). Binding studies with agonist (125I-GIP(1–30)NH2), partial agonist (125I-GIP(2–30)NH2) and competitive antagonist (125I-GIP(3–30)NH2) revealed distinct receptor conformations for these three ligand classes. Conclusions and Implications The N-terminus is crucial for GIP agonist activity. Removal of the C-terminus of the endogenous GIP(3–42) creates another naturally occurring, more potent, antagonist GIP(3–30)NH2, which like GIP(5–30)NH2, was a high-affinity competitive antagonist. These peptides may be suitable tools for basic GIP research and future pharmacological interventions.

Species-specific action of (Pro3)GIP – a full agonist at human GIP receptors, but a partial agonist and competitive antagonist at rat and mouse GIP receptors

Abstract: Background and Purpose Specific, high potency receptor antagonists are valuable tools when evaluating animal and human physiology. Within the glucose-dependent, insulinotropic polypeptide (GIP) system, considerable attention has been given to the presumed GIP receptor antagonist, (Pro3)GIP, and its effect in murine studies. We conducted a pharmacological analysis of this ligand including interspecies differences between the rodent and human GIP system. Experimental Approach Transiently transfected COS-7 cells were assessed for cAMP accumulation upon ligand stimulation and assayed in competition binding using 125I-human GIP. Using isolated perfused pancreata both from wild type and GIP receptor-deficient rodents, insulin-releasing, glucagon-releasing and somatostatin-releasing properties in response to species-specific GIP and (Pro3)GIP analogues were evaluated. Key Results Human (Pro3)GIP is a full agonist at human GIP receptors with similar efficacy (Emax) for cAMP production as human GIP, while both rat and mouse(Pro3)GIP were partial agonists on their corresponding receptors. Rodent GIPs are more potent and efficacious at their receptors than human GIP. In perfused pancreata in the presence of 7 mM glucose, both rodent (Pro3)GIP analogues induced modest insulin, glucagon and somatostatin secretion, corresponding to the partial agonist activities observed in cAMP production. Conclusions and Implications When evaluating new compounds, it is important to consider interspecies differences both at the receptor and ligand level. Thus, in rodent models, human GIP is a comparatively weak partial agonist. Human (Pro3)GIP was not an antagonist at human GIP receptors, so there is still a need for a potent antagonist in order to elucidate the physiology of human GIP.

Effect of chenodeoxycholic acid and the bile acid sequestrant colesevelam on glucagon-like peptide-1 secretion.

Abstract: Aim To evaluate the effects of the primary human bile acid, chenodeoxycholic acid (CDCA), and the bile acid sequestrant (BAS) colesevelam, instilled into the stomach, on plasma levels of glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide, glucose, insulin, C-peptide, glucagon, cholecystokinin and gastrin, as well as on gastric emptying, gallbladder volume, appetite and food intake. Methods On four separate days, nine patients with type 2 diabetes, and 10 matched healthy control subjects received bolus instillations of (i) CDCA, (ii) colesevelam, (iii) CDCA + colesevelam or (iv) placebo. At baseline and for 180 min after instillation, blood was sampled. Results In both the type 2 diabetes group and the healthy control group, CDCA elicited an increase in GLP-1 levels compared with colesevelam, CDCA + colesevelam and placebo, respectively (p < 0.05). The interventions did not affect plasma glucose, insulin or C-peptide concentrations in any of the groups. CDCA elicited a small increase in plasma insulin : glucose ratio compared with colesevelam, CDCA + colesevelam and placebo in both groups. Compared with colesevelam, CDCA + colesevelam and placebo, respectively, CDCA increased glucagon and delayed gastric emptying in both groups. Conclusions CDCA increased GLP-1 and glucagon secretion, and delayed gastric emptying. We speculate that bile acid-induced activation of TGR5 on L cells increases GLP-1 secretion, which, in turn, may result in amplification of glucose-stimulated insulin secretion. Furthermore our data suggest that colesevelam does not have an acute effect on GLP-1 secretion in humans.

Palaeolithic diet decreases fasting plasma leptin concentrations more than a diabetes diet in patients with type 2 diabetes: a randomised cross-over trial

Abstract: We have previously shown that a Palaeolithic diet consisting of the typical food groups that our ancestors ate during the Palaeolithic era, improves cardiovascular disease risk factors and glucose control compared to the currently recommended diabetes diet in patients with type 2 diabetes. To elucidate the mechanisms behind these effects, we evaluated fasting plasma concentrations of glucagon, insulin, incretins, ghrelin, C-peptide and adipokines from the same study. In a randomised, open-label, cross-over study, 13 patients with type 2 diabetes were randomly assigned to eat a Palaeolithic diet based on lean meat, fish, fruits, vegetables, root vegetables, eggs and nuts, or a diabetes diet designed in accordance with current diabetes dietary guidelines during two consecutive 3-month periods. The patients were recruited from primary health-care units and included three women and 10 men [age (mean ± SD) 64 ± 6 years; BMI 30 ± 7 kg/m2; diabetes duration 8 ± 5 years; glycated haemoglobin 6.6 ± 0.6 % (57.3 ± 6 mmol/mol)] with unaltered diabetes treatment and stable body weight for 3 months prior to the start of the study. Outcome variables included fasting plasma concentrations of leptin, adiponectin, adipsin, visfatin, resistin, glucagon, insulin, C-peptide, glucose-dependent insulinotropic polypeptide, glucagon-like peptide-1 and ghrelin. Dietary intake was evaluated by use of 4-day weighed food records. Seven participants started with the Palaeolithic diet and six with the diabetes diet. The Palaeolithic diet resulted in a large effect size (Cohen’s d = −1.26) at lowering fasting plasma leptin levels compared to the diabetes diet [mean difference (95 % CI), −2.3 (−5.1 to 0.4) ng/ml, p = 0.023]. No statistically significant differences between the diets for the other variables, analysed in this study, were observed. Over a 3-month study period, a Palaeolithic diet resulted in reduced fasting plasma leptin levels, but did not change fasting levels of insulin, C-peptide, glucagon, incretins, ghrelin and adipokines compared to the currently recommended diabetes diet. Trial registration: ClinicalTrials.gov NCT00435240

Effect of antibiotics on gut microbiota, glucose metabolism and body weight regulation: a review of the literature

Abstract: Gut bacteria are involved in a number of host metabolic processes and have been implicated in the development of obesity and type 2 diabetes in humans. The use of antibiotics changes the composition of the gut microbiota and there is accumulating evidence from observational studies for an association between exposure to antibiotics and development of obesity and type 2 diabetes. In the present paper, we review human studies examining the effects of antibiotics on body weight regulation and glucose metabolism and discuss whether the observed findings may relate to alterations in the composition and function of the gut microbiota.

Diabetic and nondiabetic patients with nonalcoholic fatty liver disease have an impaired incretin effect and fasting hyperglucagonaemia

Abstract: Objective We evaluated whether patients with histologically verified nonalcoholic fatty liver disease (NAFLD) have an impaired incretin effect and hyperglucagonaemia. Methods Four groups matched for age, sex and body mass index were studied: (i) 10 patients with normal glucose tolerance and NAFLD; (ii) 10 patients with type 2 diabetes and NAFLD; (iii) eight patients with type 2 diabetes and no liver disease; and (iv) 10 controls. All participants underwent a 50-g oral glucose tolerance test (OGTT) and an isoglycaemic intravenous glucose infusion (IIGI). We determined the incretin effect by relating the beta cell secretory responses during the OGTT and IIGI. Data are presented as medians (interquartile range), and the groups were compared by using the Kruskal–Wallis test. Results Controls exhibited a higher incretin effect [55% (43–73%)] compared with the remaining three groups (P < 0.001): 39% (44–71%) in the nondiabetic NAFLD patients, 20% (−5−50%) in NAFLD patients with type 2 diabetes, and 2% (−8−6%) in patients with type 2 diabetes and no liver disease. We found fasting hyperglucagonaemia in NAFLD patients with [7.5 pmol L−1 (6.8–15 pmol L−1)] and without diabetes [7.5 pmol L−1 (5.0–8.0 pmol L−1)]. Fasting glucagon levels were lower but similar in patients with type 2 diabetes and no liver disease [4.5 pmol L−1 (3.0–6.0 pmol L−1)] and controls [3.4 pmol L−1 (1.8–6.0 pmol L−1)]. All groups had similar glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide responses. Conclusions Patients with NAFLD have a reduced incretin effect and fasting hyperglucagonaemia, with the latter occurring independently of glucose (in)tolerance.

Involvement of glucagon‐like peptide‐1 in the glucose‐lowering effect of metformin

Abstract: Metformin is an oral antihyperglycaemic drug used in the first-line treatment of type 2 diabetes. Metformin's classic and most well-known blood glucose-lowering mechanisms include reduction of hepatic gluconeogenesis and increased peripheral insulin sensitivity. Interestingly, intravenously administered metformin is ineffective and recently, metformin was shown to increase plasma concentrations of the glucose-lowering gut incretin hormone glucagon-like peptide-1 (GLP-1), which may contribute to metformin's glucose-lowering effect in patients with type 2 diabetes. The mechanisms behind metformin-induced increments in GLP-1 levels remain unknown, but it has been hypothesized that metformin stimulates GLP-1 secretion directly and/or indirectly and that metformin prolongs the half-life of GLP-1. Also, it has been suggested that metformin may potentiate the glucose-lowering effects of GLP-1 by increasing target tissue sensitivity to GLP-1. The present article critically reviews the possible mechanisms by which metformin may affect GLP-1 levels and sensitivity and discusses whether such alterations may constitute important and clinically relevant glucose-lowering actions of metformin.

Cephalic phase secretion of insulin and other enteropancreatic hormones in humans

Abstract: Enteropancreatic hormone secretion is thought to include a cephalic phase, but the evidence in humans is ambiguous. We studied vagally induced gut hormone responses with and without muscarinic blockade in 10 glucose-clamped healthy men (age: 24.5 ± 0.6 yr, means ± SE; body mass index: 24.0 ± 0.5 kg/m(2); HbA1c: 5.1 ± 0.1%/31.4 ± 0.5 mmol/mol). Cephalic activation was elicited by modified sham feeding (MSF, aka "chew and spit") with or without atropine (1 mg bolus 45 min before MSF + 80 ng·kg(-1)·min(-1) for 2 h). To mimic incipient prandial glucose excursions, glucose levels were clamped at 6 mmol/l on all days. The meal stimulus for the MSF consisted of an appetizing breakfast. Participants (9/10) also had a 6 mmol/l glucose clamp without MSF. Pancreatic polypeptide (PP) levels rose from 6.3 ± 1.1 to 19.9 ± 6.8 pmol/l (means ± SE) in response to MSF and atropine lowered basal PP levels and abolished the MSF response. Neither insulin, C-peptide, glucose-dependent insulinotropic polypeptide (GIP), nor glucagon-like peptide-1 (GLP-1) levels changed in response to MSF or atropine. Glucagon and ghrelin levels were markedly attenuated by atropine prior to and during the clamp: at t = 105 min on the atropine (ATR) + clamp (CLA) + MSF compared with the saline (SAL) + CLA and SAL + CLA + MSF days; baseline-subtracted glucagon levels were -10.7 ± 1.1 vs. -4.0 ± 1.1 and -4.7 ± 1.9 pmol/l (means ± SE), P < 0.0001, respectively; corresponding baseline-subtracted ghrelin levels were 303 ± 36 vs. 39 ± 38 and 3.7 ± 21 pg/ml (means ± SE), P < 0.0001. Glucagon and ghrelin levels were unaffected by MSF. Despite adequate PP responses, a cephalic phase response was absent for insulin, glucagon, GLP-1, GIP, and ghrelin.

GLP-1 Restores Altered Insulin and Glucagon Secretion in Posttransplantation Diabetes.

Abstract: OBJECTIVE Development of posttransplantation diabetes (PTDM) is characterized by reduced insulin secretion and sensitivity. We aimed to investigate whether hyperglucagonemia could play a role in PTDM and to examine the insulinotropic and glucagonostatic effects of the incretin hormone glucagon-like peptide 1 (GLP-1) during fasting and hyperglycemic conditions, respectively. RESEARCH DESIGN AND METHODS Renal transplant recipients with (n = 12) and without (n = 12) PTDM underwent two separate experimental days with 3-h intravenous infusions of GLP-1 (0.8 pmol/kg/min) and saline, respectively. After 1 h of infusion, a 2-h hyperglycemic clamp (fasting plasma glucose + 5 mmol/L) was established. Five grams of arginine was given as an intravenous bolus 10 min before termination of the clamp. RESULTS Fasting concentrations of glucagon (P = 0.92) and insulin (P = 0.23) were similar between the groups. In PTDM patients, glucose-induced glucagon suppression was significantly less pronounced (maximal suppression from baseline: 43 ± 12 vs. 65 ± 12%, P CONCLUSIONS PTDM is characterized by reduced glucose-induced insulin secretion and attenuated glucagon suppression during a hyperglycemic clamp. Similar to the case in type 2 diabetes, GLP-1 infusion seems to improve (insulin) or even normalize (glucagon) these pathophysiological defects.

Diabetes and obesity treatment based on dual incretin receptor activation: 'twincretins'.

Abstract: The gut incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are secreted after meal ingestion and work in concert to promote postprandial insulin secretion and regulate glucagon secretion. GLP-1 also slows gastric emptying and suppresses appetite, whereas GIP seems to affect lipid metabolism. The introduction of selective GLP-1 receptor (GLP-1R) agonists for the treatment of type 2 diabetes and obesity has increased the scientific and clinical interest in incretins. Combining the body weight-lowering and glucose-lowering effects of GLP-1 with a more potent improvement of β cell function through additional GIP action could potentially offer a more effective treatment of diabetes and obesity, with fewer adverse effects than selective GLP-1R agonists; therefore, new drugs designed to co-activate both the GIP receptor (GIPR) and the GLP-1R simultaneously are under development. In the present review, we address advances in the field of GIPR and GLP-1R co-agonism and review in vitro studies, animal studies and human trials involving co-administration of the two incretins, as well as results from a recently developed GIPR/GLP-1R co-agonist, and highlight promising areas and challenges within the field of incretin dual agonists.

Diabetic Ketoacidosis in a Patient with Type 2 Diabetes After Initiation of Sodium-Glucose Cotransporter 2 Inhibitor Treatment.

Abstract: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) were recently introduced for the treatment of type 2 diabetes (T2D). SGLT2i lower plasma glucose by inhibiting the renal reuptake of glucose leading to glucosuria. Generally, these drugs are considered safe to use. However, recently, SGLT2i have been suggested to predispose to ketoacidosis. Here, we present a case of diabetic ketoacidosis (DKA) developed in an obese, poorly controlled male patient with T2D treated with the SGLT2i dapagliflozin. He was admitted with DKA 5 days after the initiation of treatment with the SGLT2i dapagliflozin. On admission, the primary symptoms were nausea and dizziness, and he was hypertensive (170/103) and tachycardic (119 bpm) and had mild hyperglycaemia (15.3 mmol/l), severe ketonuria and severe metabolic acidosis (pH 7.08). He responded well to infusions of insulin, glucose and saline and was discharged after 72 hr with insulin as the only glucose-lowering therapy. After 1 month, dapagliflozin was reintroduced as add-on to insulin with no recurrent signs of ketoacidosis. During acute illness or other conditions with increased insulin demands in diabetes, SGLT2i may predispose to the formation of ketone bodies and ensuing acidosis.

Inability of Some Commercial Assays to Measure Suppression of Glucagon Secretion

Abstract: Glucagon levels are increasingly being included as endpoints in clinical study design and more than 400 current diabetes-related clinical trials have glucagon as an outcome measure. The reliability of immune-based technologies used to measure endogenous glucagon concentrations is, therefore, important. We studied the ability of immunoassays based on four different technologies to detect changes in levels of glucagon under conditions where glucagon levels are strongly suppressed. To our surprise, the most advanced technological methods, employing electrochemiluminescence or homogeneous time resolved fluorescence (HTRF) detection, were not capable of detecting the suppression induced by a glucose clamp (6 mmol/L) with or without atropine in five healthy male participants, whereas a radioimmunoassay and a spectrophotometry-based ELISA were. In summary, measurement of glucagon is challenging even when state-of-the-art immune-based technologies are used. Clinical researchers using glucagon as outcome measures may need to reconsider the validity of their chosen glucagon assay. The current study demonstrates that the most advanced approach is not necessarily the best when measuring a low-abundant peptide such as glucagon in humans.

Cholecystokinin-Induced Gallbladder Emptying and Metformin Elicit Additive Glucagon-Like Peptide-1 Responses

Abstract: Context: Bile acids have been suggested to mediate glucagon-like peptide-1 (GLP-1) secretion. Metformin, too, has been shown to increase GLP-1 levels. The effect of gallbladder emptying, metformin, or a combination has, however, never been studied. Objective: We hypothesized that cholecystokinin (CCK)-8-induced gallbladder emptying stimulates human GLP-1 secretion and that metformin would potentiate this effect. Design: A double-blinded, randomized study. Setting: The study was conducted at a specialized research unit. Participants: Ten healthy male subjects with no family history of diabetes (age, 22 [range, 20–32] years; body mass index, 21.7 [19.3–24.2] kg/m2; fasting plasma glucose, 4.9 [4.7–5.3] mm; and glycosylated hemoglobin A1c, 5.1 [4.4–5.8] %). Intervention: On 4 separate days, the subjects received metformin or placebo and a concomitant 60-minute intravenous infusion of saline or CCK. Blood was sampled for 4 hours, and gallbladder volume was measured by ultrasound. Main Outcome Measures: Plasma...

A comprehensive compartmental model of blood glucose regulation for healthy and type 2 diabetic subjects

Abstract: We have expanded a former compartmental model of blood glucose regulation for healthy and type 2 diabetic subjects. The former model was a detailed physiological model which considered the interactions of three substances, glucose, insulin and glucagon on regulating the blood sugar. The main drawback of the former model was its restriction on the route of glucose entrance to the body which was limited to the intravenous glucose injection. To handle the oral glucose intake, we have added a model of glucose absorption in the gastrointestinal tract to the former model to address the resultant variations of blood glucose concentrations following an oral glucose intake. Another model representing the incretins production in the gastrointestinal tract along with their hormonal effects on boosting pancreatic insulin production is also added to the former model. We have used two sets of clinical data obtained during oral glucose tolerance test and isoglycemic intravenous glucose infusion test from both type 2 diabetic and healthy subjects to estimate the model parameters and to validate the model results. The estimation of model parameters is accomplished through solving a nonlinear optimization problem. The results show acceptable precision of the estimated model parameters and demonstrate the capability of the model in accurate prediction of the body response during the clinical studies.

Risk stratification by endocrinologists of patients with type 2 diabetes in a Danish specialised outpatient clinic: a cross-sectional study

Abstract: To target optimised medical care the Danish guidelines for diabetes recommend stratification of patients with type 2 diabetes (T2D) into three levels according to risk and complexity of treatment. The aim was to describe the T2D population in an outpatient clinic, measure the compliance of the endocrinologists’ to perform risk stratification, and investigate the level of concordance between stratification performed by the endocrinologists and objective assessments. A cross-sectional study with data collected from medical records and laboratory databases. The Danish risk stratification model contained the following criteria: HbA1c, blood pressure, metabolic complications, microvascular and macrovascular complications. Stratification levels encompassed: level 1 (uncomplicated), level 2 (intermediate risk) and level 3 (high risk). Objective assessments were conducted independently by two health professionals, and compared with the endocrinologists’ assessments. In order to test the degree of concordance, we conducted Cohen's kappa, McNemar’s test for marginal homogeneity, and Bowker’s test for symmetry. Of 245 newly referred patients, 209 (85 %) were stratified by the endocrinologists to level 1 (16 %), level 2 (55 %) and level 3 (29 %). By objective assessments, 4 % were stratified to level 1, 51 % to level 2 and 45 % to level 3. Of 419 long-term follow-up patients, 380 (91 %) were stratified by the endocrinologists to level 1 (5 %), level 2 (57 %), level 3 (38 %). By objective assessments, 3 % were stratified to level 1, 58 % to level 2 and 39 % to level 3. The concordance rate between endocrinologists’ and objective assessments was 63 % among newly referred (kappa 0.39; fair agreement) and 67 % for long-term follow-up (kappa 0.45; moderate agreement). Among newly referred patients, the endocrinologists stratified less patients at level 3 compared to objective assessments (p < 0.0001). There were no significant differences in marginal distribution within long-term follow-up patients. Type 2 diabetes patients, newly referred to or allocated for long-term follow-up in the out-patient clinic, were mainly intermediate and high-risk, complicated patients (96 % and 95 %, respectively). Compliance of stratification by endocrinologists was high. The concordance between endocrinologists’ and objective assessments was not strong. Our data suggest that clinician-support for stratification level categorisation might be needed.

Semimechanistic model describing gastric emptying and glucose absorption in healthy subjects and patients with type 2 diabetes

Abstract: The integrated glucose-insulin (IGI) model is a previously published semi-mechanistic model, which describes plasma glucose and insulin concentrations after glucose challenges. The aim of this work ...

Higher Endogenous Glucose Production During OGTT vs Isoglycemic Intravenous Glucose Infusion

Abstract: Context: Oral glucose ingestion elicits a larger insulin response and delayed suppression of glucagon compared to isoglycemic IV glucose infusion (IIGI). Objective: We studied whether these differences translate into effects on endogenous glucose production (EGP) and glucose disposal in patients with type 2 diabetes and nondiabetic control subjects. Design: This was a single-blinded, randomized, crossover study. Setting: The study was conducted at a specialized research unit. Participants: Ten patients with type 2 diabetes (age, [mean ± SD] 57.1 ± 6.7 years; body mass index, 29.0 ± 4.3 kg/m2; hemoglobin A1c, 53.8 ± 11.0 mmol/mol; duration of diabetes, 9.2 ± 5.0 years) and 10 matched nondiabetic control subjects (age, 56.0±10.7 years; body mass index, 29.8 ± 2.9 kg/m2; hemoglobin A1c, 33.8 ± 5.5 mmol/mol) participated. Interventions: Three experimental days: 75 g-oral glucose tolerance test (OGTT), IIGI, and IIGI+glucagon (IIGI with a concomitant IV glucagon infusion [0.8 ng/kg/min from 0 to 25 minutes] de...

Mechanism-Based Modeling of Gastric Emptying Rate and Gallbladder Emptying in Response to Caloric Intake.

Abstract: Bile acids released postprandially modify the rate and extent of absorption of lipophilic compounds. The present study aimed to predict gastric emptying (GE) rate and gallbladder emptying (GBE) patterns in response to caloric intake. A mechanism-based model for GE, cholecystokinin plasma concentrations, and GBE was developed on data from 33 patients with type 2 diabetes and 33 matched nondiabetic individuals who were administered various test drinks. A feedback action of the caloric content entering the proximal small intestine was identified for the rate of GE. The cholecystokinin concentrations were not predictive of GBE, and an alternative model linking the nutrients amount in the upper intestine to GBE was preferred. Relative to fats, the potency on GBE was 68% for proteins and 2.3% for carbohydrates. The model predictions were robust across a broad range of nutritional content and may potentially be used to predict postprandial changes in drug absorption.

Shared care management of patients with type 2 diabetes across the primary and secondary healthcare sectors: study protocol for a randomised controlled trial

Abstract: The prevalence of type 2 diabetes (T2D) is growing globally and hospital-based outpatient clinics are burdened with increasing numbers of patients. To ensure high quality treatment and care, it is necessary to structurally reorganise the management of patients with T2D. The objective of this study is to test if T2D patients (who are at intermediate risk of or are already having incipient diabetic complications) jointly managed by a hospital-based outpatient clinic and general practitioners (shared care programme) have a non-inferior outcome compared to an established programme in a specialised (hospital based) outpatient diabetes clinic. The study is designed as a randomised controlled trial. The shared care model will be tested during a period of 3 years, with data collection at baseline and at 12, 24 and 36 months. All patients will be offered four medical visits a year; the shared care intervention consists of one annual comprehensive check-up at the outpatient clinic and three quarterly visits at the general practitioners’ office. The control group will be followed with four quarterly visits at the outpatient clinic, including an annual comprehensive check-up. In the outpatient clinic, the patients will be treated by a specialised diabetes team, including an endocrinologist. On the basis of a predefined stratification model, we will recruit patients stratified to be at intermediate risk of or already having incipient diabetic complications. We plan to include 140 patients. The primary outcome is glycated haemoglobin. Other outcome measures include (1) the proportion of patients who meet the Danish standard indicators reflecting quality of care; (2) quality of life measured by Short Form 36; and (3) the functionality of the patients’ families measured by Family Assessment Measure III. The experiences of the patients and families when participating in the shared care program will be explored by collecting dyadic interviews. This study will evaluate the quality of a shared care programme for patients with T2D, and provide evidence about advantages and disadvantages compared with a programme in a specialised outpatient clinic. The results may provide important information on how to organise the care for patients with T2D in the future. This trial was registered with Clinicaltrials.gov on 21 October 2015, registration number: NCT02586545 .

Vagotomy and subsequent development of diabetes - A nested case-control study.

Abstract: Background Vagal signaling is involved in gastric emptying and the secretion and effect of a number of hormones regulating gluco-metabolic processes and, thus, crucial for metabolic homeostasis. Purpose We hypothesized that vagotomy would increase the risk of developing type 2 diabetes and examined the association between vagotomy and subsequent development of diabetes. Methods A nested case–control study was conducted with information on cases and controls from the Danish National Patient Registry. Cases included individuals with a diabetes diagnosis subsequent (> 12 months) to the first registration of vagotomy and/or upper gastrointestinal disease in the period 1977–2011. Controls had no subsequent diagnosis of diabetes and were matched by incidence density sampling, age and gender. Logistic regression analyses were conducted. Results 501,724 diabetes patients and 1,375,567 matched controls were included in the analysis. Vagotomy was performed on 2772 individuals and 148,489 individuals had an upper gastrointestinal diagnosis. In this combined population, 30,902 were diagnosed with diabetes. The mean follow-up was 16 years. The unadjusted odds ratio for developing diabetes following vagotomy was 0.64 (95% confidence interval (CI): 0.58–0.71) and did not change in an adjusted analysis (0.64, 95% CI: 0.58–0.70). When restricting the multivariate-adjusted analysis to patients with type 2 diabetes and type 1 diabetes, respectively, the multivariate odds ratios were 0.79 (95% CI: 0.70–0.89) and 0.75 (95% CI 0.53–1.08), respectively. Conclusion Vagotomy was associated with a significantly decreased risk of developing type 2 diabetes in a population of patients with upper gastrointestinal disease.