Daniël H. van Raalte

Glucagon-Like Peptide-1 Receptor Agonist Treatment Prevents Glucocorticoid-Induced Glucose Intolerance and Islet-Cell Dysfunction in Humans

OBJECTIVE Glucocorticoids (GCs) are regarded as diabetogenic because they impair insulin sensitivity and islet-cell function. This study assessed whether treatment with the glucagon-like peptide receptor agonist (GLP-1 RA) exenatide (EXE) could prevent GC-induced glucose intolerance. RESEARCH DESIGN AND METHODS A randomized, placebo-controlled, double-blind, crossover study in eight healthy men (age: 23.5 [20.0–28.3] years; BMI: 26.4 [24.3–28.0] kg/m2) was conducted. Participants received three therapeutic regimens for 2 consecutive days: 1) 80 mg of oral prednisolone (PRED) every day (q.d.) and intravenous (IV) EXE infusion (PRED+EXE); 2) 80 mg of oral PRED q.d. and IV saline infusion (PRED+SAL); and 3) oral placebo-PRED q.d. and intravenous saline infusion (PLB+SAL). On day 1, glucose tolerance was assessed during a meal challenge test. On day 2, participants underwent a clamp procedure to measure insulin secretion and insulin sensitivity. RESULTS PRED+SAL treatment increased postprandial glucose levels (vs. PLB+SAL, P = 0.012), which was prevented by concomitant EXE (vs. PLB+SAL, P = NS). EXE reduced PRED-induced hyperglucagonemia during the meal challenge (P = 0.018) and decreased gastric emptying (vs. PRED+SAL, P = 0.028; vs. PLB+SAL, P = 0.046). PRED+SAL decreased first-phase glucose- and arginine-stimulated C-peptide secretion (vs. PLB+SAL, P = 0.017 and P = 0.05, respectively), whereas PRED+EXE improved first- and second-phase glucose- and arginine-stimulated C-peptide secretion (vs. PLB+SAL; P = 0.017, 0.012, and 0.093, respectively). CONCLUSIONS The GLP-1 RA EXE prevented PRED-induced glucose intolerance and islet-cell dysfunction in healthy humans. Incretin-based therapies should be explored as a potential strategy to prevent steroid diabetes.

Acute and 2-week exposure to prednisolone impair different aspects of β-cell function in healthy men

OBJECTIVE Glucocorticoids (GCs), such as prednisolone, are associated with adverse metabolic effects, including glucose intolerance and diabetes. In contrast to the well known GC-induced insulin resistance, the effects of GCs on beta-cell function are less well established. We assessed the acute and short-term effects of prednisolone treatment on beta-cell function in healthy men. RESEARCH DESIGN AND METHODS A randomised, double-blind, placebo-controlled trial consisting of two protocols was conducted. In protocol 1 (n=6), placebo and a single dose of 75 mg of prednisolone were administered. In protocol 2 (n=23), participants received 30 mg of prednisolone daily or placebo for 15 days. Both empirical and model-based parameters of beta-cell function were calculated from glucose, insulin and C-peptide concentrations obtained during standardised meal tests before and during prednisolone treatment (protocols 1 and 2), and 1 day after cessation of treatment (protocol 2). RESULTS Seventy-five milligrams of prednisolone acutely increased the area under the postprandial glucose curve (AUC(gluc); P=0.005), and inhibited several parameters of beta-cell function, including AUC(c-pep)/AUC(gluc) ratio (P=0.004), insulinogenic index (P=0.007), glucose sensitivity (P=0.02) and potentiation factor ratio (PFR; P=0.04). A 15-day treatment with prednisolone increased AUC(gluc) (P<0.001), despite augmented C-peptide secretion (P=0.05). beta-cell function parameters were impaired, including the fasting insulin secretory tone (P=0.02) and PFR (P=0.007). CONCLUSIONS Acute and short-term exposure to prednisolone impairs different aspects of beta-cell function, which contribute to its diabetogenic effects.

Glucolipotoxicity and beta cells in type 2 diabetes mellitus: Target for durable therapy?

Type 2 diabetes mellitus (T2DM) is characterised by beta-cell failure in the setting of obesity-related insulin resistance. Progressive beta-cell dysfunction determines the course of the disease, regardless of the treatment used. There is mounting evidence that chronically elevated circulating levels of glucose and fatty acids contribute to relentless beta-cell function decline, by endorsing processes commonly referred to as glucolipotoxicity. Mechanisms related to glucolipotoxicity include endoplasmic reticulum (ER) stress, oxidative stress, mitochondrial dysfunction and islet inflammation. The most commonly prescribed blood-glucose lowering agents, metformin and sul-fonylurea, may temporarily improve glycaemic control, however, these drugs do not alter the continuous decline in beta-cell function in T2DM patients. Evidence exists that novel classes of drugs, the thiazolidinediones (TZDs) and incretin-based therapies, may be able to preserve beta-cell function and functional beta-cell mass, amongst others by reducing glucolipotoxicity in the beta cell. The durability of the effects of TZDs and incretin-based therapies on beta-cell function, whether given as monotherapy or combined with other treatment, should be addressed in future, long-term clinical studies.

Pancreatic steatosis in humans: cause or marker of lipotoxicity?

Purpose of reviewType 2 diabetes mellitus (T2DM) is characterized by impaired insulin secretion. Chronically increased levels of plasma nonesterified fatty acids (NEFA) and triglyceride-rich lipoproteins impair beta-cell function, a process referred to as lipotoxicity. Furthermore, when NEFA supply exceeds metabolic capacity, lipids accumulate in nonadipose tissues, such as pancreatic islets, inducing organ dysfunction. The purpose of this review is to describe the mechanisms underlying lipotoxicity in vitro, to discuss the evidence for lipotoxicity in vivo and to address whether pancreatic lipid accumulation interferes with insulin secretion in humans. Recent findingsAlthough numerous in-vitro studies have shown that chronically elevated NEFA levels induce beta-cell dysfunction and apoptosis, studies in humans are less conclusive. It has been acknowledged that concurrent hyperglycaemia amplifies the adverse effects of elevated plasma NEFA levels on beta-cell function; therefore glucolipotoxicity should be the preferred term. Lipid accumulation in pancreatic islets impaired beta-cell secretory capacity in leptin-deficient rodents. In humans, recent studies employing noninvasive magnetic resonance-technology and computed tomography-technology, lipid accumulation in the pancreas was increased in individuals with impaired glucose metabolism and T2DM. However, there was no clear association with beta-cell dysfunction. SummaryTo date, it is difficult to provide evidence that intraislet lipid accumulation truly exists in humans and that it is indeed causal to beta-cell dysfunction. Additional research is warranted to further detail the nature and role of pancreatic lipid content in humans, its consequence for the postulated processes pertinent to glucolipotoxicity and its contribution to the progressive nature of beta-cell dysfunction in prediabetes.

Role of the Gut Microbiome in the Pathogenesis of Obesity and Obesity-Related Metabolic Dysfunction

The potential role of intestinal microbiota in the etiology of various human diseases has attracted massive attention in the last decade. As such, the intestinal microbiota has been advanced as an important contributor in the development of obesity and obesity-related metabolic dysfunctions, amongst others. Experiments in animal models have produced evidence for a causal role of intestinal microbiota in the etiology of obesity and insulin resistance. However, with a few exceptions, such causal relation is lacking for humans and most publications merely report associations between intestinal microbial composition and metabolic disorders such as obesity and type 2 diabetes. Thus, the reciprocal relationship between the bacteria and these metabolic disorders remains a matter of debate. The main objective of this review is to critically assess the driving role of intestinal microbe composition in the etiology, prevention, and treatment of obesity and obesity-related metabolic dysfunction, including type 2 diabetes.

Metabolic effects of high-dose prednisolone treatment in early rheumatoid arthritis: Balance between diabetogenic effects and inflammation reduction

OBJECTIVE To investigate the dose-related effects of glucocorticoid treatment on glucose tolerance, beta cell function, and insulin sensitivity in patients with early active rheumatoid arthritis (RA). METHODS A randomized, controlled, single-blind trial was conducted in 41 patients with early active RA. At the beginning of the trial patients had not been treated for their RA, and were randomized to begin treatment with prednisolone at 60 mg/day or 30 mg/day. Before and at the end of 1 week of treatment, a frequently sampled oral glucose tolerance test was performed. The glucose area under the curve (AUC(G) ) was calculated. In addition, beta cell function and insulin sensitivity parameters were computed. RESULTS Patients (mean ± SD age 55.5 ± 14.8 years and 54.2 ± 12.6 years in the prednisone 60 mg/day and prednisone 30 mg/day groups, respectively; body mass index 24.5 ± 4.1 kg/m(2) and 25.4 ± 4.2 kg/m(2) , respectively) had active disease at baseline (mean ± SD Disease Activity Score in 44 joints 4.1 ± 0.7 and 4.0 ± 0.8, respectively; median C-reactive protein [CRP] level 14 mg/liter [interquartile range 6-34] and 19 mg/liter [interquartile range 3-39], respectively). In addition, 56% of the patients had impaired glucose tolerance at baseline, and 7% were found to have previously unrecognized type 2 diabetes mellitus (DM). Associations of the AUC(G) with erythrocyte sedimentation rate (β = 2.430 [95% confidence interval 0.179-4.681], P = 0.04) and with CRP level (β = 2.358 [95% confidence interval 0.210-4.506], P = 0.03) were demonstrated. Treatment with prednisolone at both dosages reduced CRP levels significantly. The incidence of type 2 DM increased to 24% (P < 0.001) (evenly distributed across the groups). The mean AUC(G) did not change in either treatment arm. Beta cell function improved during prednisone treatment at 60 mg/day (P = 0.02) and at 30 mg/day (P = 0.04). Disease duration was associated with changes in the AUC(G) (β = 3.626 [95% confidence interval 1.077-6.174], P = 0.007) and with deterioration of the glucose state (odds ratio 1.068 [95% confidence interval 1.017-1.122], P = 0.009). CONCLUSION In this study, short-term treatment with prednisolone 60 mg or 30 mg per day improved disease activity without deterioration of glucose tolerance in patients with active RA. However, due to individual differences, monitoring is recommended.

GLP-1 and the kidney: from physiology to pharmacology and outcomes in diabetes

The gastrointestinal tract — the largest endocrine network in human physiology — orchestrates signals from the external environment to maintain neural and hormonal control of homeostasis. Advances in understanding entero-endocrine cell biology in health and disease have important translational relevance. The gut-derived incretin hormone glucagon-like peptide 1 (GLP-1) is secreted upon meal ingestion and controls glucose metabolism by modulating pancreatic islet cell function, food intake and gastrointestinal motility, amongst other effects. The observation that the insulinotropic actions of GLP-1 are reduced in type 2 diabetes mellitus (T2DM) led to the development of incretin-based therapies — GLP-1 receptor agonists and dipeptidyl peptidase 4 (DPP-4) inhibitors — for the treatment of hyperglycaemia in these patients. Considerable interest exists in identifying effects of these drugs beyond glucose-lowering, possibly resulting in improved macrovascular and microvascular outcomes, including in diabetic kidney disease. As GLP-1 has been implicated as a mediator in the putative gut–renal axis (a rapid-acting feed-forward loop that regulates postprandial fluid and electrolyte homeostasis), direct actions on the kidney have been proposed. Here, we review the role of GLP-1 and the actions of associated therapies on glucose metabolism, the gut–renal axis, classical renal risk factors, and renal end points in randomized controlled trials of GLP-1 receptor agonists and DPP-4 inhibitors in patients with T2DM.

Causality of small and large intestinal microbiota in weight regulation and insulin resistance.

Objective The twin pandemics of obesity and Type 2 diabetes (T2D) are a global challenge for health care systems. Changes in the environment, behavior, diet, and lifestyle during the last decades are considered the major causes. A Western diet, which is rich in saturated fat and simple sugars, may lead to changes in gut microbial composition and physiology, which have recently been linked to the development of metabolic diseases. Methods We will discuss evidence that demonstrates the influence of the small and large intestinal microbiota on weight regulation and the development of insulin resistance, based on literature search. Results Altered large intestinal microbial composition may promote obesity by increasing energy harvest through specialized gut microbes. In both large and small intestine, microbial alterations may increase gut permeability that facilitates the translocation of whole bacteria or endotoxic bacterial components into metabolic active tissues. Moreover, changed microbial communities may affect the production of satiety-inducing signals. Finally, bacterial metabolic products, such as short chain fatty acids (SCFAs) and their relative ratios, may be causal in disturbed immune and metabolic signaling, notably in the small intestine where the surface is large. The function of these organs (adipose tissue, brain, liver, muscle, pancreas) may be disturbed by the induction of low-grade inflammation, contributing to insulin resistance. Conclusions Interventions aimed to restoring gut microbial homeostasis, such as ingestion of specific fibers or therapeutic microbes, are promising strategies to reduce insulin resistance and the related metabolic abnormalities in obesity, metabolic syndrome, and type 2 diabetes. This article is part of a special issue on microbiota.

Does glucagon-like peptide-1 receptor agonist therapy add value in the treatment of type 2 diabetes? Focus on exenatide

Type 2 diabetes (T2DM) is a heterogeneous syndrome, characterized by beta-cell failure in the setting of obesity-related insulin resistance. T2DM has a progressive course and is associated with a high cardiovascular disease (CVD) risk, regardless of the treatment used. The incretin hormones glucagon-like peptide (GLP)-1 and glucose-dependent insulinotropic polypeptide (GIP) are secreted in the gut upon meal ingestion and lower blood glucose by glucose-dependent stimulation of insulin secretion and production. Exogenously administered GLP-1 lowers postprandial glucose excursions by inhibiting glucagon secretion and delaying gastric emptying, improves beta-cell function, and promotes satiety and weight loss. Native GLP-1 is degraded rapidly by the ubiquitous enzyme dipeptidyl-peptidase (DPP)-4. Thus, injectable DPP-4-resistant GLP-1 receptor agonists (GLP-1RA) and oral DPP-4 inhibitors have been developed. Exenatide is the first GLP-1RA that became available for the treatment of T2DM patients. Exenatide has unique characteristics, as to date it is the only agent that addresses the multiple defects of the T2DM phenotype, including hyperglycaemia, islet-cell dysfunction, alimentary obesity, insulin resistance, hypertension and dyslipidaemia. In animals, exenatide also increased beta-cell mass. Long-term prospective studies in high-risk populations should address the potentially disease modifying effect of exenatide and its effect on CVD risk, in addition to its safety and tolerability.

Renal effects of DPP-4 inhibitor sitagliptin or GLP-1 receptor agonist liraglutide in overweight patients with type 2 diabetes: A 12-week, randomized, double-blind, placebo-controlled trial

OBJECTIVE To investigate effects of dipeptidyl peptidase-4 inhibitor (DPP-4I) sitagliptin or glucagon-like peptide 1 (GLP-1) receptor agonist liraglutide treatment on renal hemodynamics, tubular functions, and markers of renal damage in overweight patients with type 2 diabetes without chronic kidney disease (CKD). RESEARCH DESIGN AND METHODS In this 12-week, randomized, double-blind trial, 55 insulin-naïve patients with type 2 diabetes (mean ± SEM: age 63 ± 7 years, BMI 31.8 ± 4.1 kg/m2, glomerular filtration rate [GFR] 83 ± 16 mL/min/1.73 m2; median [interquartile range]: albumin-to-creatinine ratio (ACR) 1.09 mg/mmol [0.47–3.31]) received sitagliptin (100 mg/day), liraglutide (1.8 mg/day), or matching placebos. GFR (primary end point) and effective renal plasma flow (ERPF) were determined by inulin and para-aminohippuric acid clearance, respectively. Intrarenal hemodynamic variables were estimated. Absolute and fractional excretions of sodium (FENa), potassium, and urea (FEU) and renal damage markers (ACR, neutrophil gelatinase–associated lipocalin [NGAL], and kidney injury molecule-1 [KIM-1]) were measured. Plasma renin concentration (PRC) and glycated hemoglobin (HbA1c) were assessed. At weeks 2 and 6, estimated GFR and fractional electrolyte excretions were determined. RESULTS At week 12, GFR was not affected by sitagliptin (−6 mL/min/1.73 m2 [95% CI −14 to 3], P = 0.17) or liraglutide (+3 mL/min/1.73 m2 [−5 to 11], P = 0.46), compared with placebo. Sitagliptin modestly reduced estimated glomerular hydraulic pressure (PGLO; P = 0.043). ERPF, other intrarenal hemodynamic variables, renal damage markers, and PRC did not change for both treatments. Both agents reduced HbA1c. Only at week 2, sitagliptin increased FENa and FEU (P = 0.005). CONCLUSIONS Twelve-week treatment with sitagliptin or liraglutide does not affect measured renal hemodynamics. No sustained changes in tubular functions or alteration in renal damage markers were observed. The validity and clinical relevance of the slight sitagliptin-induced PGLO reduction remains speculative.