Effect of linagliptin on glucose metabolism and pancreatic beta cell function in patients with persistent prediabetes after metformin and lifestyle.

The goal of the study was to evaluate the effect of adding linagliptin to metformin and lifestyle on glucose levels and pancreatic ß-cell function in patients with persistent impaired glucose tolerance (IGT) after 12 months of metformin and lifestyle. A single center parallel double-blind randomized clinical trial with 6 months of follow-up was performed in patients with persistent IGT after 12 months of treatment with metformin and lifestyle; patients were randomized to continue with metformin 850 mg twice daily (M group, n = 12) or linagliptin/metformin 2.5/850 mg twice daily (LM group, n = 19). Anthropometric measurements were obtained by standard methods and by bioelectrical impedance; glucose was measured by dry chemistry, insulin by chemiluminescence, and pancreatic ß-cell function was calculated with the disposition index using glucose and insulin values during oral glucose tolerance test (OGTT) and adjusting by insulin sensitivity. The main outcomes were glucose levels during OGTT and pancreatic ß-cell function. Patients in the LM group had a reduction in weight (-1.7 ± 0.6, p < 0.05) and body mass index (BMI, -0.67 ± 0.2, p < 0.05). Glucose levels significantly improved in LM group with a greater reduction in the area under the glucose curve during OGTT (AUCGluc0_120min) as compared to the M group (-4425 ± 871 vs -1116 ± 1104 mg/dl/120 min, p < 0.001). Pancreatic ß-cell function measured with the disposition index, improved only in LM group (2.3 ± 0.23 vs 1.7 ± 0.27, p 0.001); these improvements persisted after controlling for OGTT glucose levels. The differences in pancreatic ß-cell function persisted also after pairing groups for basal AUCGluc0_120min. The addition of linagliptin to patients with persistent IGT after 12 months of treatment with metformin and lifestyle, improved glucose levels during OGTT and pancreatic ß-cell function after 6 months of treatment.Trial registration: Clinicaltrials.gov with the ID number NCT04088461.

Effect of pioglitazone treatment on brown adipose tissue volume and activity and hypothalamic gliosis in patients with type 2 diabetes mellitus: a proof-of-concept study.

AIMS: This study aimed to evaluate the effect of pioglitazone on brown adipose tissue function and hypothalamic gliosis in humans. Brown adipose tissue and the hypothalamus are regarded as important potential pharmacological targets to metabolic diseases, and defining the impact of current therapies on their structure and/or function could provide therapeutic advance in this field. METHODS: Six patients with type 2 diabetes were treated for 24 weeks with pioglitazone 30 mg/day as an add-on therapy. Brown adipose tissue glucose uptake and volume were determined using 18F-FDG PET/CT scans; hypothalamic gliosis was determined using MRI scans; blood was collected for hormone and biochemistry measurements. All tests were performed at inclusion and six months after pioglitazone introduction. RESULTS: Pioglitazone treatment led to a significant 3% body mass increase. There were neither changes in cold-induced brown adipose tissue glucose uptake and volume nor changes in hypothalamic gliosis. CONCLUSIONS: This is a proof-of-concept study that provides clinical evidence for a lack of action of a thiazolidinedione, pioglitazone, to promote homogeneous and measurable changes in brown adipose tissue volume and also in hypothalamic gliosis after 6 months of treatment.

Pancreatic ß-cell dysfunction in normoglycemic patients and risk factors.

AIMS: To evaluate pancreatic ß-cell function (ßf) in patients with normoglycemia (NG) and normal glucose tolerance (NGT) and related risk factors. METHODS: An observational and comparative study in 527 patients with NG and NGT that were divided by quartiles of ßf according to the disposition index derived from OGTT. Anthropometrical, clinical, nutritional, and biochemical variables were measured and associated with ßf. RESULTS: Quartiles of ßf were Q1 = DI < 1.93 n = 131, Q2 = DI 1.93-2.45 n = 134, Q3 = DI 2.46-3.1 n = 133, and Q4 = DI > 3.1 n = 129. There was a progressive reduction in pancreatic ß-cell function and it is negatively correlated with age, weight, BMI, total body fat and visceral fat, waist circumference, total cholesterol, LDL, and triglycerides (p < 0.01). Glucose levels during OGTT had a negative correlation with ßf; the product of fasting glucose by 1-h glucose had the best correlation with ßf (r = 0.611, p < 0.001) and was the best predictor of ßdf (AUC 0.816, CI 95% 0.774-0.857), even better than 1-h glucose (r = 0.581, p < 0.001). Energy, fat, and carbohydrate intake were negatively correlated with ßf (p < 0.05). Glucose levels at 1-h OGTT > 110 mg/dl were positively associated with pancreatic ßdf (OR 6.85, CI 95% 3.86-12.4). In the multivariate analysis, glucose levels during OGTT, fasting insulin, and BMI were the main factors associated with ßf. CONCLUSIONS: A subgroup of patients with NG and NGT may have a loss of 40% of their ßf. Factors related to this ßdf were age, adiposity, glucose during OGTT, and the product of fasting and 1-h glucose, as well as food intake.

Increased airway reactivity and hyperinsulinemia in obese mice are linked by ERK signaling in brain stem cholinergic neurons.

Obesity is a major risk factor for asthma, which is characterized by airway hyperreactivity (AHR). In obesity-associated asthma, AHR may be regulated by non-TH2 mechanisms. We hypothesized that airway reactivity is regulated by insulin in the CNS, and that the high levels of insulin associated with obesity contribute to AHR. We found that intracerebroventricular (ICV)-injected insulin increases airway reactivity in wild-type, but not in vesicle acetylcholine transporter knockdown (VAChT KD(HOM-/-)), mice. Either neutralization of central insulin or inhibition of extracellular signal-regulated kinases (ERK) normalized airway reactivity in hyperinsulinemic obese mice. These effects were mediated by insulin in cholinergic nerves located at the dorsal motor nucleus of the vagus (DMV) and nucleus ambiguus (NA), which convey parasympathetic outflow to the lungs. We propose that increased insulin-induced activation of ERK in parasympathetic pre-ganglionic nerves contributes to AHR in obese mice, suggesting a drug-treatable link between obesity and asthma.

Retinol-binding protein 4 is associated with impaired glucose tolerance but not with whole body or hepatic insulin resistance in Mexican Americans.

Retinol-binding protein-4 (RBP4), a novel protein secreted mainly by adipose tissue, has been associated with insulin resistance in obese subjects and in individuals with type 2 diabetes mellitus (T2DM). We examined the relationship between plasma RBP4 levels, expression of RBP4 in skeletal muscle and adipose tissue, and insulin sensitivity in Mexican Americans with varying degrees of obesity and glucose tolerance. Seventy-two subjects [16 lean normal-glucose-tolerant (NGT), 17 obese NGT, and 39 subjects with impaired fasting glucose/impaired glucose tolerance/T2DM] received an oral glucose tolerance test (OGTT) and euglycemic-hyperinsulinemic clamp. Insulin secretion was measured as insulinogenic index during OGTT. In a subset of subjects, hepatic glucose production was measured by 3-[3H]glucose infusion, biopsies of the vastus lateralis muscle and subcutaneous adipose tissue were obtained under basal conditions, and quantitative RT-PCR was performed to measure the RBP4 mRNA gene expression. Plasma RBP4 was significantly elevated in impaired glucose tolerance/T2DM compared with NGT lean or obese subjects. Plasma RBP4 levels correlated with 2-h glucose, triglycerides, and hemoglobin A1c. There was no association between RBP4 levels and whole body insulin sensitivity measured with either the euglycemic insulin clamp or OGTT, basal hepatic glucose production rates, and the hepatic insulin resistance index. There was no correlation between plasma RBP4 levels and indexes of insulin secretion. RBP4 mRNA expression in skeletal muscle was similar in lean NGT subjects, obese NGT subjects, and T2DM subjects. There was no difference in RBP4 mRNA expression in adipose tissue between lean and obese NGT subjects or between NGT and T2DM individuals. Plasma RBP4 levels are elevated in T2DM and associated with impaired glucose tolerance, but not associated with obesity or insulin resistance or impaired insulin secretion in Mexican Americans.

The multi-faceted cross-talk between the insulin and angiotensin II signaling systems.

Insulin and angiotensin II are hormones that play pivotal roles in the control of two vital and closely related systems, the metabolic and the circulatory systems, respectively. A failure in the proper action of each of these hormones results, to a variable degree, in the development of two highly prevalent and commonly overlapping diseases-diabetes mellitus and hypertension. In recent years, a series of studies has revealed a tight connection between the signal transduction pathways that mediate insulin and angiotensin II actions in target tissues. This molecular cross-talk occurs at multiple levels and plays an important role in phenomena that range from the action of anti-hypertensive drugs to cardiac hypertrophy and energy acquisition by the heart. At the extracellular level, the angiotensin-converting enzyme controls angiotensin II synthesis but also interferes with insulin signaling through the proper regulation of angiotensin II and through the accumulation of bradykinin. At an early intracellular level, angiotensin II, acting through JAK-2/IRS-1/PI3-kinase, JNK and ERK, may induce the serine phosphorylation and inhibition of key elements of the insulin-signaling pathway. Finally, by inducing the expression of the regulatory protein SOCS-3, angiotensin II may impose a late control on the insulin signal. This review will focus on the main advances obtained in this field and will discuss the implications of this molecular cross-talk in the common clinical association between diabetes mellitus and hypertension.

Interaction between leptin and insulin signaling pathways differentially affects JAK-STAT and PI 3-kinase-mediated signaling in rat liver.

Chronic leptin treatment markedly enhances the effect of insulin on hepatic glucose production unproportionally with respect to body weight loss and increased insulin sensitivity. In the present study the cross-talk between insulin and leptin was evaluated in rat liver. Upon stimulation of JAK2 tyrosine phosphorylation, leptin induced JAK2 co-immunoprecipitation with STAT3, STAT5b, IRS-1 and IRS-2. This phenomenon parallels the leptin-induced tyrosine phosphorylation of STAT3, STAT5b, IRS-1 and IRS-2. Acutely injected insulin stimulated a mild increase in tyrosine phosphorylation of JAK2, STAT3 and STAT5b. Leptin was less effective than insulin in stimulating IRS phosphorylation and their association with PI 3-kinase. Simultaneous treatment with both hormones yielded no change in maximal phosphorylation of STAT3, IRS-1, IRS-2 and Akt, but led to a marked increase in tyrosine phosphorylation of JAK2 and STAT5b when compared with isolated administration of insulin or leptin. This indicates that there is a positive cross-talk between insulin and leptin signaling pathways at the level of JAK2 and STAT5b in rat liver.