Nikolaos Perakakis

Pharmacotherapy of type 2 diabetes: An update

Type 2 diabetes (T2DM) is a leading cause of morbidity and mortality worldwide and a major economic burden. The prevalence of T2DM is rising, suggesting more effective prevention and treatment strategies are necessary. The aim of this narrative review is to summarize the pharmacologic treatment options available for patients with T2DM. Each therapeutic class is presented in detail, outlining medication effects, side effects, glycemic control, effect on weight, indications and contraindications, and use in selected populations (heart failure, renal insufficiency, obesity and the elderly). We also present representative cost for each antidiabetic category. Then, we provide an individualized guide for initiation and intensification of treatment and discuss the considerations and rationale for an individualized glycemic goal.

Obesity as a Disease

Obesity is a complex disease with many causal factors, associated with multiple comorbidities that contribute to significant morbidity and mortality. It is a highly prevalent disease that poses an enormous health and economic burden to society. This article reviews the mechanisms of obesity and its related comorbidities.

Human Krüppel-like factor 11 inhibits human proinsulin promoter activity in pancreatic beta cells.

Aims/hypothesisThe Krüppel-like factor 11 (KLF11; TIEG2), a pancreas-enriched Sp1-like transcription factor, is a known negative regulator of pancreatic exocrine cell growth. A recent study indicated KLF11-induced activation of the human proinsulin promoter (hInsP).Materials and methodsWe investigated the functional role of KLF11 in pancreatic beta cells.ResultsEndogenous KLF11 mRNA expression was found in whole rat pancreas, human pancreatic islets and INS-1E beta cells and was profoundly reduced by high glucose in INS-1E. Cotransfections of INS-1E and beta-TC3 beta cells with a human (h)KLF11 expression plasmid and an hInsP-driven reporter plasmid resulted in a substantial dose-dependent and glucose-independent inhibition of proinsulin promoter activity. 5′-deletion of hInsP demonstrated that hKLF11 acts via DNA sequences upstream of −173 and requires the beta cell-specific transcription machinery, since hKLF11-mediated inhibition of promoter activity was abolished in HEK293 cells. Besides a previously described GC box, we further identified a CACCC box within the hInsP, both putative KLF11-binding motifs. Electrophoretic mobility shift analysis (EMSA) verified binding of in vitro translated hKLF11 to the GC box, but neither hKLF11-induced inhibition nor basal hInsP activity was altered by mutation or 5′-deletion of the GC box. In contrast, CACCC box mutation substantially reduced basal promoter activity and partially diminished hKLF11 inhibition, although binding of in vitro translated hKLF11 to the CACCC box could not be verified by EMSA.Conclusions/interpretationIn rodent beta cell lines, we demonstrate hKLF11-overexpression of human proinsulin gene expression and characterise a prominent role for the CACCC box in maintaining basal proinsulin promoter activity.

Adiponectin administration prevents weight gain and glycemic profile changes in diet-induced obese immune deficient Rag1 −/− mice lacking mature lymphocytes☆

BACKGROUND Obesity is associated with chronic low-grade inflammation leading to insulin resistance and diabetes. Adiponectin is an adipokine that regulates inflammatory responses. The aim of our study was to investigate whether any effects of adiponectin against obesity and insulin-resistance may depend on the adaptive immune system. METHODS We treated high-fat-diet fed Rag1-/- mice lacking mature lymphocytes with adiponectin over 7weeks and investigated alterations in their metabolic outcome and inflammatory state. RESULTS Adiponectin protects from weight gain despite a small compensatory stimulation of energy intake in mice lacking an adaptive immune system. Additionally, adiponectin protects from dysglycemia. Minor alterations in the macrophage phenotype, but not in the circulating cytokine levels, may contribute to the protective role of adiponectin against hyperglycemia and diabetes. CONCLUSION Adiponectin or agents increasing adiponectin may be a promising therapeutic option against obesity and hyperglycemia in immune-deficient populations.

Association of Adipokines with Development and Progression of Nonalcoholic Fatty Liver Disease

Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disease affecting 30% of the general population and 40% to 70% of obese individuals. Adipose tissue plays a crucial role in its pathogenesis, as it produces and secretes pro- and anti-inflammatory cytokines called adipokines. Adiponectin and leptin have well-determined actions in terms of NAFLD pathophysiology. Adiponectin deficiency is associated with a pro-inflammatory condition, as it is observed in obesity and other metabolic disorders. On the other hand, increased leptin levels, above the normal levels, act as a pro-inflammatory stimulus. Regarding other adipokines (resistin, visfatin, chemerin, retinol-binding protein 4, irisin), data about their contribution to NAFLD pathogenesis and progression are inconclusive. In addition, pharmacological agents like thiazolidinediones (pioglitazone and rosiglitazone), that are used in the management of NAFLD exert favourable effects on adipokine levels, which in turn may contribute to the improvement of liver function. This review summarizes the current knowledge and developments in the association between adipokines and NAFLD and discusses possible therapeutic implications targeting the modulation of adipokine levels as a potential tool for the treatment of NAFLD.

Irisin in metabolic diseases

IntroductionIrisin is a myokine/adipokine induced by the exercise in mice and humans, which is proposed to induce “browning” of white adipose tissue, its primary target, thus increasing thermogenesis and energy expenditure. Since its identification, irisin has been linked to favorable effects on metabolic diseases, including obesity, type 2 diabetes mellitus (T2DM), lipid metabolism and cardiovascular disease (CVD), nonalcoholic fatty liver disease (NAFLD), polycystic ovary syndrome (PCOS), and metabolic bone diseases. Generally, despite the promising profile of irisin in rodents, its effects on human are less recognized.ReviewMost, but not all studies show a positive association between irisin and indices of adiposity. In T2DM, NAFLD, and CVD, most observational studies reported lower irisin levels in patients than controls. Regarding metabolic bone diseases, irisin is positively associated with bone mineral density and strength in athletes, and inversely associated with osteoporotic fractures in postmenopausal osteoporosis. In PCOS, data remain largely conflicting. Irisin does not seem to be further reduced when two metabolic diseases, e.g., T2DM and NAFLD, or obesity and NAFLD exist though more data are needed. Furthermore, it seems that diverse confounders may have affected the results of different clinical studies.ConclusionIrisin remains an appealing molecule from a pathophysiological point of view and an appealing therapeutic target for metabolic diseases, albeit much research is still needed.

Obesity as a risk factor for Alzheimer's disease: weighing the evidence

Alzheimers disease (AD) is the sixth leading cause of death in the USA today; therefore, it is imperative that public health initiatives and clinical strategies are developed to prevent and effectively treat AD. Despite the enormous impact that AD has on individuals, families, society, and the health care system, there are no biomarkers to clearly identify those at risk for AD, public health prevention strategies in place, or treatments to address the underlying pathology or stop the progression of AD. There is ample scientific as well as empirical evidence that obesity and its metabolic and vascular comorbidities are related to AD and likely in the causative pathway. Obesity prevention and treatment could prove to be an efficacious and safe approach to preventing AD, a serious and daunting epidemic disease. In this review, we present the current pathophysiological and clinical evidence linking obesity and obesity‐related comorbidities (eg, insulin resistance, hyperglycaemia, and type 2 diabetes) with AD. Additionally, we discuss which population to target and when to consider treatment for AD. Finally, we summarize the current evidence regarding the efficacy of anti‐obesity and anti‐diabetic pharmacotherapeutic agents for the treatment of AD.

Human Krüppel-like factor 11 differentially regulates human insulin promoter activity in β-cells and non-β-cells via p300 and PDX1 through the regulatory sites A3 and CACCC box.

Human Krüppel-like factor 11 (hKLF11) has been characterised to both activate and inhibit human insulin promoter (hInsP) activity. Since KLF11 is capable to differentially regulate genes dependent on recruited cofactors, we investigated the effects of hKLF11 on cotransfected hInsP in both β-cells and non-β-cells. hKLF11 protein interacts with hp300 but not with hPDX1. Overexpressed hKLF11 stimulates PDX1-transactivation of hInsP in HEK293 non-β-cells, but confers inhibition in INS-1E β-cells. Both hKLF11 functions can be neutralised by the p300 inhibitor E1A, increased hp300 levels (INS-1E), dominant negative (DN)-PDX1 and by mutation of the PDX1 binding site A3 or the CACCC box. In summary, hKLF11 differentially regulates hInsP activity depending on the molecular context via modulation of p300:PDX1 interactions with the A3 element and CACCC box. We postulate that KLF11 has a role in fine-tuning insulin transcription in certain cellular situations rather than representing a major transcriptional activator or repressor of the insulin gene.

Regulation of the activins-follistatins-inhibins axis by energy status: Impact on reproductive function

BACKGROUND We have previously demonstrated that the adipose tissue derived hormone leptin controls reproductive function by regulating the hypothalamic-pituitary-gonadal axis in response to energy deficiency. Here, we evaluate the activins-follistatins-inhibins (AFI) axis during acute (short-term fasting in healthy people) and chronic energy deficiency (women with hypothalamic amenorrhea due to strenuous exercise [HA]) and investigate their relation to leptin and reproductive function in healthy subjects and subjects with HA. METHODS The AFI axis was investigated in: a) A double-blinded study in healthy subjects having three randomly assigned admissions, each time for four days: in the isocaloric fed state, complete fasting with placebo treatment, complete fasting with leptin replacement, b) A case-control study comparing women with HA vs healthy controls, c) An open-label interventional study investigating leptin treatment in women with HA over a period of up to three months, d) A randomized interventional trial investigating leptin treatment vs placebo in women with HA for nine months. RESULTS The circulating levels of activin A, activin B, follistatin and follistatin-like 3 change robustly in response to acute and chronic energy deficiency. Leptin replacement in acute energy deprivation does not affect the levels of these hormones suggesting an independent regulation by these two hormonal pathways. In chronic energy deficiency, leptin replacement restores only activin B levels, which are in turn associated with an increase in the number of dominant follicles. CONCLUSIONS We demonstrate for the first time that the AFI axis is affected both by acute and chronic energy deficiency. Partial restoration of a component of the axis, i.e. activin B only, through leptin replacement is associated with improved reproductive function in women with HA.

Physiology of activins/follistatins: associations with metabolic and anthropometric variables and response to exercise.

Context Clinical trials are evaluating the efficacy of inhibitors of the myostatin pathway in neuromuscular and metabolic diseases. Activins and follistatins are major regulators of the myostatin pathway, but their physiology in relation to metabolic and anthropometric variables and in response to exercise remains to be fully elucidated in humans. Objective We investigated whether concentrations of circulating activin A, activin B, follistatin, and follistatin-like 3 (FSTL3) are associated with anthropometric and metabolic variables and whether they are affected by exercise. Design Activin A, activin B, follistatin, and FSTL3 were measured in (1) 80 subjects divided according to age (young vs old) and fitness status (active vs sedentary) before and after exercise at 70% maximal oxygen consumption (VO2max), followed by 90% of VO2max until exhaustion; and (2) 23 subjects [9 healthy and 14 with metabolic syndrome (MetS)] who completed four sessions: no exercise, high-intensity interval exercise, continuous moderate-intensity exercise, and resistance exercise for up to 45 minutes. Results At baseline, follistatin and FSTL3 concentrations were positively associated with age, fat percentage, and body mass index (P < 0.001). Follistatin was positively associated with serum cholesterol (P = 0.005), low-density lipoprotein cholesterol (P = 0.01), triglycerides (P = 0.033), and blood pressure (P = 0.019), whereas activin A and activin B were higher in physically active participants (P = 0.056 and 0.029, respectively). All exercise types increased the levels of all hormones ∼10% to 21% (P = 0.034 for activin B, P < 0.001 for the others) independent of the presence of MetS. Conclusion Concentrations of circulating activins and follistatins are associated with metabolic parameters and increase after 45 minutes of exercise.