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Diabetes mellitus has become a widespread disease worldwide. In recent years, there has been a rapid development of therapeutic options in the field of diabetology. Many new drugs and therapeutic strategies are now available or will be available in the near future, which have the potential to significantly improve the care of patients even if they do not have diabetes. In this article, we would like to present the latest therapeutic options and possible further applications. The article focuses, among other things, on the new findings of SGLT-2-inhibitors in cardiac and chronic renal failure and the further development of incretin-based drugs toward dual GIP/GLP-1-receptor agonists. Once-weekly insulin and the selective mineralocorticoid receptor antagonist finerenone will also be presented.

Introduction: Genetic polymorphisms in TCF7L2 are the strongest common risk variants for type 2 diabetes mellitus (T2D). We and others have shown that genetic variation in TCF7L2 and WFS1 affect incretin-stimulated insulin secretion. A recent genome-wide association study discovered genetic variants associated with incretin levels. We hypothesized that these SNPs (single nucleotide polymorphisms) interact with the well-known TCF7L2 variant rs7903146 on insulin secretion due to their incretin altering effect. Methods: In this retrospective analysis, we used data from the cross-sectional TUEF-cohort (n = 2929) and a hyperglycemic clamp study using additional GLP-1 infusion at the end of the clamp (n = 76). Insulin secretion was measured by evaluating OGTT-derived indexes of insulin secretion and insulin/C-peptide levels during clamp. We genotyped rs7903146 in TCF7L2, rs10010131 in WFS1, and six SNPs associated with GLP-1 and GIP levels. Results: One of the six incretin-associated SNPs, rs17681684 in GLP2R, exhibited significant SNP x SNP interactions with rs7903146 in TCF7L2 on insulin secretion (p = 0.0024) after correction for multiple testing. Three further SNP‘s showed nominally significant interactions (p < 0.05). In the hyperglycemic clamp study, rs7903146 in TCF7L2 also interacted with rs17681684 on AUC C-peptide during the GLP-1 stimulation phase, thereby replicating the above finding. Conclusion: The findings exemplify the role of SNP x SNP interactions in the genetics of type 2 diabetes mellitus and corroborate the existence of clinically relevant differences in incretin sensitivity.

GLP-1-modulating therapies are a class of anti-diabetic drugs that improve glycemic control by stimulating glucose-dependent insulin secretion from pancreatic beta-cells. In addition, GLP-1-based therapies have a variety of extrapancreatic effects, including satiety induction and gastric mobility reduction, which extend to distinct cardiovascular actions. GLP-1 was found to reduce infarct size in the context of acute myocardial ischemia which depends on the activation of prosurvival pathways including PI3-kinase, Akt, and ERK1/2. Also, GLP-1 augments the left ventricular function in dilative and metabolic cardiomyopathy, possibly by increasing insulin independent cardiomyocyte glucose uptake. Furthermore, experimental and preliminary clinical evidence suggest vasoprotective efficacy of GLP-1 mediated by improved endothelial function and anti-inflammatory capacities leading to atheroprotection. Mechanistically, the GLP-1 receptor is relevant for glucose lowering efficacy of GLP-1. However, many of its vasoprotective actions have also been described for the GLP-1 metabolite (9-37), which does not activate the GLP-1 receptor, suggesting the presence of an additional, yet unknown, signaling pathway. Ongoing research investigates the relevance of these observations in human disease and underlying mechanisms, which are reviewed in the present article.

The physiological effects of the incretin hormone glucagon-like peptide-(GLP-)1 have contributed to the important role that incretin-based therapies with GLP-1 analogs or dipeptidyl peptidase-(DPP-)4 inhibitors already play in type 2 diabetes treatment. This development is not only due to the glucose-dependent insulinotropic effect of GLP-1 as well as the positive effects on beta cell function and, probably, beta cell mass, but also to the beneficial effects on body weight.Lately, the data on positive cardiovascular effects of GLP-1 have been growing. In animal models, GLP-1 improves left ventricular function and diminishes myocardial defects in ischemia models. In clinical studies with GLP-1 analogs, a normalization of blood pressure was observed and some of the data from animal studies after myocardial infarction or after invasive cardiologic or cardiosurgical interventions were also found under clinical conditions in humans. Additionally, an improvement of cardiovascular surrogate parameters was observed with incretin-based therapies. This review gives an overview on the cardiovascular effects of GLP-1 and incretin-based therapies.

Bariatric surgery offers a safe and effective treatment of type II diabetes for morbidly obese persons with complete and permanent remission as well as a clear reduction in mortality. Current data suggest that surgical treatment could be extended to merely overweight and even slender diabetes patients. Bariatric surgery also offers invaluable new approaches for research into type II diabetes. Evidence that the foregut plays a decisive role in the pathogenesis of the disease opens promising opportunities for improved treatment of this serious disease.

In recent years new pharmacological agents have emerged, which enable us to widen the spectrum of diabetes management based on clear pathophysiological concepts. One should first of all mention the DPP4-inhibitors and the incretin mimetics, which have the potential of restoring the incretin effect in patients with type 2 diabetes mellitus. Moreover, it has been shown that the agent rimonabant, which was first used in order to achieve weight reduction, also contributed to the significant improvement of metabolic syndrome's parameters. Recent studies have shown that the dual alpha/gamma-PPAR-agonists have serious adverse effects. The thiazolidinediones (glitazones) significantly improve insulin sensitivity, diminish fat accumulation in the liver and increase circulating levels of adiponectin. Various adverse effects of glitazones have been described in recent studies. In the near future one should await the discovery of more oral antidiabetic agents acting through modulation of important enzymes in glucose metabolism and transport pathways.