Type 2 diabetes mellitus (T2DM) is one of the most prevalent noncommunicable diseases in the world. Traditional pharmacological agents for the management of glycaemic control in patients with T2DM include metformin, sulphonylureas and insulin. However, research in the past decade has uncovered new therapeutic targets for T2DM, some of which have reached clinical application. This Nature Reviews Endocrinology collection provides an overview of the emerging therapeutic targets for T2DM, discussing promising therapeutic avenues for T2DM uncovered from basic, translational and clinical research.

All content for this Collection has been chosen by the Nature Reviews Endocrinology editors and the collection has been made freely available for 6 months thanks to support from Boehringer Ingelheim


Diabetes: Human β-cell proliferation by promoting Wnt signalling

Carol Wilson


Nature Reviews Endocrinology 9, 502 (2013)

Diabetes: Betatrophin—inducing β-cell expansion to treat diabetes mellitus?

Elisabeth Kugelberg


Nature Reviews Endocrinology 9, 379 (2013)

Diabetes: Blocking RANKL signalling might prevent T2DM

Carol Wilson


Nature Reviews Endocrinology 9, 188 (2013)

Diabetes: IL-13 and glucose homeostasis

Carol Wilson


Nature Reviews Endocrinology 9, 134 (2013)

Diabetes: SFRP4—a biomarker for islet dysfunction?

Carol Wilson


Nature Reviews Endocrinology 9, 65 (2013)


Type 2 diabetes mellitus in 2012: Optimal management of T2DM remains elusive

Rury R. Holman


Nature Reviews Endocrinology 9, 67-68 (2013)


Metabolism: Adiponectin—a mediator of specific metabolic actions of FGF21

Regina Goetz


Nature Reviews Endocrinology 9, 506-508 (2013)

Diabetes: Add-on to metformin in T2DM—linagliptin or glimepiride?

Mikkel Christensen & Filip K. Knop


Nature Reviews Endocrinology 8, 576-578 (2012)

Diabetes: Insulin plus metformin for T2DM—are there benefits?

Clifford J. Bailey


Nature Reviews Endocrinology 8, 449-450 (2012)

Diabetes: Should we treat infection or inflammation to prevent T2DM?

Outi Vaarala & Hannele Yki-Järvinen


Nature Reviews Endocrinology 8, 323-325 (2012)


The role of FOXO1 in β-cell failure and type 2 diabetes mellitus

Tadahiro Kitamura


Nature Reviews Endocrinology 9, 615-623 (2013)

Resistance to insulin leads to type 2 diabetes mellitus (T2DM) but only when accompanied by pancreatic β-cell dysfunction. This Review describes the molecular mechanisms associated with pancreatic β-cell dysfunction in T2DM and discusses how modulating FOXO1 activity might serve as a new therapeutic target to treat T2DM.

Emerging combinatorial hormone therapies for the treatment of obesity and T2DM

Sharon A. Sadry & Daniel J. Drucker


Nature Reviews Endocrinology 9, 425-433 (2013)

The success of bariatric surgery, together with emerging data from preclinical studies, illustrates the rationale and feasibility of using two or more agonists for the treatment of obesity and type 2 diabetes mellitus (T2DM). This Review summarizes advances in the science of co-agonist therapy and mechanisms of action for combinations of endocrine hormones that enhance weight loss whilst preserving glucoregulatory efficacy in experimental models of obesity and T2DM.

GLP-1 receptor agonists for individualized treatment of type 2 diabetes mellitus

Juris J. Meier


Nature Reviews Endocrinology 8, 728-742 (2012)

In this Review, the possibilities for utilizing GLP-1 receptor agonists in individualized treatment for type 2 diabetes mellitus are discussed. The currently available compounds are evaluated in terms of their efficacy, duration of action and adverse effects. The feasibility of selecting a treatment option on the basis of an individual's clinical parameters and requirements is also touched upon.

Adaptive immunity in obesity and insulin resistance

Henrike Sell, Christiane Habich & Juergen Eckel


Nature Reviews Endocrinology 8, 709-716 (2012)

Obesity is a key feature of the metabolic syndrome and increased adiposity has been associated with inflammation in the visceral compartment. In this Review, the authors describe inflammatory processes that occur in adipose tissue, focussing on how adaptive immune system cells promote inflammation.

The role of Klotho in energy metabolism

M. Shawkat Razzaque


Nature Reviews Endocrinology 8, 579-587 (2012)

Excess or insufficient adipose tissue accumulation can lead to metabolic complications such as insulin resistance, type 2 diabetes mellitus, dyslipidaemia and hepatic steatosis. Klotho increases adipocyte differentiation and could affect glucose metabolism. This Review describes the role of Klotho in energy metabolism and examines its effects on adipogenesis and obesity.

SGLT2 inhibition in diabetes mellitus: rationale and clinical prospects

Ele Ferrannini & Anna Solini


Nature Reviews Endocrinology 8, 495-502 (2012)

In patients with type 2 diabetes mellitus, sodium-glucose cotransporter 2 (SGLT2) inhibition improves glycaemic control to a therapeutically useful extent by reducing glucose reabsorption in the kidneys. This Review covers the rationale, physiological consequences and clinical application of pharmacological SGLT2 inhibition and also discusses the potential clinical merits and disadvantages of these agents.

Importance of oestrogen receptors to preserve functional β-cell mass in diabetes

Joseph P. Tiano & Franck Mauvais-Jarvis


Nature Reviews Endocrinology 8, 342-351 (2012)

This Review describes developments in the role of estrogen receptors (ERs) in islet insulin biosynthesis and secretion, lipid homeostasis and survival. Moreover, the authors discuss why and how enhancing ER action in β cells without the undesirable effect of general estrogen therapy is a therapeutic avenue to preserve functional β-cell mass in patients with diabetes mellitus.

Sirtuins mediate mammalian metabolic responses to nutrient availability

Angeliki Chalkiadaki & Leonard Guarente


Nature Reviews Endocrinology 8, 287-296 (2012)

Sirtuins have emerged as important regulators of various metabolic pathways, linking nutrient signals with cellular responses to energy demands and driving metabolic cycles in reaction to fasting or calorie restriction. This Review describes the latest advances in the understanding of the function of sirtuins in regulating mammalian metabolism with a focus on their role as mediators of nutrient availability.

The emerging role of HDL in glucose metabolism

Brian G. Drew, Kerry-Anne Rye, Stephen J. Duffy, Philip Barter & Bronwyn A. Kingwell


Nature Reviews Endocrinology 8, 237-245 (2012)

High-density lipoprotein (HDL) is best known for its anti-atherosclerotic actions; however, emerging evidence suggests that it also has direct beneficial actions on plasma glucose control through multiple mechanisms. This Review discusses emerging evidence for the role of HDL-mediated glucose regulation in the pathophysiology of type 2 diabetes mellitus and the therapeutic potential for HDL elevation to prevent and manage the disease.

Resistance to type 2 diabetes mellitus: a matter of hormesis?

Hubert Kolb & Décio L. Eizirik


Nature Reviews Endocrinology 8, 183-192 (2012)

This Review discusses the emerging concept that resistance to the metabolic adverse effects of lifestyle factors is mediated by an adaptive response to cellular stress, counteracting mechanisms that otherwise lead to impaired insulin signaling and β cell failure. This response exhibits characteristics of hormesis, originally described in toxicology, whereby exposure of cells, tissues or organisms to low levels of toxin induces resistance to higher toxin concentrations.

The role of mitochondria in insulin resistance and type 2 diabetes mellitus

Julia Szendroedi, Esther Phielix & Michael Roden


Nature Reviews Endocrinology 8, 92-103 (2012)

This Review discusses the association between mitochondrial function and insulin sensitivity in various tissues, such as skeletal muscle, liver and heart, with a main focus on studies in humans, and addresses the effects of therapeutic strategies that affect mitochondrial function and insulin sensitivity.