Elsevier

The Lancet

Volume 383, Issue 9922, 22–28 March 2014, Pages 1068-1083
The Lancet

Review
Pathophysiology and treatment of type 2 diabetes: perspectives on the past, present, and future

https://doi.org/10.1016/S0140-6736(13)62154-6Get rights and content

Summary

Glucose metabolism is normally regulated by a feedback loop including islet β cells and insulin-sensitive tissues, in which tissue sensitivity to insulin affects magnitude of β-cell response. If insulin resistance is present, β cells maintain normal glucose tolerance by increasing insulin output. Only when β cells cannot release sufficient insulin in the presence of insulin resistance do glucose concentrations rise. Although β-cell dysfunction has a clear genetic component, environmental changes play an essential part. Modern research approaches have helped to establish the important role that hexoses, aminoacids, and fatty acids have in insulin resistance and β-cell dysfunction, and the potential role of changes in the microbiome. Several new approaches for treatment have been developed, but more effective therapies to slow progressive loss of β-cell function are needed. Recent findings from clinical trials provide important information about methods to prevent and treat type 2 diabetes and some of the adverse effects of these interventions. However, additional long-term studies of drugs and bariatric surgery are needed to identify new ways to prevent and treat type 2 diabetes and thereby reduce the harmful effects of this disease.

Section snippets

The epidemic of type 2 diabetes

The worldwide explosion of obesity has resulted in an ever-increasing prevalence of type 2 diabetes—a non-communicable disease that affects more than 370 million people.1 Without concerted efforts to address the pathogenesis and treatment of this syndrome, the harmful macrovascular and microvascular outcomes of type 2 diabetes will remain a major burden for decades to come. In this Review we examine aspects of the pathogenesis and treatment of type 2 diabetes, and discuss future needs if the

The past: identification of β-cell dysfunction and insulin resistance

Development of the insulin radioimmunoassay led to the finding that patients with early-maturity-onset diabetes produced insulin and secreted this hormone in response to nutrient ingestion.2 Subsequently, defects in the ability of islet β cells to respond to intravenous secretagogues (including glucose) were reported in these patients.3

Additionally, these patients did not respond well to insulin,4 and were thus deemed to be insulin insensitive. This insulin insensitivity was shown to contribute

Oral and injectable drugs: present knowledge, lessons learned, and implications for the future

The increasing prevalence of type 2 diabetes has stimulated development of many new approaches to safely treat hyperglycaemia (figure 3). The aim of these therapies is to reduce and maintain glucose concentrations as close to normal for as long as possible after diagnosis (Panel 1, Panel 2), and thereby prevent development of complications. Although some therapies have been unsuccessful because of adverse effects or negligible therapeutic efficacy, several are very well accepted and are used

The present situation

In 1998, investigators of the landmark UKPDS trial143 reported that improved glucose control (mainly with sulfonylurea antidiabetics and insulin) reduced microvascular complications in recently diagnosed patients with type 2 diabetes. The primary analysis did not show a clear benefit for macrovascular disease, and thus four large intervention studies were designed to examine the effect of more intensive lowering of glucose for cardiovascular outcomes.

Insulin was a major component of the

What does the future hold?

Several of these studies are following up participants for outcomes relevant to type 2 diabetes. In DPP, conversion from impaired glucose tolerance to diabetes has been diagnosed within 6 months; findings from this study will provide a better understanding of the natural history of microvascular and macrovascular complications, and help to establish whether some of these complications (eg, retinopathy) develop before the onset of diagnostic hyperglycaemia. In both DPP and Look AHEAD, assessment

Conclusions

In 1984, Asmal and Marble202 wrote that “despite the availability of oral hypoglycaemic drugs for nearly 30 years, their precise mode of action and role in the management of diabetes mellitus remains poorly defined and controversial”. Nearly 30 years after that statement, doctors and researchers still have a great deal to learn about the pathogenesis of type 2 diabetes and how best to use the therapies available, although great progress has been made in clarification of their modes of action.

Search strategy and selection criteria

We searched PubMed and Google Scholar, mainly for original research articles published up to May, 2013, which focused on the pathophysiology and treatment of type 2 diabetes. The main search terms used were “pathophysiology”, “type 2 diabetes”, “prediabetes”, “β-cell”, “insulin resistance”, and “treatment”. We mostly identified full-text articles written in English. We also searched ClinicalTrials.gov for information about ongoing clinical trials in type 2 diabetes.

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