Ele Ferrannini

Predominant role of reduced beta-cell sensitivity to glucose over insulin resistance in impaired glucose tolerance

Aims/hypothesisImpaired glucose tolerance (IGT) is an insulin-resistant state and a risk factor for Type 2 diabetes. The relative roles of insulin resistance and insulin deficiency in IGT have been disputed.MethodsIn 40 IGT subjects and 63 sex-, age-, and weight-matched controls with normal glucose tolerance (NGT), we measured (i) indices of insulin sensitivity of fasting glucose production (by tracer glucose) and glucose disposal (M value on a 240xa0pmol·min–1·m–2 insulin clamp) and (ii) indices of beta-cell function (glucose sensitivity, rate sensitivity, and potentiation) derived from model analysis (Am J Physiol 283:E1159–E1166, 2002) of the insulin secretory response (by C-peptide deconvolution) to oral glucose.ResultsIn comparison with NGT, IGT were modestly insulin resistant (M=29±2 vs 35±2xa0µmol·min−1·kgFFM−1, p=0.01); insulin sensitivity of glucose production also was reduced, in approximate proportion to M. Despite higher baseline insulin secretion rates, IGT was characterized by a 50% reduction in glucose sensitivity [53 (36) vs 102 (123)xa0pmol·min−1·m–2·mM–1, median (interquartile range), p=0.001] and impaired potentiation [1.6 (0.8) vs 2.0 (1.5) units, p<0.04] of insulin release, whereas rate sensitivity [1.15 (1.15) vs 1.38 (1.28) nmol·m–2·mM–1] was not significantly reduced. Glucose sensitivity made the single largest contribution (~50%) to the observed variability of glucose tolerance.Conclusion/interpretationIn IGT the defect in glucose sensitivity of insulin release quantitatively predominates over insulin resistance in the genesis of the reduced tolerance to oral glucose.

Type 2 Diabetes Mellitus

Type 2 diabetes mellitus (T2DM) is an expanding global health problem, closely linked to the epidemic of obesity. Individuals with T2DM are at high risk for both microvascular complications (including retinopathy, nephropathy and neuropathy) and macrovascular complications (such as cardiovascular comorbidities), owing to hyperglycaemia and individual components of the insulin resistance (metabolic) syndrome. Environmental factors (for example, obesity, an unhealthy diet and physical inactivity) and genetic factors contribute to the multiple pathophysiological disturbances that are responsible for impaired glucose homeostasis in T2DM. Insulin resistance and impaired insulin secretion remain the core defects in T2DM, but at least six other pathophysiological abnormalities contribute to the dysregulation of glucose metabolism. The multiple pathogenetic disturbances present in T2DM dictate that multiple antidiabetic agents, used in combination, will be required to maintain normoglycaemia. The treatment must not only be effective and safe but also improve the quality of life. Several novel medications are in development, but the greatest need is for agents that enhance insulin sensitivity, halt the progressive pancreatic β-cell failure that is characteristic of T2DM and prevent or reverse the microvascular complications. For an illustrated summary of this Primer, visit: http://go.nature.com/V2eGfN

Update and Next Steps for Real-World Translation of Interventions for Type 2 Diabetes Prevention: Reflections From a Diabetes Care Editors' Expert Forum

The International Diabetes Federation estimates that 415 million adults worldwide now have diabetes and 318 million have impaired glucose tolerance. These numbers are expected to increase to 642 million and 482 million, respectively, by 2040. This burgeoning pandemic places an enormous burden on countries worldwide, particularly resource-poor regions. Numerous landmark trials evaluating both intensive lifestyle modification and pharmacological interventions have persuasively demonstrated that type 2 diabetes can be prevented or its onset can be delayed in high-risk individuals with impaired glucose tolerance. However, key challenges remain, including how to scale up such approaches for widespread translation and implementation, how to select appropriately from various interventions and tailor them for different populations and settings, and how to ensure that preventive interventions yield clinically meaningful, cost-effective outcomes. In June 2015, a Diabetes Care Editors’ Expert Forum convened to discuss these issues. This article, an outgrowth of the forum, begins with a summary of seminal prevention trials, followed by a discussion of considerations for selecting appropriate populations for intervention and the clinical implications of the various diagnostic criteria for prediabetes. The authors outline knowledge gaps in need of elucidation and explore a possible new avenue for securing regulatory approval of a prevention-related indication for metformin, as well as specific considerations for future pharmacological interventions to delay the onset of type 2 diabetes. They conclude with descriptions of some innovative, pragmatic translational initiatives already under way around the world.

Update and Next Steps for Real-World Translation of Interventions for Type 2 Diabetes Prevention: Reflections From a Diabetes Care Editors' Expert Forum. Diabetes Care 2016; 39: 1186-1201

We thank Dr. Garvey for his letter (1) in response to our 2015 Diabetes Care Editors’ Expert Forum on the prevention of type 2 diabetes (2). We appreciate his comments regarding the importance of the topic and the need for effective preventive strategies. Dr. Garvey also pointed out two shortcomings in our paper that we would like to address.nnDr. Garvey first stated that “there was a relative lack of emphasis on medication-assisted weight loss as a primary treatment approach, whereas conventional diabetes medications were afforded greater discussion” (1). He further stated, “All five medications approved for chronic management of obesity are highly effective for treating type 2 diabetes, and published clinical trials for three of these medications also demonstrate high efficacy for type 2 diabetes prevention, namely, orlistat, liraglutide 3 mg, and phentermine/topiramate extended release (ER) [3], which was not referenced in the forum” (1). We fully agree that weight loss in the range of 10% does appear to be maximally effective and can indeed reduce progression to type 2 diabetes. However, our goal in this Expert Forum was to specifically target studies whose primary aim was primary prevention of type 2 diabetes. For instance, the study evaluating phentermine/topiramate ER trials (4) was not primarily a type 2 diabetes prevention trial but rather reported type 2 diabetes incidence as a “subanalysis of a phase 3, randomized, placebo-controlled, double-blind study of overweight/obese subjects (BMI ≥27 to ≤45 kg/m2) with two or more comorbidities.” Thus, although we appreciate Dr. Garvey’s point and do not dispute the …