This article examines the foundation of β-cell failure in type 2 diabetes (T2D) and suggests areas for future research on the underlying mechanisms that may lead to improved prevention and treatment.
...A group of experts participated in a conference on 14-16 October 2013 cosponsored by the Endocrine Society and the American Diabetes Association. A writing group prepared this summary and recommendations.
The writing group based this article on conference presentations, discussion, and debate. Topics covered include genetic predisposition, foundations of β-cell failure, natural history of β-cell failure, and impact of therapeutic interventions.
β-Cell failure is central to the development and progression of T2D. It antedates and predicts diabetes onset and progression, is in part genetically determined, and often can be identified with accuracy even though current tests are cumbersome and not well standardized. Multiple pathways underlie decreased β-cell function and mass, some of which may be shared and may also be a consequence of processes that initially caused dysfunction. Goals for future research include to (1) impact the natural history of β-cell failure; (2) identify and characterize genetic loci for T2D; (3) target β-cell signaling, metabolic, and genetic pathways to improve function/mass; (4) develop alternative sources of β-cells for cell-based therapy; (5) focus on metabolic environment to provide indirect benefit to β-cells; (6) improve understanding of the physiology of responses to bypass surgery; and (7) identify circulating factors and neuronal circuits underlying the axis of communication between the brain and β-cells.
Glucose-stimulated insulin secretion is pulsatile and driven by intrinsic oscillations in metabolism, electrical activity, and Ca2+ in pancreatic islets. Periodic variations in glucose can entrain ...islet Ca2+ and insulin secretion, possibly promoting interislet synchronization. Here, we used fluorescence microscopy to demonstrate that glucose oscillations can induce distinct 1:1 and 1:2 entrainment of oscillations (one and two oscillations for each period of exogenous stimulus, respectively) in islet Ca2+, NAD(P)H, and mitochondrial membrane potential. To our knowledge, this is the first demonstration of metabolic entrainment in islets, and we found that entrainment of metabolic oscillations requires voltage-gated Ca2+ influx. We identified diverse patterns of 1:2 entrainment and showed that islet synchronization during entrainment involves adjustments of both oscillatory phase and period. All experimental findings could be recapitulated by our recently developed mathematical model, and simulations suggested that interislet variability in 1:2 entrainment patterns reflects differences in their glucose sensitivity. Finally, our simulations and recordings showed that a heterogeneous group of islets synchronized during 1:2 entrainment, resulting in a clear oscillatory response from the collective. In summary, we demonstrate that oscillatory glucose can induce complex modes of entrainment of metabolically driven oscillations in islets, and provide additional support for the notion that entrainment promotes interislet synchrony in the pancreas.
OBJECTIVE:
This article examines the foundation of β-cell failure in type 2 diabetes (T2D) and suggests areas for future research on the underlying mechanisms that may lead to improved prevention and ...treatment.
RESEARCH DESIGN AND METHODS:
A group of experts participated in a conference on 14–16 October 2013 cosponsored by the Endocrine Society and the American Diabetes Association. A writing group prepared this summary and recommendations.
RESULTS:
The writing group based this article on conference presentations, discussion, and debate. Topics covered include genetic predisposition, foundations of β-cell failure, natural history of β-cell failure, and impact of therapeutic interventions.
CONCLUSIONS:
β-Cell failure is central to the development and progression of T2D. It antedates and predicts diabetes onset and progression, is in part genetically determined, and often can be identified with accuracy even though current tests are cumbersome and not well standardized. Multiple pathways underlie decreased β-cell function and mass, some of which may be shared and may also be a consequence of processes that initially caused dysfunction. Goals for future research include to 1) impact the natural history of β-cell failure; 2) identify and characterize genetic loci for T2D; 3) target β-cell signaling, metabolic, and genetic pathways to improve function/mass; 4) develop alternative sources of β-cells for cell-based therapy; 5) focus on metabolic environment to provide indirect benefit to β-cells; 6) improve understanding of the physiology of responses to bypass surgery; and 7) identify circulating factors and neuronal circuits underlying the axis of communication between the brain and β-cells.
The K cell is a specific sub-type of enteroendocrine cell located in the proximal small intestine that produces glucose-dependent insulinotropic polypeptide (GIP), xenin, and potentially other ...unknown hormones. Because GIP promotes weight gain and insulin resistance, reducing hormone release from K cells could lead to weight loss and increased insulin sensitivity. However, the consequences of coordinately reducing circulating levels of all K cell-derived hormones are unknown. To reduce the number of functioning K cells, regulatory elements from the rat GIP promoter/gene were used to express an attenuated diphtheria toxin A chain in transgenic mice. K cell number, GIP transcripts, and plasma GIP levels were profoundly reduced in the GIP/DT transgenic mice. Other enteroendocrine cell types were not ablated. Food intake, body weight, and blood glucose levels in response to insulin or intraperitoneal glucose were similar in control and GIP/DT mice fed standard chow. In contrast to single or double incretin receptor knock-out mice, the incretin response was absent in GIP/DT animals suggesting K cells produce GIP plus an additional incretin hormone. Following high fat feeding for 21-35 weeks, the incretin response was partially restored in GIP/DT mice. Transgenic versus wild-type mice demonstrated significantly reduced body weight (25%), plasma leptin levels (77%), and daily food intake (16%) plus enhanced energy expenditure (10%) and insulin sensitivity. Regardless of diet, long term glucose homeostasis was not grossly perturbed in the transgenic animals. In conclusion, studies using GIP/DT mice demonstrate an important role for K cells in the regulation of body weight and insulin sensitivity.
The pathways that control insulin secretion and regulate pancreatic beta-cell mass are crucial in the development of diabetes mellitus. Maturity-onset diabetes of the young comprises a number of ...single-gene disorders affecting pancreatic beta-cell function, and the consequences of mutations in these genes are so serious that diabetes develops in childhood or adolescence. A genetic basis for the more common form of type 2 diabetes, which affects 10-20% of adults in many developed countries, is less clear cut. It is also characterized by abnormal beta-cell function, but other tissues are involved as well. However, in both forms identification of causative and susceptibility genes are providing new insight into the control of insulin action and secretion, as well as suggesting new treatments for diabetes.
There are three types of cell death; apoptosis, necrosis, and autophagy. The possibility that activation of the macroautophagy (autophagy) pathway may increase beta cell death is addressed in this ...study. Increased autophagy was present in pancreatic islets from Pdx1+/− mice with reduced insulin secretion and beta cell mass. Pdx1 expression was reduced in mouse insulinoma 6 (MIN6) cells by delivering small hairpin RNAs using a lentiviral vector. The MIN6 cells died after 7 days of Pdx1 deficiency, and autophagy was evident prior to the onset of cell death. Inhibition of autophagy prolonged cell survival and delayed cell death. Nutrient deprivation increased autophagy in MIN6 cells and mouse and human islets after starvation. Autophagy inhibition partly prevented amino acid starvation-induced MIN6 cell death. The in vivo effects of reduced autophagy were studied by crossing Pdx1+/− mice to Becn1+/− mice. After 1 week on a high fat diet, 4-week-old Pdx1+/−Becn1+/− mice showed normal glucose tolerance, preserved beta cell function, and increased beta cell mass compared with Pdx1+/− mice. This protective effect of reduced autophagy had worn off after 7 weeks on a high fat diet. Increased autophagy contributes to pancreatic beta cell death in Pdx1 deficiency and following nutrient deprivation. The role of autophagy should be considered in studies of pancreatic beta cell death and diabetes and as a target for novel therapeutic intervention.
Irs2-deficient mice develop type 2-like diabetes due to a reduction in β-cell mass and a failure of pancreatic islets to undergo compensatory hyperplasia in response to insulin resistance. In order ...to define the molecular mechanisms, we knocked down Irs2 gene expression in mouse MIN6 insulinoma cells. Insulin receptor substrate 2 (IRS2) suppression induced apoptotic cell death, which was associated with an increase in expression of the BH3-only molecule Bim. Knockdown (KD) of Bim reduced apoptotic β-cell death induced by IRS2 suppression. In Irs2-deficient mice, Bim ablation restored β-cell mass, decreased the number of TUNEL-positive cells, and restored normal glucose tolerance after glucose challenge. FoxO1 mediates Bim upregulation induced by IRS2 suppression, and FoxO1 KD partially inhibits β-cell death induced by IRS2 suppression. These results suggest that Bim plays an important role in mediating the increase in β-cell apoptosis and the reduction in β-cell mass that occurs in IRS2-deficient diabetes.
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