Human beta cell mass and function in diabetes: Recent advances in knowledge and technologies to understand disease pathogenesis
TL;DR: In type 1 and type 2 diabetes impairment of beta cell function is an early feature of disease pathogenesis while a substantial decrease in beta cell mass occurs more closely to clinical manifestation, which suggests that the development of novel strategies for protection and recovery ofBeta cell function could be most promising for successful diabetes treatment and prevention.
Abstract: Background
Plasma insulin levels are predominantly the product of the morphological mass of insulin producing beta cells in the pancreatic islets of Langerhans and the functional status of each of these beta cells. Thus, deficiency in either beta cell mass or function, or both, can lead to insufficient levels of insulin, resulting in hyperglycemia and diabetes. Nonetheless, the precise contribution of beta cell mass and function to the pathogenesis of diabetes as well as the underlying mechanisms are still unclear. In the past, this was largely due to the restricted number of technologies suitable for studying the scarcely accessible human beta cells. However, in recent years, a number of new platforms have been established to expand the available techniques and to facilitate deeper insight into the role of human beta cell mass and function as cause for diabetes and as potential treatment targets.
Citations
More filters
TL;DR: It is shown that during the natural history of T1D in humans and the non-obese diabetic (NOD) mouse model, a subset of beta cells acquires a senescence-associated secretory phenotype (SASP), and clearance of senescent beta cells could be a new therapeutic approach for T1d.
204 citations
01 Oct 2019
TL;DR: The altered pathophysiological mechanisms that underlie the development of type 2 diabetes in NAFLD and vice versa are discussed and pharmacological agents currently available to treat T2D that could potentially be useful for the management of NASH are discussed.
Abstract: The worldwide prevalence of non-alcoholic fatty liver disease (NAFLD) is estimated to have reached 25% or more in adults. NAFLD is prevalent in obese individuals, but may also affect non-obese insulin-resistant individuals. NAFLD is associated with a 2- to 3-fold increased risk of developing type 2 diabetes (T2D), which may be higher in patients with more severe liver disease - fibrosis increases this risk. In NAFLD, not only the close association with obesity, but also the impairment of many metabolic pathways, including decreased hepatic insulin sensitivity and insulin secretion, increase the risk of developing T2D and related comorbidities. Conversely, patients with diabetes have a higher prevalence of steatohepatitis, liver fibrosis and end-stage liver disease. Genetics and mechanisms involving dysfunctional adipose tissue, lipotoxicity and glucotoxicity appear to play a role. In this review, we discuss the altered pathophysiological mechanisms that underlie the development of T2D in NAFLD and vice versa. Although there is no approved therapy for the treatment of NASH, we discuss pharmacological agents currently available to treat T2D that could potentially be useful for the management of NASH.
201 citations
Cites background from "Human beta cell mass and function i..."
...Several studies have now shown that individuals with NAFLD/non-alcoholic steatohepatitis (NASH) are at a higher risk of developing type 2 diabetes (T2D).2,3 A recent meta-analysis, including 296,439 individuals (30% with NAFLD) and nearly 16,000 cases of incident diabetes over a median of 5 years from 19 observational studies, has shown that the risk of incident diabetes is more than 2-fold higher in individuals with NAFLD.4 The pathophysiological mechanisms underlying the development of NAFLD are mainly the alterations in glucose and lipidmetabolism, insulin resistance (IR) and insulin secretion, explaining the close association between NAFLD and T2D....
[...]
...Pioglitazone reduces cardiovascular events in patients with and without T2D.186–189 However, because it may cause oedema, and there are reports of congestive heart failure (CHF) associated with pioglitazone use,186 many practitioners believe that it causes it....
[...]
...The confusion arises because undiagnosed heart failure with preserved ejection fraction (i.e., left ventricular diastolic dysfunction) is common in patients with NAFLD or T2D....
[...]
...Glucotoxicity and lipotoxicity are closely interrelated and both contribute to the deterioration of insulin resistance and impaired insulin secretion in T2D....
[...]
...Pioglitazone-induced weight gain ranges from 3% to 5% in patients with NASH, in RCTs lasting 6 months to 3 years173–176 or longer in patients with T2D.186–189 It tends to occur predominantly in the first 6–12 months of therapy....
[...]
TL;DR: An overview of the current conventional medications in diabetes, discovery of newer pharmacological drugs and gene therapy as a potential intervention of diabetes in the future is delivered.
Abstract: Type 1 and type 2 diabetes mellitus is a serious and lifelong condition commonly characterised by abnormally elevated blood glucose levels due to a failure in insulin production or a decrease in insulin sensitivity and function. Over the years, prevalence of diabetes has increased globally and it is classified as one of the leading cause of high mortality and morbidity rate. Furthermore, diabetes confers a huge economic burden due to its management costs as well as its complications are skyrocketing. The conventional medications in diabetes treatment focusing on insulin secretion and insulin sensitisation cause unwanted side effects to patients and lead to incompliance as well as treatment failure. Besides insulin and oral hypoglycaemic agents, other treatments such as gene therapy and induced β-cells regeneration have not been widely introduced to manage diabetes. Therefore, this review aims to deliver an overview of the current conventional medications in diabetes, discovery of newer pharmacological drugs and gene therapy as a potential intervention of diabetes in the future.
189 citations
TL;DR: Analysis of islets from 12 human donors using imaging mass cytometry revealed that β cell destruction is preceded by a β cell marker loss and by recruitment of cytotoxic and helper T cells in type 1 diabetes.
185 citations
TL;DR: The evidence that β-cells are active participants in the dialogue with the immune system during the development of type 1 diabetes mellitus is examined and it is suggested that therapies targeting β-cell health, vitality and function might prove essential, in combination with immunotherapy, to change the course of events leading to β- cell destruction.
Abstract: Type 1 diabetes mellitus is believed to result from destruction of the insulin-producing β-cells in pancreatic islets that is mediated by autoimmune mechanisms. The classic view is that autoreactive T cells mistakenly destroy healthy ('innocent') β-cells. We propose an alternative view in which the β-cell is the key contributor to the disease. By their nature and function, β-cells are prone to biosynthetic stress with limited measures for self-defence. β-Cell stress provokes an immune attack that has considerable negative effects on the source of a vital hormone. This view would explain why immunotherapy at best delays progression of type 1 diabetes mellitus and points to opportunities to use therapies that revitalize β-cells, in combination with immune intervention strategies, to reverse the disease. We present the case that dysfunction occurs in both the immune system and β-cells, which provokes further dysfunction, and present the evidence leading to the consensus that islet autoimmunity is an essential component in the pathogenesis of type 1 diabetes mellitus. Next, we build the case for the β-cell as the trigger of an autoimmune response, supported by analogies in cancer and antitumour immunity. Finally, we synthesize a model ('connecting the dots') in which both β-cell stress and islet autoimmunity can be harnessed as targets for intervention strategies.
176 citations
References
More filters
TL;DR: The correlation of the model's estimates with patient data accords with the hypothesis that basal glucose and insulin interactions are largely determined by a simple feed back loop.
Abstract: The steady-state basal plasma glucose and insulin concentrations are determined by their interaction in a feedback loop. A computer-solved model has been used to predict the homeostatic concentrations which arise from varying degrees beta-cell deficiency and insulin resistance. Comparison of a patient's fasting values with the model's predictions allows a quantitative assessment of the contributions of insulin resistance and deficient beta-cell function to the fasting hyperglycaemia (homeostasis model assessment, HOMA). The accuracy and precision of the estimate have been determined by comparison with independent measures of insulin resistance and beta-cell function using hyperglycaemic and euglycaemic clamps and an intravenous glucose tolerance test. The estimate of insulin resistance obtained by homeostasis model assessment correlated with estimates obtained by use of the euglycaemic clamp (Rs = 0.88, p less than 0.0001), the fasting insulin concentration (Rs = 0.81, p less than 0.0001), and the hyperglycaemic clamp, (Rs = 0.69, p less than 0.01). There was no correlation with any aspect of insulin-receptor binding. The estimate of deficient beta-cell function obtained by homeostasis model assessment correlated with that derived using the hyperglycaemic clamp (Rs = 0.61, p less than 0.01) and with the estimate from the intravenous glucose tolerance test (Rs = 0.64, p less than 0.05). The low precision of the estimates from the model (coefficients of variation: 31% for insulin resistance and 32% for beta-cell deficit) limits its use, but the correlation of the model's estimates with patient data accords with the hypothesis that basal glucose and insulin interactions are largely determined by a simple feed back loop.
29,217 citations
"Human beta cell mass and function i..." refers methods in this paper
...Calculation of the homeostasis model assessment (HOMA and HOMA2) [186,187] for beta cell output from fasting insulin and glucose plasma levels requires limited experimental experience, but only provides a measure of the basal state....
[...]
TL;DR: In obese individuals, adipose tissue releases increased amounts of non-esterified fatty acids, glycerol, hormones, pro-inflammatory cytokines and other factors that are involved in the development of insulin resistance.
Abstract: Obesity is associated with an increased risk of developing insulin resistance and type 2 diabetes In obese individuals, adipose tissue releases increased amounts of non-esterified fatty acids, glycerol, hormones, pro-inflammatory cytokines and other factors that are involved in the development of insulin resistance When insulin resistance is accompanied by dysfunction of pancreatic islet beta-cells - the cells that release insulin - failure to control blood glucose levels results Abnormalities in beta-cell function are therefore critical in defining the risk and development of type 2 diabetes This knowledge is fostering exploration of the molecular and genetic basis of the disease and new approaches to its treatment and prevention
4,515 citations
"Human beta cell mass and function i..." refers background in this paper
...In line with this, beta cell function is suggested to be the prerequisite factor for the onset of diabetes [63,123e127], being decreased by about 50e80% at the time of T2D diagnosis [63,122,127]....
[...]
...Beta cell compensation While obesity and insulin resistance remain major risk factors for T2D [63], the compensatory capacity of beta cells is credited to prevent most obese and insulin resistant subjects from developing T2D [64,65]....
[...]
TL;DR: Since the major defect leading to a decrease in β-cell mass in type 2 diabetes is increased apoptosis, while new islet formation andβ-cell replication are normal, therapeutic approaches designed to arrest apoptosis could be a significant new development in the management of type 2 Diabetes.
Abstract: Type 2 diabetes is characterized by impaired insulin secretion. Some but not all studies suggest that a decrease in beta-cell mass contributes to this. We examined pancreatic tissue from 124 autopsies: 91 obese cases (BMI >27 kg/m(2); 41 with type 2 diabetes, 15 with impaired fasting glucose [IFG], and 35 nondiabetic subjects) and 33 lean cases (BMI <25 kg/m(2); 16 type 2 diabetic and 17 nondiabetic subjects). We measured relative beta-cell volume, frequency of beta-cell apoptosis and replication, and new islet formation from exocrine ducts (neogenesis). Relative beta-cell volume was increased in obese versus lean nondiabetic cases (P = 0.05) through the mechanism of increased neogenesis (P < 0.05). Obese humans with IFG and type 2 diabetes had a 40% (P < 0.05) and 63% (P < 0.01) deficit and lean cases of type 2 diabetes had a 41% deficit (P < 0.05) in relative beta-cell volume compared with nondiabetic obese and lean cases, respectively. The frequency of beta-cell replication was very low in all cases and no different among groups. Neogenesis, while increased with obesity, was comparable in obese type 2 diabetic, IFG, or nondiabetic subjects and in lean type 2 diabetic or nondiabetic subjects. However, the frequency of beta-cell apoptosis was increased 10-fold in lean and 3-fold in obese cases of type 2 diabetes compared with their respective nondiabetic control group (P < 0.05). We conclude that beta-cell mass is decreased in type 2 diabetes and that the mechanism underlying this is increased beta-cell apoptosis. Since the major defect leading to a decrease in beta-cell mass in type 2 diabetes is increased apoptosis, while new islet formation and beta-cell replication are normal, therapeutic approaches designed to arrest apoptosis could be a significant new development in the management of type 2 diabetes, because this approach might actually reverse the disease to a degree rather than just palliate glycemia.
3,710 citations
TL;DR: The discovery of associated variants in unsuspected genes and outside coding regions illustrates the ability of genome-wide association studies to provide potentially important clues to the pathogenesis of common diseases.
Abstract: New strategies for prevention and treatment of type 2 diabetes (T2D) require improved insight into disease etiology. We analyzed 386,731 common single-nucleotide polymorphisms (SNPs) in 1464 patients with T2D and 1467 matched controls, each characterized for measures of glucose metabolism, lipids, obesity, and blood pressure. With collaborators (FUSION and WTCCC/UKT2D), we identified and confirmed three loci associated with T2D-in a noncoding region near CDKN2A and CDKN2B, in an intron of IGF2BP2, and an intron of CDKAL1-and replicated associations near HHEX and in SLC30A8 found by a recent whole-genome association study. We identified and confirmed association of a SNP in an intron of glucokinase regulatory protein (GCKR) with serum triglycerides. The discovery of associated variants in unsuspected genes and outside coding regions illustrates the ability of genome-wide association studies to provide potentially important clues to the pathogenesis of common diseases.
2,813 citations
TL;DR: The number of T2D loci now confidently identified to at least 10 is confirmed, and it is confirmed that variants near TCF7L2, SLC30A8, HHEX, FTO, PPARG, and KCNJ11 are associated with T1D risk.
Abstract: Identifying the genetic variants that increase the risk of type 2 diabetes (T2D) in humans has been a formidable challenge. Adopting a genome-wide association strategy, we genotyped 1161 Finnish T2D cases and 1174 Finnish normal glucose-tolerant (NGT) controls with >315,000 single-nucleotide polymorphisms (SNPs) and imputed genotypes for an additional >2 million autosomal SNPs. We carried out association analysis with these SNPs to identify genetic variants that predispose to T2D, compared our T2D association results with the results of two similar studies, and genotyped 80 SNPs in an additional 1215 Finnish T2D cases and 1258 Finnish NGT controls. We identify T2D-associated variants in an intergenic region of chromosome 11p12, contribute to the identification of T2D-associated variants near the genes IGF2BP2 and CDKAL1 and the region of CDKN2A and CDKN2B, and confirm that variants near TCF7L2, SLC30A8, HHEX, FTO, PPARG, and KCNJ11 are associated with T2D risk. This brings the number of T2D loci now confidently identified to at least 10.
2,750 citations