β-cell secretory dysfunction: a key cause of type 2 diabetes

Gordon Weir and colleagues1Weir GC Gaglia J Bonner-Weir S Inadequate β-cell mass is essential for the pathogenesis of type 2 diabetes.Lancet Diabetes Endocrinol. 2020; 8: 249-256Scopus (69) Google Scholar argue that decreased β-cell mass is a key cause of type 2 diabetes. We do not debate that the volume of pancreatic β-cells has a role in maintaining normoglycaemia, but to suggest that it is the major factor is unsupported by a wealth of clinical and experimental data. Type 2 diabetes is a heterogeneous disease of relative insulin deficiency and fasting hyperglycaemia that is not evident until more than 80% of estimated β-cell function has been lost;2Turner RC Mathews DR Holman RR Peto J Relative contributions of insulin deficiency and insulin resistance in maturity-onset diabetes.Lancet. 1982; 1: 596-598Summary PubMed Scopus (41) Google Scholar a reduction that is substantially greater than the losses of β-cell mass (up to 50%) alluded to by Weir and colleagues.1Weir GC Gaglia J Bonner-Weir S Inadequate β-cell mass is essential for the pathogenesis of type 2 diabetes.Lancet Diabetes Endocrinol. 2020; 8: 249-256Scopus (69) Google Scholar The overnight normalisation of fasting glucose in people with type 2 diabetes given glucagon-like peptide-1 (GLP-1) cannot be explained by a sudden increase in β-cell mass, but does reflect the apparent normalisation of β-cell function.3Rachman J Barrow BA Levy JC Turner RC Near-normalisation of diurnal glucose concentrations by continuous administration of glucagon-like peptide-1 (GLP-1) in subjects with NIDDM.Diabetologia. 1997; 40: 205-211Crossref PubMed Scopus (275) Google Scholar Evidence from gastric bypass surgery suggests that the change from hyperglycaemia to normoglycaemia that occurs within hours cannot result from a rapid increase in β-cell mass (which would occur over a number of months), but rather from a dramatic improvement in β-cell function.4Briatore L Salani B Andraghetti G et al.Restoration of acute insulin response in T2DM subjects 1 month after biliopancreatic diversion.Obesity (Silver Spring). 2008; 16: 77-81Crossref PubMed Scopus (56) Google Scholar Human adult β-cells (unlike rodent cells) have little, if any, proliferative capacity regardless of BMI and other lifestyle factors.5Cnop M Hughes SJ Igoillo-Esteve M et al.The long lifespan and low turnover of human islet beta cells estimated by mathematical modelling of lipofuscin accumulation.Diabetologia. 2010; 53: 321-330Crossref PubMed Scopus (166) Google Scholar A problem correlating β-cell mass to diabetes risk is that longitudinal measurements are not feasible. Mass is estimated by morphometry post-mortem, and no in vivo method is available. Type 2 diabetes could develop in some individuals with much fewer β-cells, and some genetic susceptibility genes appear to affect β-cell mass.6Rorsman P Braun M Regulation of insulin secretion in human pancreatic islets.Annu Rev Physiol. 2013; 75: 155-179Crossref PubMed Scopus (407) Google Scholar However, in most people, insulin availability far exceeds functional requirements; in a healthy pancreas, β-cells release only 5% of their insulin content in an entire day.6Rorsman P Braun M Regulation of insulin secretion in human pancreatic islets.Annu Rev Physiol. 2013; 75: 155-179Crossref PubMed Scopus (407) Google Scholar Thus, there is sufficient spare capacity to accommodate even large (up to 10-times) increases in insulin requirement (eg, in obesity and pregnancy). Weir and colleagues state that “inadequate mass comes first” and that they “are not aware of any alternative mechanism that would cause the impaired function”.1Weir GC Gaglia J Bonner-Weir S Inadequate β-cell mass is essential for the pathogenesis of type 2 diabetes.Lancet Diabetes Endocrinol. 2020; 8: 249-256Scopus (69) Google Scholar Both statements are questionable. Reduced insulin secretion (both first and second phase) is detectable in normoglycaemic first degree relatives of people with type 2 diabetes.7Gerich JE Is reduced first-phase insulin release the earliest detectable abnormality in individuals destined to develop type 2 diabetes?.Diabetes. 2002; 51: S117-S121Crossref PubMed Google Scholar There are many mechanisms that could explain the reduced β-cell function, such as impaired glucose metabolism, defective electrical activity, and interference with intracellular insulin trafficking and delivery into the circulation.6Rorsman P Braun M Regulation of insulin secretion in human pancreatic islets.Annu Rev Physiol. 2013; 75: 155-179Crossref PubMed Scopus (407) Google Scholar In conclusion, the β-cell mass concept championed by Weir and colleagues1Weir GC Gaglia J Bonner-Weir S Inadequate β-cell mass is essential for the pathogenesis of type 2 diabetes.Lancet Diabetes Endocrinol. 2020; 8: 249-256Scopus (69) Google Scholar—although provocative—does not describe the true aetiology of type 2 diabetes. Rather, insulin supply is determined by the product of β-cell number and function. Thus, we suggest that it is inadequate functional β-cell mass that underlies the pathogenesis of type 2 diabetes. We declare no competing interests. β-cell secretory dysfunction: a key cause of type 2 diabetes – Authors' replyWe appreciate the comments of Rury Holman and colleagues on our article1 because they allow us the expand on our arguments that inadequate β-cell mass is essential for the development of type 2 diabetes. Their first point is that the loss of β-cell function is very important and largely reversible. We agree completely and tried to make that clear in our Personal View.1 Yes, a 50% deficiency of β-cell mass in patients with type 1 or type 2 diabetes might be associated with an 80% reduction of β-cell functional mass and some reversal of this dysfunction with glucose lowering can be of great therapeutic value. Full-Text PDF Inadequate β-cell mass is essential for the pathogenesis of type 2 diabetesFor patients with type 1 diabetes, it is accepted among the scientific community that there is a marked reduction in β-cell mass; however, with type 2 diabetes, there is disagreement as to whether this reduction in mass occurs in every case. Some have argued that β-cell mass in some patients with type 2 diabetes is normal and that the cause of the hyperglycaemia in these patients is a functional abnormality of insulin secretion. In this Personal View, we argue that a deficient β-cell mass is essential for the development of type 2 diabetes. Full-Text PDF