Relationship between beta-cell mass and diabetes onset

Abstract

Regulation of blood glucose concentrations requires an adequate number of beta-cells that respond appropriately to blood glucose levels. beta-Cell mass cannot yet be measured in humans in vivo, necessitating autopsy studies, although both pre- and postmorbid changes may confound this approach. Autopsy studies report deficits in beta-cell mass ranging from 0 to 65% in type 2 diabetes (T2DM), and approximately 70-100% in type 1 diabetes (T1DM), and, when evaluated, increased beta-cell apoptosis in both T1DM and T2DM. A deficit of beta-cell mass of approximately 50% in animal studies leads to impaired insulin secretion (when evaluated directly in the portal vein) and induction of insulin resistance. We postulate three phases for diabetes progression. Phase 1: selective beta-cell cytotoxicity (autoimmune in T1DM, unknown in T2DM) leading to impaired beta-cell function and gradual loss of beta-cell mass through apoptosis. Phase 2: decompensation of glucose control when the pattern of portal vein insulin secretion is sufficiently impaired to cause hepatic insulin resistance. Phase 3: adverse consequences of glucose toxicity accelerate beta-cell dysfunction and insulin resistance. The relative contribution of beta-cell loss versus beta-cell dysfunction to diabetes onset remains an area of controversy. However, because cytotoxicity sufficient to induce beta-cell apoptosis predictably disturbs beta-cell function, it is naive to attempt to distinguish the relative contributions of these linked processes to diabetes onset.

Fig. 1

Blood glucose values over the years prior to diabetes onset in prospective study. Glucose effects model. Copyright ©2007 American Diabetes Association. From Ref. [37]. Reprinted with permission from The American Diabetes Association.

Fig. 2

Fractional β-cell volume in obese humans [non-diabetic (ND), impaired fasting glucose (IFG) and type 2 diabetes (T2DM)]. Copyright © 2003 American Diabetes Association. From Ref. [4]. Reprinted with permission from American Diabetes Association.

Fig. 3

Fasting glucose and arterial insulin concentrations in sham-operated dogs and in dogs that underwent 50% pancreatectomy (DPx) (top panels). Corresponding deconvolved insulin secretion rate and insulin clearance rate (middle panels), Nand corresponding representative profiles of portal vein insulin concentrations (lower panels) in sham and 50% pancreatectomized dogs (DPx). Copyright © 2003 American Diabetes Association. From Ref. [62]. Reprinted with permission from The American Diabetes Association.