Balancing needs and means: The dilemma of the β-cell in the modern world

G. Leibowitz, N. Kaiser, E. Cerasi*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

13 Scopus citations


The insulin resistance of type 2 diabetes mellitus (T2DM), although important for its pathophysiology, is not sufficient to establish the disease unless major deficiency of β-cell function coexists. This is demonstrated by the fact that near-physiological administration of insulin (CSII) achieved excellent blood glucose control with doses similar to those used in insulin-deficient type 1 diabetics. The normal β-cell adapts well to the demands of insulin resistance. Also in hyperglycaemic states some degree of adaptation does exist and helps limit the severity of disease. We demonstrate here that the mammalian target of rapamycin (mTOR) system might play an important role in this adaptation, because blocking mTORC1 (complex 1) by rapamycin in the nutritional diabetes model Psammomys obesus caused severe impairment of β-cell function, increased β-cell apoptosis and progression of diabetes. On the other hand, under exposure to high glucose and FFA (gluco-lipotoxicity), blocking mTORC1 in vitro reduced endoplasmic reticulum (ER) stress and β-cell death. Thus, according to the conditions of stress, mTOR may have beneficial or deleterious effects on the β-cell. β-Cell function in man can be reduced without T2DM/impaired glucose tolerance (IGT). Prospective studies have shown subjects with reduced insulin response to present, several decades later, an increased incidence of IGT/T2DM. From these and other studies we conclude that T2DM develops on the grounds of β-cells whose adaptation capacity to increased nutrient intake and/or insulin resistance is in the lower end of the normal variation. Inborn and acquired factors that limit β-cell function are diabetogenic only in a nutritional/metabolic environment that requires high functional capabilities from the β-cell.

Original languageAmerican English
Pages (from-to)1-9
Number of pages9
JournalDiabetes, Obesity and Metabolism
Issue numberSUPPL. 4
StatePublished - Nov 2009
Externally publishedYes


  • Animal models of diabetes
  • Gluco-lipotoxicity
  • Insulin secretion
  • MTOR
  • Prediabetes
  • Type 2 diabetes pathophysiology
  • β-cell death
  • β-cell function


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