Diabetes as a Paracrinopathy of the Islets of Langerhans


considered to be essentially a disease resulting from insulin deficiency. It has been recognised more recently that resistance to insulin may be a contributing factor, particularly for type 2 diabetes associated with excess weight or obesity.


Renewal of interest in the role of glucagon in diabetes has been recently reinforced by studies showing that inhibiting glucagon secretion markedly improves experimental diabetes in rodents18


and that knock-out of the glucagon receptor


makes insulin-deficient type 1 diabetic rodents thrive without insulin.19


Morphological studies have established that the main abnormality in the islet cell population of diabetes is a decrease in the number of β-cells without expansion of the α-cell mass.20,21


The interest of the recent proposal of Unger and Orci6 to consider


diabetes as a paracrinopathy has been to draw attention to delicate regulatory mechanisms occurring inside the islets of Langerhans. In this concept, the very high levels of insulin normally reached inside the stimulated islets exert a major inhibitory effect on glucagon secretion by the neighbouring α-cells. Conversely, a reduction in


1. Orci L, Macro- and micro-domains in the endocrine pancreas, Diabetes, 1982;31:538–65.


2. Bonner-Weir S, Orci L, New perspectives on the microvasculature of the islets of Langerhans, Diabetes, 1982;31:883–9.


3. Iwase M, Tashiro K, Uchizono Y, et al., Pancreatic islet blood flow in conscious rats during hyperglycemia and hypoglycaemia, Am J Physiol Regul Integr Comp Physiol, 2001;280:R1601–5.


4. Nyman LR, Ford E, Powers AC, et al., Glucose-dependent blood flow dynamics in murine pancreatic islets in vivo, Am J Physiol Endocrinol Metab, 2010;298:E807–14.


5. Bosco D, Armanet M, Morel P, et al., Unique arrangement of α- and β-cells in human islets of Langerhans, Diabetes, 2010;59:1202–10.


6. Unger RH, Orci L, Paracrinology of islets and the paracrinopathy of diabetes, Proc Natl Acad Sci USA, 2010;107:16009–12.


7. Samols E, Weir GC, Bonner-Weir S, Intra-islet insulin- glucagon-somatostatin relationships. In: Lefèbvre PJ (ed.), Glucagon II, Handbook of Experimental Pharmacology, Berlin: Springer, 1983;133–73.


8. Hellman B, Salehi A, Gylfe E, et al., Glucose generates coincident insulin and somatostatin pulses and anti-syncronous glucagon pulses from human pancreatic islets, Endocrinology, 2009;150:5334–40.


The suggestion that glucagon may contribute to the pathophysiology of diabetes was made more than 40 years ago but has been poorly recognised.16,17


intra-islet insulin concentrations would permit release of glucagon from the α-cells. Disruption of this mechanism appears as a key factor in the pathophysiology of diabetes.


In type 1 diabetes, “α-cells lack constant action of high insulin levels from juxtaposed β-cells. Replacement with exogenous insulin does not approach paracrine levels of secreted insulin except with high doses that ‘overinsulinize’ the peripheral insulin targets, thereby promoting glycaemic volatility.”6


In type 2 diabetes, it has


been proposed that the α-cell dysfunction results from failure of the juxtaposed β-cells to secrete the first phase of insulin.6,22


proposed in 1991 that the loss of the normal intra-islet pulsatile secretion of insulin should be considered as a critical factor in the well-recognised hyperglucagonaemia of diabetes.23,24


We This


hypothesis is now supported by the above-mentioned observations made in experimental diabetes in minipigs13,14 confirmed in human type 2 diabetes.15


and recently Whatever the mechanisms


involved, considering diabetes as a paracrinopathy of the islets of Langerhans paves the way to innovative approaches in the understanding, management and treatment of diabetes in which the α-cells of the islets and their product, glucagon, should not be forgotten. n


9. Tian G, Sandler S, Gylfe E, Tengholm A, Glucose and hormone-induced cAMP oscillations in α- and β-cells within pancreatic islets, Diabetes, 2011;60:1535–43.


10. Quesada I, Tuduri E, Ripoll C, et al., Physiology of the pancreatic alpha-cell and glucagon secretion: role in glucose homeostasis and diabetes, J Endocrinol, 2008;199:5–19.


11. Powers AC, Stein RW, New insight of islet biology and the pathophysiology of type 2 diabetes, Translational Endocrinology and Metabolism, 2011;2:95–116.


12. Rutter GA, Regulating glucagon secretion: Somatostatin in the spotlight, Diabetes, 2009;58:299–301.


13. Kjems LL, Kirby BM, Welsh EM, et al., Decrease in β-cell mass leads to impaired pulsatile insulin secretion, reduced postprandial hepatic insulin clearance, and relative hyperglucagonemia in the minipig, Diabetes, 2001;50:2001–12.


14. Meier JJ, Kjems LL, Veldhuis JD, et al., Postprandial suppression of glucagon secretion depends upon intact insulin pulsatile secretion: Further evidence for the intraislet insulin hypothesis, Diabetes, 2006;55:1051–6.


15. Menge BA, Grüber L, Jorgensen SM, et al., Loss of inverse relationship between pulsatile insulin and glucagon secretion in patients with type 2 diabetes, Diabetes, 2011;60:2160–8.


16. Unger RH, Aguilar-Parada E, Muller W, et al., Studies of pancreatic alpha-cell function in normal and diabetic subjects, J Clin Invest, 1970;49:837–48.


17. Lefèbvre PJ, Luyckx AS, Glucagon and diabetes: A reappraisal, Diabetologia, 1979;16:347–54.


18. Yu X, Park BH, Wang MY, et al., Making insulin-deficient type 1 diabetic rodents thrive without insulin, Proc Natl Acad Sci USA, 2008;105:14070–5.


19. Lee Y, Wang MY, Du XG, et al., Glucagon receptor knock-out prevents insulin-deficient type 1 diabetes in mice, Diabetes, 2011;60:391–7.


20. Meier JJ, Ueberberg S, Korbas S, et al., Diminished glucagon suppression after β-cell reduction is due to impaired β-cell function rather than an expansion of the alpha-cell mass, Am J Physiol Endocrinol Metab, 2011;300:E717–23.


21. Henquin JC, Rahier J, Pancreatic alpha cell mass in European subjects with type 2 diabetes, Diabetologia, 2011;54:1720–5.


22. Ward WK, Beard JC, Halter JB, et al., Pathophysiology of insulin secretion in diabetes mellitus, Adv Exp Med Biol, 1985;189:137–58.


23. Lefèbvre PJ, Paolisso G, Scheen A, The role of glucagon in non-insulin-dependent (type 2) diabetes mellitus. In: Sakamoto N, Angel A, Hotta H (eds), New directions in research and clinical works for obesity and diabetes mellitus, Amsterdam: Elsevier Science, 1991;25–9.


24. Paolisso G, Sgambato S, Passariello N, et al., Pulsatile insulin delivery is more efficient than continuous infusion in modulating islet-cell function in patients with type-1 diabetes, J Clin Endocrinol Metab, 1988;66:1220–6.


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