Abstract
Insulin resistance is a common pathogenetic feature of type 2 diabetes. However, hyperglycemia
would not develop if a concomitant defect in insulin secretion were not present. Impaired
insulin secretion results from functional and survival defects of the β-cell. The
functional defects can be demonstrated early in the natural history of diabetes and
they are hallmarked by abnormal pulsatility of basal insulin secretion and loss of
first-phase insulin release in response to a glucose challenge. Moreover, a significant
reduction of the β-cell mass is apparent at the time of the diagnosis of diabetes.
The progressive increase in glucose levels, that seems to characterize the natural
history of type 2 diabetes, has been claimed to be largely due to progressive reduction
of function and mass of β-cells. Although a genetic predisposition is likely to account
for impaired insulin secretion, chronic exposure to hyperglycemia and high circulating
FFA is likely to contribute to both functional and survival defects. The disturbance
in the endocrine activity of the pancreas is not limited to insulin, since a concomitant
increase in fasting plasma glucagon and impaired suppression after the ingestion of
an oral glucose load are often observed. This alteration becomes prominent after the
ingestion of a mixed meal, when plasma glucagon remains much higher in the diabetic
patient as compared to normal individuals. The disproportionate changes in the plasma
concentration of the two pancreatic hormones is clearly evident when the insulin:glucagon
molar ratio is considered. It is the latter that mainly affects hepatic glucose production.
Because of the reduction of the insulin:glucagon molar ratio basal endogenous glucose
concentration will be higher causing fasting hyperglycemia, while the hepatic glucose
output will not be efficiently suppressed after the ingestion of a meal, contributing
to excessive post-prandial glucose rise. Correcting β- and α-cell dysfunction becomes,
therefore, an attractive and rational therapeutic approach, particularly in the light
of new treatments that may directly act on these pathogenetic mechanisms of type 2
diabetes.
Key words
β-cell - α-cell - Insulin - Glucagon - Glucotoxicity - Lipotoxicity - GLP-1 - Thiazolidinediones
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Dr. S. Del Prato
Department of Endocrinology and Metabolism, Section of Diabetes, Ospedale Cisanello
Via Paradisa 2 · Pisa 56124 · Italy
Phone: +39-050995103
Fax: +39050541521 ·
Email: delprato@immr.med.unipi.it
