Defects inβ-Cell Function and Insulin Sensitivity in Normoglycemic Streptozocin-Treated Baboons: A Model of Preclinical Insulin-Dependent Diabetes*

Abstract

During the preclinical period of human insulin-dependent diabetes, both impaired pancreatic beta-cell function and increased insulin resistance are found, although normoglycemia is preserved. To better understand the changes in beta-cell function and insulin sensitivity that occur in preclinical insulin-dependent diabetes, we performed a panel of in vivo beta-cell function tests and measured insulin sensitivity in adolescent male baboons both in normal health and after a small dose of streptozocin which did not induce hyperglycemia. Nine animals were studied before (stage 1) and 1 week after receiving a low dose of streptozocin (stage 2). There was no change in fasting plasma glucose or insulin. The mean glucose disposal rate (Kg) remained within the normal range, but dropped from 2.0 +/- 0.2% +/- SE) to 1.2 +/- 0.1%/min (P less than 0.01), the acute insulin response to arginine (AIR(arg)) fell from 67.7 +/- 19.4 microU/mL (485.8 +/- 139.2 pmol/L) to 32.8 +/- 7.2 microU/mL (235.3 +/- 51.7 pmol/L; P less than 0.05), and the acute insulin response to glucose (AIR(gluc)) fell from 881 +/- 243 microU/mL.10 min (6321 +/- 1744 pmol/L.10 min) to 334 +/- 82 microU/mL.10 min (2396 +/- 588 pmol/L.10 min; P less than 0.01). The most dramatic change, however, was in the ability of hyperglycemia to potentiate AIR(arg) (expressed as the slope of potentiation). This was reduced by 94% from 1.8 +/- 0.5 to 0.1 +/- 0.1 (P less than 0.01), with almost no overlap in values between stages 1 and 2. Insulin sensitivity was also lower 1 week after streptozocin treatment. When the animals were restudied 8 weeks after streptozocin treatment (stage 3) most measures of beta-cell function were not significantly different from those in stage 1. The fasting plasma glucose level was 85.4 +/- 4.3 mg/dL (4.7 +/- 0.2 mmol/L), Kg was 1.8 +/- 0.3%/min, fasting plasma insulin was 35.9 +/- 8.5 microU/mL (257.6 +/- 61.0 pmol/L), AIR(arg) was 67.0 +/- 15.4 microU/mL (480.7 +/- 110.5 pmol/L), and AIR(gluc) was 615.3 +/- 265.3 microU/mL.10 min (4413 +/- 1901 pmol/L.10 min), and tissue insulin sensitivity was 2.7 +/- 0.4 x 10(4) min/microU.mL. These values show extensive overlap with those of stage 1, from which they are not significantly different. The slope of glucose potentiation, however, remained low in all animals at stage 3.(ABSTRACT TRUNCATED AT 400 WORDS)

Effect of nicotinic acid-induced insulin resistance on pancreatic B cell function in normal and streptozocin-treated baboons.

“…In STZ-200 animals during NA, basal insulin was 168±48 pM before glu- 'cI 10 15 20 Glucose ( mM ) (25) and allows measurement of insulin secretion and insulin sensitivity on the same day. We have shown previously, both in normal humans (3) and baboons (2), that there is an inverse correlation between insulin secretion and insulin sensitivity such that changes in either one can only be fully appreciated when considered in relation to the other (3,4). The baboons in this study showed a profound reduction in insulin sensitivity after 2-3 wk of NA treatment comparable to that seen in human adults (21).…”

“…4). (2,33). Nonenzymatic glycosylation of hemoglobin in mammals is determined by three major variables: mean plasma glucose concentration, red cell life span and red cell permeability (33).…”

“…As a model for graded B cell dysfunction, we have used streptozocin (STZ)-treated adolescent baboons (2). We have previously shown that, at low doses of STZ, the changes in pancreatic B cell function in these animals are similar to those seen in nondiabetic first-degree relatives ofIDDM patients during the preclinical period of IDDM (3,4).…”

Dynamics of insulin secretion and the clinical implications for obesity and diabetes

“…Whether β cell dysfunction or reduced β cell mass precedes clinical onset of diabetes remains an open question. However, in mice, surgical and chemical reductions of β cell volume demonstrate that the functional adaptation of the normal β cell prevents a rise in fasting glucose or reduction in the first phase of insulin secretion (92,93), suggesting that β cell dysfunction, rather than a decrease in β cell mass, is likely to be more closely associated with the pathophysiology of T2DM.…”

beta-cell dysfunction and failure in type 2 diabetes: potential mechanisms.

“…We would suggest that they are compensating for their numerical loss and are near their maximal output per cell, so that the reduced number of ␤-cells are sufficient to prevent fasting hyperglycemia. Another animal model for ␤-cell loss is the streptozotocin-treated baboon, which demonstrates a similar pattern of functional change (8).…”