Sulfonylurea therapy improves glucose disposal without changing skeletal muscle GLUT4 levels in noninsulin-dependent diabetes mellitus subjects: a longitudinal study.

A major pathological feature of noninsulin-dependent diabetes (NIDDM) is defective insulin-stimulated glucose transport in skeletal muscle. When NIDDM subjects are assessed as a group, GLUT4 gene expression in skeletal muscle varies widely and is not different from that in controls. Thus, longitudinal studies are needed to assess whether changes in GLUT4 expression in muscle of NIDDM subjects could be responsible for changes in glucose disposal. The question is timely because recent studies in transgenic mice show that increasing GLUT4 expression can increase insulin-stimulated glucose uptake in vivo and in vitro. Here we use a longitudinal design to investigate the effects of 8 weeks of therapy with the sulfonylurea gliclazide on glycemic control, glucose tolerance, insulin-stimulated glucose disposal, and GLUT4 expression in muscle of 10 obese NIDDM subjects. Subjects were on a weight-maintaining diet. Gliclazide treatment results in increased serum C-peptide, decreased hemoglobin-A1c, decreased glucose excursion on glucose tolerance test, and 35% increased insulin-stimulated glucose disposal. Gliclazide therapy is not associated with any change in DNA or protein content per g muscle or any alteration in GLUT4 levels expressed either per microgram membrane protein or per DNA. In summary, the improvement in glycemic control and glucose disposal in NIDDM subjects receiving gliclazide therapy cannot be explained by increased expression of GLUT4 in muscle. Thus, therapeutic effects on insulin-stimulated glucose disposal can be achieved in NIDDM subjects without altering GLUT4 expression in muscle.

Insulin-mediated pseudoacromegaly: clinical and biochemical characterization of a syndrome of selective insulin resistance.

We have performed clinical, physiological, in vitro biochemical and genetic studies of a patient with severe insulin resistance associated with the phenotype of "pseudoacromegaly," defined as the presence of acromegaloid features in the absence of elevated levels of GH or insulin-like growth factor-I (IGF-I). Despite marked hyperinsulinemia, insulin and IGF-I binding to circulating blood cells and cultured skin fibroblasts was normal. Insulin and IGF-I-stimulated autophosphorylation of their respective receptors in cultured skin fibroblasts was also normal. However, neither insulin nor IGF-I were able to stimulate 2-deoxy D-glucose uptake by cultured skin fibroblasts. In contrast, the ability of insulin and IGF-I (or IGF-II) to stimulate amino acid uptake and thymidine incorporation into DNA was not impaired. This unique discordant signaling defect through both insulin and IGF-I receptors appeared not to be the consequence of altered expression or primary structure of the insulin receptor or the GLUT-4 glucose transporter, as assessed by several genetic and biochemical techniques. GLUT-4 expression in muscle was normal on Western blots, and SSCP screening of all 11 exons of the gene for nucleotide variation revealed no variations from normal. DNA sequencing and SSCP screening of exons 2-22 of the insulin receptor gene revealed only one variation predicted to alter the amino acid sequence (Val985-->Met). No functional differences between Met985 and wild-type human insulin receptors were evident in studies performed with Chinese hamster ovary cell transfectants that overexpress either receptor. This data combined with our previously published epidemiological data concerning the frequency of the Met985 allele, indicate that this variant insulin receptor is not responsible for the insulin resistant glucose uptake or the clinical syndrome of pseudoacromegaly. We conclude that: 1) The molecular lesion responsible for the selective biochemical defect in this individual appears to involve a signaling intermediate required for insulin and IGF-I regulation of glucose transport, and/or an effector mechanism operative in this process. 2) Cells derived from this patient may be a valuable tool in the search for such molecular mechanisms. 3) The Met985 allele is a relatively common variant which has no demonstrable adverse consequences for insulin receptor function. 4) Pseudoacromegaly can be viewed as the expected result of hyperinsulinemia driving the unopposed mitogenic and anabolic actions of insulin.

Sequential evaluation of islet cell responses to glucose in the transplanted pancreas in humans.

We evaluated the hormonal and metabolic responses of denervated pancreas allografts in nine volunteers 3 to 12 months after the transplant (initial) and again 1 year later (follow-up). Eight of the patients received simultaneous pancreas-kidney transplants. The glucose clamp technique was used to create a square wave of hyperglycemia 5.5 mmol/L above the basal glucose level for 2 hours. A biphasic insulin response was evident in each subject, both initially and at follow-up. The initial plasma insulin response was fourfold higher in patients with pancreas-kidney transplants than in normal volunteers. However, the plasma insulin response of the patients with pancreas-kidney transplants at the follow-up study was more similar to that of the normal controls. The plasma glucagon levels were elevated in follow-up clamp studies. Hepatic glucose production and glucose disposal were similar in both studies. At the follow-up examination only, GLUT4, the major insulin-sensitive glucose transporter, was measured in muscle homogenates by immunoblotting. GLUT4 levels in the patients with pancreas-kidney transplants were only 55% as abundant as in normal volunteers. This may be due, in part, to immunosuppressive therapy or to persistent, albeit reduced, levels of hyperinsulinemia even 2 years after transplantation. We concluded that, despite systemic drainage of the pancreas and immunosuppressive therapy, pancreatic insulin secretion, peripheral insulin levels, and muscle insulin responsiveness are restored toward normal levels approximately 2 years after the transplant.