Patients with non-insulin-dependent diabetes mellitus (NIDDM) who have chronic hyperglycemia lose acute incremental insulin responses to glucose but are able to briskly respond to other p-cell secretagogues. To investigate whether this is a defect specific for glucose or represents a more general phenomenon, we measured the insulin responses to acute intravenous tolbutamide in 10 obese patients with NIDDM both before and during sulfonylurea therapy with tolazamide. Comparable glycemia was achieved with oral dextrose 2 h before intravenous testing. To assess p-cell responsiveness to a nonsulfonylurea secretagogue, 1 mg glucagon was administered intravenously during tolazamide therapy.In seven patients, the mean peak insulin increment 5 or 10 min after intravenous tolbutamide was 54 ± 11 ixU/ml when not receiving tolazamide (0.14 ± 1 . 3 |xU/ ml) with tolazamide (P < .001), even though serum insulin responded rapidly to intravenous glucagon. In four patients tested for reversibility of their refractoriness to intravenous tolbutamide during chronic tolazamide therapy, the mean peak insulin increment 1 wk after discontinuing tolazamide was 79 ± 22 (xU/ml. A relatively rapid development of refractoriness was documented in four patients who were tested only 12 h after beginning tolazamide therapy; the mean peak insulin increments 5-10 min after intravenous tolbutamide were undetectable (-0.5 (xU/ml), yet responses to intravenous glucagon were evident.In these NIDDM patients, exposure of pancreatic pcells to sustained levels of sulfonylureas induces a reversible state of refractoriness to acute stimulation with sufonylureas but not to another secretagogue. This phenomenon has features in common with the effect of sustained hyperglycemia on desensitization of the p-cell response to intravenous glucose with implications regarding the pathogenesis of NIDDM. Moreover, it suggests that the insulinotropic effect of sulfonylureas might be more effective, particularly in cases of NIDDM with "secondary failure" to sulfonylureas, if these drugs are administered either on an intermittent schedule or as "pulse" therapy, using a form with a shorter duration of action. DIABETES 1986; 35:1314-20.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by loss of immunologic self-tolerance and the subsequent development of autoantibodies. These antibodies are thought to be important in relation to the clinical manifestations of the disease. One example is the development of multiple cytopenias secondary to cytolytic or cytotoxic antibodies directed toward red blood cells, platelets, and white blood cells. Other antibodies may mediate abnormal cellular mechanisms such as those seen with neuropsychiatric manifestations of SLE. We report the occurrence of autoantibodies directed toward insulin receptors and the subsequent development of type B insulin resistance syndrome in a woman with SLE. This syndrome was treated successfully with cyclophosphamide and mycophenolate mofetil.

Nasally administered (IN) insulin has been advocated as a potentially useful alternative to subcutaneously administered regular insulin because of its more rapid onset and time to peak action and its shorter duration of action. This study further defines the pharmacodynamics of IN insulin by using a euglycemic clamp technique to determine the bioavailability of IN insulin as compared with intravenous (IV) insulin, and to ascertain whether multiple sequentially administered doses of IN insulin alter pharmacodynamics. Eight normal volunteers received 2 control doses of IV insulin (0.05 U/kg), and 3 high doses (0.7 U/kg) and 3 low doses (0.35 U/kg) of IN insulin with an absorption enhancer (tauro-24,25 dihydrofusidate) given sequentially over a 2 day period. A euglycemic clamp was performed with a Biostator (Ames) that infused dextrose to keep the subject's blood glucose at his fasting level. Analysis of dextrose infusion curves for the low and high doses of IN insulin revealed an onset of action of 9.4 +/- 0.4 and 10.5 +/- 0.3 minutes, time to peak action of 20.6 +/- 5.6 and 23.7 +/- 4.4 minutes and duration of action of 82.1 +/- 5.2 and 95 +/- 5.7 minutes respectively. Both the onset of action and time to peak action were slightly longer (P less than .05) for the high as compared with the low dose IN insulin, although this should not represent a clinically significant difference. The total dextrose requirement was 21.9 +/- 2.3 g for the low dose IN insulin and 34.1 +/- 3.3 g for the high dose IN insulin, the latter value being significantly greater (P less than .01) than the former.(ABSTRACT TRUNCATED AT 250 WORDS)

When a hypoglycemic patient denies antidiabetic medication use, we recommend sequentially performing: 1) a thorough pill inspection; 2) an interview for recently altered pill appearances; 3) a measurement of serum insulin and C-peptide levels during hypoglycemia; and 4) a blood or urine sulfonylurea screen. Discovery of an unreported sulfonylurea overdosage can eliminate the need to search for an insulinoma and prevent further overdosages from occurring.

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