Dose-response characteristics of human proinsulin and insulin in non- insulin-dependent diabetic humans

S. N. Davis, L. Monti, P. M. Piatti, M. Brown, C. Hetherington, H. Orskov, W. Sobey, C. N. Hales, K. G M M Alberti

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We compared the actions of human proinsulin and insulin on glucose turnover and on intermediary carbohydrate and lipid metabolism in non- insulin-dependent diabetes mellitus (NIDDM). Six diet-controlled weight- matched (25.4 ± 1.0 kg/m2) NIDDM subjects underwent six separate isoglycemic clamps. Glucose turnover was measured using a primed continuous infusion of [6',6'-2H2]glucose. Each subject received three low-dose intravenous infusions of both insulin and proinsulin. Blood glucose was maintained at 6.7 ± 0.3 mM during proinsulin and insulin infusion. Insulin (I) infusions gave steady-state levels of 0.12 ± 0.001 (I1), 0.18 ± 0.01 (I2), and 0.33 ± 0.01 nM (I3). Steady-state proinsulin (P) levels were 2.5 ± 0.1 (P1), 4.3 ± 0.2 (P2), and 8.8 ± 0.9 nM (P3). Hepatic glucose production was suppressed equally by proinsulin and insulin at all doses. The metabolic clearance rate of glucose was significantly increased during the insulin infusions compared with proinsulin. The use of [6',6'-2H2]glucose resulted in a mean underestimation of the glucose infusion rate of 10.0 ± 4.0 and 6.0 ± 2.5% during the two highest insulin and proinsulin doses, respectively. Proinsulin had a significantly weaker effect than insulin, at the lowest infusion dose, in percent suppression of plasma nonesterified fatty acids, blood glycerol, and β-hydroxybutyrate levels (all P <0.05). Blood lactate levels were lower during the P1 (628 ± 43 μM) and P2 (657 ± 93 μM) infusions compared with I1 (776 ± 60 μM) and I2 (878 ± 44 μM; P <0.05, P <0.02), respectively. We conclude that in NIDDM 1) proinsulin has a preferential effect on the liver compared with muscle in terms of glucose handling; 2) proinsulin's weaker peripheral action, at the lowest dose, resulted in an inability to suppress lipolysis; 3) proinsulin may produce significantly lower blood lactate levels compared with insulin; and 4) glucose turnover can be underestimated using [6',6'-2H2]glucose.

Original languageEnglish
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Issue number1 26-1
Publication statusPublished - 1992


  • glucose turnover
  • intermediary metabolism
  • stable isotope

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology
  • Physiology


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