The effects of subcutaneous human proinsulin on the production of [formula omitted] split proinsulin, glucose turnover and intermediary metabolism in non-insulin-dependent diabetic man

Abstract

We have compared the effects of subcutaneously injected human proinsulin, insulin zinc suspension and inactive diluent (control) on glucose turnover, intermediary carbohydrate and lipid metabolism in non-insulin-dependent diabetic man. Six weight-matched (24.8 ± 1.6 kg M −2) non-insulin-dependent diabetic subjects underwent 3 separate, randomized, 10 h isoglycemic clamps. Glucose turnover was measured using a primed continuous infusion of [6′6′ 2H 2] glucose. Each subject received 0.35 U/kg of hormone or control made up to isovolumetric amounts. The mean blood glucose level of 7.3 ± 0.8 mmol/l was similar at the start of each isoglycemic clamp. Incremental area under the curve proinsulin levels (1195 ± 146 nmol/l) were about 21-fold higher, on a molar basis, than insulin (62.4 ± 10 nmol/l). Des 64 65 split proinsulin increased in a parallel manner to intact proinsulin ( r = 0.99, P < 0.0001) and comprised ∼ 13% of the intact proinsulin concentration. Hepatic glucose production was suppressed similarly following proinsulin and insulin zinc injection. However, both proinsulin and insulin zinc had a significantly greater effect on suppression of hepatic glucose production compared to control ( P = 0.01, P = 0.009, respectively). Metabolic clearance rate of glucose fell significantly during the control studies compared to insulin zinc or proinsulin injections ( P < 0.05). Blood lactate, pyruvate and alanine concentrations were similar following control or hormone injections. However blood glycerol, 3-hydroxybutyrate and plasma-non-esterified fatty acids were suppressed significantly by proinsulin and insulin zinc compared to control injections. The conclusions were: (1) In overnight fasted hyperglycemic non-insulin-dependent subjects s.c. injections of proinsulin and insulin zinc can produce similar effects on glucose turnover, intermediary lipid and carbohydrate metabolism. (2) Similar carbohydrate intermediary metabolism profiles can be obtained following insulin zinc, proinsulin or control injections. (3) However lipolysis and ketogenesis were significantly suppressed by both hormones compared to control. (4) Subcutaneous proinsulin injection resulted in ∼ 13% conversion to des 64 65 split proinsulin.