In Vivo Deactivation of Proinsulin Action on Glucose Disposal and Hepatic Glucose Production in Normal Man

Glauber, Harry; Revers, Robert R.; Henry, Robert R.; Schmeiser, L; Wallace, Penny; Kolterman, Orville G.; Cohen, Robert M.; Rubenstein, Arthur H.; Galloway, John A.; Frank, Bruce H.; Olefsky, Jerrold M.

doi:10.2337/diab.35.3.311

Cited by 39 publications

(25 citation statements)

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“…Peripheral administration of proinsulin has been shown to exert a relatively greater effect on Ra than Rd [3,5], when compared with insulin although the differential was less than we have shown here with these insulin dimers. These observations are compatible with a mechanism dependent on molecular size as proinsulin is intermediate in molecular weight between insulin and insulin dimers.…”

Section: Discussioncontrasting

confidence: 43%

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Demonstration of a relatively hepatoselective effect of covalent insulin dimers on glucose metabolism in dogs

et al. 1995

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SummaryInsulin analogues with relatively greater effect on hepatic glucose production than peripheral glucose disposal could offer a more physiological approach to the treatment of diabetes mellitus. The fact that proinsulin exhibits this property to a minor degree may suggest that analogues with increased molecular size may be less able than insulin to obtain access to peripheral receptor sites. Covalent insulin dimers have previously been shown to possess lower hypoglycaemic potencies than predicted by their in vivo receptor binding affinities. Reduced rates of diffusion to peripheral target tissues might be an explanation for the lower in vivo potency compared to insulin. To test the relative hepatic and peripheral effects of covalent insulin dimers, glucose clamp procedures with D-[3-3H]glucose tracer infusions were used in anaesthetised greyhounds to establish dose-response curves for rates of hepatic glucose production and glucose disposal with insulin, N ~m, N~S'l,-suberoyl-insulin dimer, and N ~B29, N~B'29,-suberoyl-insulin dimer. With N ~B1, N~B'l,-suberoyl-insulin dimer molar potencies relative to insulin were 68%, (34-133) (mean and 95 % fiducial limits), for inhibition of hepatic glucose production and 14.7 %, (10.3-20.9) for glucose disposal. With N~B29,N~S'29,-suberoyl-insulin dimer potencies were 75%, (31-184) and 2.5%, (1.5-4.3), for inhibition of hepatic glucose production and for glucose disposal, respectively. The demonstration that both dimers exhibit a significantly greater effect on glucose production than on glu: cose disposal supports the suggestion that analogues with increased molecular size may exhibit reduced ability to gain access to peripheral target cells. [Diabetologia (1995[Diabetologia ( ) 38: 1007[Diabetologia ( -1013 Key words Insulin, insulin analogues, glucose metabolism, euglycaemic clamp, insulin action, hepatoselectivity, glucose production.Insulin influences glucose metabolism in vivo by inhibiting hepatic glucose production (Ra) and by stimulating peripheral glucose disposal (Rd) mostly in skeletal muscle [1]. There have been suggestions that

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Section: Discussioncontrasting

confidence: 43%

“…The most well-established quantitative data are derived from extensive studies with human proinsulin. It has been reported that proinsulin, in comparison to insulin, is more effective in the liver than in the periphery [3][4][5]. The reasons for this are not yet understood.…”

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confidence: 92%

Demonstration of a relatively hepatoselective effect of covalent insulin dimers on glucose metabolism in dogs

et al. 1995

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“…Results for the control subjects are similar to those of Weiss et al and would suggest that insulin levels are indeed markedly raised in our offspring of diabetic mothers. Proinsulin and 32-33 split proinsulin have longer half-lives (23)(24)(25) and are poorer substrates for insulindegrading enzymes (26) than insulin. We have previously demonstrated that insulin propeptides are more stable in cord blood than insulin and have closer relationships to fetal growth and leptin concentrations at birth than insulin (13).…”

Section: Westgate and Associatesmentioning

confidence: 99%

Hyperinsulinemia in Cord Blood in Mothers With Type 2 Diabetes and Gestational Diabetes Mellitus in New Zealand

et al. 2006

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OBJECTIVE -In genetically diabetes-prone populations, maternal diabetes during pregnancy increases the risk of their children developing diabetes and obesity (the vicious cycle of type 2 diabetes). Fetal hyperinsulinemia at birth acts as a marker of this risk. We therefore examined whether cord insulin and leptin concentrations are increased in offspring of Maori and Pacific Island mothers with type 2 and gestational diabetes mellitus (GDM) and varying degrees of glycemic control (HbA 1c ). RESEARCH DESIGNS AND METHODS -Maori and PacificIsland mothers were prospectively recruited at Middlemore Hospital, South Auckland. Cord blood was taken from umbilical vein at birth from singleton babies born after 32 weeks of gestation to 138 mothers with GDM, 39 mothers with type 2 diabetes, and 95 control mothers. , and control subjects 13 ng/ml [8 -22]; P Ͻ 0.001) in cord blood. Cord insulin concentrations Ͼ120 pmol/l were found in 29% of offspring of mothers with GDM and 31% of mothers with type 2 diabetes. Many mothers with GDM had abnormalities of glucose tolerance postpartum (20% type 2 diabetes, 34% impaired glucose tolerance or impaired fasting glucose). Higher cord insulin (57 pmol/l [40 -94]) and leptin (26 ng/ml [17-39]) concentrations were found even in offspring of GDM mothers with normal glucose tolerance postpartum. RESULTSCONCLUSIONS -Raised cord insulin and leptin concentrations are a common finding in offspring of mothers with type 2 diabetes and GDM in this population. Diabetes Care 29:1345-1350, 2006F etal hyperinsulinemia is characteristic of pregnancy complicated by maternal diabetes and underpins complications such as macrosomia (1). Cord leptin correlates with measures of adiposity at birth (2-4) and is also raised in offspring of mothers with diabetes (3,4). Assessment of insulin and leptin at birth may be a particularly useful way of monitoring whether the fetus has been exposed to abnormally high levels of glucose in utero. Fetal hyperinsulinism may also have potential prognostic implications. Several studies have suggested that the maternal intrauterine environment might result in "programming" of later disease. An increased risk of obesity (5-8) and abnormal glucose tolerance (9 -12) are observed when offspring have been exposed to maternal diabetes in utero. Fetal hyperinsulinemia acts as a marker of this increased risk, offspring of diabetic mothers with higher insulin levels in utero being at a higher risk of later metabolic complications (7,8,10).The Pacific Island and Maori peoples of New Zealand are populations at high risk of both type 2 and gestational diabetes during pregnancy. We measured concentrations of fetal insulin, insulin propeptides, and leptin, together with weight and skinfold thickness at birth, with the following hypotheses: where the mother has type 2 diabetes and gestational diabetes mellitus (GDM), fetal hyperinsulinism is common despite treatment of disease, and fetal leptin and fat mass are similarly increased; and in subgroup analysis, these effects are most pronounce...

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“…A limitation of this study was that infants were not fasted before blood sampling. As fasting infants is unethical, we selected metabolic markers that were not very sensitive to the non-fasting state (Glauber et al,1986;Karlsson et al, 2004;Gil-Campos et al, 2010). Taken together, a high level of split proinsulin at the age of 6 months likely indicates susceptibility to adverse metabolic programming in these infants.…”

Section: Discussionmentioning

confidence: 99%

“…To evaluate the infants' metabolic status, serum 32-33 split proinsulin, intact proinsulin and adiposity-derived hormones, leptin and adiponectin were chosen as metabolic markers, as these are not sensitive to the non-fasting state (Glauber et al, 1986;Karlsson et al, 2004;Gil-Campos et al, 2010) unlike blood glucose and insulin concentrations. Indeed, for obvious ethical reasons, overnight fasting was not possible at the age of 6 months.…”

Section: Samplingmentioning

confidence: 99%

Impact of maternal diet during pregnancy and breastfeeding on infant metabolic programming: a prospective randomized controlled study

et al. 2010

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Objectives: To evaluate the impact of maternal diet and intensive dietary counselling during pregnancy and breastfeeding on the infant's metabolic status. Subjects/Methods: At the first trimester of pregnancy, 256 women were randomized into a control/placebo group and two dietary counselling groups (diet/probiotics and diet/placebo). The counselling, with double-blind randomization to probiotics (Lactobacillus rhamnosus GG and Bifidobacterium lactis) or placebo, targeted excessive saturated fat and low fibre consumption. Maternal diet was evaluated repeatedly during pregnancy and postpartum by means of 3 days' food diaries. Metabolic markers, serum 32-33 split and intact proinsulin, leptin/adiponectin ratio, skinfold thickness and waist circumference were measured of 194 healthy infants at the age of 6 months, and the high levels were taken to mirror adverse metabolic status. Results: The proportion of infants with a high 32-33 split proinsulin was significantly lower in dietary counselling with probiotics (n ¼ 6/62, 9.7%) or placebo (n ¼ 7/69, 10.1%) compared with the control/placebo group (n ¼ 17/63, 27.0%). The high split proinsulin was associated with larger skinfold thickness, waist circumference and higher leptin/adiponectin ratio in the infants (Po0.05). With respect to maternal diet during pregnancy, the highest and lowest tertiles of fat intake increased the infant's risk of high split proinsulin, whereas those of butter associated correspondingly with the infant's waist circumference. Further, breastfed infants showed a reduced risk of high split proinsulin and leptin/adiponectin ratio compared with formula-fed infants. Conclusions: Modification of maternal diet during pregnancy and breastfeeding may benefit infant metabolic health. High split proinsulin reflects adverse metabolic status in infancy, which can be improved by early dietary counselling.

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In Vivo Deactivation of Proinsulin Action on Glucose Disposal and Hepatic Glucose Production in Normal Man

Cited by 39 publications

References 0 publications

Demonstration of a relatively hepatoselective effect of covalent insulin dimers on glucose metabolism in dogs

Demonstration of a relatively hepatoselective effect of covalent insulin dimers on glucose metabolism in dogs

Hyperinsulinemia in Cord Blood in Mothers With Type 2 Diabetes and Gestational Diabetes Mellitus in New Zealand

Impact of maternal diet during pregnancy and breastfeeding on infant metabolic programming: a prospective randomized controlled study

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