Determination of portal insulin absorption from peritoneum via novel nonisotopic method

Selam, J. L.; Bergman, R. N.; Raccah, D.; Jeandidier, N.; Lozano, J.; Charles, M. Arthur

doi:10.2337/diabetes.39.11.1361

Cited by 18 publications

(17 citation statements)

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“…In this model, we confirmed [4] that insulin administered by CPII is mainly absorbed by the portal vein (first-pass hepatic insulin metabolism) as shown by the hepatic increase in GHR expression and IRS-1 phosphorylation, both markers of higher insulin concentration in the liver. CPII is not associated with insulin resistance in the liver, as confirmed by the more efficient phosphorylation of Akt.…”

Section: Discussionsupporting

confidence: 74%

Portal or subcutaneous insulin infusion: efficacy and impact on liver inflammation

Dal

Jeandidier

Schaschkow

et al. 2015

Fundamemntal Clinical Pharma

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Intraperitoneal insulin allows physiological portal insulin administration and first-pass hepatic insulin extraction, but the impact on liver metabolism and inflammation is unknown. Our objective was to compare the impact, on metabolic control and liver function, of the same dose of insulin administered either intraperitoneally or subcutaneously during continuous infusion in diabetic rats. Wistar rats were randomly divided into 4 groups: control (C), untreated diabetic (streptozotocin, 100 mg/kg) and diabetic rats treated by continual subcutaneous Insuplant® infusion (CSII) and continual intraperitoneal Insuplant(®) infusion (CPII) of 2 UI/200 g/day (via an osmotic mini-pump for 1-4 weeks). Insulin signalling pathways were analysed through hepatic expression of growth hormone receptor and phosphorylated insulin receptor substrate 1. Metabolic control was determined by measurement of body weight, blood glucose and fructosamine. Liver function was assessed by measuring insulin-like growth factor-1 (IGF-1), with global inflammation assessed by levels of alpha-2-macroglobulin (α2M) and lipid peroxidation in plasma. Liver inflammation was evaluated by quantification of hepatic macrophage infiltration and reactive oxygen species production. CPII induced a better improvement in metabolic control and liver function than CSII, producing a significant decrease in blood glucose and fructosamine, coupled with increased IGF-1 and hepatic glycogen storage. Moreover, liver oxidative stress and liver inflammation were reduced. Such observations indicate that the same insulin level in CPII improves glucose control and hepatic glucose metabolism and function, attenuating the hepatic inflammatory response to diabetes. These data demonstrate the importance of focusing on therapeutics to allow first-pass hepatic insulin extraction or prevent diabetic complications.

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Section: Discussionsupporting

confidence: 74%

Portal or subcutaneous insulin infusion: efficacy and impact on liver inflammation

Dal

Jeandidier

Schaschkow

et al. 2015

Fundamemntal Clinical Pharma

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“…Physiologically, this option is quite appealing, and it has a fast dynamic effect. The pancreas secretes insulin to the liver via the portal vein, and a significant proportion of the insulin is absorbed by the liver ("first passage effect") within a few seconds after secretion before the rest enters the systemic circulation according to studies in animals (Matsuo et al 2003, Micossi et al 1986, Radziuk et al 1994, Schade et al 1979, Schade et al 1980, Schade et al 1981, Selam et al 1990) and humans (Widerøe et al 1996). I IP gives close to physiological insulin levels both in the liver and other tissues (Nelson et al 1982).…”

Section: 3mentioning

confidence: 99%

The Artificial Pancreas: A Dynamic Challenge

et al. 2016

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In patients with diabetes mellitus type 1, the pancreatic insulin production ceases, causing raise in blood glucose level (BGL) and potentially severe long-term complications. The "holy grail" of diabetes treatment is the artificial pancreas (AP), a closed-loop control system that regulates the user's BGL by infusing insulin, and possibly glucagon. Numerous attempts have been largely unsuccessful, mainly due to slow dynamics that make it difficult to avoid unwanted BGL excursions. System performance has been improved through improved sensor technology and faster-acting insulin types, but the risk of hypoglycemia is still significant unless the glucose setpoint is unnaturally high.We argue that this problem can be circumvented by choosing appropriate sites for glucose measurement and insulin infusion. While intravascular measurement and infusion provides the fastest dynamics and thus the best conditions for closed-loop control, it is only viable in inpatients mainly due to danger of infections and limited sensor durability. On the other extreme, state-ofthe-art subcutaneous systems exhibit significant time delays and diffusion dynamics, yielding poor BGL control in the event of disturbances like meals and physical activity. Avoiding dangerous hypoglycemia therefore comes at the expense of daily episodes of elevated BGL (typically 10-15 mmol/L) that increase the risk of long-term complications. Furthermore, slow insulin uptake from subcutis remains as a major challenge. Hence we advocate the double intraperitoneal (IP) AP. Here, insulin is released into the abdominal cavity (peritoneum) through a semi-permanent port, which also allows access for IP glucose sensing. This improves both sensing and absorption dynamics. Thus the closed-loop control may be significantly tighter, allowing a setpoint closer to the healthy normal BGL of approximately 4.5 mmol/L whilst potentially improving system safety. These statements are supported by results from our own research and the literature.

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“…It is evident that this approach is more physiological than either subcutaneous injection or intravenous infusion. Studies in experimental animals and man have shown that insulin given intraperitoneally is mainly absorbed via the portal circulation [18][19][20] and that 40-60 % is degraded during its first pass through the liver [18]. Consequently, peripheral insulin levels were found to be lower as compared with subcutaneous or intravenous application [21].…”

Section: Intraperitoneal Insulin Deliverymentioning

confidence: 99%

Implantable insulin pumps and metabolic control

Hepp

1994

Diabetologia

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SummaryThe development of implantable, remotecontrolled insulin pumps dates back to the early 1970's when it was recognized that conventional insulin therapy may be inadequate to control microvascular complications. For the first prototypes the intraperitoneal access route was favoured because of a physiological portal/peripheral insulin gradietlt. With intraperitoneal insulin delivery excellent metabolic control can be obtained with glycohaemoglobin values close to the upper normal range. A1-though long-term studies in insulin-dependent diabetic patients show comparable results with respect to glycaem~e control and intermediary substrate levels with intensive conventional therapy, the advantage of intraperitoneal insulin delivery may lie in the low rate of hypoglycaemic episodes. [Diabetologia (1994)

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Determination of portal insulin absorption from peritoneum via novel nonisotopic method

Cited by 18 publications

References 0 publications

Portal or subcutaneous insulin infusion: efficacy and impact on liver inflammation

Portal or subcutaneous insulin infusion: efficacy and impact on liver inflammation

The Artificial Pancreas: A Dynamic Challenge

Implantable insulin pumps and metabolic control

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