Effect of metabolic clearance rate and hepatic extraction of insulin on hepatic and peripheral contributions to hypoglycemia.

Chap, Z.; Ishida, Toshihiko; Chou, Jesse; Hartley, Craig J.; Lewis, Robert M.; Entman, Mark L.; Field, James B.

doi:10.1172/jci112231

Cited by 7 publications

(3 citation statements)

References 51 publications

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“…The present results suggest that the increased portal vein flow after oral glucose might be an important factor in the greater fractional hepatic extraction of insulin since both were abolished by separate and combined a and # adrenergic blockade. In addition, atropine infusion blocked both the increased portal plasma flow and fractional hepatic extraction of insulin after oral glucose (32). Furthermore, ingestion of meat was also associated with both increased portal plasma flow and fractional hepatic extraction of insulin (43).…”

Section: Discussionmentioning

confidence: 99%

Effects of alpha and beta adrenergic blockade on hepatic glucose balance before and after oral glucose. Role of insulin and glucagon.

Chap¹,

Ishida²,

Chou³

et al. 1986

J. Clin. Invest.

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In conscious dogs, phentolamine infusion significantly increased fasting portal vein insulin, glucagon, and decreased net hepatic glucose output and plasma glucose. Propranolol significantly decreased portal vein insulin, portal flow, and increased hepatic glucose production and plasma glucose. Phentolamine, propranolol, and combined blockade reduced glucose absorption after oral glucose. a, ft, and combined blockade abolished the augmented fractional hepatic insulin extraction after oral glucose. Despite different absolute amounts of glucose absorbed and different amounts of insulin reaching the liver, the percent of the absorbed glucose retained by the liver was similar for control and with a-or ,B blockade, but markedly decreased with combined blockade. Our conclusions are: (a) phentolamine and propranolol effects on basal hepatic glucose production may predominantly reflect their action on insulin and glucagon secretion; (b) after oral glucose, a-and fi-blockers separately or combined decrease glucose release into the portal system; (c) net hepatic glucose uptake is predominantly determined by hyperglycemia but can be modulated by insulin and glucagon; (d) direct correlation does not exist between hepatic delivery and uptake of insulin and net hepatic glucose uptake; (e) alterations in oral glucose tolerance due to adrenergic blockers, beyond their effects on glucose absorption, can be, to a large extent, mediated by their effects on insulin and glucagon secretion reflecting both hepatic and peripheral glucose metabolism.

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Section: Discussionmentioning

confidence: 99%

Effects of alpha and beta adrenergic blockade on hepatic glucose balance before and after oral glucose. Role of insulin and glucagon.

Chap¹,

Ishida²,

Chou³

et al. 1986

J. Clin. Invest.

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“…When ingested glucose is present in the intestinal lumen, splanchnic capillaries channel the absorbate via the portal vein to the liver. Splanchnic blood has approximately double the concentrations of absorbed materials and also of pancreatic hormones and incretins that are present in the systemic circulation ( 37 , 38 ; Figure 3E–G ).…”

Section: Integration Of Intestinal Glucose Absorption With Splanchnicmentioning

confidence: 99%

A computer model simulating human glucose absorption and metabolism in health and metabolic disease states

Naftalin

2016

F1000Res

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A computer model designed to simulate integrated glucose-dependent changes in splanchnic blood flow with small intestinal glucose absorption, hormonal and incretin circulation and hepatic and systemic metabolism in health and metabolic diseases e.g. non-alcoholic fatty liver disease, (NAFLD), non-alcoholic steatohepatitis, (NASH) and type 2 diabetes mellitus, (T2DM) demonstrates how when glucagon-like peptide-1, (GLP-1) is synchronously released into the splanchnic blood during intestinal glucose absorption, it stimulates superior mesenteric arterial (SMA) blood flow and by increasing passive intestinal glucose absorption, harmonizes absorption with its distribution and metabolism. GLP-1 also synergises insulin-dependent net hepatic glucose uptake (NHGU). When GLP-1 secretion is deficient post-prandial SMA blood flow is not increased and as NHGU is also reduced, hyperglycaemia follows. Portal venous glucose concentration is also raised, thereby retarding the passive component of intestinal glucose absorption. Increased pre-hepatic sinusoidal resistance combined with portal hypertension leading to opening of intrahepatic portosystemic collateral vessels are NASH-related mechanical defects that alter the balance between splanchnic and systemic distributions of glucose, hormones and incretins.The model reveals the latent contribution of portosystemic shunting in development of metabolic disease. This diverts splanchnic blood content away from the hepatic sinuses to the systemic circulation, particularly during the glucose absorptive phase of digestion, resulting in inappropriate increases in insulin-dependent systemic glucose metabolism. This hastens onset of hypoglycaemia and thence hyperglucagonaemia. The model reveals that low rates of GLP-1 secretion, frequently associated with T2DM and NASH, may be also be caused by splanchnic hypoglycaemia, rather than to intrinsic loss of incretin secretory capacity. These findings may have therapeutic implications on GLP-1 agonist or glucagon antagonist usage.

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“…It is well established that the liver is important for adequate regulation of glucose metabolism [1,2,3,4,5,6]. It is involved in regulation of blood glucose concentration 17,8,9] as well as in control of the systemic insulin concentrations [10,11,12].…”

Section: Introductionmentioning

confidence: 99%

Insulin Levels After Portal and Systemic Insulin Infusion Differ in a Dose-Dependent Fashion

Vos¹,

Haan²,

Vegter³

et al. 1998

Horm Metab Res

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The role of the liver in the regulation of systemic insulin levels is not well understood. The reported extraction rates vary between 0 to 85%, and extraction of a constant fraction of 50% of the portally delivered insulin is generally assumed. In the present study, we have investigated the role of the liver in the regulation of systemic insulin levels in the normal rat. Insulin was infused into the portal vein of conscious and freely moving rats in doses of 20, 40, 80 pmol/min during 15 min to mimic the gradual release of insulin by the native endocrine rat pancreas. The profiles of plasma insulin and glucose levels in the systemic circulation were compared to those obtained after direct infusion into the systemic circulation. The effect of intraportal and direct systemic infusion on plasma insulin and blood glucose levels were virtually similar where 20 pmol/min was applied. But, these effects were different if the dose was 40 pmol/min, and this difference increased when the dose was increased to 80 pmol/min, since hypoglycemia was less severe and normoglycemia was restored more rapidly with portal than with systemic infusion. Thus, our results show that the fraction of intraportally infused insulin reaching the systemic circulation decreases with higher doses of insulin. This suggests that the liver contains adaptable mechanisms to reduce the systemic insulin levels.

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Effect of metabolic clearance rate and hepatic extraction of insulin on hepatic and peripheral contributions to hypoglycemia.

Cited by 7 publications

References 51 publications

Effects of alpha and beta adrenergic blockade on hepatic glucose balance before and after oral glucose. Role of insulin and glucagon.

Effects of alpha and beta adrenergic blockade on hepatic glucose balance before and after oral glucose. Role of insulin and glucagon.

A computer model simulating human glucose absorption and metabolism in health and metabolic disease states

Insulin Levels After Portal and Systemic Insulin Infusion Differ in a Dose-Dependent Fashion

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