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

Richard J Naftalin

doi:10.12688/f1000research.8299.1

Abstract

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.

Highlights

The roles of apical SGLT1 and GLUT2 intestinal glucose absorption The sodium dependent glucose transporter SGLT1 is the only active component of intestinal transport sugar absorption
Integration of intestinal glucose absorption with glucose metabolism Blood flow simulation The initial aim was to model the interaction between incretininduced reduction in superior mesenteric arterial (SMA) blood flow resistance and glucose absorption
Flow and volume changes resulting from the increases in portal venous flow and splanchnic blood volume, increase splanchnic volume (Figure 2E), with consequential decreases in systemic arterial volume (Figure 2D), blood pressure: aortic BP decreases from mean level of 110 mm Hg to around 90 mm Hg

Summary

Introduction

The roles of apical SGLT1 and GLUT2 intestinal glucose absorption The sodium dependent glucose transporter SGLT1 is the only active component of intestinal transport sugar absorption. It has been argued that exposure to high intestinal luminal glucose concentrations ≥ 15mM, or more modest glucose loads, supplemented with artificial sweeteners, induces small intestinal apical membrane passive glucose transport via GLUT25,6. This process is stimulated by enterocyte AMP kinase(AMPK), triggered by opening of Cav 1.3 Ca2+ channels following SGLT1-dependent depolarization of the apical membrane potential. Whether apical GLUT2 has any functional role in net glucose absorption has been questioned. No discernible effect on net intestinal glucose absorption in vivo is observed in GLUT2 knock out, (KO) mice,

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