Melvin K. Dea

Central Role of the Adipocyte in the Metabolic Syndrome

Abstract Insulin resistance is associated with a plethora of chronic illnesses, including Type 2 diabetes, dyslipidemia, clotting dysfunction, and colon cancer. The relationship between obesity and insulin resistance is well established, and an increase in obesity in Western countries is implicated in increased incidence of diabetes and other diseases. Central, or visceral, adiposity has been particularly associated with insulin resistance; however, the mechanisms responsible for this association are unclear. Our laboratory has been studying the physiological mechanisms relating visceral adiposity and insulin resistance. Moderate fat feeding of the dog yields a model reminiscent of the metabolic syndrome, including visceral adiposity, hyperinsulinemia, and insulin resistance. We propose that insulin resistance of the liver derives from a relative increase in the delivery of free fatty acids (FFA) from the omental fat depot to the liver (via the portal vein). Increased delivery results from 1) more stored lipids in omental depot, 2) severe insulin resistance of the central fat depot, and 3) possible regulation of visceral lipolysis by the central nervous system. The significance of portal FFA delivery results from the importance of FFA in the control of liver glucose production. Insulin regulates liver glucose output primarily via control of adipocyte lipolysis. Thus, because FFA regulate the liver, it is expected that visceral adiposity will enhance delivery of FFA to the liver and make the liver relatively insulin resistant. It is of interest how the intact organism compensates for insulin resistance secondary to visceral fat deposition. While part of the compensation is enhanced B-cell sensitivity to glucose, an equally important component is reduced liver insulin clearance, which allows for a greater fraction of B-cell insulin secretion to bypass liver degradation, to enter the systemic circulation, and to result in hyperinsulinemic compensation. The signal(s) resulting in B-cell up-regulation and reduced liver insulin clearance with visceral adiposity is (are) unknown, but it appears that the glucagon-like peptide (GLP-1) hormone plays an important role. The integrated response of the organism to central adiposity is complex, involving several organs and tissue beds. An investigation into the integrated response may help to explain the features of the metabolic syndrome.

Mechanism of protracted metabolic effects of fatty acid acylated insulin, NN304, in dogs: retention of NN304 by albumin

Aims/hypothesis. The provision of stable, reproducible basal insulin is crucial to diabetes management. This study in dogs examined the metabolic effects and interstitial fluid (ISF) profiles of fatty acid acylated insulin, LysB29-tetradecanoyl, des-(B30) human insulin (NN304). Methods. Euglycaemic clamps were carried out under inhalant anaesthesia during equimolar intravenous infusions (3.6 pmol · min–1· kg–1 for 480 min) of human insulin or NN304 (n = 8 per group). Results. Steady-state total NN304 (albumin-bound and unbound) was considerably higher in plasma compared with human insulin (1895 ± 127 vs 181 ± 10 pmol/l, p < 0.001) and increased in interstitial fluid (163 ± 14 vs 106 ± 9 pmol/l, p < 0.01). The halftime for appearance of NN304 in interstitial fluid was slower than human insulin (92 vs 29 min, p < 0.001). Yet, equivalency of action was shown for glucose turnover; steady-state glucose uptake (Rd) of 7.28 ± 0.55 and 6.76 ± 0.24 mg · min–1· kg–1 and endogenous glucose production of 0.11 ± 0.12 and 0.22 ± 0.03 mg · min–1· kg–1 (p > 0.40; NN304 and human insulin, respectively). Similar to interstitial fluid, half times for Rd and endogenous glucose production were delayed during NN304 infusion (162 vs 46 min and 80 vs 31 min, respectively; p < 0.01 vs human insulin). Conclusion/interpretation. Firstly equivalency of steady-state action is found at equimolar physiologic infusions of human insulin and NN304. Secondly NN304 binding to plasma albumin results in slower NN304 appearance in the interstitial compartment compared with human insulin. Thirdly the delay in appearance of NN304 in interstitial fluid may not in itself be a source of the protracted action of this insulin analogue. The protracted effect is due primarily to albumin binding of the insulin analogue NN304. [Diabetologia (1999) 42: 1254–1263]

Rapid oscillations in omental lipolysis are independent of changing insulin levels in vivo

Abnormal fat metabolism plays an important role in the pathogenesis of obesity-related type 2 diabetes mellitus. This study examined whether free fatty acid levels (FFAs), like insulin levels, oscillate rapidly in plasma. Peripheral and portal blood samples from dogs were assayed for FFA, glycerol, glucose, and insulin. FFA and glycerol showed correlated oscillatory profiles, with about 8 pulses/hour. Omental lipolysis was also pulsatile, with about 10 pulses/hour, and insulin levels oscillated rapidly in plasma with about 7 pulses/hour. We applied an insulin clamp, beta-adrenergic blockade, or both together, to determine the driving force behind the FFA oscillation, and we analyzed our findings by approximate entropy (ApEn) for which lower values suggest regular pulses and higher values suggest disorder. Under basal conditions, ApEn was 0.3 +/- 0.2. With insulin not oscillating, FFA still cycled at about 9 pulses/hour and the ApEn was 0.2 +/- 0.1. In contrast, beta-blockade, either in the presence or absence of an insulin clamp, removed the FFA oscillation in three of nine dogs. In the other six dogs, the oscillatory profile was unchanged, but ApEn was significantly higher than basal values, suggesting that the regularity of the profile was disrupted. These results suggest that the FFA oscillation is driven by the central nervous system, not by insulin.