Intraperitoneal insulin therapy corrects abnormalities in cholesteryl ester transfer and lipoprotein lipase activities in insulin-dependent diabetes mellitus.

Abstract

Patients with insulin-dependent diabetes mellitus (IDDM) have proatherogenic disturbances in cholesteryl ester transfer (GET) despite intensive subcutaneous insulin therapy (ISC). Since CET is activated by insulin-sensitive lipoprotein lipase (LPL), which normally increases postprandially, we queried whether iatrogenic hyperinsulinism from ISC stimulated LPL and CET by studying well-controlled IDDM patients after ISC and then 6 months after lowering systemic insulin levels by intraperitoneal (IP) insulin delivery. Although glycemic control (HbA,c IDDM, 6.9±1.7%; control, 4.5% to 8%) was excellent during ISC, CET was accelerated (P<.001) and both systemic insulin levels and LPL specific activity were increased (P< .05). Following IP, basal systemic insulin levels declined by more than one half (ISC, 8.22±6.5 versus IP, 2.77±2.4 ^iU/mL; mean±SD; P<.025), and both LPL and CET activities returned to normal. Plasma triglyceride, cholesterol, high-density lipoprotein-2 (HDL 2 ) cholesterol, HDL, cholesterol, cholesteryl ester transfer protein mass, and glyce-A ssiduous diabetic management can reduce the /\ prevalence of the renal and retinal microvascu-.Z \-lar and neuropathic complications of insulindependent diabetes mellitus (IDDM) 12 but not the premature morbidity and mortality attributable to cardiovascular disease. The failure of rigorous glycemic control achieved with multiple daily injections of insulin to slow the development of diabetic macrovascular disease has led to the suspicion that the hyperinsulinemia that inevitably results from insulin therapy might actually promote atherogenesis. C 1994 American Heart Association, Inc.mic control (HbA,c, 6.3±0.8%) were unchanged and remained normal. These findings indicate that ISC is associated with high levels of basal CET and LPL. These alterations both appear to be closely linked to iatrogenic hyperinsulinemia resulting from ISC. The fact that they are both reversed when systemic insulin levels are reduced by IP suggests that insulin, acting through LPL, influences the nature of the interaction of the lipoproteins engaged in CET. Since accelerated CET is believed to result in the enrichment of certain subpopulations of apolipoprotein B-containing lipoproteins with cholesteryl ester, an alteration presumed to enhance their atherogenicity, its correction by IP therapy suggests that this more physiological mode of insulin delivery may reduce cardiovascular risk in IDDM. (Arterioscler Thromb. 1994;14:1933-1939

Normal metabolism of apolipoprotein B100-containing lipoproteins despite qualitative abnormalities in type 1 diabetic men

“…In these patients, hepatic lipase activity has been demonstrated to be inversely correlated with the LDL triglycerides : cholesterol ratio [23,25]. The relative increase in the amount of LDL triglycerides could also be explained by the increased cholesteryl ester transfer protein activity demonstrated in these patients, especially if hepatic lipase activity is low [22,26]. This reasoning is consistent with the observed trend towards cholesteryl ester enrichment of VLDL in our study.…”

“…Alternatively, a low VLDL triglycerides : apoB ratio could be attributable to increased lipoprotein lipase (LPL) activity. However, in several studies, type 1 diabetic patients and control subjects have been shown to have similar levels of LPL activity [22][23][24]. Moreover, if LPL activity were increased in type 1 diabetes mellitus, VLDL catabolism would be expected to be accelerated; however, this was not observed in the present study.…”

The effect of portal and peripheral insulin delivery on carbohydrate and lipid metabolism in a miniature pig model of human IDDM

“…Studies in humans which have examined the relative impact of subcutaneous compared to intraperitoneal insulin administration on lipid metabolism have generally [26,[63][64][65], although not always [24,66], found the intraperitoneal administration to be superior in normalising lipid metabolism. The characteristic dyslipidaemia of IDDM patients involves hypertriglyceridaemia and lowered HDL cholesterol concentrations [67].…”

Epidemiologic Characteristics of Diabetes in an Affected South Texas Population

“…However, the pancreatic hormone itself is inadequate in facilitating the activity of the CET. LPL helps activate the CET [22]. This underscores the importance of regular parenteral medication to augment the role of LPL and consequently CET especially in postprandial metabolism.…”