Journal Club 亀田メディカルセンター 糖尿病内分泌内科 Diabetes and Endocrine Department, Kameda Medical Center 松田 昌文 Matsuda, Masafumi 2007 年４月 12 日 8:20-8:50 B 棟８階 カンファレンス室

From the 1 University of Texas Medical Branch, Galveston, Texas; the 2 University of Texas Health Science Center, San Antonio, Texas; the 3 Center for Metabolic Biology, Arizona State University, Tempe, Arizona; and the 4 Carl T. Hayden VA Medical Center, Phoenix, Arizona. CTGF, connective tissue growth factor; FFA, free fatty acid; OGTT, oral glucose tolerance test; TGF, transforming growth factor.

Effect of Pioglitazone AdipocyteMuscle Pioglitazone  Maintenance of beta-cells Improved Insulin Secretion Pancreas decrerased TNF-  Reduced Oxidative stress glucotoxicitylipotoxicity improvement Liver

intramyocellular lipid triglyceride diacylglycerol fatty acyl CoA ceramides serine phosphorylation of insulin receptor substrate 1 protein kinase C isoforms phosphatases inactivate Akt INSULIN RESISTANCE and LIPOTOXICITY

Lipid oversupply insulin resistance in skeletal muscle decreasing expression of nuclearencoded mitochondrial genes increasing extracellular matrix remodeling

Experimental lipid oversupply produced by an infusion of a triglyceride emulsion is well known to produce insulin resistance Acipimox, a nicotinic acid analog that reduces plasma FFAs by suppressing lipolysis Acipimox inhibits lipolysis in peripheral tissues and induces large reduction in circulating serum-free fatty acids. The mechanism of triglyceride lowering appears to be an increase of VLDL-Tg clearance. Increases leptin levels.

Mitochondrial biogenesis and gene expression mitochondrial biogenesis Endocrine Reviews 24: 78–90, 2003

Hypothesis In insulin-resistant subjects, acipimox would decrease plasma FFAs, concomitantly decrease myocellular fatty acyl CoAs while improving insulin sensitivity, and increase expression of PGC-1– and nuclear-encoded mitochondrial genes. Reduced FFA levels would result in decreased expression of extracellular matrix genes.

Methods Insulin-resistant subjects with a family history of type 2 diabetes had euglycemic clamps and muscle biopsies before and after acipimox treatment to suppress free fatty acids. Insulin clamp muscle biopsies Insulin clamp muscle biopsies acipimox 250mg PO every 6h for 7 days (Olbetam, Pharmacia Upjohn) 80mU/m 2 per min

Under basal conditions, either before or after acipimox treatment, there was no correlation between the plasma FFA concentration and muscle total fatty acyl CoA concentration. However, at the end of 2 h of insulin infusion, plasma FFA and muscle fatty acyl CoA concentrations were positively correlated, with this relationship reaching statistical significance after acipimox treatment (R 0.70, P <0.05).

Surprisingly, PGC-1 and NRF-1 mRNA were significantly decreased after acipimox. It is possible that this pattern of decrease in mRNA expression is not reflected in protein abundance or activity A Bio-Rad ICycler (Bio-Rad Laboratories, Hercules, CA) was used to quantify mRNA levels relative to the average value for -actin, GAPDH, and cyclophilin as controls. Three genes were chosen as controls to minimize variability. Relative changes in mRNA levels were analyzed by the Ct method

Effect of Insulin After acipimox in keeping with improved systemic insulin sensitivity, insulin increased the expression of several genes, including PGC-1, NRF-1, NRF-2, and porin (all P< 0.05).

Acipimox treatment had profound effects on the suppression of extracellular matrix genes in skeletal muscle under basal conditions. Interestingly, after acipimox treatment, insulin suppressed collagen subunit mRNA. Extracellular matrix genes

An increase in mRNA for matrix proteins often reflects the action of transforming growth factor (TGF)-β and CTGF, we also quantified the mRNA for these two genes. CTGF, connective tissue growth factor

Free radical scavenger genes we also assayed the mRNA expression for superoxide dismutase 2 (SOD2), 8- oxoguanine DNA glycosylase (OGG1), glutathione peroxidase 1 (GPX1), and NAD(P)H ubiquinone oxidoreductase (NQO1, cytoplasmic free radical scavenger).

A reduction in lipid supply does not completely reverse the molecular changes associated with lipid oversupply in muscle. Changes in expression of nuclear encoded mitochondrial genes do not always correlate with changes in insulin sensitivity. Summary and Conclusions The present results confirm that a reduction in myocellular fatty acyl CoA concentrations is elicited by a decrease in lipolysis and plasma FFAs and that this is accompanied by improved insulin sensitivity. The profound changes in expression of extracellular matrix gene expression associated with changes, either up or down, in insulin sensitivity provide new evidence in favor of a role for remodeling of the extracellular matrix in insulin sensitivity in skeletal muscle

From the 1 Endocrine Section, West Los Angeles Healthcare Center, VA Greater Los Angeles Healthcare System, David Geffen School of Medicine at UCLA, Los Angeles, California; and the 2 Pulmonary and Critical Care Section, West Los Angeles Healthcare Center, VA Greater Los Angeles Healthcare System, David Geffen School of Medicine at UCLA, Los Angeles, California.

From the Departments of Intensive Care Medicine (G.V.B., P.J.W., I.M.) and Medical Intensive Care Medicine (A.W., G.H., W.M., E.V.W., H.B.) and the Laboratory for Experimental Medicine and Endocrinology (R.B.), Catholic University of Leuven, Leuven, Belgium. Address reprint requests to Dr. Van den Berghe at the Department of Intensive Care Medicine, Catholic University of Leuven, B-3000 Leuven, Belgium, or at kuleuven.be.

Diabetes Mellitus Insulin Glucose Infusion in Acute Myocardial Infarction (DIGAMI): Benefit of Tight Glycemic Control in No Insulin – Low Risk Cohort Malmberg K, et al. BMJ. 1997;314: Mortality Total CohortNo Insulin – Low Risk Years in Study Control Insulin-glucose Infusion Control p =.0111p =.004 n=133 n=139 n=314 n=306

N Engl J Med 2001;345: CONVENTIONAL TREATMENT (N=783) INTENSIVE TREATMENT (N=765) Male sex — (%) 557 (71) vs 544 (71) Age — yr 62.2±13.9 vs 63.4±13.6

Figure 4. Kaplan–Meier Curves for In-Hospital Survival. The effect of intensive insulin treatment on the time from admission to the intensive care unit (ICU) until death is shown for the intention-to-treat group (Panel A) and the subgroup of patients staying in the ICU for three or more days (Panel B). Patients discharged alive from the hospital were considered survivors. P values calculated by the log-rank test were 0.40 for the intention-to-treat group and 0.02 for the subgroup staying in the ICU for three or more days. P values calculated by proportional-hazards regression analysis were 0.30 and 0.02, respectively. P=0.02

Clinical Recommendation In 2004, the American Diabetes Association (ADA) and American Association of Clinical Endocrinologists (AACE) issued position statements for tight glycemic control of patients with critical illness in the surgical ICU recommended blood glucose target during critical illness was 110 mg/dl.

Background Our initial experience with an insulin protocol was notable for excess hypoglycemia and suboptimal dose titration. This led to the following review of published insulin protocols and comparison of insulin recommendations in a hyperglycemic MICU patient.

Aim To review performance characteristics of 12 insulin infusion protocols. Hypothesis: The major assumption was that the change in glucose would be the same for all of the protocols, allowing comparison of recommended insulin dosing.

Methods A search for intravenous insulin protocols was performed using PubMed, the National Library of Medicine search engine, and the terms “insulin protocol” and “intravenous insulin.” Protocols were limited to those designed for critically ill ICU patients. There is extensive experience with glucoseinsulin- potassium infusions in myocardial infarction, and excluded.

Identified 12 different protocols

Insulin recommendations for a sample patient are calculated to highlight differences between protocols, including the patterns and ranges of insulin dose recommended (range 27–115 units [meanSD ]), amount recommended for glucose readings 200 mg/dl, and adjustments nearing target glucose.

Importance of glucose level adjustment Cross-sectional data from Krinsley and Finney suggest the upper threshold with respect to mortality lies somewhere between initial values of 145 and 180 mg/dl. In another analysis, increased mortality at a glucose of 150 mg/dl wasnoted but not apparent until 30 days had elapsed.

Some protocols have been incorporated into a computer program, accessed with a handheld computer or desktop. The Davidson protocol is one program and, while primarily a computerized program, is also available with options for bedside calculations. This protocol is also available in a drip-chart format that lists pre-calculated values. Other computerized guidelines have been reported but were not included because of their limited availability. One program by Thomas was based on the Van den Berghe protocol.

The ideal insulin infusion protocol should achieve glycemic control in a reasonable timeframe, with minimal hypoglycemia, low operator error rate, and minimal nursing time required. The selection of a protocol requires careful investigation and must take the type of patient into account. The best incorporate bolus doses, adjust for the direction and rate of glucose decline, and permit “offprotocol” adjustments. SUMMARY

While “one protocol fits all” is a common practice, the diversity of patients call for a reexamination of this approach. CONCLUSIONS