L E T T E R S
OBSERVATIONS Effects of Angiotensin II Type 1 Receptor Blockade on -Cell Function in Humans
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vidence indicates that activation of the angiotensin II type 1 receptor (AT1R) acutely decreases insulin secretion in animals and humans (1–3), mediated at least partially by reductions in islet blood flow and proinsulin biosynthesis (1,2). In contrast, AT1R blockade increased insulin secretion by 40 – 60% in Zucker diabetic fatty (ZDF) rats (4) and in obese db/db mice (5), thereby delaying the otherwise premature onset of diabetes in the latter animal model. If this were the case in humans, it would provide an explanation for the finding that AT1R antagonist treatment reduces the incidence of type 2 diabetes by ⬃25% in high-risk individuals in clinical trials despite no improvement in insulin sensitivity in most human studies using the euglycemic clamp technique (6). We therefore studied the effects of 6 weeks of treatment with the AT1R antagonist valsartan (80 mg b.i.d.) on -cell function and insulin sensitivity in 16 subjects with impaired glucose tolerance (75% male; age 58 ⫾ 2 years; BMI 33 ⫾ 2 kg/m2), using a double-blind, placebocontrolled, randomized, cross-over design. We ensured that all subjects had a blood pressure ⬍130/80 mmHg with or without antihypertensive medications (other than ACE inhibitors or AT1R antagonists) before the study, so as to minimize any potential influence of blood pressure lowering by AT1R antagonist treatment on metabolic outcomes. Threehour hyperglycemic clamps (⬃10 mmol/l) with [3-3H]glucose infusion and indirect calorimetry, followed by intravenous arginine infusion (5 g over 30 s), were performed at the end of both treatment periods for the measurement of glucose-stimulated first- and second-phase insulin secretion, insulin secretory capacity, as well as different aspects of insulin sensitivity. The study was designed to detect 12.5% increases in first- and secondphase insulin secretion with 90% power. Contrary to our hypothesis, AT1R DIABETES CARE, VOLUME 30, NUMBER 1, JANUARY 2007
blockade had no effect on either glucosestimulated first- (188 ⫾ 13 vs. 184 ⫾ 15 pmol/l, P ⬎ 0.6) and second-phase insulin secretion (362 ⫾ 35 vs. 337 ⫾ 31, P ⬎ 0.2) or insulin secretory capacity (1,731 ⫾ 128 vs. 1,714 ⫾ 136 pmol/l, P ⬎ 0.8). Moreover, whole-body insulin sensitivity, suppression of endogenous glucose production, and stimulation of glucose disposal and glucose oxidation remained unchanged during the clamp (all P ⬎ 0.6); suppression of plasma free fatty acid and glucagon also remained unaltered (both P ⬎ 0.4). The present study provides the novel information that, contrary to the studies in rodents (4,5), short-term AT1R blockade does not improve -cell function in humans who have impaired glucose tolerance, which may be due to species differences. Interestingly, in ZDF rats the improved -cell function by AT1R blockade was associated not only with increased islet proinsulin content but also with attenuated islet fibrosis and -cell apoptosis (4). If attenuated islet fibrosis and -cell apoptosis were important for improved insulin secretion by AT1R blockade in humans, it would probably be seen only with more prolonged treatment than that tested in the present study. We conclude that short-term AT1R antagonist treatment improves neither -cell function nor insulin responsiveness in various insulin-sensitive tissues in humans. Whether more prolonged AT1R antagonist treatment can benefit human -cell function remains to be determined. SYED BOKHARI, MD ZARMEN ISRAELIAN, MD JONELLE SCHMIDT, RN ELIOT BRINTON, MD CHRISTIAN MEYER, MD From the Division of Endocrinology, Carl T. Hayden VA Medical Center, Phoenix, Arizona. Address correspondence to Dr. Christian Meyer, MD, Carl T. Hayden VA Medical Center, 650 East Indian School Rd., Phoenix, AZ 85012. E-mail:
[email protected].. E.B. is presently associated with the Department of Cardiovascular Genetics, University of Utah School of Medicine, Salt Lake City, Utah, and is a Speaker’s Bureau Member for GlaxoSmithKline, Takeda, Pfizer, and Merck. DOI: 10.2337/dc06-1745 © 2007 by the American Diabetes Association.
Acknowledgments — The present work was supported in part by an unrestricted investigator-initiated research grant from Novartis Pharmaceuticals and an American Diabetes
Association Career Development Award to C.M. ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●
References 1. Carlsson PO, Berne C, Jansson L: Angiotensin II and the endocrine pancreas: effects on islet blood flow and insulin secretion in rats. Diabetologia 41:127– 133, 1998 2. Lau T, Carlsson PO, Leung PS: Evidence for a local angiotensin-generating system and dose-dependent inhibition of glucose-stimulated insulin release by angiotensin II in isolated pancreatic islets. Diabetologia 47:240 –248, 2004 3. Fliser D, Schaefer F, Schmid D, Veldhuis JD, Ritz E: Angiotensin II affects basal, pulsatile, and glucose-stimulated insulin secretion in humans. Hypertension 30: 1156 –1161, 1997 4. Tikellis C, Wookey PJ, Candido R, Andrikopoulos S, Thomas MC, Cooper ME: Improved islet morphology after blockade of the renin-angiotensin system in the ZDF rat. Diabetes 53:989 –997, 2004 5. Chu KY, Lau T, Carlsson P-O, Leung PS: Angiotensin II type 1 receptor blockade improves -cell function and glucose tolerance in a mouse model of type 2 diabetes. Diabetes 55:367–374, 2006 6. Scheen AJ: Prevention of type 2 diabetes mellitus through inhibition of the reninangiotensin system. Drugs 64:2537– 2565, 2004
Use of TobramycinImpregnated Calcium Sulphate Pellets in Addition to Oral Antibiotics An alternative treatment to minor amputation in a case of diabetic foot osteomyelitis
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o supplement surgical debridement, pellets of calcium sulfate (CS) were used as vehicles for local antibiotic delivery in treating osteomyelitis (1). We are aware of one case series in which diabetic pedal osteomyelitis was resolved with postoperatively implanted polymethylmethacrylate antibiotic beads and intravenous antibiotics (2). We now present a case of radiologically successful, nonsurgical management of diabetic foot osteomyelitis with tobramycin-impregnated CS pellets, in addition to oral antibiotic treatment, following our previous 181
Letters report on the pellets’ anecdotal success in treating diabetic infected wounds (3). A 41-year-old male with type 1 diabetes referred to the diabetic foot clinic had radiological findings of septic arthritis and diffuse osteomyelitis (anatomic stage IV) of the right fourth metatarsal head and adjacent phalanx overlying a chronic neuropathic ulcer. He refused to undergo a ray excision of the infected bones despite the suggestion of our surgical colleagues. Local therapy with prefabricated tobramycin-impregnated CS pellets, which were inserted twice into a deep cavity beneath the small foot ulcer, was then added to supplement oral Ciprofloxacin and Clindamycin and later to Amoxicillin/ clavulanic acid treatment due to drugrelated diarrhea. Further radiographs of the right forefoot after 4 and 6 weeks of the above treatment revealed radiological improvement of osteomyelitis and signs of bone reconstruction in the affected bones (online appendix Fig. 1 [available at http://care.diabetesjournals.org]). In a randomized study (4), high local antibiotic bioavailability from implantable beads in infected joint arthroplasties was found to be as effective as conventional parenteral antibiotic treatment. The nonadherent state of CS pellets versus bone substitutes, like polymethylmethacrylate, could be advantageous for antibiotic delivery in chronic osteomyelitis with antibiotic resistance (5). The potential role of local administration of antibiotics from CS pellets in healing and bone repair
is reported in a case series of patients with osteomyelitis (6). In the infected nonischemic diabetic foot, the possible synergistic effect of tobramycin-impregnated CS pellets as an additional treatment to systemic antibiotics should be further investigated in clinical trials. ELEANNA V. SALGAMI, MD, PHD1 FRANK L. BOWLING, BSC (HONS), DPOD, MED1 RICHARD W. WHITEHOUSE, MD, FRCR2 ANDREW J.M. BOULTON, MD, FRCP1,3 From the 1University Department of Medicine and Diabetes, Manchester Royal Infirmary, Manchester, U.K.; the 2Radiology Department, Manchester Royal Infirmary, Manchester, U.K.; and the 3Division of Endocrinology, Metabolism, and Diabetes, University of Miami School of Medicine, Miami, Florida. Address correspondence to Eleanna V. Salgami, MD, PhD, c/o Professor A.J.M. Boulton, University Department of Medicine and Diabetes, Manchester Royal Infirmary, Oxford Road, M13 9WL, Manchester, U.K. E-mail: eleanna.salgami@manchester. ac.uk. Additional information for this article can be found in an online appendix at http://care.diabetes journals.org. DOI: 10.2337/dc06-1792 © 2007 by the American Diabetes Association. ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●
References 1. McKee MD, Wild LM, Schemitsch EH, Waddell JP: The use of an antibiotic-impregnated, osteoconductive, bioabsorbable bone substitute in the treatment of infected long bone defects: early results of a prospective trial. J Orthop Trauma 16: 622– 627, 2002
2. Roeder B, Van Gils CC, Maling S: Antibiotic beads in the treatment of diabetic pedal osteomyelitis. J Foot Ankle Surg 39: 124 –130, 2000 3. Armstrong DG, Findlow AH, Oyibo SO, Boulton AJM: The use of absorbable antibiotic-impregnated calcium sulphate pellets in the management of diabetic foot infections. Diabet Med 18:942–943, 2001 4. Nelson CL, Evans RP, Blaha JD, Calhoun J, Henry SL, Patzakis MJ: A comparison of gentamicin-impregnated polymethylmethacrylate bead implantation to conventional parenteral antibiotic therapy in infected total hip and knee arthroplasty. Clin Orthop Relat Res 295:96 –101, 1993 5. Webb LX, Holman J, De Araujo B, Zaccaro DJ, Gordon ES: Antibiotic resistance in staphylococci adherent to cortical bone. J Orthop Trauma 8:28 –33, 1994 6. Gitelis S, Brebach GT: The treatment of chronic osteomyelitis with a biodegradable antibiotic-impregnated implant. J Orthop Surg (Hong Kong) 10:53– 60, 2002
Acute Renal Failure Following Oral Sodium Phosphate Bowel Preparation in Diabetes
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ecently there is renewed interest in the association between type 2 diabetes and colorectal carcinoma (1). Some authorities have advocated more in-
Table 1—Clinical presentation and biochemical findings of two patients with diabetes presenting with acute renal failure after sodium phosphate bowel preparation
Age/sex Other medical history Baseline creatinine Diabetes medications Other medications Presenting complaint Days after colonoscopy Sodium (mmol/l) Potassium (mmol/l) Urea (mmol/l) Creatinine (mol/l) Calcium (mmol/l) Phosphate (mmol/l) Lactate (mmol/l) Dialysis required Last creatinine (mol/l)
Patient 1 (T.T.H.)
Patient 2 (U.T.)
75/male Hypertension, microalbuminuria, paroxysmal atrial fibrillation 80 (62–106 mol/l) Gliclazide, metformin Perindopril, warfarin, sotalol, nifedipine Diarrhea, decreased consciousness 4 133 6.8 21.4 924 (62–106) 2.51 4.19 17.3 CRRT for 5 days 115
80/female Hypertension, hyperlipidemia, diabetic retinopathy 79 (44–80 mol/l) Gliclazide, metformin Aspirin, amitriptyline, famotidine Hypoglycemia, diarrhea and vomiting 3 132 4.7 16.8 629 (44–80) 2.16 2.04 7.2 No 101
Normal range
134–145 3.5–5.1 3.4–8.9 2.15–2.55 0.82–1.40 0.7–2.1
CRRT, continuous renal replacement therapy.
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