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(12) Patent Application Publication (10) Pub. No.: US 2009/0042279 A1 YAMAKOSH Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2009/0042279 A1 YAMAKOSH Et Al US 20090042279A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2009/0042279 A1 YAMAKOSH et al. (43) Pub. Date: Feb. 12, 2009 (54) METHOD OF DETECTING MILD IMPAIRED Related U.S. Application Data St.RE.N E OR INSULIN (62) Division of application No. 10/509,120, filed on Nov. 29, 2004, now Pat. No. 7,452,687, filed as application No. PCT/JP03/03771 on Mar 27, 2003. (75) Inventors: Masaru YAMAKOSHI, (30) Foreign Application Priority Data Mishima-shi (JP); Takuji Kouzuma, Mishima-shi (JP) Mar. 22, 2002 (JP) ................................... 2002-97.121 Publication Classification (51) Int. Cl. Correspondence Address: CI2P I/00 (2006.01) BRCH STEWARTKOLASCH & BRCH (52) U.S. Cl. ........................................................ 435/262 PO BOX 747 FALLS CHURCH, VA 22040-0747 (US) (57) ABSTRACT It is intended to provide a noninvasive method of conve niently detecting mild impaired glucose tolerance and/or (73) Assignee: Asahi Kasei Pharma Corporation, insulin hyposecretion at the early stage with the use of an Tokyo (JP) enzyme. Namely, mild impaired glucose tolerance and/or insulin hyposecretion at the early stage are detected by quan tifying myoinositol Secreted into the urine before loading glucose and after loading glucose for a definite period of time (21) Appl. No.: 12/248,876 with the use of a reagent and comparing the increase (or the increase ratio) in the myoinositol content thus measured with a characteristic level which has been preliminarily deter (22) Filed: Oct. 9, 2008 mined in normal Subjects. 200 y = 3.4753x + 477.1 1000 g 3. 2 600 2. 400 A 200 -50 O 50 OO 50 200 A myo-inositol (ug/mg Cre) Patent Application Publication Feb. 12, 2009 Sheet 1 of 7 US 2009/0042279 A1 Fig. 1 O 500 OOO 500 2000 2500 3000 myo-inositol (LLM) Fig. 2 -- Tris -- Tricine - A - Bicine -e-TAPS -e- CHES --TEA -A-AMPSO Patent Application Publication Feb. 12, 2009 Sheet 2 of 7 US 2009/0042279 A1 Fig. 3 O 2 4. 6 8 O glucose (g/dL) Fig. 4 4500 400.0 () 350.0 300.0 250.0 2000 50.0 100.0 500 O.O O OOO 2000 3000 4000 myo-inositol (uM) Patent Application Publication Feb. 12, 2009 Sheet 3 of 7 US 2009/0042279 A1 Fig. 5 200 y = 3.4753x + 477.1 1000 S., 800 S. a 600 . 8. 400 (t) A 200 O -50 O 50 OO 150 200 A myo-inositol (ug/mg Cre) Fig. 6 200 80 t g 60 (> O 140 Sd 120 %€b 9 Ae st UU S 80 {& 3 8 60 4. S 40 e > () 20 e -100 000 1.00 2.00 3.00 4.00 5.00 AIRlso-o/APGso-o Patent Application Publication Feb. 12, 2009 Sheet 4 of 7 US 2009/0042279 A1 Fig. 7 400 1 200 000 800 600 400 200 myo-inositol myo-inositol + myo-inositol + urinary glucose - urinary glucose - urinary glucose + Fig. 8 P = 5 x 10 - 4.80 P K 0.0 - 440 -p g 0.05 - 4.00 3.60 3.20 2.80 N 2.40 k 2.00 1.60 20 0.80 0.40 0.00 myo-inositol myo-inositol + myo-inositol + urinary glucose urinary glucose urinary glucose + Patent Application Publication Feb. 12, 2009 Sheet 5 of 7 US 2009/0042279 A1 Fig. 9 A group Fig. 10 30 2 A group Patent Application Publication Feb. 12, 2009 Sheet 6 of 7 US 2009/0042279 A1 Fig. 11 300 Y - 1.044X-2.0 250 r 0.83 200 P K 0.0001 50 100 50 -50 O 50 OO 150 200 250 300 75g OGTT A myo-inositol (ug/mg Cr) Fig. 12 80 60 P< O.OOO P & O.OOO5 40 A 80 60 40 20 75gOGTT Meal Load Patent Application Publication Feb. 12, 2009 Sheet 7 of 7 US 2009/0042279 A1 Fig. 13 11 OO OOO 9 OO 8OO 7OO 5OO XPG=530 3OO A myo-inositol ( x8 ) ( -- ) nF22 E10 US 2009/0042279 A1 Feb. 12, 2009 METHOD OF DETECTING MILD IMPARED 0006. The term “impaired glucose tolerance' or “glucose GLUCOSE TOLERANCE OR INSULIN tolerance failure' refers to the condition of an increase in SECRETORY DEFECT blood glucose level caused by insufficient uptake of blood glucose into peripheral tissues such as skeletal muscle, liver, FIELD OF THE INVENTION and adipocyte after glucose is introduced into the blood through meals. In addition, the term "mild impaired glucose 0001. The present invention relates to a method of exam tolerance' refers to that the increment is slightly higher than ining mild impaired glucose tolerance or insulin secretory that of healthy individuals. defect using a sample such as urine. In addition, the present 0007 Insulin is a hormone secreted from beta cells of invention can be applied to a method for predicting or diag pancreas and acts on skeletal muscle, liver and adipose tissue nosing a disease that stems from mild impaired glucose tol to lower the blood glucose level. The term “insulin secretory erance or insulin secretory defect, such as diabetes mellitus, defect” refers to the condition of insufficient insulin secretion arteriosclerosis, or hypertension; a method of determining to uptake a Sufficient amount of blood glucose into peripheral effects of prevention of treatment of, or medical advice on tissues such as skeletal muscle, liver, and adipocyte after those diseases; and a method of evaluating therapeutic agents glucose is introduced into the blood through meals or the like. for treatment of those diseases. Among the insulin secretory defect the condition of insuffi cient insulin secretion to uptake the blood glucose into BACKGROUND OF THE INVENTION peripheral tissues just after glucose is introduced into the 0002. A final goal of diabetic treatment is to prevent the blood is referred to as “impaired early insulin secretion'. onset of diabetic complications and to inhibit the develop According to the guideline of the Japan Diabetes Society, the ment thereof. As demonstrated by clinical tests for achieving term “impaired early insulin secretion” refers to the condition this goal, it is important to find any abnormality and start in which the insulinogenic index I.I is less than 0.4. Insulino treatment thereof at the earliest possible stage e.g., Diabetes genic index II is defined as AIRI (30-0)/APG (30-0) wherein Research and Clinical Practice, 28, 103 (1995). AIRI (30-0) means between the difference between the blood 0003. Further, it is considered effective as a more insulin levels at 30 min after glucose load and before glucose advanced preventive method to find individuals with predia load; and APG (30-0) means the difference between the blood betes or at prestage of diabetes, or individuals with mild glucose levels at 30 min after glucose load and before glucose impaired glucose tolerance or insulin Secretory defect, who load. are not prediabetic at present but are highly likely to develop 0008 Assays of blood glucose levels and insulin levels for diabetes or prediabetes in the near future, and give them those diagnoses are invasive procedures that require blood treatment or advice for exercise and dietary. Clinical tests drawing more than once within a short time, giving the Sub have been conducted to Scientifically demonstrate this e.g., jects considerable pains. Therefore, there is a need for a Diabetes Care, 21, 1720 (1998). Therefore, detecting indi simple assay with lower invasiveness, which can solve these viduals with prediabetes will be important for prevention of disadvantages, preferably a noninvasive assay. diabetes mellitus and also complications thereof. Further 0009. On the other hand, the quantitative determination of more, diagnosing individuals with mild impaired glucose myo-inositol in a biological sample has been considered use tolerance or insulin secretory defect, who are not prediabetic ful for the diagnosis of diabetes mellitus and the following at present but are highly likely to develop diabetes or predia reports have been provided. betes in the near future, is considered most important for 0010 (a) In diabetes mellitus, there was an increase in the purpose of preventing diabetes mellitus at an earlier date. urinary myo-inositol level Lamer J. et al., New Eng.J.Med., 0004 An example of the diagnostic method for diabetes 323,373-378 (1990). mellitus is an oral glucose tolerance test. After a 75 gram oral (0011 (b) No difference was found between NGT and the glucose load, a group of individuals with the fasting blood borderline type with respect to the urinary myo-inositol level glucose level being less than 110 mg/dl and the 2-hour post Susumu Suzuki, Diabetes Care, Vol. 17, No. 12 (1994) 1465 load blood glucose level being less than 140 mg/dl is defined 1468. as normal glucose tolerance (NGT). In addition, a group of (0012 (c) The borderline type (IFG, IGT) and diabetes individuals with the fasting blood glucose level being not less mellitus showed higher urinary myo-inositol level than that of than 110 mg/dl but less than 126 mg/dl and the 2-hour post NGT (JP 2001-190299A). load blood glucose level being less than 140 mg/dl is defined 0013 The above reports (a) and (b) show the results as impaired fasting glycemia (IFG); and a group of individu obtained by determining the urinary myo-inositol levels with als with the fasting blood glucose level being less than 126 GC/MS. Nevertheless, the data are problematic in reproduc mg/dl and the 2-hour postloadblood glucose level being not ibility and reliability because they varied among different less than 140 mg/dl but less than 200 mg/dl is defined as examiners. On the other hand, in the report (c), the results are impaired glucose tolerance (IGT); and both groups IFG+IGT more precise and reliable than those obtained by GC/MS are defined as borderline type.
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