Method of detection of occult pancreatic beta cell dysfunction in normoglycemic patients

Abstract

This invention relates to a method for detecting the presence of or likelihood of a patient of developing occult pancreatic beta cell dysfunction, and a method for detecting the presence of or likelihood of a patient of developing clinically significant post-prandial hyperglycemia. The methods involve (a) measuring a level of alpha-hydroxybutyrate (AHB) in a single fasting baseline biological sample of the patient; (b) comparing the level of AHB in the single fasting baseline biological sample to a reference AHB level; and (c) determining the presence of or likelihood of developing the disorder in the patient based on the comparison in step (b). An increased AHB level at fasting baseline indicates that a normoglycemic, normo-insulinemic and/or non-dyslipidemic patient has developed or has an increased likelihood of developing occult pancreatic beta cell dysfunction. An increased AHB level at fasting baseline and an elevated glucose level of at least about 155 mg/dL at 30 minutes and/or 1 hour indicates that a normoglycemic, normo-insulinemic and/or non-dyslipidemic patient has developed or has an increased likelihood of developing clinically significant post-prandial hyperglycemia.

I/we claim: 
     
         1 . A method for detecting the presence of or likelihood of developing occult pancreatic beta cell dysfunction in a patient, comprising:
 a. measuring a level of alpha-hydroxybutyrate (AHB) in a single fasting baseline biological sample of the patient;   b. comparing the level of AHB in the single fasting baseline biological sample to a reference AHB level; and   c. determining the presence of or likelihood of developing occult pancreatic beta cell dysfunction in said patient based on the comparison in step (b), wherein an increased AHB level at fasting baseline indicates that a normoglycemic, normo-insulinemic and/or non-dyslipidemic patient has developed or has an increased likelihood of developing occult pancreatic beta cell dysfunction.   
     
     
         2 . The method of  claim 1 , wherein the level of AHB is greater than 4.5 mg/dl. 
     
     
         3 . The method of  claim 1 , further comprising measuring one or more additional biomarkers in one or more biological samples of the patient. 
     
     
         4 . The method of  claim 3 , wherein the one or more biomarkers are selected from the group consisting of glucose, insulin, HDL, HDL-c, triglycerides, LDL, LDL-c, C-peptide, 1,5-anhydroglucitol, and pro-insulin. 
     
     
         5 . The method of  claim 3 , wherein the one or more biomarkers are selected from the group consisting of auto-antibodies present in type-1 diabetes; viral nucleic acids; biomarkers to autoimmune diseases; viral DNAs, viral RNAs and antibodies to viral capsid proteins for members of the Enterovirus family. 
     
     
         6 . The method of  claim 3 , wherein the one or more biomarkers are selected from the group consisting of glucose, insulin, anti-islet cell cytoplasmic (anti-ICA) auto-antibodies, glutamic acid decarboxylase (anti-GAD) auto-antibodies, 1,5-anhydroglucitol, hemoglobin (Hb) Alc, fructosamine, mannose, D-mannose, mannose-binding lectin (MBL) amount, mannose binding lectin (MBL) activity, 1,5-anhydroglucitol (1,5 AG), glycation gap (glycosylation gap), serum amylase, c-peptide, intact pro-insulin, leptin, adiponectin, leptin/adiponectin ratio, ferritin, free fatty acids, lipoprotein-associated phospholipase A2 (Lp-PLA2), fibrinogen, myeloperoxidase, cystatin C, homocysteine, F2-isoprostanes, a-hydroxybutyrate (AHB), linoleoyl glycerophosphocholine (L-GPC), oleic acid (OA), analytes associated with IR score, analytes associated with HOMA (Homeostasis Model Assessment) IR score, analytes associated with CLIX score, gamma-glutamic transferase (GGT), uric acid, vitamin B12, homocysteine, 25-hydroxyvitamin D, TSH, estimated glomerular filtration rate (eGFR), and serum creatinine. 
     
     
         7 . The method of  claim 3 , wherein the one or more biomarkers are selected from the group consisting of body mass index (BMI); free fatty acids; low density lipoprotein particle number (LDL-P); LDL-cholesterol (LDL-C); triglyceride; high density lipoprotein particle number (HDL-P); high density lipoprotein-cholesterol (HDL-C); high sensitivity C-reactive protein (hs-CRP); remnant-like lipoproteins (RLPs); RLP-(cholesterol measures); apolipoprotein A-1; HDL2; ApoB:ApoA-1 ratio; Lp(a) mass; Lp(a) cholesterol; large VLDL-P; small LDL-P; large HDL-P; VLDL-size; LDL size; HDL size; LP-IR score; apolipoprotein A-1 (ApoA-1); apolipoprotein B (ApoB); apolipoprotein C (ApoC); apolipoprotein E (ApoE); and ApoE sub-species, variations, fragments, PTMs and isoforms thereof 
     
     
         8 . The method of  claim 3 , wherein the one or more biomarkers are selected from the group consisting of campesterol, sitosterol (β-sitosterol), cholestanol, desmosterol, lathosterol, and squalene. 
     
     
         9 . The method of  claim 3 , wherein the one or more biomarkers are biomarkers for coagulation or dyslipidemia. 
     
     
         10 . The method of  claim 1 , further comprising determining the increased likelihood of an impaired first phase insulin secretion response, based on the determination in 1(c). 
     
     
         11 . The method of  claim 1 , wherein the presence of or increased likelihood of developing occult pancreatic beta cell dysfunction also indicates that said patient is at risk of a diabetic condition selected from the group consisting of cardiodiabetes, gestational diabetes, latent autoimmune diabetes of adults (LADA), mixed phenotype diabetic conditions, and atypical forms of type 1 diabetes. 
     
     
         12 . The method of  claim 1 , wherein the presence of or increased likelihood of developing pancreatic beta cell dysfunction is used to predict an increased likelihood of a requirement for exogenous insulin supplementation. 
     
     
         13 . The method of  claim 1 , wherein the patient is at risk for a cardiodiabetic disease associated with post-prandial hyperglycemia. 
     
     
         14 . The method of  claim 13 , wherein the cardiodiabetic disease is selected from the group consisting of retinopathy, neuropathy, nephropathy, atherosclerosis, stroke, myocardial infarction, gestational diabetes, pre-term labor, and the birth of high birth-weight infants. 
     
     
         15 . The method of  claim 11 , wherein the atypical form of type 1 diabetes is insulin autoimmune syndrome (IAS). 
     
     
         16 . The method of  claim 1 , wherein the patient shows no apparent beta cell dysfunction, as detected by conventional diagnostic techniques. 
     
     
         17 . The method of  claim 1 , wherein the determination in step (c) is performed without having the patient provide multiple biological samples separated by a period of time. 
     
     
         18 . The method of  claim 1 , further comprising assigning a health risk value for the patient based on the determination in step (c), wherein the health risk value is selected from the group consisting of low risk, moderate risk and high risk of occult pancreatic beta cell dysfunction. 
     
     
         19 . A method for detecting the presence of or likelihood of a patient of developing occult pancreatic beta cell dysfunction, comprising:
 a. measuring a level of alpha-hydroxybutyrate (AHB) in a biological sample of the patient;   b. comparing the level of AHB in the baseline biological sample to a reference AHB level; and   c. determining the presence of or likelihood of the patient to develop occult pancreatic beta cell dysfunction based on the comparison in step (b),   wherein the determination in step (c) is performed without having the patient provide multiple biological samples separated by a period of time; and   wherein an elevated AHB baseline level indicates that a normoglycemic, normo-insulinemic and/or non-dyslipidemic patient has developed or has an increased likelihood of developing occult pancreatic beta cell dysfunction.   
     
     
         20 . A method for monitoring the progression or remission or a patient's response to treatment of a diabetic condition due to occult pancreatic beta cell dysfunction in a patient, comprising:
 a. measuring a first level of alpha-hydroxybutyrate (AHB) in a biological sample of the patient;   b. measuring a second level of alpha-hydroxybutyrate (AHB) in the biological sample of the patient after a period of time;   c. comparing the first level and the second level of AHB in the biological sample based on the measurements in steps (a) and (b) to determine whether the level of AHB has changed; and   d. monitoring the patient's progression or remission or the patient's response to treatment of the diabetic condition based on the comparison in step (c),   wherein an increased AHB level or an unchanged AHB level indicates that the diabetic condition is still in progression and/or a normoglycemic, normo-insulinemic and/or non-dyslipidemic patient is not responding to the treatment and   wherein a decreased AHB level indicates that the diabetic condition is in remission and/or a normoglycemic, normo-insulinemic and/or non-dyslipidemic patient is responding to the treatment.