Relationship between metformin use, vitamin B12 deficiency, hyperhomocysteinemia and vascular complications in patients with type 2 diabetes.

Aim of the study was to clarify the relationship between metformin-induced vitamin B12 (B12) deficiency, hyperhomocysteinemia and vascular complications in patients with type 2 diabetes. Serum B12 concentrations, homocysteine plasma levels, the presence of retinopathy and history of macroangiopathy (stroke or coronary heart disease) were analyzed in patients without renal dysfunction (serum creatinine<115 µmol/L). Firstly, B12 status was analyzed in 62 consecutive metformin-treated patients. Secondly, the relationship between B12, homocysteine and vascular complications was analyzed in 46 metformin-treated and 38 age- and sex-matched non-metformin-treated patients. Among the 62 consecutive metformin-treated patients, B12 was deficient (<150 pmol/L) in 8 (13%) and borderline-deficient (150-220 pmol/L) in 18 (29%): the larger the metformin dosage, the lower the B12 (P=0.02, Spearman's ρ=-0.30). There were independent correlations between metformin use and B12 lowering (P=0.02, r = -0.25), and B12 lowering and elevation of homocysteine (P<0.01, r=-0.34). Elevation of homocysteine was a risk for retinopathy (P=0.02, OR 1.26, 95%CI 1.04-1.52). There was no significant relation between homocysteine and macroangiopathy. Correlation between B12 and homocysteine was stronger in metformin-treated (P<0.01, r=-0.48) than non-metformin-treated (P=0.04, r=-0.38) patients. In ten B12 deficient patients, B12 supplementation (1,500 µg/day) for 2.2±1.0 months with continued use of metformin raised B12 levels: 152±42 and 299±97 pmol/L before and after treatment, respectively (P<0.01). Metformin-induced B12 lowering in diabetes was associated with elevation of homocysteine, and hyperhomocysteinemia was independently related to retinopathy. Metformin-induced B12 deficiency was correctable with B12 supplementation.

Fulminant type 1 diabetes with robust recovery of insulin secretion: a case report.

In fulminant type 1 diabetes (FT1D), irreversible destruction of pancreatic beta-cells occurs abruptly, leading to sudden diabetic ketoacidosis (DKA) in the absence of diabetes-related autoantibodies. This is the first case report of FT1D in which beta-cell was rescued with the commencement of insulin therapy during the evolution of FT1D.

Elevation of thyrotropin upon accidental hypothermia in an elderly man.

BACKGROUND: Although "polar triiodothyronine (T(3)) syndrome" in chronic dwellers/workers in Antarctica has been established, alteration of the pituitary thyroid-axis upon accidental hypothermia is not well recognized. We report here a rare case of elevation of thyrotropin (TSH) upon accidental hypothermia. PATIENT FINDINGS: A 75-year-old man was admitted because of consciousness disturbance.The mean outside temperature was approximately -2.0°C (28.4°F) but his house was inadequately heated. His rectal temperature was 29.5°C (85.1°F). Goiter was not palpable and pitting edema, not myxedema, was present. Serum TSH was elevated (28.3 mU/L, reference range 0.27-4.2), and free T(3) (FT(3)) and free thyroxine (FT(4)) lowered (FT(3), 3.25 pmol/L with a reference range of 4.00-7.85, and FT(4), 9.18 pmol/L with a reference range of 12.87-23.179), but thyroid-related autoantibodies were all negative. By the next morning, body temperature had risen to >36°C (>96.8°F) and there was no further recurrence of hypothermia. Serum TSH decreased exponentially and the patient's condition had become normal by day 22. FT(3) and FT(4) were found to be slightly lowered and elevated, respectively, during the same period, in the subnormal range. At the end of the observation period, the patient settled into the state known as "nonthyroidal illness syndrome." SUMMARY: Elevation of TSH in an elderly patient with accidental hypothermia was normalized after restoration of normal body temperature. Elevation of TSH upon accidental hypothermia was probably an adaptive response. CONCLUSIONS: In patients with accidental hypothermia, the possibility of an adaptive elevation of TSH should be borne in mind. This clearly warrants further studies of the adaptation of the pituitary-thyroid axis in patients with accidental hypothermia.

Systematic analysis of risk factors for coronary heart disease in Japanese patients with type 2 diabetes: a matched case-control study.

AIM: To identify predictors of coronary heart disease (CHD) in Japanese patients with type 2 diabetes (T2DM). METHODS: A matched case-control study was performed using 800 patients with T2DM admitted for treatment of hyperglycemia from January 2002 to June 2010. Cases comprised 16 patients who had developed acute myocardial infarction and/or received a coronary artery bypass by June 2010, and controls comprised 48 age- and sex-matched patients without CHD events. The mean age, glycated hemoglobin (HbA1c), and body mass index (BMI) were 61.5 yrs, 9.7% and 24.4 kg/m(2), respectively. The relationship of baseline variables, including lipid values, HbA1c, BMI, blood pressure, fasting blood sugar, 2h-post-breakfast blood sugar, delta blood sugar(0-2h), urinary albumin excretion, estimated glomerular filtration rate and treatment modalities (insulin/sulfonylurea/biguanide), to CHD development was analyzed by conditional logistic regression analysis. RESULTS: Total cholesterol (TC) (OR 2.35, 95%CI 1.11-4.98, p=0.03), non-HDL-cholesterol (OR 3.07, 95%CI 1.33-7.10, p=0.009), LDL-cholesterol (OR 2.84, 95%CI 1.24-6.51, p=0.01), non-HDL-cholesterol/HDL-cholesterol (OR 2.07, 95%CI 1.10-3.90, p=0.02) and LDL-cholesterol/ HDL-cholesterol (OR 2.74, 95%CI 1.22-6.15, p=0.01) were significantly related to CHD. Fold risk increment per 1-SD increase in basal TC, non-HDL-cholesterol, LDL-cholesterol, non-HDL-cholesterol/HDL-cholesterol and LDL-cholesterol/HDL-cholesterol was 2.33, 2.89, 2.52, 2.37 and 2.60, respectively. Only non-HDL-cholesterol was an independent risk factor. From the receiver operating characteristic curve, 3.89 mmol/L non-HDL-C was the best cutoff value. None of the non-lipid variables were significantly related to CHD. CONCLUSION: Non-HDL-cholesterol was the most dominant predictor of the development of CHD in Japanese patients with T2DM.

Index of glucose effectiveness derived from oral glucose tolerance test.

Aim of this study was to formulate an index for glucose effectiveness (Sg), SgIo, based on 3-point (0, 30 and 120 min) 75 g oral glucose tolerance test (OGTT). The equation for SgI(O) was developed in the Chikuma cohort (n = 502). Firstly, post-loading plasma glucose without insulin action and Sg (PPG-without insulin and Sg) was calculated as follows: fasting plasma glucose (mg/dl) + [0.75 × 75,000]/[0.19 × BW(kg) × 10]. Secondly, 'PPG-without insulin/with Sg' was obtained from inverse correlation between log(10)DI(O) and 2-h post-glucose plasma glucose at OGTT (2hPG) in each glucose tolerance category: DI(O) denotes oral disposition index, a product of the Matsuda Index and δIRI(0-30)/δPG(0-30). Thirdly, expected 2hPG (2hPG(E)) of a given subject was obtained from the regression, and the ratio of 2hPG to 2hPG(E) (2hPG/2hPG(E)) was determined as an adjustment factor. Lastly, SgI(O) ([mg/dl]/min) was calculated as [PPG-without insulin and Sg]-[PPG-without insulin / with Sg] x [(2hPG) / 2hPG(E)]. SgI(O) was validated against Sg obtained by frequently sampled intravenous glucose tolerance test in the Jichi cohort (n = 205). Also, the accuracy of prediction of Sg by SgIo was tested by the Bland-Altman plot. SgI(O) was 3.61 ± 0.73, 3.17 ± 0.74 and 2.15 ± 0.60 in subjects with normal glucose tolerance (NGT), non-diabetic hyperglycemia and diabetes, respectively, in the Chikuma cohort. In the Jichi cohort, SgI(O) was significantly correlated with Sg in the entire group (r = 0.322, P < 0.001) and in subjects with NGT (r = 0.286, P < 0.001), and SgIo accurately predicted Sg. In conclusion, SgI(O) could be a simple, quantitative index for Sg.

Paradoxical surge of corticotropin after glucocorticoid replacement in central adrenal insufficiency.

A 78-yr-old man was admitted in emergency with fatigue, anorexia, vomiting, hypothermia (35.1 °C on a hot August day), hypotension (89/56 mmHg) and hyponatraemia (126 mEq/l). Plasma corticotropin and cortisol were severely depressed: 0.84 pmol/L and 33.1 nmol/L respectively (reference range, 1.5-13.9 pmol/L and 110-505 nmol/L, respectively). Thyroid stimulating hormone was low-normal and free-triiodothyronine and free-thyroxine were subnormal. Magnetic resonance imaging revealed swelling of the pituitary gland and the stalk. The patient recovered after glucocorticoid replacement (200 mg/day intravenous hydrocortisone on Day 1 followed by tapering). Central diabetes insipidus which had become apparent had been treated with 1-desamino-8-D-arginine vasopressin. A surge of corticotropin and cortisol, 19.4 pmol/L and 712.1 nmol/L respectively, was found on Day 5 when luteinizing hormone, follicle stimulating hormone, and testosterone were subnormal and prolactin was slightly elevated. Subsequently, corticotropin and cortisol levels normalized together with normalization of luteinizing hormone, follicle stimulating hormone, anti-diuretic hormone, thyroid stimulating hormone, prolactin, testosterone and thyroid hormone levels. Shrinkage of the pituitary gland occurred after one month. Serum immunoglobulin G4 was elevated (3.21 and 6.02 g/l at 1- and 3-month follow-ups respectively). In conclusion, a paradoxical surge of corticotropin after glucocorticoid replacement was observed in a patient with central adrenal insufficiency due to immunoglobulin G4-related hypophysitis. Surge of ACTH in central adrenal insufficiency after glucocorticoid replacement has rarely been reported, and this is the second such case report.

Hyperbolic correlation between insulin sensitivity and insulin secretion fades away in lean subjects with superb glucose regulation.

The relationship between insulin sensitivity (Si) and insulin secretion (ß) was analyzed in 533 health examinees. The subjects underwent a 75 g oral glucose tolerance test, with plasma glucose (PG) and immunoreactive insulin (IRI) determined at fasting, 30 min and 120 min, and were classified according to the current criteria as normal glucose tolerance (NGT, n=328), non-diabetic hyperglycemia (NDH, n=113) including impaired fasting glucose and impaired glucose tolerance, and diabetes mellitus (DM, n=72). NGT was subdivided by fasting PG (FPG) tertile, ≤4.9, 5.0-5.4 and 5.5-6.0 mM, into NGT(FPG1), NGT(FPG2) and NGT(FPG3), or by body mass index (BMI) tertile, ≤21.8, 21.9-24.4 and ≥24.5 kg/m², into NGT(BMI1), NGT(BMI2) and NGT(BMI3). As an index of Si and ß, Matsuda index=10,000/sqrt[FPG·FIRI·2hPG·2hIRI] and δIRI0₋30/δPG0₋30, were employed respectively: FIRI, 2hPG and 2hIRI denote fasting IRI, 2h-post glucose PG and IRI, respectively. Correlation between Si and ß was evaluated by Spearman's rank correlation and the parameters for [ß]=a·[Si](b) were obtained by standardized major axis (SMA) regression. Si-ß correlation was strongest in NDH (Spearman's rho=-0.546, SMA regression r²=0.277), intermediate in DM (rho=-0.432, r²=0.193) and weakest in NGT (rho=-0.201, r²=0.039). Spearman's rho for the Si-ß correlation was significantly lower in NGT than in NDH (p=0.003). Si-ß correlation was significant in NGT(FPG3), NGT(FPG2) and NGT(BMI3), but not in NGT(FPG1), NGT(BMI2) and NGT(BMI1). The slope, b, was -1.184˜-1.530 without significant differences between any groups. In conclusion, the hyperbolic Si-ß correlation was weaker in NGT than in NDH and absent in NGT subjects belonging to the lowest FPG or BMI tertile.

Pancreatic nonfunctioning neuroendocrine tumor with the main pancreatic duct obstruction presenting as excessive hyperglycemia: a case report and review of the literature.

We present the case of a 65-year-old man with a pancreatic nonfunctioning neuroendocrine tumor causing main pancreatic duct obstruction that presented as excessive hyperglycemia. We considered the tumor elicited worsening of diabetes in this case, and we performed review of the relevant literature.

Hypoglycaemic coma due to adrenal failure in a chronic haemodialysis patient.

A 62-year-old man, receiving chronic haemodialysis and suffering from alcoholic liver cirrhosis and chronic pancreatitis, presented with hypoglycaemic coma. Plasma cortisol was undetectable (< 5.5 nmol/L) with suppressed adrenocorticotropic hormone (ACTH), which established a diagnosis of adrenal failure due to ACTH deficiency. Twenty-five milligrams of oral hydrocortisone eradicated hypoglycaemia. Presentation of adrenal failure in this patient was atypical because he was hypertensive, serum electrolytes including sodium were normal and anaemia was unremarkable, which were all due to end-stage renal disease and its treatment with haemodialysis. As far as we are aware, this is the first case report of hypoglycaemic coma due to adrenal failure in a chronic haemodialysis patient.