Comparison of 1,5-anhydroglucitol, HbA1c, and fructosamine for detection of diabetes mellitus

To evaluate the use of serum 1,5-anhydroglucitol (AG) levels in screening for diabetes mellitus, we compared the sensitivity and specificity of HbA1c, fructosamine (FA), and AG in 1620 randomly selected subjects in 11 institutions throughout Japan. Most individuals were receiving diet and/or drug therapy for diabetes. Subjects were separated into four groups based on World Health Organization criteria: nondiabetic control subjects, subjects with impaired glucose tolerance (IGT), patients with diabetes, and patients with other disorders without IGT. The overlap of AG values between each group was less than that of HbA1c or FA values. AG levels were significantly correlated with fasting plasma glucose (r = -0.627), HbA1c (r = -0.629), and FA (r = -0.590) levels. If we took 14 micrograms/ml as the normal lower limit, AG level was highly specific (93.1%), and a decreased AG level indicated diabetes mellitus (84.2% sensitivity). According to the selectivity index (sensitivity value times specificity value), AG determinations were superior to both HbA1c and FA measurements for diabetes screening. When combinations of these tests were used, only AG and HbA1c together were slightly better than AG alone. Thus, together with other advantages of AG, e.g., its wide variance with relatively fair glycemic control and the negligible influence of the sampling conditions, AG level has more potential than HbA1c or FA level as a screening criterion for diabetes.     

Liver transplantation improves cirrhosis-associated impaired oral glucose tolerance

BACKGROUND: Thirty-five percent to 80% of cirrhotic patients have impaired glucose tolerance (IGT) or diabetes mellitus (DM). Diabetic cirrhotics have higher morbidity and mortality than nondiabetics. Therefore, it would be worthwhile to determine whether liver transplantation improves glucose homeostasis in these patients. METHOD: A total of 26 patients awaiting liver transplantation were evaluated for impaired glucose homeostasis by fasting blood glucose and/or oral glucose tolerance tests (OGTT). Five patients underwent transplant surgery within 1 year of OGTT and had a repeat OGTT 3-6 months after transplantation. RESULTS: Sixty-five percent (17/26) of the patients had abnormal glucose homeostasis. Twenty-three percent (6/26) met American Diabetes Association criteria for DM, and another 42.3% (11/26) had IGT. All patients had normal HbA1C levels. After transplantation, the 2-hr blood glucose improved in four patients and the mean 2-hr glucose level was reduced (204 +/- 94 vs. 132 +/- 53 mg/dl [mean +/- SD, P=0.051]). CONCLUSION: Liver transplantation can reverse cirrhosis-associated impaired glucose tolerance.     

Risk factors for impaired glucose tolerance in obese children and adolescents

AIM: To investigate which obese children have an increased risk for impaired glucose tolerance (IGT), a risk factor for later diabetes.METHODS: We studied 169 European untreated obese children and adolescents with normal glucose tolerance at baseline. Waist circumference, fasting glucose, lipids, blood pressure, pubertal stage, 2 h glucose in oral glucose tolerance test (oGTT), and HbA1c were determined at baseline and 1 year later.RESULTS: One year after baseline, 19 (11.2%) children demonstrated IGT, 4 (2.4%) children had impaired fasting glucose, no (0%) child suffered from diabetes, and 146 (86%) children still showed normal glucose tolerance. At baseline, the children with IGT and with normal glucose tolerance in a one-year follow-up did not differ significantly in respect of any analyzed parameter, apart from pubertal stage. The children developing IGT entered puberty significantly more frequently (37% vs 3%, P < 0.001). One year after baseline, the children with IGT demonstrated significantly increased waist circumference, blood pressure values, insulin and triglyceride concentrations, and insulin resistance index HOMA. The children remaining in the normal glucose tolerance status 1 year after baseline did not demonstrate any significant changes.CONCLUSION: During the study period of 1 year, more than 10% of the obese children with normal glucose tolerance converted to IGT. Repeated screening with oGTT seems meaningful in obese children entering puberty or demonstrating increased insulin resistance, waist circumference, blood pressure, or triglyceride concentrations.     

Hemoglobin A1c in early postpartum screening of women with gestational diabetes

AIM: To assess the utility of hemoglobin A1c (HbA1c) in the early postpartum screening of women with gestational diabetes mellitus (GDM).METHODS: Over a 3 years period, HbA1c estimations were undertaken in addition to and simultaneously with the traditional oral glucose tolerance test (OGTT), in 203 women with GDM as a part of early postpartum screening for dysglycaemia, at 6 wk post-partum. World Health Organization criteria was used for diagnosing diabetes: fasting blood glucose (FBG) ≥ 7.0 mmol/L and/or 2-h postprandial blood glucose (PPBG) ≥ 11.1 mmol/L and/or HbA1c ≥ 48 mmol/mol; and impaired glycaemiastate: impaired fasting glucose 6.1-6.9 mmol/L and/or impaired glucose tolerance 7.8-11.0 mmol/L and/or HbA1c: 42-47 mmol/mol.RESULTS: Mean FBG, 2-h PPBG and HbA1c were 4.9 ± 0.7 mmol/L, 5.6 ± 2.0 mmol/L and 38 ± 5 mmol/mol respectively. FBG, 2-h PPBG and HbA1c detected 6 (3%), 7 (3.5%) and 11 (5.4%) cases of diabetes respectively, and 11 (5.4%), 25 (12.3%) and 23 (11.3%) cases of pre-diabetes state respectively. HbA1c values ≥ 48 mmol/mol (≥ 6.5%) showed a diagnostic sensitivity of 71.4% and specificity of 98.5% for diabetes in comparison to OGTT in receiver operating characteristics curve analysis. At HbA1c cut-off 44 mmol/mol, sensitivity and specificity were 100% and 92.3% respectively [area under the curve: 0.98 (95%CI: 0.96-1.00)]. Sensitivity and specificity for detecting high risk “impaired glycaemia” state [HbA1c 42 mmol/mol (6.0%)] were 28% and 80%, respectively.CONCLUSION: HbA1c level ≥ 48 mmol/mol (≥ 6.5%) has reasonable sensitivity and high specificity in comparison to OGTT for early postpartum screening of diabetes in GDM. At 6^th week postpartum screening, if FBG is normal and HbA1c < 44 mmol/mol OGTT is not recommended.     

Insulin secretion and insulin sensitivity in relation to glucose tolerance: lessons from the Botnia Study

Recently, a new stage in glucose tolerance, impaired fasting glucose (IFG) (fasting plasma glucose level of 6.1-6.9 mmol/l), was introduced in addition to impaired glucose tolerance (IGT) (2-h glucose level of 7.8-11.0 mmol/l). It is not clear whether IFG and IGT differ with respect to insulin secretion or sensitivity. To address this question, we estimated insulin secretion (by measuring both insulin levels and the ratio of insulin-to-glucose levels in 30-min intervals) and insulin sensitivity (by using the homeostasis model assessment [HOMA] index) from an oral glucose tolerance test (OGTT) in 5,396 individuals from the Botnia Study who had varying degrees of glucose tolerance. There was poor concordance between IFG and IGT: only 36% (303 of 840) of the subjects with IFG had IGT, whereas 62% (493 of 796) of the subjects with IGT did not have IFG. Compared with subjects with normal glucose tolerance (NGT), subjects with IFG were more insulin resistant (HOMA-insulin resistance [IR] values 2.64 +/- 0.08 vs. 1.73 +/- 0.03, P < 0.0005), had greater insulin responses during an OGTT (P = 0.0001), had higher waist-to-hip ratios (P < 0.005), had higher triglyceride and total cholesterol concentrations (P < 0.0005), and had lower HDL cholesterol concentrations (P = 0.0001). Compared with subjects with IFG, subjects with IGT had a lower incremental 30-min insulin-to-glucose area during an OGTT (13.8 +/- 1.7 vs. 21.7 +/- 1.7, P = 0.0008). Compared with subjects with IGT, subjects with mild diabetes (fasting plasma glucose levels <7.8 mmol/l) showed markedly impaired insulin secretion that could no longer compensate for IR and elevated glucose levels. A progressive decline in insulin sensitivity was observed when moving from NGT to IGT and to subjects with diabetes (P < 0.05 for trend), whereas insulin secretion followed an inverted U-shaped form. We conclude that IFG is characterized by basal IR and other features of the metabolic syndrome, whereas subjects with IGT have impaired insulin secretion in relation to glucose concentrations. An absolute decompensation of beta-cell function characterizes the transition from IGT to mild diabetes.     

Hemoglobin South Florida. New variant with normal electrophoretic pattern mistaken for glycosylated hemoglobin

An 8.75-yr-old Caucasian boy was discovered to have a markedly elevated (14.8%) hemoglobin A1c (HbA1c) as estimated by ion-exchange chromatography (Bio Rex 70). Glycohemoglobin (GHb) measured by a colorimetric method with thiobarbituric acid (TBA) was normal (equivalent to a 6.4% HbA1c). Nondiabetic quantities of GHb were found with affinity chromatography, and the glucose tolerance test was normal. Intensive efforts to identify an abnormal variant hemoglobin by several electrophoretic methods were unsuccessful. A family survey identified a similar abnormality in 11 other individuals, revealing an autosomal-dominant pattern. None of the affected individuals had any other hematologic abnormality. Structural analysis in one family member revealed a new hemoglobin variant (approximately 45% of the total hemoglobin) with the substitution of methionine for valine at the beta-NH2-terminal. In addition, the initiator methionine residue was preserved. Approximately 20% of the variant hemoglobin was modified by acetylation of the NH2-terminal methionine. The modified variant coeluted with HbA1c. We suggest that patients who do not have an explanation for their elevated HbA1c should have GHb measured by the TBA method or affinity chromatography because hemoglobin electrophoresis does not identify this confounding artifact.     

Study in Tanzania of impaired glucose tolerance. Methodological myth?

During a study of diabetes prevalence in six rural Tanzanian communities, a repeat oral glucose tolerance test (OGTT) was carried out in 514 subjects greater than or equal to 15 yr of age within 1 wk of an initial 75-g OGTT. In 498 subjects, blood glucose was measured 2 h after the glucose load on both occasions, and in 175 subjects, fasting blood glucose measurement was also repeated. Of the 498 subjects, 245 had normal glucose tolerance in the first test and were selected at random for further testing; 223 subjects had impaired glucose tolerance (IGT), and 30 had diabetic values. Diabetes and IGT were diagnosed on the basis of the 2-h blood glucose values. In the second test, 241 (98.4%) of the 245 subjects with normal tolerance continued in this category and 4 (1.6%) showed IGT. Of the 223 with IGT in the first test, 171 (76.2%) reverted to normal on the second test, 7 (3.1%) had diabetic values, and 45 (20.2%) persisted with IGT. Of the 30 subjects diagnosed as diabetic in the first test, 8 (26.7%) remained with diabetic values, 11 (36.7%) had IGT, and 11 (36.7%) were normal. Based on the second test, the population-prevalence rates of diabetes and IGT would have been 0.5 and 3.3% vs. 1 and 7.6% based on the first test. There was a significant downward trend in the mean 2-h blood glucose values in all three diagnostic groups. Regression toward the mean could not account for the downward shift in blood glucose values observed on retesting.(ABSTRACT TRUNCATED AT 250 WORDS)     

Type I diabetes manifested solely by 2-h oral glucose tolerance test criteria

The clinical presentation of type 1 diabetes usually involves symptoms such as polyuria and polydipsia. However, investigators in the Diabetes Prevention Trial of Type 1 Diabetes (DPT-1) have detected a group of subjects with type 1 diabetes who have a different phenotype. These subjects are asymptomatic, have normal (<6.1 mmol/l) (group A) or impaired (6.1- <7.0 mmol/l) (group B) fasting glucose, but have 2-h glucose values >11.1 mmol/l on their oral glucose tolerance tests (OGTT). Of the 585 OGTTs performed on islet cell antibody (ICA)-positive relatives with insulin autoantibodies (IAA) or low first-phase insulin response (FPIR), normal glucose tolerance (NGT) was found in 427 subjects; impaired glucose tolerance (IGT) was found in 87 subjects, and diabetes was found by 2-h OGTT criteria alone in 61 subjects. Despite marked differences in 2-h glucose values (NGT 5.8 +/- 1.1 mmol/l, IGT 8.9 +/- 0.9 mmol/l, and group A 13.5 +/- 2.5 mmol/l), there were no significant differences in fasting glucose values among NGT (4.8 +/- 0.5 mmol/l), IGT (5.03 +/- 0.5 mmol/l), and group A (4.99 +/- 0.7 mmol/l) categories. Mean FPIR was higher in subjects with NGT compared with subjects with IGT and subjects diagnosed by 2-h OGTT criteria alone. However, the correlation between FPIR and 2-h glucose value was low (r2 = 0.114). Multivariate analysis demonstrated that additional independent variables provide smaller contributions to the 2-h glucose value. In conclusion, there are asymptomatic type 1 diabetic subjects whose diabetes was diagnosed by the 2-h criteria on OGTT alone. Despite the importance of beta-cell dysfunction in the pathogenesis of type I diabetes, factors other than impaired FPIR must also contribute to postprandial glucose tolerance in these subjects.     

The use of oral glucose tolerance tests to risk stratify for new-onset diabetes after transplantation: An underdiagnosed phenomenon

BACKGROUND: Fasting glucose measurements are insensitive at detecting new-onset diabetes after transplantation (NODAT) and ignore the diagnosis of impaired glucose tolerance (IGT). Both NODAT and IGT confer a higher risk of developing cardiovascular disease. IGT is also a risk factor for NODAT. The aim of this study was to use an oral glucose tolerance test (OGTT) to risk stratify for NODAT and IGT in renal transplant recipients and to relate cardiovascular and phenotypic risk with glycemic dysregulation. METHODS: In all, 858 renal transplant recipients are under follow up at the University Hospital of Wales, Cardiff, UK. Excluded patients had pretransplant diabetes (78), NODAT (89), or were transplanted less than six months (47), leaving 646 recipients. All remaining recipients with two fasting blood glucoses between 5.6 and 6.9 mmol/L were invited to have an OGTT. A diagnosis of NODAT, IGT, and impaired fasting glucose (IFG) was based on World Health Organization guidelines. RESULTS: We identified 134 patients who fulfilled the inclusion criteria, of whom 122 had an OGTT (91% of cohort). In all, 51% of patients were found to have abnormal glucose metabolism: 10% NODAT, 14% combined IGT/IFG, 9% IGT alone, and 18% IFG alone. Clinical phenotype was not predictive of diabetic risk on multivariate analysis. CONCLUSIONS: Our results confirm fasting glucose underestimates the prevalence of NODAT and ignores the prevalence of IGT. These findings suggest routine use of an OGTT in renal transplant recipients is a valuable clinical tool to risk stratify each patient for the development of NODAT and cardiovascular disease.     

β-Cell Function,Incretin Effect,and Incretin Hormones in Obese Youth Along the Span of Glucose Tolerance From Normal to Prediabetes to Type 2 Diabetes

Using the hyperglycemic and euglycemic clamp, we demonstrated impaired β-cell function in obese youth with increasing dysglycemia. Herein we describe oral glucose tolerance test (OGTT)-modeled β-cell function and incretin effect in obese adolescents spanning the range of glucose tolerance. β-Cell function parameters were derived from established mathematical models yielding β-cell glucose sensitivity (βCGS), rate sensitivity, and insulin sensitivity in 255 obese adolescents (173 with normal glucose tolerance [NGT], 48 with impaired glucose tolerance [IGT], and 34 with type 2 diabetes [T2D]). The incretin effect was calculated as the ratio of the OGTT-βCGS to the 2-h hyperglycemic clamp-βCGS. Incretin and glucagon concentrations were measured during the OGTT. Compared with NGT, βCGS was 30 and 65% lower in youth with IGT and T2D, respectively; rate sensitivity was 40% lower in T2D. Youth with IGT or T2D had 32 and 38% reduced incretin effect compared with NGT in the face of similar changes in GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) in response to oral glucose. We conclude that glucose sensitivity deteriorates progressively in obese youth across the spectrum of glucose tolerance in association with impairment in incretin effect without reduction in GLP-1 or GIP, similar to that seen in adult dysglycemia.     

Insulin sensitivity of suppression of endogenous glucose production is the single most important determinant of glucose tolerance

Hyperglycemia results from an imbalance between endocrine pancreatic function and hepatic and extrahepatic insulin sensitivity. We studied 57 well-matched Swedish men with normal glucose tolerance (NGT), impaired glucose tolerance (IGT), or mild diabetes. Oral glucose tolerance and insulin release were assessed during an oral glucose tolerance test (OGTT). Insulin sensitivity and glucose turnover were determined during a two-step euglycemic insulin clamp (infusion 0.25 and 1.0 mU. kg(-1). min(-1)). High-performance liquid chromatography-purified [6-(3)H]glucose was used as a tracer. During low-insulin infusion, the rate of endogenous glucose production (EGP) decreased more in subjects with NGT than in subjects with IGT or diabetes (delta rate of appearance [R(a)] 1.25 +/- 0.10 vs. 0.75 +/- 0.14 vs. 0.58 +/- 0.09 mg. kg(-1). min(-1), P < 0.001). The corresponding rates of glucose infusion during the high-dose insulin infusion (M values) were 8.3 +/- 0.6 vs. 5.4 +/- 0.9 vs. 4.7 +/- 0.4 mg. kg(-1). min(-1) (P < 0.001). A total of 56% of the variation in glucose area under the curve (AUC) during OGTT (glucose AUC) was mainly explained by delta R(a) (increase in multiple R(2) 0.42) but also by delta R(d) (rate of disappearance) (increase in multiple R(2) 0.05), and the early insulin response during OGTT contributed significantly (increase in multiple R(2) 0.07). When M value was included in the model, reflecting extrahepatic insulin sensitivity, it contributed to 20% of the variation in glucose AUC, and together with the incremental insulin response (increase in multiple R(2) 0.21), it explained 45% of the variation. In conclusion, insulin sensitivity of suppression of EGP plays the most important role in the determination of blood glucose response during OGTT.     

Validity of glycated haemoglobin to diagnose new onset diabetes after transplantation

Diagnosing new onset diabetes after transplantation (NODAT) by glycated haemoglobin (HbA1c) has not been validated against the gold‐standard oral glucose tolerance test (OGTT). We analysed the predictive and optimum value of HbA1c to diagnose NODAT amongst nondiabetic renal transplant recipients. Assessment of glucose metabolism (OGTT and HbA1c) was prospectively undertaken at 3 and 12 months post‐transplantation in 71 nondiabetic renal transplant recipients. Receiver operator characteristic (ROC) curve analyses were performed to determine accuracy, sensitivity, specificity and area under curve (c‐statistic). Incidence of NODAT at 3 and 12 months post‐transplantation was 14.3% and 9.5% respectively. At 3 months, optimum HbA1c cut‐off value for predicting NODAT based on fasting glucose was 7.35 [AUC 1.00 (sensitivity 100.0%, specificity 100.0%, P = 0.004)] and for postprandial glucose‐defined NODAT was 6.20 [AUC 0.98 (sensitivity 100.0%, specificity 88.9%, P < 0.001)]. At 12 months, optimum HbA1c cut‐off value for both fasting‐ and postprandial glucose‐defined NODAT was 6.45 [AUC 0.92 (sensitivity 100.0%, specificity 87.5%, P = 0.048) and AUC 0.84 (sensitivity 75.0%, specificity 89.5%, P = 0.026) respectively]. Concordance between diagnosis of NODAT (OGTT+, HbA1c+) and nondiagnosis of NODAT (OGTT?, HbA1c?) was 88.9% and 98.7% respectively. To conclude, HbA1c (≥6.5%) can be utilized to diagnose NODAT beyond 3 months post‐transplantation but the OGTT remains the gold‐standard tool.     

Long-term follow-up of glucose tolerance function after pancreaticoduodenectomy: comparison between pancreaticogastrostomy and pancreaticojejunostomy

BACKGROUND: The objectives of the present study are to determine the long-term changes in glucose tolerance function after pancreaticoduodenectomy and to compare the effects of pancreaticojejunostomy (PJ) and pancreaticogastrostomy (PG).Patients and methods The present study consisted of 51 patients who received a pancreaticoduodenectomy for tumors of the pancreatic head area and survived more than 7 postoperative years without tumor recurrence. According to the type of pancreatic anastomosis, they were classified into 2 groups of 25 PJ patients and 26 PG patients. Changes in the patterns of a 75-g oral glucose tolerance test (OGGT) (normal, impaired glucose tolerance [IGT], and diabetic [DM] patterns) and the need for beginning diabetic treatment (oral hypoglycemic agents or insulin) were compared between groups. RESULTS: Within 3 months after surgery, 14 (56%) patients in the PJ group had normal OGTT patterns, 8 (32%), IGT patterns, and 3 (25%), DM patterns. In the PG group, the patterns of OGTT were similar with 16 (62%) normal patterns, 6 (23%) IGT patterns, and 4 (15%) DM patterns. During the first 7 postoperative years, the 2 groups showed similar results: (1) none of the patients with normal patterns developed functional decline in glucose tolerance; (2) a high percentage of patients with initial IGT or DM patterns developed worsening glucose intolerance (7 [64%] of 11 PJ patients vs 7 [70%] of 10 PG patients); (3) the onset of functional decline in glucose tolerance occurred predominantly within the first 3 postoperative years; and (4) no specific causative event prior to the subsequent functional decline was detected. CONCLUSION: The decline of glucose tolerance after pancreaticoduodenectomy seems to be associated with a low reserve of endocrine function rather than anastomotic procedures or their related complications. Regardless of the types of pancreatic anastomosis, a close follow-up of glucose tolerance function is recommended during the first 3 postoperative years, especially among IGT or DM patients.     

Adaptation of Insulin Clearance to Metabolic Demand Is a Key Determinant of Glucose Tolerance

With the development of insulin resistance (IR), there is a compensatory increase in the plasma insulin response to offset the defect in insulin action to maintain normal glucose tolerance. The insulin response is the result of two factors: insulin secretion and metabolic clearance rate of insulin (MCR_I). Subjects (104 with normal glucose tolerance [NGT], 57 with impaired glucose tolerance [IGT], and 207 with type 2 diabetes mellitus [T2DM]), divided in nonobese and obese groups, received a euglycemic insulin-clamp (40 mU/m² ⋅ min) and an oral glucose tolerance test (OGTT) (75 g) on separate days. MCR_I was calculated during the insulin-clamp performed with [3-³H]glucose and the OGTT and related to IR: peripheral (glucose uptake during the insulin clamp), hepatic (basal endogenous glucose production × fasting plasma insulin [FPI]), and adipocyte (fasting free fatty acid × FPI). MCR_I during the insulin clamp was reduced in obese versus nonobese NGT (0.60 ± 0.03 vs. 0.73 ± 0.02 L/min ⋅ m², P < 0.001), in nonobese IGT (0.62 ± 0.02, P < 0.004), and in nonobese T2DM (0.68 ± 0.02, P < 0.03). The MCR_I during the insulin clamp was strongly and inversely correlated with IR (r = −0.52, P < 0.0001). During the OGTT, the MCR_I was suppressed within 15–30 min in NGT and IGT subjects and remained suppressed. In contrast, suppression was minimal in T2DM. In conclusion, the development of IR in obese subjects is associated with a decline in MCR_I that represents a compensatory response to maintain normal glucose tolerance but is impaired in individuals with T2DM.     

Endocrinometabolic effects of whole versus segmental pancreas allotransplantation in diabetic patients--a two-year follow-up

We have investigated the metabolic effects of segmental (neoprene-injected) pancreas transplantation versus whole (enteric-diverted) pancreas transplantation. Seventeen uremic insulin-dependent diabetes mellitus (IDDM) patients received a simultaneous pancreaticorenal transplant: in a prospective, randomized study, 9 patients received a segmental neoprene-injected graft (group A) while 8 patients received a total pancreaticoduodenal graft, with enteric diversion (group B). The immunosuppressive therapy was based on ALG, CsA, azathioprine, and steroids. Three months after surgery, patients were submitted to the following metabolic investigation: i.v. and oral glucose tolerance tests, Hba1, i.v. arginine test, and a 24-hr metabolic profile. The OGTT, HbA1, and metabolic profile were repeated 12 and 24 months after transplantation. At 3 months after transplantation, the OGTT showed delayed insulin secretion and higher blood glucose levels in group A. Serum insulin levels after IVGTT or arginine were higher in group B than in group A. OGTT at 12 and 24 months were unchanged in group B, while in group A a higher incidence of impaired glucose tolerance (IGT) and diabetes mellitus response were observed. HbA1 and blood glucose levels during the 24-hr profile showed good metabolic control in both groups at 3, 12, and 24 months. We can conclude that both the segmental and total pancreas transplantation restore a good metabolic control in IDDM patients, though a higher incidence of IGT and DM responses were observed after OGTT in the patients receiving a segmental graft. These abnormalities do not seem to interfere with metabolic control in everyday life. These results seem to be the consequence of the different B cell masses transplanted with these two techniques.     

Insulin action and insulin secretion in identical twins with MODY. Evidence for defects in both insulin action and secretion

To evaluate the pathogenetic mechanisms responsible for development of diabetes in the genetically inherited disease maturity-onset diabetes of the young (MODY), we have investigated a pair of identical twins (19 yr old) from a MODY family. One twin had nondiabetic fasting plasma glucose values but impaired glucose tolerance (IGT), whereas the other suffered from frank diabetes (fasting plasma glucose 12.5 mM). Differences in insulin secretion pattern and/or insulin action between the twins is supposed to be responsible for development of hyperglycemia in MODY. On the other hand, identical defects in insulin secretion and action in the twins may point to the primary genetic defect in MODY. Therefore, our aim was to investigate insulin secretion and insulin action in the twins to find these differences and similarities. We found that fasting plasma insulin and C-peptide values were slightly increased in the twins, whereas the responses of insulin and C-peptide to oral glucose tolerance tests (OGTT) and meals were similar in the twins and within normal range. The insulin responses to OGTT were, however, lower than expected from the glucose values, indicating a beta-cell defect. Despite elevated plasma insulin levels, basal hepatic glucose output (HGO) was normal in the IGT twin but increased by 75% in the diabetic twin. The maximally inhibitory effect of insulin on HGO, when estimated at euglycemia, was normal in the IGT twin but reduced by 60% in the diabetic twin. Furthermore, the maximal insulin-mediated glucose uptake in peripheral tissues was reduced by 40% in the diabetic twin.(ABSTRACT TRUNCATED AT 250 WORDS)     

beta-Cell dysfunction rather than insulin resistance is the main contributing factor for the development of postrenal transplantation diabetes mellitus

BACKGROUND: Our study was undertaken to investigate the pathogenesis and possible risk factors for postrenal transplantation diabetes mellitus (PTDM). METHODS: We recruited 114 patients with normal glucose tolerance (NGT) and performed both 75-g oral glucose tolerance tests (OGTT) and short insulin tolerance tests 1 week before and 9-12 months after transplantation. RESULTS: The subjects were classified into three groups by World Health Organization criteria on the basis of OGTT after transplantation: (a) 36 (31.6%) subjects with normal glucose tolerance; (b) 51 (45.7%) subjects with impaired glucose tolerance (IGT); and (c) 27 (23.7%) subjects with postrenal transplantation diabetes mellitus. Dosages of steroid and cyclosporine were equivalent among the three groups. Before transplantation, the fasting and 2-hr plasma glucose and proinsulin/insulin (PI/I) ratios were significantly higher in the IGT and PTDM groups than in the NGT group, but the insulin sensitivity index (ISI) was not significantly different among the three groups. In addition, the area under the curve-insulin on OGTT was significantly lower in the PTDM group than in the NGT group. After transplantation, however, the ISI was increased in all groups. Furthermore, the ISI and PI/I ratios revealed significantly higher values in the PTDM group than in the NGT group after transplantation. CONCLUSIONS: These results revealed that fasting and 2-hr plasma glucose levels, as well as the proinsulin/insulin ratio before transplantation, are both possible indicators of beta-cell dysfunction and may be predictors for the development of PTDM. Furthermore, beta-cell dysfunction, rather than insulin resistance, was proven to be the main factor for the pathogenesis of PTDM.     

Influence of lifestyle modification in renal transplant recipients with postprandial hyperglycemia

INTRODUCTION: Lifestyle modification is recommended as first-line therapy to manage new-onset diabetes after transplantation (NODAT) and impaired glucose tolerance (IGT). No data currently demonstrate the efficacy of this approach specifically for transplant recipients. This study aimed to assess the benefit of intensive lifestyle modification in this high-risk group and to contrast this with the natural evolution of glucose metabolism after transplantation. METHODS: Baseline oral glucose tolerance test (OGTT) stratified 115 patients into two groups. Group 1 had glucose intolerance, IGT (n=28) and NODAT (n=8), and received intensive lifestyle modification (dietician referral, exercise program, weight loss advice). Group 2 had normal glucose tolerance (n=79) and received lifestyle modification leaflets. Both groups had follow-up OGTT after 6 months to assess change in glycemic status. RESULTS: Excluding all patients who received steroid weaning or withdrawal as part of their management, 111 patients were included in the analysis. Lifestyle modification in group 1 resulted in 15% improvement in 2-hr postprandial glucose versus 12% deterioration in group 2. In group 1, 44% (n=11) of IGT patients developed normal glucose tolerance, whereas only 4% (n=1) developed NODAT. Fifty-eight percent (n=4) of NODAT patients showed improvement (29% to IGT and 29% to normal). Glucose metabolism deteriorated in group 2 with 14% (n=10) developing IGT and 3% (n=2) developing NODAT. CONCLUSIONS: Glucose metabolism can deteriorate in transplant recipients despite passive lifestyle modification advice. This study shows active lifestyle modification benefits high-risk transplant recipients with glucose intolerance and should be aggressively pursued.     

Mortality risk in post‐transplantation diabetes mellitus based on glucose and HbA1c diagnostic criteria

Current diagnostic criteria for post‐transplantation diabetes mellitus (PTDM) are either fasting plasma glucose ≥7.0 mmol/l (≥126 mg/dl) or postchallenge plasma glucose ≥11.1 mmol/l (≥200 mg/dl) 2 h after glucose administration [oral glucose tolerance test (OGTT) criterion]. In this retrospective cohort study of 1632 renal transplant recipients (RTRs) without known diabetes mellitus at the time of transplantation, we estimated mortality hazard ratios for patients diagnosed with PTDM by either conventional glucose criteria or the proposed glycated haemoglobin (HbA1c) criterion [HbA1c ≥6.5% (≥48 mmol/mol)]. During a median follow‐up of 7.0 years, 311 patients died. Compared with nondiabetic patients and after adjustment for confounders, patients diagnosed with PTDM based on chronic hyperglycaemia early after transplantation (manifest PTDM) or by the OGTT criterion at 10 weeks post‐transplant suffered a higher mortality risk (HR 1.59, 95% CI 1.06–2.38, P = 0.02 and HR 1.56, 95% CI 1.04–2.38, P = 0.03, respectively). In contrast, patients diagnosed with PTDM by the HbA1c criterion at 10 weeks or between 10 weeks and 1 year post‐transplant were not associated with mortality (HR 0.96, 95% CI 0.61–1.51, P = 0.86 and 1.58, 95% CI 0.74–3.36, P = 0.24 respectively). After adjustment for confounders and competing risks, only patients with manifest PTDM had a significantly higher cardiovascular mortality risk (subdistributional HR 2.31, 95% CI 1.19–4.47, P < 0.001). Since many cases with PTDM were only identified by the OGTT, we recommend monitoring fasting plasma glucose early after renal transplantation followed by an OGTT at 2–3 months post‐transplant in patients without overt diabetes mellitus.     

Beta-cell function is a major contributor to oral glucose tolerance in high-risk relatives of four ethnic groups in the U.S

First-degree relatives of individuals with type 2 diabetes are at increased risk of developing hyperglycemia. To examine the prevalence and pathogenesis of abnormal glucose homeostasis in these subjects, 531 first-degree relatives with no known history of diabetes (aged 44.1 +/- 0.7 years; BMI 29.0 +/- 0.3 kg/m(2)) underwent an oral glucose tolerance test (OGTT). Newly identified diabetes was found in 19% (n = 100), and impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT) was found in 36% (n = 191). Thus, only 45% (n = 240) had normal glucose tolerance (NGT). The homeostasis model assessment of insulin resistance (HOMA-IR) was used to estimate insulin sensitivity; beta-cell function was quantified as the ratio of the incremental insulin to glucose responses over the first 30 min during the OGTT (DeltaI(30)/DeltaG(30)). This latter measure was also adjusted for insulin sensitivity as it modulates beta-cell function ([DeltaI(30)/DeltaG(30)]/HOMA-IR). Decreasing glucose tolerance was associated with increasing insulin resistance (HOMA: NGT 12.01 +/- 0.54 pmol/mmol; IFG/IGT 16.14 +/- 0.84; diabetes 26.99 +/- 2.62; P < 0.001) and decreasing beta-cell function (DeltaI(30)/DeltaG(30): NGT 157.7 +/- 9.7 pmol/mmol; IFG/IGT 100.4 +/- 5.4; diabetes 57.5 +/- 7.3; P < 0.001). Decreasing beta-cell function was also identified when adjusting this measure for insulin sensitivity ([DeltaI(30)/DeltaG(30)]/HOMA-IR). In all four ethnic groups (African-American, n = 55; Asian-American, n = 66; Caucasian, n = 217; Hispanic-American, n = 193), IFG/IGT and diabetic subjects exhibited progressively increasing insulin resistance and decreasing beta-cell function. The relationships of insulin sensitivity and beta-cell function to glucose disposal, as measured by the incremental glucose area under the curve (AUCg), were examined in the whole cohort. Insulin sensitivity and AUCg were linearly related so that insulin resistance was associated with poorer glucose disposal (r(2) = 0.084, P < 0.001). In contrast, there was a strong inverse curvilinear relationship between beta-cell function and AUCg such that poorer insulin release was associated with poorer glucose disposal (log[DeltaI(30)/DeltaG(30)]: r(2) = 0.29, P < 0.001; log[(DeltaI(30)/DeltaG(30))/HOMA-IR]: r(2) = 0.45, P < 0.001). Thus, abnormal glucose metabolism is common in first-degree relatives of subjects with type 2 diabetes. Both insulin resistance and impaired beta-cell function are associated with impaired glucose metabolism in all ethnic groups, with beta-cell function seeming to be more important in determining glucose disposal.