Phosphorus-31 magnetic resonance spectroscopy of skeletal muscle in maternally inherited diabetes and deafness A3243G mitochondrial mutation carriers.

PURPOSE: To investigate high-energy phosphate metabolism in striated skeletal muscle of patients with Maternally Inherited Diabetes and Deafness (MIDD) syndrome. MATERIALS AND METHODS: In 11 patients with the MIDD mutation (six with diabetes mellitus [DM] and five non-DM) and eight healthy subjects, phosphocreatine (PCr) and inorganic phosphate (Pi) in the vastus medialis muscle was measured immediately after exercise using (31)P-magnetic resonance spectroscopy (MRS). The half-time of recovery (t1/2) of monoexponentially fitted (PCr+Pi)/PCr was calculated from spectra obtained every 4 seconds after cessation of exercise. A multiple linear regression model was used for statistical analysis. RESULTS: Patients with the MIDD mutation showed a significantly prolonged t1/2 (PCr+Pi)/PCr after exercise as compared to controls (13.6+/-3.0 vs. 8.7+/-1.3 sec, P = 0.01). No association between the presence of DM and t1/2 (PCr + Pi)/PCr was found (P = 0.382). CONCLUSION: MIDD patients showed impaired mitochondrial oxidative phosphorylation in skeletal muscle shortly after exercise, irrespective of the presence of DM.

Gallstone formation after pancreas and/or kidney transplantation: an analysis of risk factors.

Pancreas and kidney transplantation (SPK) is the treatment of choice for patients with type 1 diabetes mellitus and end-stage renal failure. Gallstones are common after SPK transplantation but little is known about the true incidence and etiology of gallstones in this group. We therefore evaluated the incidence of gallstones and the presence of transplant-related risk factors in patients after SPK and kidney transplantation alone (KTA). Data were evaluated of 56 consecutive patients who underwent SPK transplantation and compared the results with those of 91 consecutive nondiabetic patients who underwent KTA transplantation at the Leiden University Medical Center between 1987 and 1994. Of the 58 evaluable KTA patients, 20.7% developed gallstones during 7.7 yr of follow-up and in the SPK group 43.9% of the 41 evaluable patients developed gallstones during 7.1 yr of follow-up. Postoperative weight loss and cyclosporin A-related hepatotoxicity correlated with gallstone formation both in SPK and KTA patients. In addition, the duration of postoperative fasting and autonomic neuropathy correlated with gallstones in SPK patients. It is concluded that both in patients after SPK transplantation and in patients after KTA transplantation, the risk to develop gallstones is significantly increased. Physicians should be aware of the high incidence of gallstones in SPK recipients.

New insights in the molecular pathogenesis of the maternally inherited diabetes and deafness syndrome.

The 3243A>G mutation in mitochondrial DNA (mtDNA) is a genetic variant that is associated with a high risk of developing diabetes during life. Enhanced aging of pancreatic beta-cells, a reduced capacity of these cells to synthesize large amounts of insulin,and a resetting of the ATP/ADP-regulated K-channel seem to be the pathogenic factors involved.

Long-term follow-up study on bone mineral density and fractures after simultaneous pancreas-kidney transplantation.

BACKGROUND: In type 1 diabetic patients with end-stage renal failure, low bone mass is prevalent and the incidence of fractures high after simultaneous pancreas kidney transplantation (SPK). Data are scarce on preexisting skeletal morbidity or the long-term effects of SPK on bone mass and risk of fractures. METHODS: We conducted a prospective study addressing these issues in 19 consecutive SPK recipients before and at 3, 6, and 12 months, and 2.5 to 4 years after establishment of graft function. RESULTS: Prior to transplantation, 13 patients (68%) had hyperparathyroidism, 7 of whom had osteoporosis. Mean bone mineral density (BMD) was significantly lower at the femoral neck than at the lumbar spine (T-scores -2.0 +/- 0.89 vs. -0.66 +/- 0.84). There was a significant decrease in BMD at both lumbar spine and femoral neck at 6 months post-transplantation (-6.0 +/- 5.4% and -6.9 +/- 4.3%, respectively). No further loss was observed in the following 6 months. At 1 year post-transplantation, 9 patients had osteoporosis associated with hyperparathyroidism in 8, and none had sustained a clinical fracture. A significant albeit small increase in BMD was observed 6 months after start of alfacalcidol 0.25 microg/day. At end-evaluation, osteoporosis and hyperparathyroidism persisted in the patients in whom it was documented at 1 year. Five patients who had lower BMD at the femoral neck pretransplantation sustained a clinical fracture. CONCLUSION: Cortical osteoporosis is prevalent in SPK recipients at the time of transplantation, progresses early post-transplantation, and is associated with relatively high incidence of fractures. Reversal of persistent hyperparathyroidism with the use of alfacalcidol may contribute to a decrease in skeletal morbidity.

Mitochondrial diabetes: molecular mechanisms and clinical presentation.

Mutations in mitochondrial DNA (mtDNA) associate with various disease states. A few mtDNA mutations strongly associate with diabetes, with the most common mutation being the A3243G mutation in the mitochondrial DNA-encoded tRNA(Leu,UUR) gene. This article describes clinical characteristics of mitochondrial diabetes and its molecular diagnosis. Furthermore, it outlines recent developments in the pathophysiological and molecular mechanisms leading to a diabetic state. A gradual development of pancreatic beta-cell dysfunction upon aging, rather than insulin resistance, is the main mechanism in developing glucose intolerance. Carriers of the A3243G mutation show during a hyperglycemic clamp at 10 mmol/l glucose a marked reduction in first- and second-phase insulin secretion compared with noncarriers. The molecular mechanism by which the A3243G mutation affects insulin secretion may involve an attenuation of cytosolic ADP/ATP levels leading to a resetting of the glucose sensor in the pancreatic beta-cell, such as in maturity-onset diabetes of the young (MODY)-2 patients with mutations in glucokinase. Unlike in MODY2, which is a nonprogressive form of diabetes, mitochondrial diabetes does show a pronounced age-dependent deterioration of pancreatic function indicating involvement of additional processes. Furthermore, one would expect that all mtDNA mutations that affect ATP synthesis lead to diabetes. This is in contrast to clinical observations. The origin of the age-dependent deterioration of pancreatic function in carriers of the A3243G mutation and the contribution of ATP and other mitochondrion-derived factors such as reactive oxygen species to the development of diabetes is discussed.

Impact of simultaneous pancreas and kidney transplantation on progression of coronary atherosclerosis in patients with end-stage renal failure due to type 1 diabetes.

OBJECTIVE: Mortality in type 1 diabetic patients with end-stage renal failure is high and dominated by coronary atherosclerotic events. With regard to prognosis, simultaneous transplantation of pancreas and kidney (SPK) may be superior to kidney transplantation alone (KTA) in type 1 diabetic patients, because normalization of blood glucose levels may reduce progression of coronary atherosclerosis and because it is well known that progression of coronary atherosclerosis is one of the major factors that determines clinical prognosis. However, no data are available on progression of coronary atherosclerosis after SPK. RESEARCH DESIGN AND METHODS: We performed an observational angiographic study comparing progression of coronary atherosclerosis, analyzed with quantitative coronary angiography, in patients with (n = 26) and those without (n = 6) a functioning pancreas graft after SPK, to test the hypothesis that normalization of blood glucose levels by SPK may indeed reduce progression of coronary atherosclerosis in type 1 diabetic patients and thereby improve prognosis. RESULTS: Mean follow-up was 3.9 years. Average glucose control was significantly worse for the patients without a pancreas graft than for patients with a functioning pancreas graft: 11.3 (SD 3.5) vs. 5.9 mmol/l (SD 1.1) (P = 0.03). Mean segment diameter loss (progression of diffuse coronary atherosclerosis) was 0.024 mm/year (SD 0.067) in patients with a functioning pancreas graft, compared with 0.044 mm/year (SD 0.038) in patients in whom the pancreas graft was lost. Minimum obstruction diameter loss (progression of focal coronary atherosclerosis) was 0.037 mm/year (SD 0.086) in patients with a functioning pancreas graft compared with 0.061 mm/year (SD 0.038) in patients in whom the pancreas graft was lost. Regression of atherosclerosis occurred in 38% of patients with a functioning pancreas graft compared with 0% of patients of whom the pancreas graft was lost (P = 0.035). CONCLUSIONS: Our study provides, for the first time, evidence that in patients who have undergone SPK, progression of coronary atherosclerosis in patients with a functioning pancreas graft is reduced compared with patients with pancreas graft failure. Our observation is an important part of the explanation for the observed improved mortality rates reported in type 1 diabetic patients with end-stage renal failure after SPK compared with KTA. In light of these findings described above, SPK must to be carefully considered for all diabetic transplant candidates.