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Several lines of evidence indicate that NIDDM is a heterogeneous disease that results from a combination of abnormalities in both insulin secretion and insulin action. Nevertheless, beta-cell autoimmunity, which is characteristic of IDDM, is present in up to 10 to 33 percent of subjects diagnosed clinically with NIDDM. Therefore, up to approximately four million Americans may have an autoimmune type of NIDDM. There is increasing interest in using a combined determination of immunological markers of IDDM for the identification of subjects at risk of developing clinical IDDM in first degree relatives of IDDM patients and in the general population. It is hypothesized that the presence of a combination of immunological markers of autoimmune diabetes such as autoantibodies to GAD, IA-2 and insulin, in the serum of patients should predict a more rapid loss in beta-cell function, and subsequent insulin dependency, in a subgroup of NIDDM patients who have beta-cell autoimmunity.
To determine who among these individuals will be more prone to develop the disease and consequently be exposed to its pathologic consequences, including for example, heart failure, the Institute will recruit approximately 300 NIDDM patients per year. Glycemic control will be assessed by periodic monitoring of glycated hemoglobin; a 10-minute intravenous glucose tolerance test (IVGTT) to assess first phase insulin release (FPIR); C-peptide and total insulin; as well as by home blood glucose monitoring performed by the patients. Each subject will have an HLA typing and an annual examination of beta-cell autoimmunity markers.
This study will provide information regarding the feasibility to predict a loss of beta-cell function in patients clinically diagnosed with NIDDM by using a combined analysis of immunological as well as genetic markers of beta-cell autoimmunity and will give new insight for the selection of candidates for safe prevention of insulin dependency among NIDDM patients.
The metabolism of free fatty acids (FFA) by skeletal muscle in patients with NIDDM is abnormal. In healthy nondiabetic individuals, FFA are the predominant oxidative substrate of skeletal muscle during post-absorptive conditions. We have found FFA oxidation by skeletal muscle is reduced in NIDDM during conditions of fasting hyperglycemia, despite elevated fasting FFA. Gas exchange across the leg was measured to perform regional indirect calorimetry in order to determine leg glucose and lipid oxidation. In more recent clinical investigations involving limb balance studies, we have added measurements of FFA fractional extraction and uptake across the leg by determining arterio-venous differences of 3H-palmitate (assayed by HPLC). We find that post-absorptive rates of leg FFA uptake are reduced in NIDDM and that leg Rq is increased, indicative of impaired FFA uptake and oxidation respectively.
The first hypothesis is that hyperglycemia is the principal cause of impaired skeletal muscle FFA uptake and oxidation in NIDDM. The second hypothesis is that activity of muscle carnitine-palmitoyl transferase (CPTI) is reduced in NIDDM, caused by allosteric inhibition from muscle malonyl CoA, which we postulate to be increased due to hyperglycemia. The hypothesis that FFA uptake is reduced by hyperglycemia during post-absorptive conditions can be tested in two clinical investigations.
In NIDDM subjects, post-absorptive leg FFA uptake and oxidation is assessed during fasting hyperglycemia and after overnight euglycemia, and compared to respective rates in nondiabetics. Another clinical investigation assesses the effects of hyperglycemia on muscle FFA uptake and oxidation in healthy volunteers, while post-absorptive levels of insulin are maintained using a pancreatic clamp (somatomedin infusion with growth hormone and glucagon replacement). Leg balance methods to measure glucose uptake, net lactate balance, limb indirect calorimetry (leg gas exchange), fractional extraction of palmitate and blood flow are used to ascertain skeletal muscle metabolism.
The third hypothesis of this proposal is that during moderate intensity exercise, rates of FFA oxidation are reduced in NIDDM. During 40 minutes of moderate intensity exercise (40 percent of maximal VO2), rates of systemic glucose and FFA utilization and oxidation are determined in NIDDM subjects and in obese and nonobese nondiabetics. Continuous indirect calorimetry is used to assess oxidative metabolism, and isotopic methods will be used to study FFA and glucose utilization. Pre- and post-exercise muscle biopsy is done to assess effects on CPT-I activity and malonyl CoA concentration. These exercise conditions are associated in nondiabetics with increased oxidation of FFA, concomitantly, a strong reliance on plasma glucose for energy production, and a decrease in muscle malonyl CoA. Therefore, these exercise conditions should be an appropriate metabolic context to examine regulation of FFA oxidation and CPT-I activity in skeletal muscle of patients with NIDDM.
We have been able to identify a new hormone, which we have named "PTH-related protein" or "PTHrP." This is a new hormone that has been shown to be produced in every tissue in the body and is essential for life, since transgenic mice that have this gene deleted, die in late embryonic life. One of the tissues which produce PTHrP is the pancreas, specifically the insulin-producing beta-cells of the islet. These cells also have receptors for PTHrP, suggesting that PTHrP must have some function within the islet. To try to define this, we prepared transgenic mice that overproduce PTHrP in the pancreatic islet using the insulin promoter. These mice have a striking finding: they are hyperinsulinemic, hypoglycemic and have marked islet hyperplasia. These findings indicate that PTHrP must play a role in increasing islet mass. This is significant because both type 1 and type 2 diabetics have inadequate islet mass and function. Up to the present, there have been no clear demonstrations that introducing a gene of interest in the islets could enhance islet mass.
Thus, to identify a new hormone that could increase the size and number of islets and induce insulin hypersecretion is highly significant. It suggests the PTHrP could be used to increase and maintain islet mass in human diabetics when delivered by gene therapy to isolated human islets administered by islet transplantation. With these early results, we have now created islet hyperfunction in other transgenic mice using related growth factors. We have also selected a viral vector for delivering PTHrP to the islet and are currently performing these types of studies.
These studies have led us to be very excited and to change the focus of our laboratory in a major way to focus in therapy of type 1 and 2 diabetes using gene therapy strategies
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