James T. Lane

Functional relationship of thyroid hormone-induced lipogenesis, lipolysis, and thermogenesis in the rat.

Metabolic balance studies were carried out to determine the interrelationships of thyroid hormone-induced lipogenesis, lipolysis, and energy balance in the free-living rat. Intraperitoneal doses of 15 micrograms triiodothyronine (T3)/100 g body wt per d caused an increase in caloric intake from 26.5 +/- 1.7 (mean +/- SEM) kcal/100 g per d to 38.1 +/- 1.5 kcal/100 g per d. Food intake, however, rose only after 4-6 d of treatment and was maximal by the 8th day. In contrast, total body basal oxygen consumption rose by 24 h and reached a maximum by 4 d. Since total urinary nitrogen excretion and hepatic phosphoenolpyruvate carboxykinase mRNA did not rise, gluconeogenesis from protein sources did not supply the needed substrate for the early increase in calorigenesis. Total body fat stores fell approximately 50% by the 6th day of treatment and could account for the entire increase in caloric expenditure during the initial period of T3 treatment. Total body lipogenesis increased within 1 d and reached a plateau 4-5 d after the start of T3 treatment. 15-19% of the increased caloric intake was channeled through lipogenesis, assuming glucose to be the sole substrate for lipogenesis. The metabolic cost of the increased lipogenesis, however, accounted for only 3-4% of the T3-induced increase in calorigenesis. These results suggest that fatty acids derived from adipose tissue are the primary source of substrate for thyroid hormone-induced calorigenesis and that the early increase in lipogenesis serves simply to maintain fat stores. Since the mRNAs coding for lipogenic enzymes rise many hours before oxygen consumption and lipolysis, these results suggest that T3 acts at least in part by an early coordinate induction of the genes responsible for these processes.

Accelerated cholesteryl ester transfer in noninsulin-dependent diabetes mellitus

Alterations in core lipid composition of lipoproteins in noninsulin-dependent diabetes mellitus (NIDDM) patients have suggested that the heteroexchange of neutral lipids between HDL and the apo B-containing lipoproteins may be enhanced. For this reason, we studied cholesteryl ester transfer (CET) in ten sulfonylurea-treated patients with stable NIDDM. CET measured in all NIDDM subjects with an assay of mass transfer was significantly greater than that of controls at 1 and 2 h (P < 0.001); the transfer of radiolabeled CE also was increased in a subset of four of the NIDDM group (NIDDM k = 0.21 +/- 0.04 vs. control k = 0.10 +/- 0.05; P < 0.05). A weak correlation was demonstrable between the mass of CE transferred at 1 h and diabetic control expressed as plasma fructosamine (r = 0.58, P < 0.09). To characterize this disturbance in CET further, the donor (HDL + VHDL) and acceptor (VLDL + LDL) lipoprotein fractions were isolated by ultracentrifugation at d 1.063 g/ml from NIDDM and control plasma and a series of recombination experiments were performed. Combining NIDDM acceptor with control donor fractions that contained HDL and CETP and not the combination of NIDDM donor and control acceptor lipoproteins resulted in an accelerated CET response identical to that observed in NIDDM whole plasma. This observation indicated that the abnormality in CET in NIDDM was associated with the VLDL + LDL fraction.(ABSTRACT TRUNCATED AT 250 WORDS)

Metabolic Response to Cottage Cheese or Egg White Protein, With or Without Glucose, in Type II Diabetic Subjects

Test meals with 25 g protein in the form of cottage cheese or egg white were given with or without 50 g glucose to male subjects with mild to moderately severe, untreated, type II diabetes. Water was given as a control meal. The glucose, insulin, C-peptide, alpha amino nitrogen (AAN), glucagon, plasma urea nitrogen (PUN), nonesterified fatty acid (NEFA), and triglyceride area responses were determined using the water meal as a baseline. The glucose area responses following ingestion of cottage cheese or egg white were very small compared with those of the glucose meal, and were not significantly different from one another. The serum insulin area response was 3.6-fold greater following ingestion of cottage cheese compared with egg white (309 v 86 pmol/L.h). The simultaneous ingestion of glucose with cottage cheese or egg white protein decreased the glucose area response to glucose by 11% and 20%, respectively. When either protein was ingested with glucose, the insulin area response was greater than the sum of the individual responses, indicating a synergistic effect (glucose alone, 732 pmol/L.h; glucose with cottage cheese, 1,637 pmol/L.h; glucose with egg white, 1,213 pmol/L.h). The C-peptide area response was similar to the insulin area response. The AAN area response was approximately twofold greater following ingestion of cottage cheese compared with egg white. Following ingestion of glucose, it was negative. When protein was ingested with glucose, the AAN area responses were additive. The glucagon area response was similar following ingestion of cottage cheese or egg white protein. Following glucose ingestion, the glucagon area response was negative.(ABSTRACT TRUNCATED AT 250 WORDS)

Carotid intima media thickness decreases after pancreas transplantation

BACKGROUND Pancreas transplantation (PTX) improves diabetic microvascular complications, but it is unknown whether PTX alters macrovascular disease. Carotid intima media thickness (IMT) has been shown to correlate with cardiovascular events, so this study was designed to evaluate changes in carotid IMT after PTX. METHODS Four groups were studied: PTX candidates (n=60); successful PTX recipients (n=89; mean time since PTX=4.0+/-0.3 years); patients with type 1 diabetes but without nephropathy (n=20); and normal controls (n=32). Mean IMT and mean of maximum carotid IMT measurements (mean-max IMT), hemoglobin A1C, serum creatinine, body mass index (BMI), blood pressure, smoking status, use of hypolipidemic medications, and fasting lipids were determined in all groups. RESULTS Age, gender distribution, and BMI were not different among the groups. Duration of diabetes was also equal between pre- and post-PTX groups. Mean and mean-max IMT were greatest pre-PTX and decreased after PTX (P<0.05) to a value that was not different from controls. Hemoglobin A1C and creatinine decreased, and high density lipoprotein (HDL) increased after PTX (P<0.05), but there were no significant differences in other lipids, BMI, use of lipid lowering agents, blood pressure, or smoking status. CONCLUSIONS Carotid IMT is lower after PTX, suggesting a reduction in overall cardiovascular risk independent of changes in use of hypolipidemic agents, smoking, blood pressure, BMI, or lipids, except HDL. Improved carotid IMT after successful PTX predicts a reduction in future vascular disease events and suggests that the macrovascular disease of type 1 diabetes is at least partially reversible with improved glucose control.

Randomized Trial of Single-Dose Versus Divided-Dose Rabbit Anti-Thymocyte Globulin Induction in Renal Transplantation : An Interim Report

Background. The optimal dosing protocol for rabbit anti-thymocyte globulin (rATG) induction in renal transplantation has not been determined, but evidence exists that rATG infusion before renal allograft reperfusion improves early graft function. Infusing a large rATG dose over a short interval has not previously been evaluated for its effect on renal function and allograft nephropathy in a prospective, randomized comparison against conventional rATG induction. Methods. Between April 20, 2004 and December 26, 2007 we enrolled renal transplant patients into a prospective, randomized, nonblinded trial of two rATG dosing protocols (single dose, 6 mg/kg vs. divided doses, 1.5 mg/kg every other day×4; target enrollment=160) followed after 6 months by calcineurin-inhibitor withdrawal. Primary endpoints are renal function by calculated glomerular filtration rate (GFR) and chronic allograft nephropathy at protocol biopsy. We now present the early GFR data of all 160 patients and safety and efficacy data of the first 142 patients with 6 months follow up and before calcineurin inhibitor withdrawal (average follow up=23.3±11.6 months). Results. There were no differences between groups in rATG-related adverse events, patient and graft survival, acute rejection, or chronic allograft nephropathy rate at 6 months. Calculated &Dgr;GFR (POD 1–4) was significantly better in the single-dose group (P=0.02), with a trend toward improved renal function from months 2 to 6 in recipients of deceased donor kidneys (P=0.08). Conclusions. This study demonstrates that administering 6 mg/kg of rATG over 24 hr is safe and is associated with improved early renal function compared with administering rATG in alternate-day doses.

Approach to the Patient with New-Onset Diabetes after Transplant (NODAT)

New-onset diabetes after transplantation (NODAT) refers to the occurrence of diabetes in previously nondiabetic persons after organ transplantation. The incidence rates of NODAT vary by organ transplanted and posttransplant interval. The estimated rates at 12 months posttransplant are 20-50% for kidney transplants, 9-21% for liver transplants, and approximately 20% for lung transplants. NODAT is associated with increased risks of graft rejection, infection, cardiovascular disease, and death. Besides the traditional risk factors for type 2 diabetes (age, family history, obesity, and ethnicity), exposure to immunosuppressive agents often precedes the occurrence of NODAT. Identification of risk factors through pretransplant screening is desirable, as is prompt diagnosis and appropriate treatment. NODAT is consistent with type 2 diabetes and responds to the usual antidiabetes agents. However, severe hyperglycemia during the early posttransplant period may necessitate the use of iv insulin infusion. Also, high-dose glucocorticoid therapy for induction of immunosuppression (or treatment of acute rejection) may require the use of insulin therapy for glycemic control. After hospital discharge, close monitoring of blood glucose during the first month and every 3 months for the first year is recommended. Consideration should be given to drug toxicities or interactions when prescribing antidiabetes agents in the posttransplant patient. In addition to hyperglycemia, the control of comorbidities such as dyslipidemia and hypertension needs to be optimized. Future areas of investigation include the development of immunosuppressive regimens with minimal diabetogenic effects, determination of the role of glycemic control on graft survival, and interventions for primary prevention of NODAT.

The metabolic response to various doses of fructose in type II diabetic subjects

Eight men with untreated type II diabetes were given 480 mL water containing 15 g, 25 g, 35 g, and 50 g fructose orally, in random sequence. The same subjects were given the same volume of water as a control. They also were given 50 g glucose on two occasions for comparative purposes. Plasma glucose, urea nitrogen, and glucagon, and serum insulin, C-peptide, alpha-amino-nitrogen (AAN), nonesterified fatty acids (NEFA), and triglycerides were determined over the subsequent 5-hour period. The area responses to each dose of fructose were calculated and compared with the water control. The integrated glucose area dose-response was curvilinear, with little increase in glucose until 50 g fructose was ingested. With the 50-g dose, the area response was 25% of the response to 50 g glucose. The insulin response also was curvilinear, but the curve was opposite to that of the glucose curve. Even the smallest dose of fructose resulted in a relatively large increase in insulin, and a near-maximal response occurred with 35 g. The area response to 50 g fructose was 39% of that to 50 g glucose. The C-peptide data were similar to the insulin data. The AAN area response to fructose ingestion was negative. However, the response was progressively less negative with increasing doses. The glucagon area response was positive, but a dose-response relationship was not apparent. The glucagon area response was negative after glucose ingestion, as expected. The urea nitrogen area response was negative, but again, a dose-response relationship to fructose ingestion was not present.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of 24 hours of starvation on plasma glucose and insulin concentrations in subjects with untreated non-insulin-dependent diabetes mellitus.

Adherence to a low-calorie diet often results in a decrease in blood glucose concentration in persons with non-insulin-dependent diabetes mellitus (NIDDM). Whether this is due to the resultant weight loss or to a decrease in caloric intake has been uncertain. We have obtained data previously that indicated a very short-term reduction in caloric intake (5 hours) resulted in a significant decrease in plasma glucose concentration in subjects with NIDDM. The purpose of the present study was to determine if a further decrease in glucose would occur if the fast was extended from 5 to 24 hours. Seven male subjects with untreated NIDDM were studied after an 11-hour overnight fast. For the subsequent 24-hour period, subjects were given only water. Blood was obtained for glucose, insulin, C-peptide, triglycerides, nonesterified fatty acids (NEFA) alpha-amino acid nitrogen, urea nitrogen, and glucagon at hourly intervals for 24 hours beginning at 8 AM. The amount of glycogen degraded was calculated based on the potassium balance. Plasma glucose decreased from 158 mg/dL at 8 AM to a nadir of 104 mg/dL at 7 PM. It then increased by 30 mg/dL. Corresponding changes occurred in insulin and C-peptide. Serum glucagon remained unchanged. Serum alpha-amino acid nitrogen and urea nitrogen decreased. Triglycerides and NEFA increased. The calculated glycogen utilized over this period was approximately 167 g. This would provide approximately 700 kcal energy. The elevated blood glucose concentration in mild to moderately severe untreated NIDDM subjects was normalized following short-term fasting. Plasma insulin concentrations also decreased to within normal limits. These decreases were highly significant. Glycogenolysis is an important source of fuel during this period.

Assessing treatment barriers in young adults with type 1 diabetes

AIMS The current study was designed to identify barriers that prevent young adults with DM1 from achieving glycemic control. METHODS Eighty-three young adult patients with DM1 [age 22.2 ± 2.8 years (mean ± SD), duration diabetes 11.3 ± 5.6 years, HbA1c 8.8 ± 2.1%] completed a battery of surveys assessing potential barriers to achieving glycemic control. Results of questionnaires were correlated with the patients most recent HbA1c, and a multiple regression analysis was conducted to determine what barriers were significantly associated with HbA1c levels. RESULTS Questionnaires that significantly correlated with HbA1c levels included the Conflict Subscale of the Diabetes Responsibility and Conflict Scale (r = .55, p < .01), the Modified Barriers to Adherence Questionnaire (r = .42, p < .01), and the Hospital Anxiety and Depression Scale (r = .31, p < .05). An item analysis of the Modified Barriers to Adherence Scale suggested that patient confidence with carbohydrate counting was most statistically associated with HbA1c [F(3, 80) = 12.95, p < .01, R²=.35]. CONCLUSIONS Results suggest that despite attempts to educate patients; barriers such as family conflict, psychological issues, and carbohydrate counting remain obstacles impeding glycemic control in young adults with DM1.

Single-dose rATG induction at renal transplantation: superior renal function and glucoregulation with less hypomagnesemia.

Stevens RB, Lane JT, Boerner BP, Miles CD, Rigley TH, Sandoz JP, Nielsen KJ, Skorupa JY, Skorupa AJ, Kaplan B, Wrenshall LE. Single‐dose rATG induction at renal transplantation: superior renal function and glucoregulation with less hypomagnesemia. 
Clin Transplant 2012: 26: 123–132. 
© 2011 John Wiley & Sons A/S.