Long-term efficacy of sitagliptin as either monotherapy or add-on therapy to metformin: improvement in glycemic control over 2 years in patients with type 2 diabetes.

OBJECTIVE: To evaluate the efficacy of once daily sitagliptin 100 mg as monotherapy or as add-on to metformin in patients with type 2 diabetes mellitus (T2DM) over 2 years of treatment. RESEARCH DESIGN AND METHODS: The monotherapy analysis used pooled 104 week data from 64 patients in two randomized, double-blind trials evaluating the safety and efficacy of sitagliptin monotherapy. Data used were from patients who were randomized to sitagliptin 100 mg/day, were not on an antihyperglycemic agent at the screening visit, had baseline A1C of 7.0%-10.0%, and had Week 104 A1C measurements. The add-on to metformin analysis used pooled data from 347 patients in two randomized double-blind trials evaluating the safety and efficacy of sitagliptin + metformin combination therapy. Data used were from patients who were randomized to sitagliptin 100 mg/day + metformin ≥1500 mg/day, had baseline A1C of 7%-10%, and had Week 104 A1C measurements. Excluded from either analysis were patients who discontinued prior to 2 years (e.g., due to lack of efficacy, a need for rescue medications, or adverse experiences). Analysis endpoints were A1C, fasting plasma glucose (FPG), HOMA-ß, proinsulin/insulin (P/I) ratio, and for monotherapy, 2 hour post-meal plasma glucose (PMG). RESULTS: For the pooled monotherapy cohort, after 2 years of treatment, mean A1C, FPG, and 2 hour PMG decreased from baseline values of 7.9%, 156 mg/dL, and 223 mg/dL to 6.9%, 143 mg/dL, and 191 mg/dL, respectively, while HOMA-ß increased from 67% to 85% and P/I ratio improved from 0.57 to 0.28. For the pooled add-on to metformin cohort, after 2 years of treatment, mean A1C and FPG decreased from baseline values of 7.7% and 160 mg/dL to 6.9% and 140 mg/dL, respectively, while HOMA-ß increased from 50% to 62% and P/I ratio improved from 0.33 to 0.28. These analyses are limited in that only patients who were able to complete 104 weeks of study were included. CONCLUSION: In the subset of patients with T2DM who maintained and completed treatment for 2 years with sitagliptin as monotherapy or as add-on to metformin, improvements in glycemic control and measures of ß-cell function were observed over the course of treatment.

The incidence of hypoglycaemia in Muslim patients with type 2 diabetes treated with sitagliptin or a sulphonylurea during Ramadan: a randomised trial.

AIMS: To compare the incidence of symptomatic hypoglycaemia in fasting Muslim patients with type 2 diabetes treated with sitagliptin or a sulphonylurea during Ramadan. METHODS: Patients with type 2 diabetes (age ≥ 18 years) who were treated with a stable dose of a sulphonylurea with or without metformin for at least 3 months prior to screening, who had an HbA(1c) < 10% and who expressed their intention to daytime fast during Ramadan were eligible for this open-label study. Patients were randomised in a 1 : 1 ratio to either switch to sitagliptin 100 mg qd or to remain on their prestudy sulphonylurea. Patients completed daily diary cards to document information on hypoglycaemic symptoms and complications. The primary end-point was the overall incidence of symptomatic hypoglycaemia recorded during Ramadan. RESULTS: Of the 1066 patients randomised, 1021 (n = 507 for sitagliptin and n = 514 for sulphonylurea) returned at least one completed diary card and were included in the analysis. The proportion of patients who recorded one or more symptomatic hypoglycaemic events during Ramadan was lower in the sitagliptin group (6.7%) compared with the sulphonylurea group (13.2%). The risk of symptomatic hypoglycaemia was significantly decreased with sitagliptin relative to sulphonylurea treatment (Mantel-Haenszel relative risk ratio [95% CI] = 0.51 [0.34, 0.75]; p < 0.001). There were no reported events that required medical assistance (i.e. visits to physician or emergency room or hospitalisations) or were considered severe (i.e. events that caused loss of consciousness, seizure, coma or physical injury) during Ramadan. CONCLUSIONS: In Muslim patients with type 2 diabetes who observed the fast during Ramadan, switching to a sitagliptin-based regimen decreased the risk of hypoglycaemia compared with remaining on a sulphonylurea-based regimen. The incidence of hypoglycaemia was lower with gliclazide relative to the other sulphonylurea agents and similar to that observed with sitagliptin.

Efficacy and safety of monotherapy of sitagliptin compared with metformin in patients with type 2 diabetes.

AIM: To compare the efficacy and safety of monotherapy with sitagliptin and metformin in treatment-naïve patients with type 2 diabetes. METHODS: In a double-blind study, 1050 treatment-naïve patients (i.e. not taking an antihyperglycaemic agent for > or =16 weeks prior to study entry) with type 2 diabetes and an HbA(1c) 6.5-9% were randomized (1:1) to treatment with once-daily sitagliptin 100 mg (N = 528) or twice-daily metformin 1000 mg (N = 522) for 24 weeks. Metformin was up-titrated from 500 to 2000 mg per day (or maximum tolerated daily dose > or =1000 mg) over a period of 5 weeks. The primary analysis used a per-protocol (PP) approach to assess whether sitagliptin was non-inferior to metformin based on HbA(1c) change from baseline at week 24. Non-inferiority was to be declared if the upper boundary of the 95% confidence interval (CI) for the between-group difference in this endpoint was <0.40%. RESULTS: From a mean baseline HbA(1c) of 7.2% in the PP population, HbA(1c) change from baseline was -0.43% with sitagliptin (n = 455) and -0.57% with metformin (n = 439). The between-group difference (95% CI) was 0.14% (0.06, 0.21), thus confirming non-inferiority. Baseline HbA(1c) influenced treatment response, with larger reductions in HbA(1c) observed in patients with baseline HbA(1c)> or =8% in the sitagliptin (-1.13%; n = 74) and metformin (-1.24%; n = 73) groups. The proportions of patients at week 24 with HbA(1c) values at the goals of <7 or <6.5% were 69 and 34% with sitagliptin and 76 and 39% with metformin, respectively. Fasting plasma glucose changes from baseline were -11.5 mg/dL (-0.6 mmol/l) and -19.4 mg/dl (-1.1 mmol/l) with sitagliptin and metformin, respectively (difference in LS mean change from baseline [95% CI] = 8.0 mg /dl [4.5,11.4]). Both treatments led to similar improvements from baseline in measures of homeostasis model assessment-beta cell function (HOMA-beta) and insulin resistance (HOMA-IR). The incidence of hypoglycaemia was 1.7% with sitagliptin and 3.3% with metformin (p = 0.116). The incidence of gastrointestinal-related adverse experiences was substantially lower with sitagliptin (11.6%) compared with metformin (20.7%) (difference in incidence [95% CI] = -9.1% [-13.6,-4.7]), primarily because of significantly decreased incidences of diarrhoea (3.6 vs. 10.9%; p < 0.001) and nausea (1.1 vs. 3.1%; p = 0.032). Body weight was reduced from baseline with both sitagliptin (LS mean change [95% CI] = -0.6 kg [-0.9,-0.4]) and metformin (-1.9 kg [-2.2, -1.7]) (p < 0.001 for sitagliptin vs. metformin). CONCLUSIONS: In this 24-week monotherapy study, sitagliptin was non-inferior to metformin in improving HbA(1c) in treatment-naïve patients with type 2 diabetes. Although both treatments were generally well tolerated, a lower incidence of gastrointestinal-related adverse experiences was observed with sitagliptin.

Alterations in cardiac contractility and gene expression during low-T3 syndrome: prevention with T3.

The low-T3 syndrome is a metabolic response resulting in a decreased serum triiodothyronine (T3) concentration that has uncertain effects on thyroid hormone-responsive gene expression and function. We measured cardiac myocyte gene expression and cardiac contractility in young adult female rats using chronic calorie deprivation as a model of the low-T3 syndrome. Sarcoplasmic reticulum calcium adenosinetriphosphatase (SERCA2) and myosin heavy chain (MHC) isoform mRNA content were measured after 28 days on a 50% calorie-restricted diet (low T3) with or without T3 treatment (6 micrograms.kg body wt-1.day-1). The low-T3 animals had decreased maximal rates of contraction (-13%; P < 0.05) and relaxation (-18%; P < 0.05) compared with the control and the T3-treated groups. There was a 21% (P < 0.05) increase in left ventricular (LV) relaxation time in the low-T3 animals vs. both control and T3-treated groups. The LV content of the SERCA2 mRNA was decreased significantly (37%) in the low-T3 rats and was increased (P < 0.05) with T3 treatment vs. controls. The alpha-MHC mRNA isoform decreased in the low-T3 animals but was unchanged in the T3-treated animals. T3 supplementation normalized both cardiac function and phenotype of calorie-restricted animals, suggesting a role for the low-T3 syndrome in the pathophysiological response to calorie restriction.

The effects of long-term aerobic exercise and energy restriction on protein synthesis.

Long-term aerobic exercise and energy intake regulate body composition in a complex manner. To study the combined effects of exercise and energy restriction on muscle mass, we measured skeletal and cardiac muscle protein synthesis after 28 days of two levels of energy restriction with or without daily running-wheel exercise in female rats. Protein synthesis was measured as 3H-Phe incorporation 10 minutes' postbolus of a flooding pulse injection. The two exercise plus energy-restriction groups had greater skeletal muscle and cardiac muscle mass compared with their food-matched groups. Cardiac, gastrocnemius, and soleus muscle protein synthetic rates were proportional to their muscle masses. Exercise-induced energy deficits preserved cardiac and soleus mass to a greater extent than gastrocnemius mass, whereas the effects of energy restriction were similar in all three muscles. These findings suggest that energy intake and exercise have independent effects on the regulation of muscle mass and protein synthesis.

Effects of exercise on protein synthesis and myosin heavy chain gene expression in hypothyroid rats.

Hypothyroidism suppresses muscle growth and alters myosin heavy chain (MHC) gene expression. To study the role of thyroid hormones in exercise-induced muscle growth and protein synthesis, we measured skeletal and cardiac muscle protein synthesis and MHC gene expression in hypothyroid rats allowed to exercise voluntarily. Female Sprague-Dawley rats (200-210 g) were separated into four groups for 28 days of treatment: control, hypothyroid (TX), hypothyroid plus running-wheel exercise (TX+Ex), and hypothyroid plus 25% overfed (TX+OF). Fractional protein synthesis rates (% incorporation/day) were measured using [3H]phenylalanine incorporation 10 min postinjection. The heart weight-to-body weight ratios of the TX and the TX+OF groups showed marked cardiac atrophy over the 28-day period (2.76 +/- 0.12 and 2.50 +/- 0.22 vs. 3.37 +/- 0.18 mg/g, respectively; P < 0.01). However, the TX+Ex group prevented heart, gastrocnemius, and soleus muscle atrophy over the same time period. Heart, gastrocnemius, and soleus muscles had markedly suppressed protein synthesis rates in the TX and TX+OF groups vs. the euthyroid controls (mean fall -72%; P < 0.01, analysis of variance). However, exercise increased protein synthesis rate by 50% (P < 0.05) compared with TX alone in all three muscle groups. Exercise did not modify hypothyroid-induced alterations of cardiac myosin isoform expression. Exercise-mediated effects on skeletal and cardiac muscle growth but not cardiac MHC gene expression appear to be independent of thyroid hormones.

Impaired peripheral thyroid hormone metabolism in genetic obesity.

The obese Zucker rat has alterations in thyroid hormone metabolism resulting in a lower serum T3 concentration and T3 plasma appearance rate compared to its lean littermates. This study was undertaken to measure the contribution of specific nonthyroidal tissues to the total production of T3 in vivo in the Zucker fatty rat. Simultaneous pulse kinetic studies of T4 and T3 were performed in lean and obese Zucker littermates and analyzed according to a three-pool model of distribution and metabolism. The serum concentration and plasma appearance rate of T3 were both decreased in the obese vs. lean Zucker phenotype (P < 0.05) despite an elevated serum concentration and plasma appearance rate for T4. The quantity of T4 within the fast pool (i.e. liver and kidney) available for deiodination was equal for both phenotypes; however, generation of T3 within the fast pool was impaired for the obese compared to the lean group (-25%; P < 0.05). The tissue content of radiolabeled T3 generated within the liver 24 h post injection of T4 for the obese group was 48% lower (P < 0.02) vs. the lean group. A separate group of lean and obese littermates were surgically thyroid-ectomized and replaced with T4 to maintain a euthyroid state. The obese Zucker group had lower serum T3 concentrations and T3 plasma appearance rates compared to similarly treated lean Zucker animals despite similar T4 serum concentrations. Treatment with propylthiouracil produced a decline in serum T3 plasma appearance rate T3 PAR (-55%; P < 0.02) in the T4-replaced lean rat but no alteration in T3 metabolism in the fatty Zucker rat. We conclude that the obese Zucker rat has impaired T3 synthesis in tissues containing Type I 5-deiodinase despite adequate T4 availability as substrate for deiodination to T3.

Maintenance of thyroid hormone production during exercise-induced weight loss.

Calorie restriction reduces thyroxine (T4) and 3,5,3'-triiodothyronine (T3) production, but the effects of exercise-induced weight loss on thyroid hormone metabolism in rodents are unclear. We studied the effects of chronic exercise on T4 and T3 metabolism comparing exercising (exercise) rats pair fed to sedentary (control) rodents and to weight-matched underfed sedentary animals (underfed; caloric intake 75% of ad libitum-fed controls). The exercise group utilized voluntary running wheels (28 days), and thyroid hormone metabolism was assessed using a three-compartment kinetics model. The exercise and underfed groups were equivalent in weight, but protein mass was greater in the exercise vs. underfed groups (30.4 +/- 0.5 vs. 27.9 +/- 0.5 g; P less than 0.05). During exercise, the T4 plasma clearance rate (PCR) was decreased (-39.2%; P less than 0.01) and the T4 concentration in serum was increased (48.6%; P less than 0.01), resulting in an unchanged T4 plasma appearance rate (PAR) vs. the control group. The decrease in T4 PCR in the exercise group was associated with a lower transport rate of T4 out of the slow pool (P less than 0.01). In the underfed group there was a reduction in both T4 serum concentration and PAR (-36%; P less than 0.01) compared with the control group, which was associated with a decrease in the volume of distribution (-25%; P less than 0.01). T3 PAR decreased 38.7% (P less than 0.01) during underfeeding but only 16.9% (P = not significant) during exercise vs. the control group.(ABSTRACT TRUNCATED AT 250 WORDS)

Calorie restriction and iopanoic acid effects on thyroid hormone metabolism.

We measured the effects of iopanoic acid on thyroid hormone metabolism in obese men during severe calorie restriction to study the nutrition regulation of thyroid hormone metabolism. Eight morbidly obese men received a weight-maintenance diet followed by 6 wk of 600 kcal/d. During underfeeding, patients received iopanoic acid or placebo for 2-wk periods in a double-blind crossover fashion. Underfeeding alone (UF) produced a 28.3% decline in the serum triiodothyronine (T3) concentration, and iopanoic acid plus underfeeding (IOP) produced a 49.5% decline in T3 concentration from baseline. Serum reverse T3 concentrations increased 289% during IOP compared with UF alone (p less than 0.001). Serum TSH concentration was unchanged by underfeeding but increased twofold during IOP treatment. Thyroid hormone kinetics demonstrated a decrease in T3 production during IOP compared with UF. These findings suggest that calorie restriction regulates T3 production by modulating only type I 5'-deiodinase activity.

Increasing age impairs the thyroid hormone response to overfeeding.

Aging in both man and rodent is associated with increases in body weight and body fat. In young adult rats, mixed calorie overfeeding increases triiodothyronine production and decreases weight gain efficiency compared with chow diets. This study was undertaken to determine whether 4- and 14-month-old adult rats have similar responses in thyroxine (T4) and triiodothyronine (T3) metabolism during mixed calorie overfeeding. Four- and 14-month-old male Sprague-Dawley rats were each separated into two groups (n = 14): control (CHOW) versus chow + mixed calorie (CAFE) overfeeding for 28 days. The 4-month-old CAFE-fed rats ingested 662 +/- 54 extra kcal over 28 days and gained 147 +/- 7 vs 113 +/- 5 g (P less than 0.01) for their age-matched CHOW group. The 14-month-old CAFE group ingested 309 +/- 45 extra kcal and gained 58 +/- 6 g weight vs -12 +/- 5 g for their age-matched CHOW group (P less than 0.01). Serum T4 concentrations were unchanged during overfeeding or aging. The serum T3 concentration was increased 24% in the 4-month-old CAFE group compared with the age-matched CHOW group (P less than 0.05), but there was no difference in the serum T3 concentration between the 14-month-old CAFE and CHOW groups. The metabolic clearance and production rates of T3 and T4 were decreased in the 14-month-old vs 4-month-old groups (P less than 0.01). The T3 metabolic clearance rate was increased in the CAFE versus CHOW group in the 4-month-old groups (137.3 +/- 11.2 vs 103.0 +/- 10.1 ml/kg/hr, P less than 0.01) but unchanged in the 14-month-old CAFE and CHOW groups (47.6 +/- 6.6 vs 53.4 +/- 5.3 ml/kg/hr, not significant). Liver type I iodothyronine 5'-deiodinase activity increased during overfeeding in the young (63.6%, P less than 0.02) but not in the older rat group. T4 and T3 production rates were decreased in the older rats and did not increase during overfeeding as observed in the young adult rat.

Decreased thermic effect of a mixed meal during overnutrition in human obesity.

Short-term mixed calorie overfeeding increases basal energy expenditure in man but its effects on the thermic effect of a meal (TEM) are unclear. The thermogenic and hormonal responses to an 800-kcal liquid mixed meal were measured in six lean and six obese subjects during weight maintenance, during 18 d of overfeeding 1000 kcal/d, and during 18 d of a 589 kcal/d diet (obese subjects only). There was no change in the TEM in lean subjects between weight maintenance and overfeeding. In the obese group the TEM was lower during both overfeeding (p less than 0.05) and underfeeding (p less than 0.05) compared with weight maintenance. Overfeeding increased rates of net postprandial glucose oxidation and decreased lipid oxidation in the lean subjects only. Alterations in glucose oxidation rates and the insulin response to meals may contribute to an impaired TEM in human obesity during overnutrition.

Transdermal delivery of human insulin to albino rabbits using electrical current.

The transdermal route of administration for medication has many potential advantages over other routes of administration. However, the stratum corneum is an effective barrier to the absorption of most chemicals from the external environment into the body. To evaluate techniques for alteration of transdermal permeability, the authors studied the effect of low levels of electrical current on transport of a protein across the stratum corneum. Transcutaneous insulin absorption was used as an indicator of altered permeability. Twenty-six albino rabbits had acute diabetes mellitus induced by the intravenous administration of 125 mg/kg of alloxan. The animals then received either cutaneous patches containing insulin and an electrical current of 0.4 mA (active) or patches containing an equal amount of insulin but without electrical current (passive). At 10 and 12 hours after the placement of the patches, animals with active patches had significant elevations in serum insulin levels (p less than .05) and reduction in blood glucose levels (p less than .01). No changes were seen in controls. Animals with active patches also had significant differences from control animals in mean insulin response and peak insulin response (p less than .05). No cutaneous toxicity was observed in any of the animals. The authors conclude that low levels of electrical current can induce changes in stratum corneum permeability that are sufficient to produce the transdermal absorption of physiologic doses of a protein such as human insulin.

Exercise regulation of triiodothyronine metabolism.

Negative caloric balance reduces triiodothyronine (T3) production in both humans and rodents. The effects of chronic voluntary exercise and various levels of caloric intake and balance on T3 metabolism were studied in adult male C57/BL6 mice to determine if exercise had any direct effects on T3 production in vivo and in vitro. Chronic voluntary exercise was induced by the addition of running wheels to cages for 28 days. Ad libitum-fed exercising mice ingested 20% greater calories (P less than 0.02), maintained body weight, and increased T3 production (53.1 +/- 5.3 vs. 42.3 +/- 3.4 ng.h-1.100 mg body wt-1; P less than 0.01). Exercising animals pair fed to sedentary ad libitum-fed controls decreased their body mass to an equivalent degree as underfed sedentary animals (caloric intake 75% of ad libitum-fed controls) but had increased T3 clearance compared with weight-matched underfed sedentary control (P less than 0.05). Animals that were underfed and exercised decreased their body weight to a greater extent (P less than 0.01) compared with the sedentary underfed group, but T3 production rates were equal. Activity of liver 5'-deiodinase activity was decreased almost 50% (P less than 0.01) during both exercise plus pair feeding and exercise plus caloric restriction but decreased only 28% during caloric restriction alone (P less than 0.01). T3 metabolic clearance and production rates in vivo were correlated to caloric intake (r = 0.73, P less than 0.01), but an interaction between exercise and caloric balance was observed. Chronic voluntary exercise modulates T3 metabolism via several mechanisms. Exercise has an apparent stimulatory effect independent of caloric intake, but also there are regulatory effects dependent on the absolute level of caloric intake and relative caloric balance.(ABSTRACT TRUNCATED AT 250 WORDS)

Altered triiodothyronine metabolism in Zucker fatty rats.

Genetically obese Zucker fatty rats require two autosomal recessive genes (fa/fa) to express the obese phenotype. The obese Zucker rat (fa/fa) has decreased total and free serum T3 concentrations, but normal serum T4 concentrations, compared to those in their lean littermates. To elucidate the mechanism of these differences, we measured the MCR and production rate (PR) of T4 and T3 in the three genotypes of 4-month-old male Zucker rats (Fa/Fa, Fa/fa, and fa/fa). In addition, 5'-deiodinase activity in liver, kidney, and brown adipose tissue homogenates was determined. T4 MCRs were equivalent in all three genotypes, but a decreased T3 MCR was seen in Fa/fa and fa/fa rats. An additive effect of the fa gene was noted with respect to the decrease in T3 MCR (Fa/Fa, 42.0 +/- 1.5; Fa/fa, 38.7 +/- 2.4; fa/fa, 34.7 +/- 3.4 ml/h; P less than 0.05). Whole body T4 PRs were equal in all three genotypes, but the T3 PR was decreased in the fa/fa rat by 25% compared to that in the homozygous lean rats (15.7 +/- 2.1 vs. 21.2 +/- 2.4 ng/h; P less than 0.005). Liver and kidney 5'-deiodinase activities were decreased in the fa/fa rat by 34% (P less than 0.005) and 20% (P less than 0.01), respectively. Brown adipose tissue and pituitary 5'-deiodinase activity were similar in all three genotypes. These results show a reduction in T3, but not T4, MCR in obese Zucker rats. Whole body T3 production and type I 5'-deiodinase activity were decreased in the obese (fa/fa) rats. These results suggest that decreased T4 to T3 conversion is responsible for the decreased T3 production rate in the fatty rat and may contribute to its obesity.

Effect of diet on energy expenditure and plasma norepinephrine in lean and obese Pima Indians.

To assess whether thermogenesis or sympathetic nervous system (SNS) function might differ between lean and obese human subjects, studies of thermic and sympathetic responses to standard stimuli were undertaken in Pima Indians, an ethnic group with a high prevalence of obesity. Plasma levels of norepinephrine (NE) and energy expenditure at rest and in response to feeding, exercise, and graded infusions of NE were compared in five lean and five obese Indians during a period of weight maintenance (WM), after 3 weeks of overfeeding (OF) and, in the obese, also after 6 weeks of underfeeding (UF). Basal energy expenditure, when adjusted for fat free mass, was equivalent during WM and increased 3% with OF (P less than 0.01) in both groups. Thermic responses to exercise or a test meal did not differ in lean and obese and did not change with OF, while thermic responses to NE infusion fell during OF to a greater degree in obese than lean (P less than 0.05). A similar pattern (decreased effect in obese with OF) was also noted in the glycemic response to infused NE (P less than 0.05). Although not quantitatively different in lean and obese, the plasma NE concentration appeared to vary more in response to feeding or dietary alteration in the obese than lean, a finding that may reflect lower plasma clearance of NE in the obese. These studies, therefore, raise the possibility that overfeeding in obese Pima Indians may limit the contribution of sympathetically mediated thermogenesis to energy expenditure, though the implications of this for body weight regulation are speculative.

Indirect calorimetry: comparison of hood and mask systems for measuring resting energy expenditure in healthy volunteers.

Controversy exists as to the validity and reliability of hood and mask systems in measuring indirect calorimetry. The purpose of this study was to evaluate the accuracy and reproducibility of repeat measurements of resting energy expenditure (REE) in volunteers. Paired REE measurements were performed in 23 subjects after an overnight fast using hood and mask systems. Lean body mass was calculated from four skinfold measurements and body weight determinations. Data were normalized to body weight and lean body mass and were calculated as percent predicted REE in paired tests taken within 5 minutes on the same subject. No significant difference in mean REE was noted between hood and mask systems. Linear regression analysis showed a strong positive correlation (r = 0.91, p less than 0.001) between hood and mask measurements of REE.

Metabolic studies in human obesity during overnutrition and undernutrition: thermogenic and hormonal responses to norepinephrine.

Overfeeding increases the thermogenic response of norepinephrine (NE) in normal but not in certain genetically obese rodents. It has been suggested that human obesity may be associated with a similar thermogenic defect. To determine whether there are differences in the thermogenic sensitivity to NE in human obesity, energy expenditure in response to graded infusions of NE (0.05, 0.10, 0.15, 0.20 micrograms/min/kg fat-free mass) was measured in six lean and six obese subjects (9.5 +/- 1.8 v 36.3 +/- 3.8% body fat P less than 0.005). Resting metabolic rate (RMR), thermogenic response to NE, and thermogenic response to exercise were measured during weight maintenance and during the third week of feeding 1000 extra Kcal/d in the lean and obese subjects. These components of energy expenditure were also measured in the obese subjects during the third week of a 589 Kcal/d diet. Resting metabolic rate increased during overfeeding in lean (6.6%, P less than 0.05) but not in the obese subjects (2.7%, P = NS) and fell during underfeeding in the obese (-9.1%, P less than 0.02). There was a logarithmic increment above baseline in VO2 v plasma NE concentration during the NE infusions (r = 0.75, P less than 0.005) in lean subjects which was unaltered by overfeeding. The obese exhibited equivalent VO2 responses to NE to that measured in the lean. Supine plasma NE concentrations were lower but metabolic clearance rates (MCR) of NE were similar in the obese compared to lean subjects during both weight maintenance and overfeeding. Overfeeding minimally increased plasma concentration but not MCR of NE in both groups. The thermogenic response to exercise was similar in the lean and obese subjects and was unaltered by overfeeding or underfeeding. The increments in plasma glycerol and free fatty acid in response to the NE infusions were proportional to the total fat mass of each individual and were greater in the obese subjects. Overfeeding partially suppressed the lipolytic response to NE in both groups and underfeeding increased the lipolytic response in the obese. There are no differences in thermogenic responses to NE in human obesity to account for excessive fat deposition. Overfeeding does not increase the thermogenetic responses to NE in humans as has been reported in small mammals.

C-peptide measurement in the differentiation of type 1 (insulin-dependent) and type 2 (non-insulin-dependent) diabetes mellitus.

To determine whether individual subjects with Type 1 (insulin-dependent) diabetes or Type 2 (non-insulin-dependent) diabetes, who are treated with insulin, could be reliably distinguished, C-peptide concentrations and urinary C-peptide excretion were measured in 10 Caucasoids and 10 Pima Indians. All the subjects had developed diabetes before 21 years of age and were receiving insulin treatment. Fasting C-peptide concentrations were significantly higher in the Pima Indians (0.73 +/- 0.17 versus 0.02 +/- 0.01 nmol/l in Caucasoids; p less than 0.001), but there were slight overlaps in individual values. Urinary C-peptide excretion, an index of 24-h-insulin excretion, was also higher in the Pima Indian group (27.6 +/- 1.85 versus 0.72 +/- 0.18 pmol/min in Caucasoids; p less than 0.001) and there was no overlap in the individual values between the groups. The Pima Indians with early onset diabetes have been previously shown to have Type 2 diabetes, and the Caucasoids with an early onset are most likely to have Type 1 diabetes. These results suggest that distinction between these two major types of diabetes can be made effectively by using C-peptide measurements provided that overt renal disease is absent. This differentiation between insulin-treated patients will be useful for a variety of research applications and possibly in making clinical management decisions.

The sympathetic nervous system in human obesity.

No evidence for increased thermic sensitivity to NE during mixed nutrient overfeeding in humans was found by the authors although in small rodents increased NE sensitivity is an important regulator of adaptive thermogenesis. Additionally no intrinsic defect in the thermic response of NE in two separate groups of obese individuals was found by the authors but an apparent decrease in the plasma appearance rate of NE in one group of homogeneously obese subjects was noted, the clinical significance of which remains to be determined.