Short-term exposure to exenatide can restore the insulin secretory pattern in response to acute rises in glucose concentrations in DM2 patients who, in the absence of exenatide, do not display a first phase of insulin secretion. Loss of first-phase insulin secretion in DM2 patients may be restored by treatment with exenatide.

These results support continued evaluation of pramlintide as a potential treatment for obesity.

OBJECTIVE -To assess long-term weight loss efficacy and safety of pramlintide used at different dosing regimens and in conjunction with lifestyle intervention (LSI).RESEARCH DESIGN AND METHODS -In a 4-month, double-blind, placebocontrolled, dose-ranging study, 411 obese subjects were randomized to receive pramlintide (six arms: 120, 240, and 360 g b.i.d. and t.i.d.) or placebo in conjunction with a structured LSI program geared toward weight loss. Of the 4-month evaluable subjects (n ϭ 270), 77% opted to continue preexisting treatment during an 8-month single-blind extension (LSI geared toward weight maintenance).RESULTS -At month 4, mean weight loss from baseline in the pramlintide arms ranged from 3.8 Ϯ 0.7 to 6.1 Ϯ 0.8 kg (2.8 Ϯ 0.8 kg with placebo). By month 12, initial 4-month weight loss was regained in the placebo group but was maintained in all but the 120-g b.i.d. group. Placebo-corrected weight loss with 120 g t.i.d. and 360 g b.i.d. averaged 3.2 Ϯ 1.2 kg (3.1 Ϯ 1.1% body wt) and 3.3 Ϯ 1.1 kg (3.1 Ϯ 1.0% body wt), respectively, at month 4 (both P Ͻ 0.01; 4-month evaluable n ϭ 270) and 6.1 Ϯ 2.1 kg (5.6 Ϯ 2.1% body wt) and 7.2 Ϯ 2.3 kg (6.8 Ϯ 2.3% body wt), respectively, at month 12 (both P Ͻ 0.01; 12-month evaluable n ϭ 146). At month 12, 40 and 43% of subjects treated with 120 g t.i.d. and 360 g b.i.d., respectively, achieved Ն10% weight loss (vs. 12% for placebo). Nausea, the most common adverse event with pramlintide in the 4-month study (9 -29% pramlintide vs. 2% placebo), was generally mild to moderate and occurred in Ͻ10% of subjects during the extension. CONCLUSIONS -When used over 12 months as an adjunct to LSI, pramlintide treatment, with low-dose three-times-daily or higher-dose two-times-daily regimens, helped obese subjects achieve greater initial weight loss and enhanced long-term maintenance of weight loss.

. Overexpression of hexokinase II increases insulin-and exercise-stimulated muscle glucose uptake in vivo. Am. J. Physiol. 276 (Endocrinol. Metab. 39): E70-E77, 1999.-The hypothesis of this investigation was that glucose uptake would be increased in skeletal muscle of transgenic mice (TG) overexpressing hexokinase II (HK II) compared with their nontransgenic littermates (NTG) during euglycemic hyperinsulinemia and treadmill exercise. For insulin experiments, catheters were surgically implanted in the jugular vein and carotid artery for infusions and sampling, respectively. Conscious mice underwent experiments ϳ5 days later in which 4 mU·kg Ϫ1 · min Ϫ1 insulin and variable glucose (n ϭ 7 TG and n ϭ 7 NTG) or saline (n ϭ 5 TG and n ϭ 4 NTG) was infused for 140 min. Over the last 40 min of the experiments, 2-deoxy-[ 3 H]glucose ([2-3 H]DG) was infused, after which muscles were removed. For the exercise experiments, jugular vein catheters were surgically implanted. Five days later, mice received a bolus of [2-3 H]DG and then remained sedentary (n ϭ 6 TG and n ϭ 8 NTG) or ran on a motorized treadmill (n ϭ 12 TG and n ϭ 8 NTG) for 30 min. TG and NTG had similar muscle [2-3 H]DG 6-phosphate ([2-3 H]DGP) accumulation in the basal state (P Ͼ 0.05). In the hyperinsulinemic experiments, TG required ϳ25% more glucose to maintain euglycemia (P Ͻ 0.05), and muscle [2-3 H]DGP accumulation normalized to infusate [2-3 H]DG was similarly increased (P Ͻ 0.05). In the exercise experiments, muscle [2-3 H]DGP accumulation was significantly greater in TG than NTG (P Ͻ 0.05). In conclusion, we did not detect an effect of HK II overexpression on muscle [2-3 H]DGP accumulation under basal conditions. Hyperinsulinemia and exercise shift the control of muscle glucose uptake so that phosphorylation is a more important determinant of the rate of this process. transgenic mice; glucose phosphorylation; 2-deoxyglucose

Evidence from rodent studies indicates that the β-cell-derived neurohormone amylin exerts multiple effects on eating behavior, including reductions in meal size, intake of highly palatable foods, and stress-induced sucrose consumption. To assess the effect of amylin agonism on human eating behavior we conducted a randomized, blinded, placebo-controlled, multicenter study investigating the effects of the amylin analog pramlintide on body weight, 24-h caloric intake, portion sizes, “fast food” intake, and perceived control of eating in 88 obese subjects. After a 2-day placebo lead-in, subjects self-administered pramlintide (180 μg) or placebo by subcutaneous injection 15 min before meals for 6 wk without concomitant lifestyle modifications. Compared with placebo, pramlintide treatment elicited significant mean reductions from baseline in body weight on day 44 (−2.1 ± 0.3 vs. +0.1 ± 0.4%, P < 0.001), 24-h caloric intake (−990 ± 94 vs. −243 ± 126 kcal on day 3, P < 0.0001; −680 ± 86 vs. −191 ± 161 kcal on day 43, P < 0.01), portion sizes, and caloric intake at a “fast food challenge” (−385 ± 61 vs. −109 ± 88 kcal on day 44, P < 0.05). Pramlintide treatment also improved perceived control of eating, as demonstrated by a 45% placebo-corrected reduction in binge eating scores ( P < 0.01). The results of this translational research study confirm in humans various preclinical effects of amylin agonism, demonstrating that pramlintide-mediated weight loss in obese subjects is accompanied by sustained reductions in 24-h food intake, portion sizes, fast food intake, and binge eating tendencies.

Preclinical evidence suggests that pharmacotherapy for obesity using combinations of agents targeted at distinct regulatory pathways may produce robust additive or synergistic effects on weight loss. This randomized placebo‐controlled trial examined the safety and efficacy of the amylin analogue pramlintide alone or in combination with either phentermine or sibutramine. All patients also received lifestyle intervention. Following a 1‐week placebo lead‐in, 244 obese or overweight, nondiabetic subjects (88% female; 41 ± 11 years; BMI 37.7 ± 5.4 kg/m2; weight 103 ± 19 kg; mean ± s.d.) received placebo subcutaneously (sc) t.i.d., pramlintide sc (120 µg t.i.d.), pramlintide sc (120 µg t.i.d.) + oral sibutramine (10 mg q.a.m.), or pramlintide sc (120 µg t.i.d.) + oral phentermine (37.5 mg q.a.m.) for 24 weeks. Treatment was single‐blind for subjects receiving subcutaneous medication only and open‐label for subjects in the combination arms. Weight loss achieved at week 24 with either combination treatment was greater than with pramlintide alone or placebo (P < 0.001; 11.1 ± 1.1% with pramlintide + sibutramine, 11.3 ± 0.9% with pramlintide + phentermine, −3.7 ± 0.7% with pramlintide; −2.2 ± 0.7% with placebo; mean ± s.e.). Elevations from baseline in heart rate and diastolic blood pressure were demonstrated with both pramlintide + sibutramine (3.1 ± 1.2 beats/min, P < 0.05; 2.7 ± 0.9 mm Hg, P < 0.01) and pramlintide + phentermine (4.5 ± 1.3 beats/min, P < 0.01; 3.5 ± 1.2 mm Hg, P < 0.001) using 24‐h ambulatory monitoring. However, the majority of subjects receiving these treatments remained within normal blood pressure ranges. These results support the potential of pramlintide‐containing combination treatments for obesity.

The hypothesis of this investigation was that insulin and muscle contraction, by increasing the rate of skeletal muscle glucose transport, would bias control so that glucose delivery to the sarcolemma (and t tubule) and phosphorylation of glucose intracellularly would exert more influence over glucose uptake. Because of the substantial increases in blood flow (and hence glucose delivery) that accompany exercise, we predicted that glucose phosphorylation would become more rate determining during exercise. The transsarcolemmal glucose gradient (TSGG; the glucose concentration difference across the membrane) is inversely related to the degree to which glucose transport determines the rate of glucose uptake. The TSGG was determined by using isotopic methods in conscious rats during euglycemic hyperinsulinemia [Ins; 20 mU/(kg. min); n = 7], during treadmill exercise (Ex, n = 6), and in sedentary, saline-infused rats (Bas, n = 13). Rats received primed, constant intravenous infusions of trace 3-O-[3H]methyl-D-glucose and [U-14C]mannitol. Then 2-deoxy-[3H]glucose was infused for the calculation of a glucose metabolic index (Rg). At the end of experiments, rats were anesthetized, and soleus muscles were excised. Total soleus glucose concentration and the steady-state ratio of intracellular to extracellular 3-O-[3H]methyl-D-glucose (which distributes on the basis of the TSGG) were used to calculate ranges of possible glucose concentrations ([G]) at the inner and outer sarcolemmal surfaces ([G]im and [G]om, respectively). Soleus Rg was increased in Ins and further increased in Ex. In Ins, total soleus glucose, [G]om, and the TSGG were decreased compared with Bas, while [G]im remained near 0. In Ex, total soleus glucose and [G]im were increased compared with Bas, and there was not a decrease in [G]om as was observed in Ins. In addition, accumulation of intracellular free 2-deoxy-[3H]glucose occurred in soleus in both Ex and Ins. Taken together, these data indicate that, in Ex, glucose phosphorylation becomes an important limitation to soleus glucose uptake. In Ins, both glucose delivery and glucose phosphorylation influence the rate of soleus glucose uptake more than under basal conditions.

The incretin mimetic exenatide improved glycemic control and reduced body weight in patients with type 2 diabetes inadequately controlled with metformin+/-a sulfonylurea. We assessed postprandial beta-cell function by mathematical modeling, independent of confounding effects from differing ambient glucose levels among treatments. Subjects were 63% males, 55+/-10 years, BMI 33+/-6 kg/m2, HbA1C 8.1+/-1.1% (+/- SD) randomized to 5 microg exenatide or placebo twice daily for 4 weeks. Subsequently, one arm remained at 5 microg twice daily, one arm escalated to 10 microg twice daily, and one treatment arm remained on placebo for 26 weeks. Subjects continued metformin+/-a sulfonylurea. A subset with meal tests at baseline and week 30 were analyzed (n=73). Outcome measures were the model-based beta-cell function parameters dose-response relating insulin secretion to glucose concentration, rate sensitivity, and potentiation. Exenatide reduced postprandial glucose excursions. Modeling predicted an upward shift of the beta-cell dose-response. Model-predicted insulin secretion rate at a reference glucose concentration increased 72% (10 microg), increased 40% (5 microg), or decreased 21% (placebo) at week 30 [ p=0.015 (10 microg); p=0.045 (5 microg); vs. placebo]. At week 30, the 2-hour post-meal to basal potentiation factor ratio was increased to 1.53+/-0.10 (10 microg; p=0.0142 vs. placebo) or 1.40+/-0.08 (5 microg; p=0.0402 vs. placebo) compared with 1.15+/-0.06 (placebo). Exenatide caused an upward shift of the beta-cell dose-response and enhanced potentiation of insulin secretion. This model suggests exenatide improved beta-cell function in patients with type 2 diabetes treated with metformin+/-a sulfonylurea.