Robert H. Coker

Prevention and treatment of type 2 diabetes: current role of lifestyle, natural product, and pharmacological interventions.

Common complications of type 2 diabetes (T2D) are eye, kidney and nerve diseases, as well as an increased risk for the development of cardiovascular disease and cancer. The overwhelming influence of these conditions contributes to a decreased quality of life and life span, as well as significant economic consequences. Although obesity once served as a surrogate marker for the risk of T2D, we know now that excess adipose tissue secretes inflammatory cytokines that left unchecked, accelerate the progression to insulin resistance and T2D. In addition, excess alcohol consumption may also increase the risk of T2D. From a therapeutic standpoint, lifestyle interventions such as dietary modification and/or exercise training have been shown to improve glucose homeostasis but may not normalize the disease process unless weight loss is achieved and increased physical activity patterns are established. Furthermore, utilization of natural products may serve as a significant adjunct in the fight against insulin resistance but further research is needed to ascertain their validity. Since it is clear that pharmaceutical therapy plays a significant role in the treatment of insulin resistance, this review will also discuss some of the newly developed pharmaceutical therapies that may work in conjunction with lifestyle interventions, and lessen the burden of behavioral change as the only strategy against the development of T2D.

The Impact of Exercise Training Compared to Caloric Restriction on Hepatic and Peripheral Insulin Resistance in Obesity

CONTEXTnIt has been difficult to distinguish the independent effects of caloric restriction versus exercise training on insulin resistance.nnnOBJECTIVEnUtilizing metabolic feeding and supervised exercise training, we examined the influence of caloric restriction vs. exercise training with and without weight loss on hepatic and peripheral insulin resistance.nnnDESIGN, PARTICIPANTS, AND INTERVENTIONnThirty-four obese, older subjects were randomized to: caloric restriction with weight loss (CR), exercise training with weight loss (EWL), exercise training without weight loss (EX), or controls. Based on an equivalent caloric deficit in EWL and CR, we induced matched weight loss. Subjects in the EX group received caloric compensation. Combined with [6,6(2)H(2)]glucose, an octreotide, glucagon, multistage insulin infusion was performed to determine suppression of glucose production (SGP) and insulin-stimulated glucose disposal (ISGD). Computed tomography scans were performed to assess changes in fat distribution.nnnRESULTSnBody weight decreased similarly in EWL and CR, and did not change in EX and controls. The reduction in visceral fat was significantly greater in EWL (-71 +/- 15 cm(2)) compared to CR and EX. The increase in SGP was also almost 3-fold greater (27 +/- 2%) in EWL. EWL and CR promoted similar improvements in ISGD [+2.5 +/- 0.4 and 2.4 +/- 0.9 mg x kg fat-free mass (FFM)(-1) x min(-1)], respectively.nnnCONCLUSIONSnEWL promoted the most significant reduction in visceral fat and the greatest improvement in SGP. Equivalent increases in ISGD were noted in EWL and CR, whereas EX provided a modest improvement. Based on our results, EWL promoted the optimal intervention-based changes in body fat distribution and systemic insulin resistance.

Glucoregulation During Exercise The Role of the Neuroendocrine System

AbstractUnder normal healthy conditions, exercise initiates simultaneous elevations in hepatic glucose production (glucose Ra) and glucose utilisation. As a result, circulating glucose levels are maintained at a relatively constant level. This relatively simple and effective relationship between the liver and the skeletal muscle is maintained by a complex interplay of circulating and locally released neuroendocrine controllers. In large part, exercise-induced changes in the pancreatic secretion of glucagon and insulin are primarily responsible for the stimulation of glucose Ra during moderate exercise. However, exercise imposed on an additional metabolic stress (heavy exercise and poorly controlled diabetes mellitus) can increase sympathetic drive and has been suggested for decades to play a significant role in glucoregulation. In addition, blood-borne feedback and afferent reflex mechanisms may further modulate the glucose Ra response to exercise. This article discusses new findings from novel animal and human experiments specifically designed to examine the regulatory components of the neuroendocrine system and their influence on glucoregulation during exercise.n

Bed Rest Promotes Reductions in Walking Speed, Functional Parameters, and Aerobic Fitness in Older, Healthy Adults

CONTEXTnThe exact relationship between the bed rest-induced loss of skeletal muscle and reductions in muscle strength and physical performance in the older individuals is still unclear.nnnOBJECTIVEnWe examined the effect of 10 days of bed rest on changes in regional body composition, muscle strength, and functional status, and the relationship between these variables in older individuals.nnnDESIGN, PARTICIPANTS, AND INTERVENTIONnRegional body composition was measured using dual energy x-ray absorptiometry. We also determined changes in leg strength and several indices of functional status, including walking speed.nnnRESULTSnBody weight, body mass index, and total and lower extremity lean mass decreased with bed rest. There were also significant reductions in knee extension one repetition maximum, isometric knee extension, knee extension 60° concentric, stair ascent time, stair ascent power, stair descent time, VO2 max, floor transfer test, 5-minute walk time, and chair stand. The overall change in total and lower extremity lean mass was also directly related to bed rest-induced reductions in one repetition maximum knee extension.nnnCONCLUSIONSnBed rest promoted overall declines in muscle mass, muscle strength, and physical function in older individuals. The changes in lean tissue were closely correlated with the bed rest-induced decline of muscle strength.

Influence of Exercise Intensity on Abdominal Fat and Adiponectin in Elderly Adults

To examine the influence of moderate-intensity (50% of VO(2peak)) exercise training (MI) versus high-intensity (75% of VO(2peak)) exercise training (HI) on regional fat distribution and plasma adiponectin, we randomized 18 overweight (body mass index [BMI] = 30 +/- 1 kg/m(2)) elderly (71 +/- 1 years) to HI, MI, or a control group (CON). Subjects enrolled in HI or MI completed a 12-week exercise training protocol designed to expend 1000 kcal/week. Body composition testing was completed prior to and following the exercise training using dual energy X-ray absorptiometry and a computed tomography scan. Plasma adiponectin was measured using enzymelinked immunoassay (ELISA). VO(2peak) improved in HI and MI, whereas there was no change in VO(2peak) in CON. No significant change in body weight, BMI, and % fat occurred in MI, HI, or CON. Although there was a significant reduction in visceral fat with HI (-39 cm(2)), there was no change in the MI or CON groups. In addition, there was a significant increase in thigh muscle attenuation in the HI group. There were no changes in thigh muscle attenuation in the MI and CON groups. Also, there was no change in plasma adiponectin in the MI, HI, or CON groups. In summary, our direct comparison of exercise intensity without weight loss promotes the efficacy of HI in the reduction in visceral fat, even without changes in adiponectin.

Adipose triglyceride lipase expression in human adipose tissue and muscle. Role in insulin resistance and response to training and pioglitazone

Adipose triglyceride lipase (ATGL) catalyzes the first step in adipocyte and muscle triglyceride hydrolysis, and comparative gene identification-58 (CGI-58) is an essential cofactor. We studied the expression of ATGL and CGI-58 in human adipose and muscle and examined correlations with markers of muscle fatty acid oxidation. Nondiabetic volunteers were studied. Subjects with impaired glucose tolerance were treated with pioglitazone or metformin for 10 weeks. Subjects with normal glucose tolerance underwent a 12-week training program. We examined changes in ATGL and CGI-58 with obesity and insulin resistance, and effects of exercise and pioglitazone. Adipose triglyceride lipase messenger RNA (mRNA) expression showed no correlation with either body mass index or insulin sensitivity index in either adipose or muscle. However, adipose ATGL protein levels were inversely correlated with body mass index (r = -0.64, P < .02) and positively correlated with insulin sensitivity index (r = 0.67, P < .02). In muscle, ATGL mRNA demonstrated a strong positive relationship with carnitine palmitoyltransferase I mRNA (r = 0.82, P < .0001) and the adiponectin receptors AdipoR1 mRNA (r = 0.71, P < .0001) and AdipoR2 mRNA (r = 0.74, P < .0001). Muscle CGI-58 mRNA was inversely correlated with intramyocellular triglyceride in both type 1 (r = -0.35, P < .05) and type 2 (r = -0.40, P < .05) fibers. Exercise training resulted in increased muscle ATGL, and pioglitazone increased adipose ATGL by 31% (P < .05). Pioglitazone also increased ATGL in adipocytes. Adipose ATGL protein is decreased with insulin resistance and obesity; and muscle ATGL mRNA is associated with markers of fatty acid oxidation in muscle, as is CGI-58. The regulation of ATGL and CGI-58 has important implications for the control of lipotoxicity.

Bed Rest Worsens Impairments in Fat and Glucose Metabolism in Older, Overweight Adults

BACKGROUNDnThe effects of bed rest on the dysregulation of fatty acid and glucose metabolism have not been addressed in the older population.nnnOBJECTIVEnWe examined the effect of 10 days of bed rest on fatty acid kinetics and hepatic and peripheral insulin resistance in aging.nnnMETHODSnWe utilized an octreotide, basal glucagon replacement, multistage insulin infusion, and the concomitant infusion of [6,6 (2)H₂]glucose to derive insulin-mediated suppression of glucose production and insulin-stimulated glucose disposal in nine older, overweight individuals (body mass index 28.1 ± 1.7 kg m(-2); 39.9% ± 1.9% fat). During the multistage insulin infusion, we also infused [1-(13)C]palmitate to examine free fatty acid rate of appearance (R(a)).nnnRESULTSnBody weight, % body fat, and energy metabolism did not change with bed rest. There was a significant decrease (-2291 ± 316 cm(3)) in visceral fat, and no change in abdominal subcutaneous fat with bed rest. Insulin-mediated suppression of glucose production was modest prior to bed rest and was further reduced (>15% ± 2%) by bed rest. There was also a minor decrease in the insulin-mediated suppression of free fatty acid R(a) after bed rest and, as a consequence, a small variation in plasma free fatty acid from pre- to post-bed rest in the first stage of the multistage insulin infusion. There was also a significant bed rest-induced decline (>2.0 ± 0.6 mg kg FFM(-1) min(-1)) in insulin-stimulated glucose disposal.nnnCONCLUSIONSnPreexisting impairments in insulin sensitivity are worsened by bed rest and seem linked to alterations in the regulation of free fatty acid in older, overweight individuals.

Visceral Fat and Adiponectin: Associations with Insulin Resistance Are Tissue-Specific in Women

Body fatness and its distribution are strongly and independently associated with peripheral insulin action. However, these associations are limited in their ability to predict the independent nature of hepatic and peripheral insulin resistance, especially in obese women. To define the relationships more precisely between regional fat distribution and adiponectin, and hepatic and peripheral insulin resistance, we studied 22 obese (43 +/- 0.1%) women who underwent a dual-energy X-ray absorptiometry scan and a computed tomography scan at the L4-L5 level. An octreotide (60 ng x kg(-1) x min(-1)), glucagon (0.65 ng x kg(-1) x min(-1)), and two-step insulin (0.25 mU x kg(-1) x min(-1) and 1.0 mU x kg(-1) x min(-1)) infusion was performed to quantify insulin-mediated suppression of hepatic glucose production (SGP) and insulin-stimulated glucose disposal (ISGD) in a simultaneous fashion. Hepatic glucose production (HGP) was measured using a primed, constant infusion of [6,6(2)H(2)] glucose. Mean plasma insulin increased from 5.6 +/- 0.1 microU/mL at baseline to 15.1 +/- 1.5 microU/mL in the first stage, and to 80.7 +/- 0.5 microU/mL in the second stage. Although there was no significant relationship between visceral adipose tissue (VAT) and basal HGP (r = 0.34, p = 0.117), there was a significant inverse correlation (r = -0.67, p = 0.003) between VAT and SGP. There was a significant correlation (r = 0.55, p = 0.008) between adiponectin and ISGD. In conclusion, these data support: (1) the inability of basal glucose metabolism to accurately reflect hepatic insulin resistance, (2) the deleterious role of VAT in the development of insulin resistance in the liver, and (3) provide additional support for the positive influence of adiponectin against peripheral insulin resistance in obese, postmenopausal women.

Acute lysine supplementation does not improve hepatic or peripheral insulin sensitivity in older, overweight individuals

ContextLysine supplementation may have a positive influence on the regulation of glucose metabolism but it has not been tested in the geriatric population. Objective: We evaluated the impact of acute lysine supplementation using three randomized experimental scenarios: 1) oral glucose alone (control), 2) oral glucose and low-dose lysine (2 grams), and oral glucose and high dose lysine (5 grams) lysine in 7 older (66u2009±u20091xa0years/age), overweight/obese (BMIu2009=u200928u2009±u20092xa0kg/m2) individuals.MethodsWe utilized a dual tracer technique (i.e., [6,6-2H2] glucose primed constant infusion and 1-[13C] glucose oral ingestion) during an oral glucose tolerance test (OGTT) to examine differences in hepatic and peripheral insulin sensitivity under all three scenarios.ResultsPost-absorptive plasma glucose and insulin concentrations were not different between the three trials. Similarly, the response of glucose and insulin concentrations during the oral glucose tolerance tests (OGTT) was similar in the three trials. The results of the Matsuda index (ISI/M) were also not different between the three trials. As an index of hepatic insulin sensitivity, there were no significant differences in the endogenous glucose rate of appearance (glucose Ra) for control, 2xa0g lysine and 5xa0g lysine (1.2u2009±u20090.1, 1.1u2009±u20090.1, 1.3u2009±u20090.1xa0mg•kg-1•min-1), respectively. With respect to peripheral insulin sensitivity, there were no significant differences in the glucose rate of disappearance (glucose Rd) for control, 2xa0g lysine and 5xa0g lysine (4.2u2009±u20090.1, 4.3u2009±u20090.2, and 4.5u2009±u20090.4xa0mg•kg-1•min-1), respectively.ConclusionsPrevious studies in younger participants have suggested that lysine may have a beneficial effect on glucose metabolism. However, acute lysine supplementation in the older population does not facilitate beneficial changes in glucose Ra or glucose Rd.

Aerobic exercise training versus the aetiology of insulin resistance.

Abstract Type 2 diabetes represents an epidemic disease that has become a widespread healthcare problem throughout the world. The prevalence of a sedentary lifestyle and excess caloric intake promotes the aetiology of insulin resistance that results in the development of the metabolic condition, Type 2 diabetes. Despite numerous investigations that have demonstrated the positive influence of aerobic exercise training on a reduction in the severity of insulin resistance, many of these exercise programmes yield benefits that are only short-lived and promote only modest reductions in the severity of the disease aetiology. Therefore, the efficacy of exercise training as a therapeutic intervention against the development of Type 2 diabetes rests on its ability to normalize insulin resistance in the liver and skeletal muscle using a progressive approach that combines the beneficial influences of exercise training and weight loss.