Short-term fasting lowers glucagon levels under euglycemic and hypoglycemic conditions in healthy humans.

Fasting is associated with increased susceptibility to hypoglycemia in people with type 1 diabetes, thereby making it a significant health risk. To date, the relationship between fasting and insulin-induced hypoglycemia has not been well characterized, so our objective was to determine whether insulin-independent factors, such as counterregulatory hormone responses, are adversely impacted by fasting in healthy control individuals. Counterregulatory responses to insulin-induced hypoglycemia were measured in 12 healthy people during 2 metabolic studies. During one study, participants ate breakfast and lunch, after which they underwent a 2-hour bout of insulin-induced hypoglycemia (FED). During the other study, participants remained fasted prior to hypoglycemia (FAST). As expected, hepatic glycogen concentrations were lower in FAST, and associated with diminished peak glucagon levels and reduced endogenous glucose production (EGP) during hypoglycemia. Accompanying lower EGP in FAST was a reduction in peripheral glucose utilization, and a resultant reduction in the amount of exogenous glucose required to maintain glycemia. These data suggest that whereas a fasting-induced lowering of glucose utilization could potentially delay the onset of insulin-induced hypoglycemia, subsequent reductions in glucagon levels and EGP are likely to encumber recovery from it. As a result of this diminished metabolic flexibility in response to fasting, susceptibility to hypoglycemia could be enhanced in patients with type 1 diabetes under similar conditions.

C-peptide enhances glucagon secretion in response to hyperinsulinemia under euglycemic and hypoglycemic conditions.

Several studies have associated the presence of residual insulin secretion capability (also referred to as being C-peptide positive) with lower risk of insulin-induced hypoglycemia in patients with type 1 diabetes (T1D), although the reason is unclear. We tested the hypothesis that C-peptide infusion would enhance glucagon secretion in response to hyperinsulinemia during euglycemic and hypoglycemic conditions in dogs (5 male/4 female). After a 2-hour basal period, an intravenous (IV) infusion of insulin was started, and dextrose was infused to maintain euglycemia for 2 hours. At the same time, an IV infusion of either saline (SAL) or C-peptide (CPEP) was started. After this euglycemic period, the insulin and SAL/CPEP infusions were continued for another 2 hours, but the glucose was allowed to fall to approximately 50 mg/dL. In response to euglycemic-hyperinsulinemia, glucagon secretion decreased in SAL but remained unchanged from the basal period in CPEP condition. During hypoglycemia, glucagon secretion in CPEP was 2 times higher than SAL, and this increased net hepatic glucose output and reduced the amount of exogenous glucose required to maintain glycemia. These data suggest that the presence of C-peptide during IV insulin infusion can preserve glucagon secretion during euglycemia and enhance it during hypoglycemia, which could explain why T1D patients with residual insulin secretion are less susceptible to hypoglycemia.

Liver glycogen-induced enhancements in hypoglycemic counterregulation require neuroglucopenia.

Iatrogenic hypoglycemia is a prominent barrier to achieving optimal glycemic control in patients with diabetes, in part due to dampened counterregulatory hormone responses. It has been demonstrated that elevated liver glycogen content can enhance these hormonal responses through signaling to the brain via afferent nerves, but the role that hypoglycemia in the brain plays in this liver glycogen effect remains unclear. During the first 4 h of each study, the liver glycogen content of dogs was increased by using an intraportal infusion of fructose to stimulate hepatic glucose uptake (HG; n = 13), or glycogen was maintained near fasting levels with a saline infusion (NG; n = 6). After a 2-h control period, during which the fructose/saline infusion was discontinued, insulin was infused intravenously for an additional 2 h to bring about systemic hypoglycemia in all animals, whereas brain euglycemia was maintained in a subset of the HG group by infusing glucose bilaterally into the carotid and vertebral arteries (HG-HeadEu; n = 7). Liver glycogen content was markedly elevated in the two HG groups (43 ± 4, 73 ± 3, and 75 ± 7 mg/g in NG, HG, and HG-HeadEu, respectively). During the hypoglycemic period, arterial plasma glucose levels were indistinguishable between groups (53 ± 2, 52 ± 1, and 51 ± 1 mg/dL, respectively), but jugular vein glucose levels were kept euglycemic (88 ± 5 mg/dL) only in the HG-HeadEu group. Glucagon and epinephrine responses to hypoglycemia were higher in HG compared with NG, whereas despite the increase in liver glycogen, neither increased above basal in HG-HeadEu. These data demonstrate that the enhanced counterregulatory hormone secretion that accompanies increased liver glycogen content requires hypoglycemia in the brain.NEW & NOTEWORTHY It is well known that iatrogenic hypoglycemia is a barrier to optimal glycemic regulation in patients with diabetes. Our data confirm that increasing liver glycogen content 75% above fasting levels enhances hormonal responses to insulin-induced hypoglycemia and demonstrate that this enhanced hormonal response does not occur in the absence of hypoglycemia in the brain. These data demonstrate that information from the liver regarding glycogen availability is integrated in the brain to optimize the counterregulatory response.

Exercise-Induced Improvements to Whole Body Glucose Metabolism in Type 2 Diabetes: The Essential Role of the Liver.

Type 2 diabetes (T2D) is a metabolic disease characterized by obesity, insulin resistance, and the dysfunction of several key glucoregulatory organs. Among these organs, impaired liver function is recognized as one of the earliest contributors to impaired whole-body glucose homeostasis, with well-characterized hepatic insulin resistance resulting in elevated rates of hepatic glucose production (HGP) and fasting hyperglycemia. One portion of this review will provide an overview of how HGP is regulated during the fasted state in healthy humans and how this process becomes dysregulated in patients with T2D. Less well-appreciated is the liver's role in post-prandial glucose metabolism, where it takes up and metabolizes one-third of orally ingested glucose. An abundance of literature has shown that the process of hepatic glucose uptake is impaired in patients with T2D, thereby contributing to glucose intolerance. A second portion of this review will outline how hepatic glucose uptake is regulated during the post-prandial state, and how it becomes dysfunctional in patients with T2D. Finally, it is well-known that exercise training has an insulin-sensitizing effect on the liver, which contributes to improved whole-body glucose metabolism in patients with T2D, thereby making it a cornerstone in the management of the disease. To this end, the impact of exercise on hepatic glucose metabolism will be thoroughly discussed, referencing key findings in the literature. At the same time, sources of heterogeneity that contribute to inconsistent findings in the field will be pointed out, as will important topics for future investigation.

Exercise and the metabolic syndrome with weight regain.

Weight loss improves metabolic syndrome (MetS) factors, but risk may return with weight regain. This study was designed to determine if exercise training can maintain improvements in MetS risk factors during weight regain. In a randomized control trial,102 overweight or obese (body mass index 25.0-39.9 kg/m(2)) men and women (age 21-52 yr), with characteristics of the MetS, lost 10% of body weight with supervised walking/jogging at 60% of maximal oxygen consumption (Vo(2 max)) (-400 kcal/session), 5 days/wk, and caloric restriction (-600 kcal/day) over a 4- to 6-mo period. After weight loss, 77 remaining subjects underwent programmed weight regain (+50% of lost weight) for 4-6 mo with random assignment to two groups: no exercise (NoEX) or continued supervised exercise (EX). Blood pressure, regional fat, glucose homeostasis, lipids, and inflammatory markers were assessed at baseline, post-weight loss, and post-weight regain. Groups were compared by two-way repeated-measures ANOVA on the 67 subjects. After weight loss (9.7 +/- 0.2% of body weight), significant (P < 0.05) improvements were observed in almost all parameters assessed. Following weight regain (54.4 +/- 1.6% of lost weight), the NoEX group exhibited deterioration in most metabolic markers, while the EX group maintained improvements in Vo(2 max), blood pressures, glucose homeostasis, high- and low-density lipoprotein cholesterol (HDL-C and LDL-C), oxidized LDL, and other markers of inflammation, but did not maintain improvements in triglyceride and cholesterol concentrations or abdominal fat. Results of this design of controlled human weight regain suggest that aerobic exercise can counter the detrimental effects of partial weight regain on many markers of disease risk.

The effects of resistance training on metabolic health with weight regain.

To determine whether resistance training effectively maintains improvements in cardiometabolic syndrome risk factors during weight regain, 9 individuals lost 4% to 6% of their body weight during an 8- to 12-week diet- and aerobic exercise-induced weight loss phase followed by a controlled weight regain phase (8-12 weeks), during which they regained approximately 50% of the lost weight while participating in a supervised resistance training program. Following weight loss (6.0%+/-0.3%), body mass index, body fat percentage, waist circumference, all abdominal adipose tissue depots, total cholesterol, low-density lipoprotein cholesterol, insulin, and homeostasis model assessment (HOMA) were significantly reduced, while quantitative insulin-sensitivity check index (QUICKI) and cardiorespiratory fitness (maximal oxygen consumption) significantly increased. During weight regain (48.3%+/-3.3% of lost weight), body fat percentage, waist circumference, and maximal oxygen consumption were maintained and muscular strength and lean body mass significantly increased. Abdominal adipose tissue depots, insulin, HOMA, and QUICKI did not significantly change after weight regain. Resistance training was effective in maintaining improvements in metabolic health during weight regain.

Predicting postprandial lipemia in healthy adults and in at-risk individuals with components of the cardiometabolic syndrome.

To determine whether a single-point triglyceride (TG) concentration could estimate the 8-hour postprandial lipemic (PPL) response, men and women performed baseline PPL (n=188) and postexercise PPL (n=92) trials. Correlations were generated between TG concentrations at baseline and at various time points after a high-fat meal vs 8-hour area under the TG curve (TG-AUC) and peak TG level. Stepwise multiple regression and bootstrap simulations using TG level and additional predictor variables of sex, age, percentage of body fat, training status, and maximal oxygen consumption indicated that the 4-hour TG concentrations accounted for >90% of the variance in TG-AUC and peak TG responses during the PPL trials. Equations were confirmed by cross-validation in healthy as well as at-risk individuals with components of the cardiometabolic syndrome. Our data suggest that the 4-hour TG value is highly related to the total 8-hour PPL response and can be used for accurate estimation of PPL in a clinical or research setting.

Changes in visceral adipose tissue mitochondrial content with type 2 diabetes and daily voluntary wheel running in OLETF rats.

Using the hyperphagic, obese, Otsuka Long-Evans Tokushima Fatty (OLETF) rat, we sought to determine if progression to type 2 diabetes alters visceral white adipose tissue (WAT) mitochondrial content and if these changes are modified through prevention of type 2 diabetes with daily exercise. At 4 weeks of age, OLETF rats began voluntary wheel running (OLETF-EX) while additional OLETF rats (OLETF-SED) and Long-Evans Tokushima Otsuka (LETO-SED) rats served as obese and lean sedentary controls, respectively, for 13, 20 and 40 weeks of age (n = 6-8 for each group at each age). OLETF-SED animals displayed insulin resistance at 13 and 20 weeks and type 2 diabetes by 40 weeks. OLETF-SED animals gained significantly (P < 0.001) more weight and omental fat mass compared with OLETF-EX and LETO-SED. Markers of WAT mitochondrial protein content (cytochrome c, COXIV-subunit I, and citrate synthase activity) significantly increased (P < 0.05) from 13 to 40 weeks in the LETO-SED, but were significantly attenuated in the OLETF-SED rats. Daily exercise normalized WAT cytochrome c and COXIV-subunit I protein content in the OLETF-EX to the healthy LETO-SED animals. In conclusion, increases in omental WAT mitochondrial content between 20 and 40 weeks of age in LETO control animals are attenuated in the hyperphagic, obese OLETF rat. These alterations occurred in conjunction with the progression from insulin resistance to type 2 diabetes and were prevented with daily exercise. Reduced ability to increase WAT mitochondrial content does not appear to be a primary cause of insulin resistance, but may play a key role in the worsening of the disease condition.

Exercise and diet induced weight loss improves measures of oxidative stress and insulin sensitivity in adults with characteristics of the metabolic syndrome.

Obesity and insulin resistance (IR) increase the risk for coronary heart disease; however, much of this risk is not attributable to traditional risk factors. We sought to determine whether weight loss associated with supervised aerobic exercise beneficially alters biomarkers of oxidative stress and whether these alterations are associated with improvements in measures of insulin resistance. Twenty-five sedentary and overweight to obese [body mass index (BMI) = 33.0 +/- 0.8 kg/m(2)] individuals, with characteristics of the metabolic syndrome, participated in a 4- to 7-mo weight loss program that consisted of energy restriction (reduced by approximately 500 kcal/day) and supervised aerobic exercise (5 days/wk, 45 min/day at 60% Vo(2 max); approximately 375 kcal/day). IR and insulin sensitivity were assessed by the calculation of the homeostasis model assessment (HOMA) and quantitative insulin sensitivity check index (QUICKI), respectively. Oxidative stress was assessed by oxidized LDL (oxLDL), myeloperoxidase (MPO), and low- and high- density lipoprotein (LDL and HDL) lipid hydroperoxide concentrations in serum. Indexes for antioxidative status included apolipoprotein A1 (apoA1) concentrations and paraoxonase-1 (PON1) activity and protein concentrations. Exercise- and diet-induced weight loss ( approximately 10%) significantly (P < 0.05) increased insulin sensitivity and reduced IR, oxLDL, and LDL lipid hydroperoxides but did not alter HDL lipid hydroperoxides or MPO concentrations. Lifestyle modification impacted systemic antioxidative status by increasing apoA1 concentrations and reducing serum PON1 protein and activity. Changes in oxidative stress were not associated with alterations in HOMA or QUICKI. Diet- and exercise-induced weight loss ( approximately 10%) improves measures of insulin sensitivity and beneficially alters biomarkers of oxidative status.