Striatal dopamine regulates systemic glucose metabolism in humans and mice.

The brain is emerging as an important regulator of systemic glucose metabolism. Accumulating data from animal and observational human studies suggest that striatal dopamine signaling plays a role in glucose regulation, but direct evidence in humans is currently lacking. We present a series of experiments supporting the regulation of peripheral glucose metabolism by striatal dopamine signaling. First, we present the case of a diabetes patient who displayed strongly reduced insulin requirements after treatment with bilateral deep brain stimulation (DBS) targeting the anterior limb of the internal capsule. Next, we show that DBS in this striatal area, which induced dopamine release, increased hepatic and peripheral insulin sensitivity in 14 nondiabetic patients with obsessive-compulsive disorder. Conversely, systemic dopamine depletion reduced peripheral insulin sensitivity in healthy subjects. Supporting these human data, we demonstrate that optogenetic activation of dopamine D1 receptor-expressing neurons in the nucleus accumbens increased glucose tolerance and insulin sensitivity in mice. Together, these findings support the hypothesis that striatal neuronal activity regulates systemic glucose metabolism.

Subthalamic nucleus stimulation does not influence basal glucose metabolism or insulin sensitivity in patients with Parkinson's disease.

Animal studies have shown that central dopamine signaling influences glucose metabolism. As a first step to show this association in an experimental setting in humans, we studied whether deep brain stimulation (DBS) of the subthalamic nucleus (STN), which modulates the basal ganglia circuitry, alters basal endogenous glucose production (EGP) or insulin sensitivity in patients with Parkinson's disease (PD). We studied 8 patients with PD treated with DBS STN, in the basal state and during a hyperinsulinemic euglycemic clamp using a stable glucose isotope, in the stimulated and non-stimulated condition. We measured EGP, hepatic insulin sensitivity, peripheral insulin sensitivity (Rd), resting energy expenditure (REE), glucoregulatory hormones, and Parkinson symptoms, using the Unified Parkinson's Disease Rating Scale (UPDRS). Basal plasma glucose and EGP did not differ between the stimulated and non-stimulated condition. Hepatic insulin sensitivity was similar in both conditions and there were no significant differences in Rd and plasma glucoregulatory hormones between DBS on and DBS off. UPDRS was significantly higher in the non-stimulated condition. DBS of the STN in patients with PD does not influence basal EGP or insulin sensitivity. These results suggest that acute modulation of the motor basal ganglia circuitry does not affect glucose metabolism in humans.

Effects of a hypercaloric diet on ß-cell responsivity in lean healthy men.

OBJECTIVE: Insulin resistance and hyperinsulinaemia precede the onset of obesity-induced DM2. The early adaptation of the ß-cell during the initial phase of overfeeding and weight gain has only been partly elucidated. We studied the early changes in insulin clearance and ß-cell responsivity during a positive and negative energy balance in lean healthy men. DESIGN: We studied in nine healthy lean men [age, 37 (27-43) years; BMI, 23·6 (20·6-25·6) kg/m(2) ] insulin sensitivity, insulin clearance, insulin secretion and static and dynamic ß-cell responsivity at baseline and after the hypercaloric and subsequent hypocaloric diet. RESULTS: Participants gained 7 [5·1-7·6]% of their initial body weight on the hypercaloric diet. Compared to baseline, insulin sensitivity and insulin clearance decreased, while glucose-stimulated insulin secretion was higher. The GLP-1 response to oral glucose did not change. The dynamic ß-cell responsivity index increased but the basal and static responsivity indexes did not change. Total and static disposition indexes (DIs) in the hypercaloric state showed a trend towards a decrease. During the hypocaloric diet, insulin sensitivity, glucose-stimulated insulin secretion and insulin clearance returned to baseline. The responsivity and the DIs were not different in the hypocaloric phase compared to baseline. CONCLUSION: A positive energy balance resulting in weight gain in lean men induces hyperinsulinaemia, which is explained by a combined effect on insulin clearance and insulin secretion. Increased insulin secretion was related to insulin resistance-induced higher glucose concentrations but also to increased dynamic ß-cell responsivity. Glucose sensitivity of the ß-cell did not change. These early adaptations are completely reversible during a negative energy balance after loss of the gained weight.

Short-term increase of plasma free fatty acids does not interfere with intrinsic mitochondrial function in healthy young men.

Free fatty acid (FFA)- and obesity-induced insulin resistance has been associated with disturbed mitochondrial function. Elevated plasma FFA can impair insulin-induced increase of adenosine triphosphate synthesis and downregulate the expression of genes important in the biogenesis of mitochondria in human skeletal muscle. Whether FAs have a direct effect on intrinsic mitochondrial capacity remains to be established. Therefore, we measured ex vivo mitochondrial respiratory capacity in human skeletal muscle after exposure to hyperinsulinemia and high levels of plasma FFA. Nine healthy lean men were studied during a 6-hour hyperinsulinemic (600 pmol/L) euglycemic clamp with concomitant infusion of Intralipid (Fresensius Kabi Nederland, Den Bosch, the Netherlands) (FFA clamped at 0.5 mmol/L) or saline. Mitochondrial respiratory capacity was measured by high-resolution respirometry in permeabilized muscle fibers using an Oxygraph (OROBOROS Instruments, Innsbruck, Austria). Each participant served as his own control. Peripheral glucose uptake (rate of disappearance) was significantly lower during infusion of the lipid emulsion compared with the control saline infusion (68 µmol/kg·min [saline] vs 40 µmol/kg·min [lipid], P = .008). However, adenosine diphosphate-stimulated and maximal carbonylcyanide-4-(trifluoromethoxy)-phenylhydrazone-stimulated uncoupled respiration rates were not different in permeabilized skeletal muscle fibers after exposure to high levels of FFA compared with the control condition. We conclude that short-term elevation of FFA within the physiological range induces insulin resistance but does not affect intrinsic mitochondrial capacity in skeletal muscle in humans.

Intermittent fasting does not affect whole-body glucose, lipid, or protein metabolism.

BACKGROUND: Intermittent fasting (IF) was shown to increase whole-body insulin sensitivity, but it is uncertain whether IF selectively influences intermediary metabolism. Such selectivity might be advantageous when adapting to periods of food abundance and food shortage. OBJECTIVE: The objective was to assess effects of IF on intermediary metabolism and energy expenditure. DESIGN: Glucose, glycerol, and valine fluxes were measured after 2 wk of IF and a standard diet (SD) in 8 lean healthy volunteers in a crossover design, in the basal state and during a 2-step hyperinsulinemic euglycemic clamp, with assessment of energy expenditure and phosphorylation of muscle protein kinase B (AKT), glycogen synthase kinase (GSK), and mammalian target of rapamycine (mTOR). We hypothesized that IF selectively increases peripheral glucose uptake and lowers proteolysis, thereby protecting protein stores. RESULTS: No differences in body weight were observed between the IF and SD groups. Peripheral glucose uptake and hepatic insulin sensitivity during the clamp did not significantly differ between the IF and SD groups. Likewise, lipolysis and proteolysis were not different between the IF and SD groups. IF decreased resting energy expenditure. IF had no effect on the phosphorylation of AKT but significantly increased the phosphorylation of glycogen synthase kinase. Phosphorylation of mTOR was significantly lower after IF than after the SD. CONCLUSIONS: IF does not affect whole-body glucose, lipid, or protein metabolism in healthy lean men despite changes in muscle phosphorylation of GSK and mTOR. The decrease in resting energy expenditure after IF indicates the possibility of an increase in weight during IF when caloric intake is not adjusted. This study was registered at www.trialregister.nl as NTR1841.