Effects of Insulin on Brain Glucose Metabolism

In This Article

Abstract and Introduction

Abstract

Objective—Insulin stimulates brain glucose metabolism, but this effect of insulin is already maximal at fasting concentrations in healthy subjects. It is not known whether insulin is able to stimulate glucose metabolism above fasting concentrations in patients with impaired glucose tolerance.
Research Design And Methods—We studied the effects of insulin on brain glucose metabolism and cerebral blood flow in 13 patients with impaired glucose tolerance and nine healthy subjects using positron emission tomography (PET). All subjects underwent PET with both [¹⁸F]fluorodeoxyglucose (for brain glucose metabolism) and [¹⁵O]H₂O (for cerebral blood flow) in two separate conditions (in the fasting state and during a euglycemic-hyperinsulinemic clamp). Arterial blood samples were acquired during the PET scans to allow fully quantitative modeling.
Results—The hyperinsulinemic clamp increased brain glucose metabolism only in patients with impaired glucose tolerance (whole brain: +18%, P = 0.001) but not in healthy subjects (whole brain: +3.9%, P = 0.373). The hyperinsulinemic clamp did not alter cerebral blood flow in either group.
Conclusions—We found that insulin stimulates brain glucose metabolism at physiological postprandial levels in patients with impaired glucose tolerance but not in healthy subjects. These results suggest that insulin stimulation of brain glucose metabolism is maximal at fasting concentrations in healthy subjects but not in patients with impaired glucose tolerance.

Introduction

Peripheral insulin resistance is a hallmark of metabolic syndrome and type 2 diabetes, but it is unclear if the brain also shows insulin resistance. Peripheral insulin crosses the blood-brain barrier via an active transport mechanism and binds to insulin receptors on neurons and glial cells. Insulin has a catabolic effect; in addition, it influences memory functions by modulating neurotransmitter release and synaptic plasticity.^[1–4] Therefore, determining whether insulin resistance also occurs in the brain in metabolic syndrome is important.^[5] Obese individuals have a decreased cerebrospinal fluid–to–plasma insulin ratio,^[6] diminished catabolic responses to intranasal insulin,^[7] and decreased cortical brain activity after insulin,^[8] suggesting brain insulin resistance.^[1,5] However, these indirect studies do not establish the relationship between insulin and brain glucose metabolism, which is important given the role of the brain in glucose sensing.^[9]

Direct evidence on the effects of insulin on the brain may be obtained with positron emission tomography (PET) and ¹⁸F-labeled fluorodeoxyglucose ([¹⁸F]FDG). Studies in healthy subjects have shown that brain glucose metabolism does not increase after increasing plasma insulin concentrations above physiological fasting levels^[10,11] but decreases after decreasing plasma insulin concentration below physiological fasting levels,^[12,13] suggesting that the insulin effect is already saturated at fasting concentrations in healthy subjects. In contrast, Anthony et al.^[12] recently demonstrated that reducing plasma insulin does not reduce brain glucose metabolism in patients with impaired glucose tolerance. However, it is not known whether insulin stimulates brain glucose metabolism above fasting levels in these patients or whether this effect is already saturated at fasting levels, as in healthy subjects.^[12,13]

To characterize the dose-response relationship of plasma insulin and brain glucose metabolism in patients with impaired glucose tolerance, we used [¹⁸F]FDG PET to measure brain glucose metabolism in two conditions (in the fasting state and during a euglycemic-hyperinsulinemic clamp) in both healthy subjects and patients with impaired glucose tolerance. [¹⁸F]FDG is a glucose analog that is taken up in the brain and trapped after phosphorylation; thus, the measured signal approximates uptake of glucose. The euglycemic-hyperinsulinemic clamp allows close monitoring and adjustment of plasma glucose while inducing a constant insulin stimulation. In a subset of subjects, we also measured the effects of insulin on cerebral blood flow with [¹⁵O]H₂O PET.

Cite this: Effects of Insulin on Brain Glucose Metabolism in Impaired Glucose Tolerance - Medscape - Feb 02, 2011.

Table 1. Demographic and metabolic characteristics of the study groups
Characteristics	Healthy subjects	Impaired glucose tolerance	P
n	9	13
Baseline data
Sex (female/male)	4/5	8/5	0.6
Age (years)	38 ± 12	49 ± 8	0.04
Weight (kg)	75 ± 10	112 ± 20	<0.001
BMI (kg/m²)	24 ± 2	38 ± 8	<0.001
Fat (bioimpedance) (%)	28 ± 4	44 ± 9	<0.001
Waist circumference (cm)	85 ± 10	119 ± 14	<0.001
Fasting plasma glucose (mmol/L)	5.3 ± 0.5	5.9 ± 0.5	0.01
2-h oral glucose tolerance test (plasma glucose) (mmol/L)	5.1 ± 1.0	8.6 ± 1.0	<0.001
During PET: fasting state
Plasma glucose (mmol/L)	5.4 ± 0.4	5.8 ± 0.6	0.06
Serum insulin (mU/L)	4 ± 3	11 ± 4	<0.001
During PET: hyperinsulinemia
Plasma glucose (mmol/L)	5.1 ± 0.3	4.8 ± 0.8	0.2
Serum insulin (steady state) (mU/L)	58 ± 5	73 ± 19	0.02
Whole-body glucose uptake (M value) (μmol · kg⁻¹ · min⁻¹)	30.3 ± 6.0	11.9 ± 4.2	<0.001

Data are means ± SD.

Table 2. Regional brain glucose metabolism values in the fasting and clamp conditions in healthy subjects and in patients with impairedglucose tolerance
Region	Healthy subjects (n = 9)				Impaired glucose tolerance (n = 13)				Group × condition interaction P
	Brain glucose metabolism (μmol · 100 g⁻¹ · min⁻¹)		Change		Brain glucose metabolism (μmol · 100 g⁻¹ · min⁻¹)		Change
	Fast	Clamp	%	P	Fast	Clamp	%	P
FRO	15.9 ± 1.2	16.4 ± 1.5	3.3	0.506	15.8 ± 2.1	18.6 ± 2.5	18.0	<0.001	0.009
LTEMP	16.5 ± 1.2	17.2 ± 1.7	4.2	0.364	16.0 ± 1.8	18.8 ± 2.2	18.2	<0.001	0.010
PAR	14.0 ± 0.8	14.6 ± 1.6	4.5	0.283	14.7 ± 1.9	17.2 ± 2.5	17.7	<0.001	0.009
OCC	16.7 ± 0.9	17.6 ± 2.2	5.5	0.231	17.8 ± 2.2	20.7 ± 2.9	17.1	<0.001	0.015
MTEMP	12.8 ± 0.6	12.9 ± 1.1	1.2	0.778	13.0 ± 1.6	15.3 ± 1.9	18.3	<0.001	0.003
INS	17.5 ± 1.2	17.7 ± 1.7	1.6	0.777	16.3 ± 1.9	19.0 ± 2.0	17.5	<0.001	0.003
STR	16.9 ± 0.9	17.5 ± 1.6	3.8	0.340	16.2 ± 2.3	19.2 ± 2.2	20.2	<0.001	0.013
CER	10.6 ± 1.2	10.9 ± 1.5	3.4	0.529	10.7 ± 1.9	12.2 ± 2.0	16.5	0.035	0.150
THA	16.4 ± 1.6	17.1 ± 2.3	5.0	0.327	16.2 ± 2.9	19.5 ± 2.6	22.9	<0.001	0.020

P values are from paired samples t tests except for the last column, where P values are from the group × condition interaction in repeated-measures ANOVA. P values denoting statistical significance (P < 0.05) appear in boldface. CER, cerebellum; FRO, frontal cortex; INS, insula; LTEMP, lateral temporal cortex; MTEMP, mesialtemporal cortex; OCC, occipital cortex; PAR, parietal cortex; STR, striatum; THA, thalamus.

Commenting is limited to medical professionals. To comment please Log-in.

Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.

My Alerts