Physiology of

Glucose Homeostasis
and Insulin Therapy
i n Typ e 1 a nd Typ e 2
Diabetes
Ele Ferrannini, MD

KEYWORDS
 Type 2 diabetes  Type 1 diabetes  Glucose homeostasis
 Insulin therapy

Glucose homeostasis is the maintenance of plasma glucose concentrations within

a very narrow band under most circumstances. In normal subjects, plasma glucose
oscillations rarely exceed 3 mmol/L (54 mg/dL), whereas lipid substrates, for example,
free fatty acids (FFA), can range up to 20-fold between a prolonged fast and the
postcibal period. A tightly homeostatic variable, such as eg, tissue perfusion pressure,
requires a multiple, redundant set of controls, and a coordinated deployment of
primary and subsidiary mechanisms. In the hierarchy, insulin is by far the chief regu-
lating element of plasma glucose in both the short and long time frames. Several other
factors play a secondary role, glucagon being next in charge.
A preliminary consideration is the unique organization of the insulin/glucagon
system. For many protein and nonprotein hormones, action is modulated by at least
1, and often 2, hierarchical hormonal feedback pathways (eg, corticotropin-
releasing hormone and corticotropin for cortisol, gonadotropin-releasing hormone
and gonadotropins for sex steroids). In these cases sensitivity is provided by the circu-
lating hormone concentrations, which act on specific receptors located on target
tissues as well as on the master gland of the feedback loop (eg, the pituitary). In the
case of insulin and glucagon, there is no pituitary or hypothalamic relay; target tissues
control secretion directly. Thus, the circulating concentrations of substrates (mostly
glucose but also amino acids, FFA, and ketone bodies), which result from insulin
action on intermediary metabolism in different tissues, feed signals back to the
b-cell and the a-cell. Sensitivity gating is provided by insulin and glucagon receptors
on target tissues.

The author has nothing to disclose.

Department of Internal Medicine, University of Pisa School of Medicine, Via Roma 67, 56100
Pisa, Italy
E-mail address: ferranni@ifc.cnr.it

Endocrinol Metab Clin N Am 41 (2012) 25–39

doi:10.1016/j.ecl.2012.01.003 endo.theclinics.com
0889-8529/12/$ – see front matter Ó 2012 Elsevier Inc. All rights reserved.
26 Ferrannini

An additional level of regulation is autocrine/paracrine in nature, that is, insulin

receptors on the b-cell and a-cell, respectively. b-Cells are richly endowed with insulin
receptors and their intracellular signaling machinery. Historically, insulin has been
thought to exert a negative feedback on b-cells. However, more recent in vitro and
animal data provide evidence for a positive role of insulin in transcription, translation,
ion flux, insulin secretion, proliferation, and b-cell survival (see Ref.1 for a comprehen-
sive review). In healthy nondiabetic subjects, both insulin exposure and insulin sensi-
tivity modulate the b-cell secretory response under normoglycemic conditions.2 Thus,
a higher degree of preinsulinization and better insulin sensitivity translate into a stimu-
latory action of insulin on its own secretion, whereas insulin resistance and antecedent
relative hypoinsulinemia determine an inhibitory effect of insulin on b-cell secretion.
Likewise, under hyperglycemic conditions a higher degree of antecedent insulin expo-
sure causes a higher endogenous insulin response to glucose stimulation.3 a-Cells
also carry insulin receptors, which transduce an inhibitory action of insulin on glucagon
release.4 This response too is modulated by insulin sensitivity, as fasting glucagon
levels are inversely related to insulin sensitivity independently of other factors.5

GLUCOSE HOMEOSTASIS: THE FASTING STATE

Glucose control can be simplified to an input-output problem (Fig. 1). At any given
time, the glucose concentration in the glucose space (which averages 250 mL/kg of
body weight, of which 70 mL/kg is the intravascular space) represents the balance

Fig. 1. Diagram of the primary hormonal control of plasma glucose concentrations orga-
nized as an input-output system centered on plasma glucose level. (1) stimulation; ( ) inhi-
bition. GLP-1, glucagon-like peptide 1.
 Glucose Homeostasis and Insulin Therapy 27

between entry of glucose into, and exit from, the circulation via cellular metabolism or
excretion: excessive release or defective removal (or combinations of the two) will
result in rising glucose levels. After an overnight fast (or in interprandial states), the liver
contributes greater than 90% of endogenous glucose release (the remainder being
released by the kidney), derived in equal parts from breakdown of glycogen and de
novo glucose synthesis from 3-carbon precursors.6 An endogenous glucose input
of 11 mmol/min/kg (extrapolating to 1.1 mmol [5 200 g] per day in a 70-kg adult) main-
tains a fasting plasma concentration of approximately 5 mmol/L (90 mg/dL) in the
glucose space as the same amount of glucose is disposed of by all body tissues.
Glucose output is directly related to fat-free mass (FFM), that is, to the mass of
metabolically active tissues, indicating that the metabolic need is the main factor
driving hepatic glucose release.7 Independently of FFM, glucose output is also directly
related to fasting plasma glucose concentrations even within the nondiabetic range
(ie, 4–7 mmol/L) (Fig. 2).
The dominant hormonal control of the fasting rate of glucose release is the insulin/
glucagon ratio in the prehepatic venous plasma, with insulin inhibiting, and glucagon
stimulating, both glycogenolysis and gluconeogenesis (see Fig. 1).8–11 Eighty percent
of the blood supply to the liver comes from the portal vein, which carries pancreatic
endocrine secretions, while 20% flows from the hepatic artery. Because of this double
vascular connection, in parallel to the left heart and in series with the endocrine
pancreas, the liver is exposed to higher hormone concentrations than are peripheral
tissues.12 Fasting insulin secretion rates can be calculated from fasting C-peptide
concentrations using the deconvolution method.13 In nondiabetic subjects (with
a body mass index [BMI] from lean to very obese), fasting insulin secretion ranges
from 50 to 120 pmol/min/m2; extrapolated over 24 hours, basal insulin output ranges
from 0.35 to 0.56 U/kg per day. The corresponding fasting plasma insulin concentra-
tions also are progressively higher as a function of the degree of obesity (Fig. 3).
Assuming a portal plasma flow of 12 L/min/kg, prehepatic insulin concentrations

Fig. 2. Simultaneous dependence of fasting endogenous glucose output on fat-free mass

and fasting plasma glucose concentrations. The P values refer to the significance of the
partial correlation coefficients of the lines of best fit (blue lines) and their 95% confidence
intervals (dotted red lines) from a general linear regression model also adjusting for sex,
age, and body mass index. Data (Ferrannini E, unpublished data, 2012) from 330 nondiabetic
subjects in the RISC study. (Data from Ferrannini E, Balkau B, Coppack SW, et al. RISC Inves-
tigators. Insulin resistance, insulin response, and obesity as indicators of metabolic risk. J Clin
Endocrinol Metab 2007;92:2885–92.)
28 Ferrannini

Fig. 3. Basal (fasting) insulin release (extrapolated to 24 hours) (blue symbols) and fasting
plasma insulin concentrations (red symbols) by body mass index (BMI). Data (Ferrannini E,
unpublished data, 2012) from 1151 nondiabetic subjects from the RISC Study. Plots are
mean  SD. (Data from Ferrannini E, Balkau B, Coppack SW, et al. RISC Investigators. Insulin
resistance, insulin response, and obesity as indicators of metabolic risk. J Clin Endocrinol
Metab 2007;92:2885–92.)

can be estimated from the insulin secretion rate and the relative contribution of hepatic
arterial flow. As shown in Fig. 4, in nondiabetic subjects prehepatic insulin levels are 2-
to 4-fold higher than peripheral insulin concentrations. This portosystemic gradient is
due to insulin being abundantly degraded by the liver, for the most part by receptor-
mediated processes; because its first-pass extraction exceeds 50%, in normal
subjects approximately 80% of the hormone is eventually metabolized in liver tissues,
the remainder being degraded by the kidney.14

Fig. 4. Linear relationship between estimated fasting prehepatic and peripheral plasma
insulin concentrations in the nondiabetic subjects in Fig. 3. The r and P values refer to the
significance of the line of best fit (red line). Data (Ferrannini E, unpublished data, 2012)
from 1151 nondiabetic subjects from the RISC Study. (Data from Ferrannini E, Balkau B,
Coppack SW, et al. RISC Investigators. Insulin resistance, insulin response, and obesity as
indicators of metabolic risk. J Clin Endocrinol Metab 2007;92:2885–92.)
 Glucose Homeostasis and Insulin Therapy 29

In contrast to insulin, glucagon is minimally, if at all, degraded by hepatocytes (most

of its catabolism taking place in the kidney); therefore, the portosystemic glucagon
gradient is roughly equal to the ratio of portal blood flow to cardiac output.15 In the
nondiabetic cohort in Fig. 4, the prehepatic insulin/glucagon ratio has a median value
of 5 ng/ng (or a molar ratio of 3). As expected, the higher this ratio, the lower the rate of
fasting glucose release (Fig. 5). The fact that this relationship is somewhat weak even
in a relatively large group of subjects certainly depends on the variability of the
measures and the uncertainty of the estimates, but may also signal the involvement
of additional control mechanisms (such as portal glucose sensing16 and brain insulin
action17).
An empiric index of hepatic insulin resistance can be constructed by multiplying
fasting endogenous glucose output by the estimated fasting prehepatic insulin
concentration.18 In lean individuals with normal glucose tolerance, this index has
a median value of 1760 mmol/min/kgFFM/pM (with an interquartile range of 1200–
2300), gradually increasing in obese or otherwise insulin-resistant subjects. In fact,
hepatic insulin resistance is generally coherent with peripheral insulin resistance (as
measured by a euglycemic hyperinsulinemic clamp) throughout the range of these
variables seen in humans (Fig. 6).
Fasting glucose disposal occurs in both insulin-dependent (skeletal muscle,
adipose tissue, myocardium) and insulin-independent tissues; among the latter, the
brain, an obligate glucose consumer, alone accounts for half the amount of hepatic
glucose output. Of note is that in all body tissues, glucose uptake, whether insulin
sensitive or not, also occurs by mass action, that is, in proportion to the glucose
concentration itself.19
In practical terms, the physiologic organization of the insulin system is such that if
fasting insulin secretion were totally absent (as in C-peptide–negative type 1 diabetes),
one would have to infuse between 0.35 and 0.56 U/kg per day intraportally to repro-
duce the peripheral fasting plasma insulin concentrations observed in nondiabetic
subjects over a wide BMI range. By contrast, if the same peripheral plasma insulin
levels were to be maintained by peripheral insulin administration, the insulin infusion

Fig. 5. Power function linking fasting endogenous glucose output and the estimated prehe-
patic insulin-to-glucagon ratio in the nondiabetic subjects in Fig. 2. The P value refers to the
significance of the partial correlation coefficient of the line of best fit (blue line) and its 95%
confidence intervals (dotted red lines) from a general linear regression model also adjusting
for sex, age, and body mass index. Note the log transformation of both axes.
30 Ferrannini

Fig. 6. Reciprocal relationship between the liver Insulin Resistance (IR) index (calculated as
the product of fasting endogenous glucose output and estimated prehepatic plasma insulin
concentration) and whole-body insulin sensitivity (M/I, calculated as the M value from the
euglycemic insulin clamp normalized by the steady-state plasma insulin concentrations
during the clamp) in the nondiabetic subjects in Fig. 2. The r and P values refer to the signif-
icance of the partial correlation coefficient of the line of best fit (red line) and its 95% confi-
dence intervals (dotted red lines) from a general linear regression model also adjusting for
sex, age, and body mass index. Note the log transformation of both axes.

rate would have to range between 0.08 and 0.11 U/kg per day. In the latter case,
however, peripheral tissues would be normally insulinized, whereas the liver would
be exposed to hypoinsulinemia; hepatic glucose output would be insufficiently
restrained by insulin, thereby contributing to hyperglycemia. Conversely, adequate
insulinization of the liver by peripheral insulin administration would create peripheral
hyperinsulinemia, with the attendant risk of hypoglycemia. The difficulty in achieving
and maintaining normoglycemia in insulin-treated type 1 diabetes largely originates
from the obligate peripheral route of insulin administration. Because of erratic absorp-
tion and bioavailability, delivery of oral insulin is not feasible at present.
In summary, short-term control of glucose homeostasis in the fasting or interpran-
dial state is delegated mostly to the liver, with a marginal contribution of peripheral
tissues, in which glucose uptake is either independent of insulin or only slightly stim-
ulated by fasting insulin levels. It is nevertheless important to consider that in the
longer term the setpoint of fasting glucose release is dictated by the tissue metabolic
requirements (see the strong relation of fasting glucose output to FFM in Fig. 2).7 This
fact implies that signals expressing the energy status of bodily tissues reach the liver
and modulate its delivery of glucose to the periphery. Although the nature of these
signals is incompletely understood, it is clear that glucose occupies a dominant posi-
tion among energy-rich substrates in metabolic control.
The pharmacokinetics of insulin outlined here do not readily translate into an insulin
effect because of the different dose-response relationships of insulin action on the
liver (inhibition of glucose release) and peripheral tissues (enhancement of glucose
disposal), and the sizeable activation and deactivation times of the hormone. In
fact, the dose-response curve for hepatic insulin action is shifted to the left relative
to the dose-response curve of peripheral insulin action (Fig. 7).19 Thus, the half-
maximal portal insulin concentration for glucose output is approximately 300 pmol/L
(w50 mU/mL), whereas the half-maximal peripheral insulin concentration for glucose
 Glucose Homeostasis and Insulin Therapy 31

Fig. 7. Dose-response curves for the effect of insulin on fasting endogenous glucose output
(red line) and clamp-derived whole-body glucose disposal (blue line) in normal individuals.
The plasma insulin concentrations on the horizontal axis are peripheral insulin levels for
glucose disposal and estimated prehepatic plasma insulin concentrations for glucose output.
The dashed vertical lines plot to the respective half-maximal plasma insulin concentrations
of glucose output and disposal. (Data from DeFronzo RA, Ferrannini E, Hendler R, et al.
Regulation of splanchnic and peripheral glucose uptake by insulin and hyperglycemia in
man. Diabetes 1983;32:35–45.)

disposal is approximately 860 pmol/L (w150 mU/mL), 3 times higher. For example, at
plasma insulin levels at which glucose output is halved, peripheral glucose disposal is
hardly enhanced at all. As a consequence, dose and route of delivery determine which
tissues, in what order, will respond to insulin. In addition, the activation times of insulin
action are much shorter for liver than for peripheral tissues, both being inversely
related to the insulin dose (Fig. 8).20 Significantly longer activation times at the
level of both liver and peripheral tissues characterize insulin action in obese,
insulin-resistant subjects. Conversely, deactivation times are longer for liver than for
peripheral tissues, and progressively longer with increasing insulin dose. Moreover,
deactivation is faster in obese, insulin-resistant subjects than in lean individuals.
Thus, progressively higher levels of insulin engage the intracellular glucose effector
pathway more rapidly than do lower levels, particularly in the liver and peripheral
tissues, but action persists longer at both sites. These pharmacodynamic character-
istics account for the clinical observations of a delay in insulin action when levels are
raised (by stimulation of b-cell release or exogenous administration) and the pro-
tracted hypoglycemic action when secretion is turned off (or exogenous administra-
tion stopped). Such characteristics also highlight the role of the liver in whole-body
insulin action, and predict that a strong insulinization enhances the risk of prolonged
hypoglycemia, predominantly on account of a protracted inability of the liver to
respond to falling glucose levels. In insulin-resistant individuals, activation is delayed
and liver deactivation is anticipated; thus not only do insulin-resistant subjects need
more insulin than do insulin-sensitive subjects to attain a given glucose-lowering
effect, but the effect itself is manifested in a time pattern that suggests reduced
efficacy.

THE FASTING STATE IN DIABETES

In patients with type 2 diabetes, fasting insulin secretion rates are generally normal or
higher, because of the persistent stimulus of fasting hyperglycemia, and glucose
32 Ferrannini

Fig. 8. Half-maximum times of activation (top panels) and deactivation (bottom panels) for
glucose disposal and glucose output as a function of exogenous insulin infusion rates during
euglycemic clamps in lean subjects (blue lines) and obese subjects (red lines). Data are mean
 SEM. (Data from Prager R, Wallace P, Olefsky JM. In vivo kinetics of insulin action on
peripheral glucose disposal and hepatic glucose output in normal and obese subjects. J Clin
Invest 1986;78:472–81.)

output is not elevated in absolute terms until fasting glucose exceeds 10 to 15 mmol/L
(180–270 mg/dL).18,21 Plasma glucagon concentrations are generally higher than
normal.15 When the maximal absorptive capacity for glucose of the proximal renal
tubule is exceeded, glycosuria provides an additional sink for plasma glucose. As
shown by numerous studies,22 marked insulin resistance is typically present both at
the level of peripheral tissues (ie, the M value on an insulin clamp) and in the liver
(eg, the hepatic insulin resistance index). Subjects with impaired fasting glycemia
and/or impaired glucose tolerance exhibit intermediate patterns between those of nor-
motolerant subjects and type 2 patients for all the parameters of the input-output
system shown in Fig. 1. In other words, for all the quantitative relationships described
so far, subjects with preserved glucose tolerance and individuals with various degrees
of dysglycemia/hyperglycemia are essentially part of the same continuum.23
In type 1 diabetes, fasting insulin secretion is absent or profoundly decreased,
glucagon is elevated, and endogenous glucose output may be elevated in absolute
terms.24 A similar, if less severe, picture may also be found in patients with advanced,
decompensated type 2 diabetes.

GLUCOSE HOMEOSTASIS: THE FED STATE

As exogenous glucose is absorbed (from an oral glucose load or a mixed meal), the
splanchnic area retains a quota for its own metabolic use (in humans, a small
 Glucose Homeostasis and Insulin Therapy 33

extraction fraction, mostly insulin independent25,26), and passes the remainder to the
post-hepatic veins and on to the arterial circulation. Intestinal glucose absorption is
a rapid and high-capacity phenomenon27; therefore, arterial plasma glucose concen-
trations (Fig. 9) and the appearance of oral glucose (Fig. 10) rise and fall over a time
course that is dictated essentially by the rate of gastric emptying. Typically an early
peak in glucose absorption and plasma glucose occurs 30 to 40 minutes following
ingestion, and a second, flatter peak is frequently evident at 120 to 150 minutes
(see Fig. 10). Of note is that at the time when plasma glucose levels have returned
to baseline, the metabolic perturbation is far from extinguished (eg, absorption of
oral glucose is still ongoing 5 hours after ingesting a mixed meal at rates different
from zero) (see Fig. 10).
The increments in plasma glucose and, in the case of a mixed meal, also in circu-
lating amino acids, signal to b-cells to augment insulin release. In normal subjects,
insulin secretion rises promptly, and tailgates glucose levels closely (see Fig. 9).
The portosystemic insulin gradient is maintained at the levels obtained during the fast-
ing state, but starts to attenuate at prehepatic insulin concentrations of 800 to 1000
pmol/L (130–170 mU/mL) because of the saturation of hepatic clearance capacity.14

Fig. 9. Mean plasma glucose concentration, plasma glucagon concentration, and insulin
secretion profiles in patients with type 2 diabetes (T2D) and age- and weight-matched non-
diabetic controls following the ingestion of a mixed meal (Ferrannini E, unpublished data,
2012).
34 Ferrannini

Fig. 10. Time course of appearance of oral and endogenous glucose in patients with type 2
diabetes (T2D) and age- and weight-matched nondiabetic controls (shaded areas are mean
 SEM) following the ingestion of a mixed meal (Ferrannini E, unpublished data, 2012).

At peak postglucose insulinemia, the portosystemic gradient typically falls below

1.5 (Fig. 11), indicating that more pancreatic insulin bypasses the liver onto the
systemic circulation. In liver cirrhosis, saturation of hepatic insulin degradation occurs
at lower insulin levels, because of both parenchymal insufficiency and portosystemic
shunts.28 Plasma glucagon concentrations, though suppressed when glucose alone is
ingested, increase in small and brief bursts in response to a mixed meal (see Fig. 9).
A standard oral glucose load (75 g) releases an average 0.12 U/kg of insulin above
basal output over 2 hours. A mixed meal will release more insulin over a longer period
of time, depending on caloric content and composition. Thus, a 70-kg nonobese adult
consuming 3 mixed meals over 24 hours needs a total of 40 to 50 units of insulin to
maintain normoglycemia (with a rather large scatter around this value29).
Passage of glucose through the gastrointestinal tract triggers an increased release
of hormones by endocrine cells of the intestinal mucosa. Prominent among these
hormones is glucagon-like peptide 1 (GLP-1), which potentiates glucose-induced
insulin release by a direct action on b-cells and simultaneously restrains glucagon
release (see Fig. 1).30 Thus, following glucose ingestion the prehepatic insulin-to-
glucagon ratio increases to higher than in the fasting state. As a result, endogenous
glucose output is suppressed by an average of 50%, thereby keeping some 20 g of
endogenous glucose from appearing in the systemic circulation throughout 5 hours
 Glucose Homeostasis and Insulin Therapy 35

Fig. 11. Nonlinear relationship between estimated prehepatic and peripheral plasma insulin
concentrations in the nondiabetic subjects in Fig. 3. The r and P values refer to the signifi-
cance of the partial correlation coefficient of the line of best fit (green line) and its 95% con-
fidence intervals (dotted green lines). Data (Ferrannini E, unpublished data, 2012) from 1151
nondiabetic subjects from the RISC Study. (Data from Ferrannini E, Balkau B, Coppack SW,
et al. RISC Investigators. Insulin resistance, insulin response, and obesity as indicators of
metabolic risk. J Clin Endocrinol Metab 2007;92:2885–92.)

of postcibal period. As approximately 55 g of oral glucose enters the circulation over

the same time period, total glucose disposal (75 g) takes place under the combined
effect of hyperglycemia (mass action) and insulin stimulation. Because total insulin
output averages 25 U over 5 hours, it can be calculated that the net metabolic effi-
ciency of the hormone is approximately 0.3 units per gram of glucose disposed. Post-
prandial glucose homeostasis is therefore imposed on both the liver, to curtail its
glucose release, and peripheral tissues, to stimulate their glucose uptake, in an
approximate proportion of 1:3.
Of note is that if similar plasma glucose and insulin levels to those achieved with
glucose or mixed-meal ingestion were created by an intravenous glucose infusion,
endogenous glucose output would be fully suppressed.19 This conspicuous difference
clearly speaks for the activation of neuroendocrine processes specific to the physio-
logic route of nutrient entry. Examples are increases in splanchnic blood flow,31–33
splanchnic adrenergic activation,33 release of multiple peptides exerting both local
and systemic effects, and excitation of autonomic neural arches eventually firing
back to liver and other peripheral tissues.34

THE FED STATE IN DIABETES

In typical type 2 diabetes, the response to a mixed meal features higher plasma
glucose and glucagon concentrations (see Fig. 9). The meal GLP-1 response may
be sluggish,35 but potentiation of glucose-induced insulin secretion and inhibition
of glucagon release are definitely impaired.36,37 However, rates of oral glucose
36 Ferrannini

appearance, endogenous glucose output, and whole-body glucose disposal are

similar to those of nondiabetic individuals (see Fig. 10). Thus, overall glucose flux
balance and metabolic insulin efficiency are apparently unaltered, except that the
glucose area is double the normal value and the incremental glucose area is triple
the normal value. Higher glucose in the face of normal or high insulin level is the defi-
nition of insulin resistance: at the level of the liver, hyperglycemia fails to fully inhibit
glucose release (which it normally does with a very sensitive dose-response relation-
ship19), in peripheral tissue glucose clearance is reduced, and hyperglycemia
promotes glucose uptake by mass action. One can then recalculate metabolic insulin
efficiency as the ratio of secreted insulin to plasma glucose clearance: in the represen-
tative subjects in Figs. 9 and 10, this value is 32 U/L (of plasma cleared of glucose) in
controls and 56 U/L in diabetic patients. Given the logarithmic relationship between
peripheral plasma insulin concentrations and glucose disposal rates (see Fig. 7), to
normalize metabolic insulin efficiency requires raising plasma insulin levels 3- to
4-fold.
In decompensated type 2 diabetes38 and in type 1 diabetes,39 feeding may not
suppress, and may actually enhance, endogenous glucose output and fail to stimulate
total glucose disposal because of marked insulin deficiency. Postabsorptive glycemic
excursions will be exacerbated, and the disposal of meal-derived glucose will be pro-
tracted for several hours, such that the patient will be rarely, if at all, in a state of meta-
bolic fast.
It should be mentioned that in vitro insulin secretion occurs in discrete bursts that
are synchronous with 4-minute oscillations of cytoplasmic calcium concentrations.40
In vivo, both high-frequency (5–10 minutes) and ultradian (w2 hours) oscillations can
be demonstrated by combining frequent blood sampling with C-peptide deconvolu-
tion (to reconstruct insulin secretion rate). At least part of these oscillations can be
entrained by high-frequency plasma glucose pulses, a typical feature of feedback
systems.41 By exposing the liver to peaks of insulin concentration, secretory oscilla-
tions in portal blood enhance the ability of insulin to suppress glucose output.42 The
oscillatory pattern is altered early in the course of type 2 diabetes,43 and may have
pathogenetic significance.44 However, whether abnormal pulsatility is a cause or
effect of the b-cell defect at the root of type 2 diabetes has not been determined.

SUMMARY

Insulin resistance and b-cell dysfunction are the main defects of type 2 diabetes; they
also predict45 and precede overt hyperglycemia in individuals at risk.46,47 b-Cell mass
is likely to be variably reduced48 (and a-cell mass relatively increased49) in long-
standing type 2 diabetes, and is virtually lost at onset in type 1 diabetes. Regardless
of the pathophysiological basis of these abnormalities, an input-output schematiza-
tion of plasma glucose homeostasis provides quantitative information on glucose
fluxes and their control by insulin. In a nutshell, insulin action is dependent on target
tissue (liver vs peripheral tissues), dose-response characteristics, route of delivery
(intraportal vs peripheral), and kinetics of activation and deactivation. Under normal
conditions, the closed-loop control of minute-by-minute insulin release by arterial
glucose levels protects against both hyperglycemia and hypoglycemia. Open-loop
insulin therapy faces the complexities of insulin pharmacokinetics and pharmacody-
namics outlined in this article. Thus, despite the science of the glucose-insulin system
being arguably the most precisely known in physiology, insulin therapy remains defi-
antly empiric, and an engrossing challenge to both the patient and physician.
 Glucose Homeostasis and Insulin Therapy 37

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