Bell, APD, CDE, University of Sydney, Sydney, Australia, presented pooled data
from six randomized controlled trials conducted over a 10-year period showing
that carbohydrate counting had no significant effect on glycemic control.
counting has become the gold standard for adjusting prandial insulin dose despite
limited evidence to recommend it over other dietary interventions for improving
glycemic control in type 1 diabetes (T1D). Most international guidelines have
based their recommendations on narrative reviews and the results of the few
available studies; however, carbohydrate counting does not take into account
differing effects of carbohydrates on blood glucose levels and the many different
factors associated with stimulation of insulin secretion.
objective of this meta-analysis was to assess the efficacy of carbohydrate
counting on glycemic control in adults and children with T1D. Six studies that
assessed the management of T1D with and without carbohydrate counting were
included [DAFNE Study Group. BMJ 2002; Gilbertson HR et al. Diabetes
Care 2001; Kalergis M et al. Diabetes Obes Metab 2000; Laurenzi A et
al. Diabetes Care 2011; Scavone G et al. Diabet Med 2010; Trento
M et al. J Endocrinol Invest 2011]. The control groups received usual
care, general nutrition advice, or low glycemic index dietary advice. All
studies were of at least 3 months' duration; patients (503 adults; 104 children
aged 8 to 13 years) could be on flexible or fixed insulin therapy.
primary outcome was improvement in glycated hemogloblin (HbA1C). Secondary
measures included the number and severity of hypoglycemic episodes, fasting
plasma glucose, insulin dose required to maintain glycemic control, body
weight, and quality of life.
was no significant improvement in HbA1C in patients who practiced carbohydrate counting
compared with those who did not (Figure 1). The overall change in HbA1C was
-0.3% points (p=0.185). Four studies favored carbohydrate counting (range,
-1.0% to +0.14%); two favored the control (range, -0.3% to +0.24%).
Figure 1. Carbohydrate Counting
Does Not Significantly Improve HbA1C
permission from K Bell, APD, CDE.
the low number of studies and inconsistencies in reporting metrics, the results
for the secondary outcomes are weak. However, there were trends for reduced
risk of hypoglycemia, improved quality of life, and no changes in insulin dose,
weight, or fasting plasma glucose level. The literature shows a wide variation
in carbohydrate counting ability with greater accuracy and precision associated
with lower HbA1C levels. However, skill and compliance were not measured in
analysis shows, carbohydrate counting may not result in optimal blood glucose
control and clinicians need to realize some patients may fail with this
approach. Many people with T1D have difficulty managing postprandial blood
glucose levels despite their best efforts. In addition, carbohydrate counting
has been linked to unhealthy food beliefs, fats and protein intake that exceed
nutritional recommendations, and increased reliance on packaged foods.
Clinicians need to emphasize healthy eating with insulin matched to food
choices rather than choosing foods to limit insulin or making dosing easier.
Additional research is needed to support the use of carbohydrate counting in clinical
practice, particularly in children and adolescents. Recent studies examining
the effect of protein and fat on insulin requirements show promising results
and could provide an alternative method for determining prandial insulin dose.
concerning hypoglycemia benefits patients with type 1 diabetes (T1D) with
impaired awareness of hypoglycemia, regardless of the system used to deliver insulin
and monitor blood glucose, according to Stuart Little, MBBS, Newcastle
University, Newcastle, United Kingdom, who reported on the Prevention of
Recurrent Severe Hypoglycaemia: A Definitive Randomized Controlled Trial
Comparing Optimised MDI and CSII With or Without Adjunctive Real-time
Continuous Glucose Monitoring [HypoCOMPaSS; EUCTR2009-015396-27].
~25% of patients with T1D have an impaired awareness of hypoglycemia. This lack
of knowledge can lead to a markedly higher risk of life-threatening episodes of
study, 96 T1D patients with impaired awareness of hypoglycemia were randomized
to either the conventional multiple daily injections of insulin aspart or
insulin glargine (n=50) or pump-mediated delivery of insulin aspart (n=46). In
both groups, glucose was either episodically or continuously monitored. All
participants received a standardized 2-hour information program concerning the
recognition of risk factors and symptoms of hypoglycemia, which proved equally
effective in reducing episodes of hypoglycemia. The primary endpoint was the difference
in awareness of hypoglycemia as determined using the Gold score at 24 weeks.
Secondary endpoints were measures of overall glycemic control and patient reported
outcomes including fear of hypoglycemia and treatment satisfaction.
participants had a mean age of 49 years (range, 18 to 74 years), mean duration
of diabetes of 29 years, and were C-peptide negative. Their impaired awareness
of hypoglycemia was ≥4, as measured using the Gold score, which queries
knowledge of the onset of hypoglycemia, with the response ranked on a 7-point
scale ranging from 1 ("always aware”) to 7 ("never aware”) [Gold AE et al. Diabetes
Care 1994]. Two thirds of the participants were women, two thirds had
retinopathy, one quarter had nephropathy, and one quarter had concomitant
immune-treated thyroid disease. The mean HbA1C level was 8.2%.
weeks, biochemical hypoglycemia measured by continuous monitoring was significantly
reduced from 53.3 minutes (3.7% of time) to 24.5 minutes (1.7% of time), ~30
minutes less each day (p<0.001 vs baseline). The reduction was sustained
over the remaining 20 weeks. At 24 weeks, a statistically significant
improvement in the median Gold score from 5 to 4 was evident for all
participants regardless of the method of insulin, compared with the baseline
number of episodes of severe hypoglycemia, defined by the American Diabetes
Association as hypoglycemia that requires assistance for treatment, was reduced
from 9 at baseline to <1 at 24 weeks (p<0.001), with the proportion of
patients affected declining from 92% and 77% at 1 year and 6 months prior to
the trial, respectively, to just 19% during the trial.
number of insulin doses decreased significantly by about 8 units over the
24-week trial (p<0.001). Both treatment arms displayed similarities in HbA1C
values, Gold score, number of episodes of severe hypoglycemia, mean insulin
dose, and fear of hypoglycemia. Participants who received insulin via a pump
expressed greater satisfaction with treatment.
Little and his colleagues concluded that impaired awareness of hypoglycemia can
be improved and recurrent hypoglycemia can be prevented through strategies targeted
at avoiding severe biochemical hypoglycemia in a high-risk population affected
by diabetes for almost 30 years. This benefit of education is more influential
than the technology of insulin delivery.
strategies to preserve insulin production and closed-loop continuous glucose monitoring
and insulin delivery systems are attractive options for exogenous insulin
delivered through several daily injections for patients with type 1 diabetes
Brusko, PhD, University of Florida, Gainesville, Florida, USA, provided an
update on advances in cellular-based therapies for T1D, noting that regulatory
T cells (Tregs) are central in controlling T-cell activation and preventing the
development of T1D, and could represent a new therapeutic paradigm because of
the diversity of their functional capacity. Tregs have the ability not only to
block autoreactive effector T cells, the cells that elicit b cell destruction,
but also to limit inflammation. Therefore, harnessing Tregs and directing them
to sites of inflammation could specifically target autoimmune disease.
function of Tregs in patients with T1D is not defective, he said. Rather, a
subset of patients has defects in the suppressor function of Tregs, thereby
influencing the pathogenesis of T1D. Autologous umbilical cord blood, which
contains a robust population of "naïve” highly functional Tregs, is being
explored as a source of these immunomodulatory cells for the treatment of
autoimmune diseases including T1D. A trial involving infusing Tregs into adults
with T1D is underway led by Jeffrey Bluestone, PhD, University of California,
San Francisco, San Francisco, California, USA. Efforts are currently underway
to developing additional Treg therapies from umbilical cord blood.
Tregs have been shown to prevent and even reverse diabetes in animal models. Efforts
to generate antigen-specific human Tregs to suppress the immune response
targeting islet b cells, while leaving intact the immune response to foreign
agents, are ongoing, said Dr. Brusko. In
addition, his laboratory is developing a "negative vaccine” in an attempt to
block the immune response directed at insulin that is present in patients with
T1D. The vaccine uses time-released biomaterials loaded with autoantigens to
direct T-cell responses to one of immunologic tolerance and nonresponsiveness
to specific proteins such as insulin.
Sanda, MD, University of California, San Francisco, San Francisco, California,
USA, reviewed attempts to prevent the development of T1D. The decision to use
drugs in prevention is not yet informed by a mechanistic understanding of why
the drugs have been successful in the new-onset population, she said. In one
study, modulation of costimulatory signals between T cell and
antigen-presenting cells using abatacept slowed the decline of b cell function
over 2 years in a study of patients with recent-onset T1D (Figure 1) [Orban T
et al. Lancet 2011]. The ideal time to apply immunotherapeutic agents to
potentially prevent T1D remains unknown.
Figure 1. Decline in Cell
Function Over Time According to C-Peptide Levels
Reproduced from Orban T
et al. Co-stimulation modulation with abatacept in patients with recent-onset
type 1 diabetes: a randomised, double-blind, placebo-controlled trial. Lancet2011;378(9789):412-419. With permission from Elsevier.
of innate inflammation in new-onset T1D is evident by elevations in expression of
interleukin (IL) 1B by immune effector cells, leading to hyperglycemia-induced
b cell dysfunction. Antagonists of IL-1 (canakinumab and anakinra), however,
did not improve b cell function in T1D of recent onset in randomized,
double-blind, placebo-controlled trials [Moran A et al. Lancet 2013].
Other data indicate that signaling through receptors that use the MyD88 adaptor
protein is critical for development of T1D, and deficiency of MyD88 changes the
composition of distal gut microbiota to that interaction between intestinal
microbes and the innate immune system is critical to a predisposition to T1D
[Wen L et al. Nature 2008]. Factors that influence b cell function
before a clinical diagnosis of T1D, the relevant perturbations in the immune
system prior to clinical diagnosis, the timing of their occurrence in relation
to disease progression, and the mechanisms by which therapies induce a clinical
response in the new-onset period require further study, said Dr. Sanda.
A. Bremer, MD, PhD, Vanderbilt University, Nashville, Tennessee, USA, provided
an update of closedloop therapy. The goal of an artificial pancreas is the coupling
of a continuous glucose monitor and insulin pump therapy with a control
algorithm to deliver insulin in a continuous glucose-responsive manner.
control algorithms respond with insulin infusion that reacts to current
glucose, accounts for glucose level over time, and can adjust for the rate of
change in glucose. Insulin delivery algorithms based on b cell physiology use
an insulin feedback feature that reduces insulin delivery in a manner analogous
to the "insulin-onboard” feature of the insulin pump [Palerm CC. Comput Methods
Programs Biomed 2011]. Modified algorithms have been able to control
hyperglycemia and reduce late postmeal hypoglycemia even with the additional
challenge of daytime exercise [Steil GM et al. J Clin Endocrinol Metab 2011].
predictive control (MPC) is an algorithm that seeks to optimize blood glucose
over time based on models that take into account previous continuous blood glucose
measurements and insulin infusion rates, and uses these data to predict future
glucose and insulin infusion requirements. The model is then updated based on
error in prediction, thereby minimizing the difference between the blood
glucose level the model predicts and the target blood glucose.
bihormonal closed-loop system using insulin and glucagon in separate pumps
under individual control algorithms (MPC-based for insulin,
proportional-integralderivative-based for glucagon) achieved a mean blood glucose
concentration of 140 mg/dL and prevented hypoglycemia while achieving a mean
blood glucose concentration of 164 mg/dL in separate experiments in patients
with T1D [El-Khatib FH et al. Sci Transl Med 2010].
inpatient hybrid closed-loop therapy initiated within 7 days of a diagnosis of
T1D rapidly reversed glucose toxicity and established near-normal glycemic
control, with mean glucose concentration falling from 240 mg/dL on initiation
to 146 mg/dL on Day 1, a level of control that was sustained on Days 2 and 3
(Figure 2) [DirecNet Study Group. Diabetes Technol Ther 2013].
Figure 2. Effects of Inpatient
Hybrid Closed-Loop Therapy Started Within 7 Days of Type 1 Diabetes Diagnosis
DirecNet Study Group. The Effects of Inpatient Hybrid Closed-Loop Therapy Initiated
Within 1 Week of Type 1 Diabetes Diagnosis Diabetes Research in Children
Network (DirecNet) and Type 1 Diabetes TrialNet Study Groups*. Diabetes
Technol Ther 2013;15(5):401-408. With permission from Mary Ann/Liebert,
ambulatory closed-loop systems that integrate continuous glucose monitoring,
continuous subcutaneous insulin infusion, and a controller algorithm onto a
Smartphone device are under investigation. Sandra Puczynski, PhD, Southern
Illinois University, Springfield, Illinois, USA, discussed patient hopes for a
cure for T1D in the face of the reality of research efforts in this endeavor.
At least $1.8 billion annually, diabetes research expenditures are not keeping
up with the costs associated with diabetes, she said. The status of research is
often misrepresented in the media, with discoveries sometimes portrayed as
being further along in clinical development than they actually are, causing
premature excitement among patients.
Previously published results from the Action to Control Cardiovascular
Risk in Diabetes study [ACCORD; ACCORD Study Group. N Engl J Med 2008]
showed an increased risk of all-cause and cardiovascular (CV) mortality in the
intensive control group (HbA1C target, <6.0%) compared with the less intensive
group (HbA1C target, 7.0% to 7.9%). "This brought a huge puzzle to the diabetes
community, to figure out why we were seeing this result,” said Elias S. Siraj,
MD, Temple University School of Medicine, Philadelphia, Pennsylvania, USA.
Several post hoc analyses have been conducted to date to determine what factors
may have influenced this outcome [ACCORD Study Group. N Engl J Med 2008;
Bonds DE et al. BMJ 2010; Riddle MC et al. Diabetes Care 2010; Seaquist
ER et al. Diabetes Care 2012]. These analyses did not find a conclusive
link between the ACCORD results and factors such as hypoglycemia, low HbA1C,
the rapid decline in HbA1C during the first year of the study, weight gain, and
specific medication use.
better understand the findings of this study, ACCORD investigators hypothesized
that higher doses of exogenous insulin may be associated with the CV mortality results
from the ACCORD trial. To investigate this idea, data for insulin exposure and
CV mortality from 10,163 patients were analyzed. HRs and 95% CIs were
calculated, and multivariable Cox regression performed to choose the most appropriate
baseline covariates and models.
updated average total, basal, and bolus insulin doses were significantly higher
in the intensive-control arm (all p<0.0001). In addition, there was a
significant linear association between the updated average HbA1C level and
updated average insulin dose in both groups (both p<0.0001). Four different
Cox proportional hazards models were employed to determine HRs for CV
mortality. The first model controlled for the following 14 baseline covariates:
age, history of CV disease, heart failure, QTindex, baseline HbA1C value,
high-density lipoprotein, amputation, presence of peripheral neuropathy, serum creatinine,
urinary ratio of albumin to creatinine, use of angiotensin receptor blockers,
educational status, presence of integrated health plan, and presence of certified
diabetes educator on staff at randomization. Model 2 added assignment to blood
pressure or lipid trial, treatment assignment within these, severe
hypoglycemia, and weight change. Model 3 added the updated average HbA1C, and Model
4 added the glycemic treatment arm assignment. Results from all 4 models by
total, basal, and bolus insulin are presented in Table 1.
Table 1. HRs for CV Mortality of
Insulin Dose (per 1 unit/kg) From Cox Proportional Hazards Model
the unadjusted HRs, a daily insulin dose increase by 1 unit/kg of body weight
was associated with a 1.83- (total insulin), 2.29- (basal insulin) and
3.36-fold increase in risk of CV mortality (all p<0.0001). However, results
from the four models did not confirm these findings. After adjustment for baseline
covariates in Model 1, the HRs became nonsignificant indicating no association
of insulin dose with CV mortality. Additionally, no association between insulin
dose and CV mortality emerged after adjustments were made for on-treatment
Dr. Siraj concluded
that these results do not support the idea that insulin dose is an independent
risk factor for CV mortality in the ACCORD population.
with type 1 diabetes (T1D) experienced a gradual decline in certain cognitive
functions, but the decline was not comparable to mild cognitive impairment,
which is a precursor of dementia. The decline in brain volume loss was
associated with higher baseline systolic blood pressure (SBP), while a decline
in executive function was associated with baseline elevated HbA1C in patients with
T1D, according to Eelco van Duinkerken, PhD, Vrije Universiteit Medical Center,
Amsterdam, The Netherlands, who presented the 4-year follow-up data.
study of cognitive decline compared the brain function of 25 patients with T1D
and 25 matched controls. All participants had to be free of diseases affecting
the brain and psychiatric comorbidities, and had to be right-handed. To explore
the theory that microangiopathy is related to cognitive decline, all diabetic
patients had proliferative retinopathy as a marker of angiopathy, and diabetes duration
of at least 10 years.
baseline, the mean age for all was ~45 years (range, 18 to 56 years), and the
mean duration of diabetes was 35 years. The SBP was 133.9 mm Hg in the diabetes
group, compared with 126.9 mm Hg in the control group (p=0.045). The baseline
HbA1C values were 7.9% and 5.4% (p<0.001) in the diabetes and control
was no difference in general cognitive ability, information processing speed,
or attention at follow-up. The researchers noted a slight increase in
performance over time in patients with diabetes, but not in the control group;
however, this lacked statistical significance.
an accelerated decrease in executive function was found in T1D patients
relative to the controls, which was ascertained by asking the subjects to identify
the color of ink or state how many animals they could think of in 2 minutes.
changes in brain volume from baseline to follow-up (mean, 4.28 years T1D group;
4.73 years control group) are measured by MRI. The decrease in brain volume was
1.34% in the patients with T1D compared with 0.68% in the control patients
brain volume loss was most notable in the frontal and central areas of the
right hemisphere, which are associated with executive function performance
(p=0.021). While the baseline SBP was found to correlate with brain volume loss
and baseline elevated HbA1C was found to correlate with executive function
loss, there was no correlation with severe hypoglycemic events. The change in
brain volume was not seen in speed-related domains, as some researchers had
T1D patients with
angiopathy face the possibility of progressive cognitive decline, which is
unrelated to mild cognitive impairment.
with type 2 diabetes mellitus (T2DM) appear to have dysfunctional islet β cells
due to unknown mechanisms [Leahy JL and Pratley RE. Translational Endo Metab 2011]. Multiple new pharmacologic agents
that are under development for the treatment of T2DM specifically target islet
cells. Jack L. Leahy, MD, University of Vermont, Burlington, Vermont, USA,
presented two signaling pathways in β cells that may be important drug targets.
Leahy pointed out that there are several therapeutic targets within β cells for
the treatment of T2DM [Bailey CJ. Lancet2012]. One target is an unsaturated medium- to long-chain free fatty acid
receptor called GPR40 (also called FFAR1) that plays a role in free fatty
acid-induced insulin secretion [Mancini AD, Poitout V. Trends Endocrinol Metab 2013]. Studies have demonstrated decreased
insulin secretion in GPR40 null mice compared with controls [Steneberg P et al.Cell Metab 2005; Kebede M et al. Diabetes 2008]. Interestingly, GPR40
expression in human pancreas islet cells is decreased in patients with T2DM by
up to 80%, when compared with controls [Del Guerra S et al. Nutr Metab Cardiovasc Dis 2010].
Leahy highlighted data from a Phase 2 trial in which 426 patients with T2DM
were treated with the GPR40 agonist TAK-875, glimepiride, or placebo for 12
weeks [Burant CF et al. Lancet 2012].
Patients were counseled on diet and exercise and may or may not have been
stable on metformin. A significant improvement in HbA1C levels was observed in
patients who received TAK-875 or glimepiride, compared with those who received
placebo (Figure 1). Patients treated with TAK-875 or glimepiride did not have improved
insulin sensitivity or fasting glucagon levels. Additionally, treatment-related
adverse events were similar among patients who received TAK-875 or placebo.
However, a greater number of patients who received glimepiride demonstrated
hypoglycemic events, as compared with those who received placebo or TAK-875.
Figure 1. Effects
of TAK-875, Glimepiride, and Placebo on Glycemia
from Burant CF et al. TAK-875 versus placebo or glimepiride in type 2 diabetes
mellitus: a phase 2, randomised, double-blind, placebo-controlled trial. Lancet 21012;379(9824):1403-1411. With
permission from Elsevier.
Leahy gave an example of identifying new therapeutic targets in well-studied
signaling pathways in β cells, such as the FoxO1 and PPAR-g pathway in β cells
that is important for β cell survival, function, metabolism, and response to
incretin. Rats with hyperglycemia demonstrate reduced signaling through the
FoxO1/PPAR-g pathway due to the potentially impaired translocation of FoxO1
from the nucleus to the cytoplasm [Gupta D et al. Diabetes 2010]. Treatment of hyperglycemic rats with the DPP-4
inhibitor alogliptin appears to restore FoxO1/PPAR-g signaling [Gupta D et al.
ADA 2013 (poster 2275)].
A. Tahrani, MD, PhD, University of Birmingham, Edgbaston, United Kingdom,
discussed the mechanisms underlying insulin resistance and potential drug
targets. Prof. Tahrani pointed out that the most important factor associated
with insulin resistance is obesity; however, he noted that it is difficult to
treat obesity. Targets for the treatment of insulin resistance include obesity
and the mechanisms of insulin resistance such as inflammation, oxidative
stress, lipotoxicity, and glucotoxicity, as well as targeting the insulin
receptor and insulin post-receptor signaling.
Tahrani highlighted several drugs that target insulin resistance. The compounds
demethylasterriquinone B1, compound 2, and D-410639 target insulin receptor activation
[Zhang B et al. Science 1999;
Strowski MZ et al. Endocrinology 2004; Tsai KW et al. J Biomed Sci 2009]. Some agents prolong phosphorylation of the b
subunit of the insulin receptor following insulin binding [Cohen P et al. Nat Rev Mol Cell Biol 2006], such as the
agent TLK16998 [Manchem VP et al. Diabetes2001]. Other targets include interleukin-6 [Ridker PM et al. Circulation 2012], resveratrol [Ito-Nagahata
T et al. Biosci Biotechnol Biochem2013], and inhibitor k-B kinase-b inhibitors [Kamon J et al. Biochem Biophys Res Commun 2004].
insulin signaling may also harbor potential targets for the treatment of
insulin resistance. Prof. Tahrani highlighted signaling molecules within the
insulin signaling pathway that may be ideal targets, such as inhibition of protein
kinase C [Naruse K et al. Diabetes2006], promotion of phosphatidylinositol-3 kinase [Croze ML et al. Biochimie2013], inositol metabolites, inhibition of PTEN [Pal A et al. N Engl J
Med 2012], and inhibition of inositol phosphatases.
Tahrani pointed out that nonpharmacologic interventions, such as weight loss,
adequate sleep, and obstructive sleep apnea are also important to consider. For
example, patients who were sleep restricted in a laboratory study had a
significant decrease in glucose tolerance, acute insulin response to glucose,
glucose effectiveness, and insulin sensitivity as compared with a well-rested
state [Leproult R, Van Cauter E. Endocr Dev 2010].
R. Henry, MD, University of California, San Diego, La Jolla, California, USA,
presented information on treating inflammation in adipose and skeletal tissues.
Individuals that tend to accumulate adipose tissue in the visceral region are
more likely to have inflammation in their adipose tissue. In addition, patients
with T2DM have greater fat deposition in the visceral versus subcutaneous region,
as compared with patients without diabetes.
Henry highlighted that adipose tissue produces chemicals called adipokines,
which can have autocrine, paracrine, or endocrine signaling effects [Blüher M. Diabetes
Metab J 2012]. As adiposity increases, the adipokines that are secreted
become predominantly proinflammatory.
prevailing theory of a mechanism underlying insulin resistance in obesity is
lipotoxicity [Johnson AM, Olefalsy JM. Cell 2013]. Excessive caloric
intake can result in cellular stress and tissue inflammation, which can lead to
insulin resistance [Odegaard JI, Chawla A. Science 2013]. Ultimately,
inflamed adipose tissue with some level of metabolic dysfunction demonstrates
an altered milieu as compared with lean adipose tissue with normal metabolic function
[Ouchi N et al. Nat Rev Immunol 2011]. Adipocytes that live in an
inflamed tissue have reduced insulin action [Odegaard JI, Chawla A et al. Science2013].
recent study demonstrated that treatment with salsalate, a tumor necrosis
factor-a inhibitor, resulted in a significant decrease in white blood cell
count, neutrophil count, and lymphocyte count over a 48-week period [Goldfine
AB et al. Diabetalogia 2013]. In addition, salsalate treatment caused a
reduction in nuclear factor kappalight chain enhancer (NF-κB) activity in
visceral adipose tissue, compared with placebo, after 12 weeks of treatment. Importantly,
NF-κB is a major player in inflammatory signaling pathways [Reilly SM et al. Nat
of skeletal muscle is increased in obese patients compared with lean patients,
as measured by macrophage infiltration and, as body mass index increases, so
does the macrophage content of skeletal muscle [Varma V et al. Am J Physiol
Endocrinol Metab 2009]. However, other studies have suggested that this
finding may be due to cross-contamination by adipose tissue that is found
within skeletal tissue [Tam CS et al. Obesity 2012].
Zinman, CM, MD, Samuel Lunenfeld Research Institute, Mount Sinai Hospital,
University of Toronto, Toronto, Canada, discussed targeting mechanisms of
glucose absorption and excretion in the treatment of T2DM. The
alpha-glucosidase inhibitors [AGI] are a drug class that modifies glucose
absorption by inhibiting the breakdown of carbohydrates in the upper intestine.
Interestingly the AGIs also modify the secretion of gastrointestinal (GI)
peptides like GLP1 but have modest efficacy. However, the tolerability of AGI
is a major problem and their widespread acceptance in the United States has
been limited by frequent GI side effects, such as diarrhea, flatulence, and
new strategy focuses on targeting the sodium glucose cotransporter-2 (SGLT-2),
which is an important mechanism responsible for the filtered glucose to be
reabsorbed in the proximal tuble of the kidney. Nonetheless the capacity of the
two transporters, SGLT-1 [high-affinity, low-capacity] and SGLT-2
[low-affinity, high-capacity] to reabsorb glucose is limited; therefore, excess
blood glucose levels above ~180 mg/dL causes glucose to remain in the urine
filtrate [Gerich JE et al. Diabetic Med 2010]. However, in patients with
poorly controlled diabetes there is an adaptive response whereby SGLT-2 is upregulated
so that reabsorption of glucose is increased. Thus SGLT-2 inhibitors reduce
glucose reabsorption in the kidney and with resultant glucosuria [increased
urinary glucose]. Several SGLT-2 inhibitors that have shown promising results in
clinical trials include empagliflozin [Hach T et al. Diabetes 2013],
canagliflozin (Figure 2) [Schernthaner G et al. Diabetes Care 2013], and
dapagliflozin [FDA. Dapagliflozin Advisory Committee Meeting.
Published July 19, 2011].
Figure 2. Effect of
Canagliflozin Versus Sitagliptin on HbA1C Levels
Reproduced from Schernthaner G et al.
Canagliflozin Compared With Sitagliptin for Patients With Type 2 Diabetes Who
Do Not Have Adequate Glycemic Control With Metformin Plus Sulfonylurea: A
52-week randomized trial. Diabetes Care 2013;36(4):908-913. With
permission from the American Diabetes Association.
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