An inventive approach to treating type 2 diabetes
Original article:
Inhibition of dipeptidyl peptidase IV improves metabolic control over a
4-week study period in type 2 diabetes. Ahrén B, Simonsson E, Larsson H,
Landin-Olsson M, Torgeirsson H, Jansson P-A, Sandqvist M, Båvenholm P,
Efendic S, Eriksson JW, Dickinson S, Holmes D. Diabetes Care 2002; 25(5):
869–75.
Summary
Glucose-stimulated insulin secretion can be significantly potentiated by the
incretin hormones glucagon-like peptide-1 (GLP-1) and gastric inhibitory
polypeptide (GIP) which are released in response to a meal. GLP-1 has
several additional beneficial effects on glucose homeostasis and thus may be
of potential benefit in the treatment of type 2 diabetes; however, GLP-1 is
rapidly degraded in plasma by the enzyme dipeptidyl peptidase IV (DPP-IV),
which has a half-life of 1 min, thus making its use unattractive in patient
care. One approach to circumvent this problem is to prolong the endogenous
half-life of GLP-1 by inhibiting DPP-IV activity. This is possible with an
orally active and selective DPP-IV inhibitor, acting competitively and
reversibly, called NVP DPP728, which has previously been tested in animals.
Ahrén et al. report the results of a 4-week randomized, double-blind,
placebo-controlled study of the effects of NVP DPP728 in 92 type 2 diabetic
patients with no evidence of end-organ disease. Of these, 32 were treated
with placebo, 30 with NVP DPP728 100 mg t.i.d. and 30 with NVP DPP728 150 mg
b.i.d.
After 4 weeks of treatment, the difference in mean 24-h blood glucose was
–1.0 mmol/l and in mean 24-h plasma insulin –26 pmol/l for both treatment
groups compared with placebo (Fig. 1).
Fig. 1: Twenty-four-hour glucose and insulin levels
before and after 4 weeks of treatment with placebo or NVP DPP728 in subjects
with type 2 diabetes (means ± SEM).
Similarly, after 4 weeks, fasting plasma glucose was significantly
reduced by –1.0 mmol/l in the 100 mg t.i.d. group and by –0.7 mmol/l in the
150 mg b.i.d. group, with 35% and 37%, respectively, of the patients
achieving a fasting plasma glucose of 7 mmol/l in the treatment groups and
3% in the placebo group (Fig. 2).
Fig. 2: Fasting blood glucose and HbA1c values during
the 4-week run-in period and after 4 weeks’ treatment (left), and the 4-h
glycemic response to breakfast ingestion before and after the 4-week
treatment period with placebo or NVP DPP728 in subjects with type 2 diabetes
(means ± SEM).
The prandial glucose excursion was also reduced in both treatment groups
by –1.2 and –1.3 mmol/l, respectively (Fig. 2), while fasting and
postprandial insulin levels remained unaltered. Although the duration of the
study was only 4 weeks, HbA1c was slightly reduced by –0.5% in both
treatment groups and by –0.1% in the placebo group (Fig. 2). Body weight did
not change during the study period.
Treatment with NVP DPP728 was generally well tolerated except for one
episode of hypoglycemia and five of pruritus. Of more concern, one patient
developed transient nephrotic syndrome during the first week of treatment.
Comment
This is the first demonstration that pharmacological inhibition of DPP-IV
results in an improvement in glucose homeostasis in type 2 diabetic
patients. Incretin hormones are gut hormones that synergize with nutrients
to increase insulin secretion. Two hormones are probably responsible for
this effect in humans, GLP-1 and GIP [1]; however, these hormones have
additional effects on glucose homeostasis. For instance, GLP-1 stimulates
insulin biosynthesis and inhibits glucagon secretion; it also exerts trophic
effects on b-cells by stimulating b-cell proliferation and differentiation.
Finally, GLP-1 inhibits gastrointestinal secretion and motility as well as
appetite and food intake [2–4]. The use of inhibitors of DPP-IV is supposed
to decrease degradation of GLP-1, GIP and several other peptides and thus
lead to increases in plasma hormone levels and enhanced biological effects
[5].
The improvement in glucose homeostasis observed in this study may thus be
theoretically explained by an increased insulin response to glucose, a
decrease in glucagon secretion and a delay in gastric emptying, all
described effects of GLP-1 and/or GIP. The study, however, was not designed
to answer these questions; indeed GLP-1, GIP and plasma glucagon levels were
not measured. Furthermore, mean plasma insulin levels were decreased rather
than increased, potentially indirectly as a result of decreases in mean
blood glucose levels. We are thus left with hypotheses. The study, however,
constitutes a first step and encourages further investigation of DPP-IV
inhibition.
As always with a new potential treatment for type 2 diabetes, several
important questions are raised by preliminary studies. How effective will
the treatment be and how will it compare to existing treatments? What type
of patients will be most responsive to DPP-IV inhibitors? Most importantly,
what will be the range of side effects, given that more than 20 endogenous
peptides are degraded by DPP-IV that may also be involved in T cell
activation and proliferation? Furthermore, the occurrence of one case of
transient nephrotic syndrome must alert investigators to the possibility of
an important side effect.
But let us be optimistic and welcome a new potential treatment for type 2
diabetes that has derived from creative and fruitful basic research.
References
1. Fehmann HC, Göke R. Cell and molecular biology of the
incretin hormones glucagon-like peptide-I and glucose dependent insulin
releasing polypeptide. Endocr Rev 1995; 16: 390–410.
2. Drucker DJ. Glucagon-like peptides. Diabetes 1998; 47: 159–69.
3. Ku G, Stoffers DA, Habener JF, Bonner-Weir S. Exendin-4 stimulates both
beta-cell replication and neogenesis, resulting in increased beta-cell mass
and improved glucose tolerance in diabetic rats. Diabetes 1999; 48(12):
2270–6.
4. Zhou J, Wang X, Pineyro MA, Egan JM. Glucagon-like peptide 1 and
exendin-4 convert pancreatic AR42J cells into glucagon- and
insulin-producing cells. Diabetes 1999; 48(12): 2358–66.
5. Holst JJ, Deacon CF. Inhibition of the activity of dipeptidyl-peptidase
IV as a treatment for type 2 diabetes. Diabetes 1998; 47(11): 1663–70.
Summary and Comment:
Jacques Philippe, Geneva, Switzerland
