obesity | VOLUME 16 NUMBER 1 | JANUARY 2008 77
nature publishing group
intervention and prevention
Restoration of Acute Insulin Response
in T2DM Subjects 1 Month After
Lucia Briatore1, Barbara Salani1, Gabriella Andraghetti1, Cristina Danovaro1, Elsa Sferrazzo1,
Nicola Scopinaro2, Gian F. Adami2, Davide Maggi1 and Renzo Cordera1
objective: Biliopancreatic diversion (BPD) restores normal glucose tolerance in a few weeks in morbid obese subjects
with type 2 diabetes, improving insulin sensitivity. However, there is less known about the effects of BPD on insulin
secretion. We tested the early effects of BPD on insulin secretion in obese subjects with and without type 2 diabetes.
Methods and Procedures: Twenty-one consecutive morbid obese subjects, 9 with type 2 diabetes (T2DM) and 12 with
normal fasting glucose (NFG) were evaluated, just before and 1 month after BPD, by measuring body weight (BW),
glucose, adipocitokines, homeostasis model assessment of insulin resistance (HOMA-IR), acute insulin response (AIR)
to e.v. glucose and the insulinogenic index adjusted for insulin resistance ([∆I5/∆G5]/HOMA-IR).
Results: Preoperatively, those with T2DM differed from those with NFG in showing higher levels of fasting glucose,
reduced AIR (57.9 ± 29.5 vs. 644.9 ± 143.1 pmol/l, P < 0.01) and reduced adjusted insulinogenic index (1.0 ± 0.5 vs.
17.6 ± 3.9 1/mmol2, P < 0.001). One month following BPD, in both groups BW was reduced (by ~11%), but all subjects
were still severely obese; HOMA-IR and leptin decreased significanlty, while high-molecular weight (HMW) adiponectin
and adjusted insulinogenic index increased. In the T2DM group, fasting glucose returned to non-diabetic values. AIR
did not change in the NFG group, while in the T2DM group it showed a significant increase (from 58.0 ± 29.5 to 273.8 ±
47.2 pmol/l, P < 0.01). In the T2DM group, the AIR percentage variation from baseline was significantly related to
changes in fasting glucose (r = 0.70, P = 0.02), suggesting an important relationship exists between impaired AIR and
Discussion: BPD is able to restore AIR in T2DM even just 1 month after surgery. AIR restoration is associated with
normalization of fasting glucose concentrations.
Obesity (2008) 16, 77–81. doi:10.1038/oby.2007.9
Type 2 diabetes mellitus (T2DM) is a complex disease resulting
from a dual defect: the association of insulin resistance with
failure of insulin secretion (1). The observation of increased
prevalence of T2DM in overweight and obese people (2),
together with the demonstrated possibility of T2DM preven-
tion in subjects with impaired glucose tolerance by means
of dieting and exercise (3–5), support the theory that exces-
sive fat deposition plays a key element in the development
of T2DM. Reduction of body weight (BW) is a pivotal tool
in the anti-diabetic armamentarium. Unfortunately durable
BW reduction is almost an unrealistic target in clinical prac-
tice. For this reason, bariatric surgery is becoming a relatively
common therapeutic strategy for patients with morbid obes-
ity, complicated by T2DM. Several prospective studies have
shown that bariatric surgery is often associated with recovery
from T2DM and with its prevention (6). Glucose concentra-
tions normalize in ~50% of obese patients with T2DM after
the restrictive procedure, with results substantially dependent
on weight loss. The recovery rate following gastric bypass and
biliopancreatic diversion (BPD), conversely, is respectively 80
and 95% (6,7). BPD often normalizes blood glucose before a
substantial weight loss (8), suggesting that other mechanisms
beyond weight reduction might play a role.
Several observations suggest there is the possibility of
improved beta-cell function acting as a mechanism by
which bariatric surgery normalizes glucose metabolism. It
has been shown that lack of early insulin secretion or acute
insulin response (AIR), elicited by e.v. glucose, is the most
striking defect of beta-cell dysfunction in T2DM (9) and
1Department of Endocrinology and Medicine, University of Genova, Genova, Italy; 2Department of Surgery, University of Genova, Genova, Italy.
Correspondence: Renzo Cordera (firstname.lastname@example.org)
Received 10 February 2007; accepted 10 May 2007. doi:10.1038/oby.2007.9
VOLUME 16 NUMBER 1 | JANUARY 2008 | www.obesityjournal.org
intervention and prevention
that this alteration does not revert following weight loss
(10). Recently it has been reported that BPD increases AIR
between 3 and 12 months after the operation (11), leaving
it unclear as to the relative role of BPD itself and progres-
sive weight loss on beta-cell function. Moreover, there has
been shown to be increased beta-cell sensitivity on admin-
istration of the oral glucose test as early as 1 week after the
The aim of this investigation was to directly evaluate the
early effects of BPD on insulin secretion measuring the AIR to
glucose in both diabetic and non-diabetic severely obese sub-
jects before and 1 month after BPD, when subjects still remain
methods and procedures
The study was carried out in 21 consecutive severely obese subjects
(9 male) undergoing BPD: 9 with T2DM and 12 with normal fasting
glucose (NFG). All consecutive patients who agreed to participate in the
investigations were enrolled. All patients were free of neoplastic, immu-
nologic, endocrine disease or severe diabetic complications, and gave
their informed consent to the study before the operation. The diagnosis
of diabetes was established according to the criteria of the American
Diabetes Association (13). The duration of diabetes ranged from 2 to
6 years and four subjects were treated with oral hypoglycemic agents.
Hypoglycemic drugs were discontinued 7 days before the study.
BPD consists of a distal gastrectomy with a very long Roux-en-Y recon-
struction at 50 cm from the ileocecal valve (14). Because of the new
anatomical condition created by the operation, subjects develop a per-
manent and selective maldigestion and then malabsorption of energy-
rich substrates, in prevalence fat, due to the displacement of digestive
juices with respect to the food transit in the small gut.
Subjects were evaluated the day before and 1 month following BPD,
on the occasion of the first follow-up visit. During the first month fol-
lowing BPD, the overall food consumption, assessed by an accurate ali-
mentary interview, was in all cases nearly half of the preoperative one.
BW and height were measured in the morning to the nearest 0.1 kg and
0.5 cm, respectively. Blood was drawn after a 12-h overnight fast to test
for glucose, insulin, leptin, adiponectin and for high-molecular weight
(HMW) isoforms adiponectin determination and intravenous glucose
tolerance test (IVGTT).
Intravenous glucose tolerance test
Between 8:30 and 9:30 am after a 12-h overnight fast, blood samples
were collected just 10 min before the e.v. infusion of 35 g glucose (35%
wt/vol, over 2 min), and 2, 3, 5, 10, 20, and 30 min after the end of
infusion. The first phase of insulin or AIR was calculated as the dif-
ference of the mean insulin concentration at 2, 3, 5, and 10 min minus
the mean insulin concentration at −10 and 0 min of the test. The dif-
ference between the baseline value and the value at 5 min after glu-
cose infusion was considered as the incremental serum insulin (∆I5)
and glucose (∆G5) response. An expression of beta-cell function is the
insulinogenic index, expressed as the ratio of incremental insulin to
glucose responses. Because insulin sensitivity is an essential modulator
of insulin response, we used an adjusted insulinogenic index obtained
dividing ([∆I5/∆G5]/HOMA-IR) (15). Homeostasis model assessment
of insulin resistance (HOMA-IR) was calculated as reported (16).
After separation, serum samples were stored at –20 °C until analysis.
Glucose and insulin concentrations were measured by commercial
enzymatic method (Randox Laboratories, Crumlin, UK) and sandwich
immunoradiometric assay (Immunotech, a.s., Prague, Czech Republic),
respectively. Serum adiponectin and leptin were measured in basal
conditions by commercial radioimmunoassay (DRG Instruments,
Marburg, Germany). Adiponectin isoforms were evaluated as previ-
ously reported (17).
Data are reported as mean ± s.e. Two-sided P < 0.05 was considered
significant. The Mann–Whitney U-test was used for a non-parametric
evaluation of differences between groups and Wilcoxon’s signed-rank
test was used to compare data from the same subject before and after
BPD. Predictors of AIR changes were tested using the Spearman corre-
lation. Multiple linear regression was then used to fit models to predict
AIR changes after BPD.
effects of Bpd on weight loss and adipocytokines
Baseline age, anthropometric findings, serum leptin and adi-
ponectin concentrations and serum HMW (percentage) adi-
ponectin were similar in T2DM obese subjects and in the NFG
group (Table 1). One month following BPD, a slight (~11%)
reduction of mean BW and BMI values was observed in both
T2DM and NFG obese patients, without differences between the
two groups. A sharp reduction of serum leptin concentration
was observed in both groups. In the NFG group, postoperative
table 1 anthropometric characteristics and adipocitokines
Type 2 diabetes NFG
Pre-BPDPost-BPDBPD effect* Pre-BPDPost-BPDBPD effect*
Age (years) 42.1 ± 2.1 36.1 ± 2.5
Weight (kg) 134.8 ± 8.5 119.9 ± 7.9 +130.4 ± 4.6 114.9 ± 3.5+
BMI (kg/m2)48.7 ± 3.241.7 ± 3.0+48.4 ± 2.0 42.6 ± 1.3+
Leptin (ng/ml)35.1 ± 24.216.1 ± 9.2+36.3 ± 5.920.1 ± 3.8**+
Adiponectin (μg/ml)7.1 ± 1.59.9 ± 2.28.8 ± 0.610.3 ± 0.9
HMW (%)36.2 ± 5.146.3 ± 6.1 +40.4 ± 3.249.0 ± 2.5 +
Data are means ± s.e.m.
HMW (%), percentage of high molecular weight adiponectin; NFG, normal fasting glucose.
*The plus sign indicates P ≤ 0.05 for the difference between pre- and post-BPD. **P ≤ 0.01 vs. type 2 diabetes subjects.
obesity | VOLUME 16 NUMBER 1 | JANUARY 2008 79
intervention and prevention
leptin concentrations were greater than in the T2DM patients.
No changes in total serum adiponectin concentration were
found, while after 1 month the adiponectin HMW increased
significantly both in T2DM and in NFG subjects.
effects of Bpd on insulin resistance, insulin secretion
and fasting glucose
Before BPD, the T2DM group had significantly higher fast-
ing glucose concentrations compared with the NFG group
(Table 2), despite there being no significant difference in
insulin values and HOMA-IR, suggesting that the degree
of insulin resistance was similar in the two groups of obese
subjects. On the contrary, AIR was very low or absent in
all subjects with T2DM in comparison with those with
NFG, as well as the insulinogenic index adjusted for insu-
lin resistance. In all T2DM subjects, 1 month after BPD,
fasting plasma glucose was <6.1 mmol/l and only slightly
higher than the glucose values for NFG subjects (5.13 ± 0.05
vs. 4.73 ± 0.10 mmol/l, P = 0.05). Post BPD fasting insulin
concentrations and HOMA-IR were reduced in T2DM and
NFG groups compared to pre-surgery values, whereas insuli-
nogenic index adjusted for insulin resistance was increased
in both groups. When comparing the post-BPD values of
fasting insulin, HOMA-IR and insulinogenic index between
T2DM and NFG groups, there were not found any significant
differences. One month after BPD in diabetic subjects AIR
showed a significant increase, while in the NFG group BPD
did not affect AIR. All diabetic subjects increased their AIR
after BPD (Figure 1).
In T2DM subjects the AIR percentage variation from base-
line was significantly related to the change in fasting glucose
(r = 0.7, P = 0.02) and to the percentage variation in BMI (r =
0.68, P = 0.023).
In subjects with diabetes a multivariate model was consid-
ered, using as the dependent variable changes in AIR and as
independent variables the percent variation of BMI, HMW
adiponectin, leptin, HOMA-IR and fasting glucose changes.
The only independent variable that significantly predicted
post-BPD AIR changes was fasting glucose variations, explain-
ing 56% of AIR changes.
The two main findings of this study are that BPD reduces insu-
lin resistance in both NFG and T2DM morbid obese subjects;
furthermore in T2DM, together with the normalization of fast-
ing glucose, BPD restores AIR. These effects are present within
a few weeks after surgery, when in all subjects BW still remains
in the obese range, suggesting that the effects are at least in part
independent of weight loss.
The effects of BPD on insulin sensitivity and glucose toler-
ance have been widely documented (8,18,19). In agreement
with previous studies (12,20), in obese subjects a marked
reduction of insulin resistance and a normalization of fast-
ing blood glucose concentrations in diabetic subjects were
observed soon after BPD. Several mechanisms might play a
role in the increase in insulin sensitivity after bariatric surgery:
weight loss and negative energy balance with reduction of fat
mass, action of intestinal hormones (21) and, in the case of
BPD, selective fat malabsorption (22,23).
Reduction of body fat and insulin resistance are important
mechanisms responsible for improvement of glucose metab-
olism. In addition, beta-cell function and insulin secretion
seem to be modified by bariatric surgery. We studied the
effects of BPD on insulin secretion, focusing on AIR. The
absence of AIR to glucose has been recognized as a specific
and irreversible marker of beta-cell dysfunction in T2DM.
Polyzogopoulou et al. (11) reported a restoration of AIR
in T2DM 3 and 12 months after BPD, leaving unsolved the
table 2 Fasting glucose, insulin resistance and insulin secretion parameters
Type 2 diabetesNFG
Pre-BPDPost-BPD BPD effect*Pre-BPD Post-BPDBPD effect*
Fasting glucose (mmol/l)10.81 ± 3.32 5.24 ± 0.21+ 5.13 ± 0.05**4.73 ± 0.10
Fasting insulin (pmol/l)137.5 ± 87.5 68.7 ± 14.1+ 115.2 ± 15.979.3 ± 11.8+
AIR (pmol/l)57.9 ± 29.5 273.8 ± 47.1+ 644.9 ± 143.1***632.5 ± 84.8**
Adjusted-ins. index1.0 ± 0.5 76.6 ± 26.0+ 17.6 ± 3.9** 116.1 ± 17.5+
HOMA-IR8.7 + 2.3 2.4 + 0.6+ 3.8 + 0.62.4 + 0.4+
Data are means ± s.e.m.
Adjusted-ins. index, adjusted insulinogenic index; AIR, acute insulin response.
*The plus sign indicates P ≤ 0.05 for the difference between pre- and post-BPD. **P ≤ 0.05 vs. type 2 diabetes subjects; ***P ≤ 0.01 vs. type 2 diabetes subjects.
Figure 1 Acute insulin respose (AIR) in type 2 diabetic subjects pre- and
1 month post-biliopancreatic diversion (BPD).
VOLUME 16 NUMBER 1 | JANUARY 2008 | www.obesityjournal.org
intervention and prevention
relative role of bariatric surgery itself and weight loss, respec-
tively, on beta-cell function. In the present study we have
shown that AIR was already restored 1 month after BPD
when the weight loss was only ~11%, suggesting that the
improvement of AIR induced by BPD is rapid and not com-
pletely dependent on weight loss.
Restoration of AIR after BPD could be due to changes of
gastrointestinal (GI) hormones, BW, adipokines, gluco- and
Glucagon-like peptide-1 and gastrointestinal peptide (GIP)
are important regulators of beta-cell function and insulin
secretion and changes in their secretion patterns have been
described following gastric bypass and BPD (24,25). It has been
proposed that alterations in GIP secretion might be involved in
the metabolic effect of gastric bypass (24,26). AIR is only mini-
mally affected, if any, by gastric bypass suggesting that GIPs
do not play a critical role in AIR rescue. However, since gluca-
gon-like peptide-1 has a stimulatory effect on glucose induced
insulin secretion, the role of GIP on AIR improvement follow-
ing bariatric surgery cannot be excluded.
Although AIR is an abnormality at least in part inherited
(27,28), many environmental and metabolic conditions might
affect early insulin secretion. In subjects with glucose intoler-
ance, weight gain leads to a relative impairment in AIR (29). In
T2DM obese patients weight reduction obtained by dieting is
unable to restore AIR (10), while contrasting data are reported
after gastric bypass (10,30). In the present study we initially
found a correlation between BW change and AIR improvement,
which failed to persist after multivariate analysis, suggesting a
non primary role for weight reduction in rescue of AIR.
It is well known also that moderate hyperglycemia seems
to reduce first-phase insulin secretion even in non-diabetic
subjects (31), but in type 2 diabetes questions arise about the
reversibility of the altered AIR also after normalization of
plasma glucose with insulin treatment (32,33). In previous
studies in obese diabetic subjects weight loss was not associ-
ated with a normalization of fasting plasma glucose (10). The
importance of these results for restoration of AIR, even if clear,
is not completely understood. In fact high glucose concentra-
tions affect AIR and conversely AIR is important for glucose
regulation (34). To our knowledge BPD is the only measure
able to induce an early improvement of AIR, but not only by
the normalization of glucose concentrations. The significant
correlation between changes in glucose concentrations and
improvement in AIR that we observed confirms the important
bi-directional connections between glucotoxicity and acute
A relationship between adipocyte-derived factors and beta-
cell function has been suggested. In fact both leptin and adi-
ponectin receptors are localized in the pancreatic beta cell.
In vitro leptin suppresses insulin secretion from human islets
(35) while in islets from insulin resistant mice adiponectin
shows a dual effect: at lower glucose concentrations it inhib-
its, but at higher glucose concentrations it increases insulin
secretion (36). After BPD we observed a significant reduc-
tion of leptin, but we did not found any relation between
acute insulin secretion and leptin changes, as well as between
adiponectin and insulin secretion. A possible explanation
could be the small changes in adiponectin after BPD with a
prevalent increase of HMW form. The effect of there isoforms
on insulin secretion is still unknown.
BPD causes a selective malabsorbtion of lipid substrate.
There has been reported an increase of Glut4 expression in
the muscles of obese subjects after BPD (37). This result and
its effect on insulin resistance have been associated with the
intramyocellular fat depletion induced by BPD. Recently in a
murine model it has been demonstrated that diabetes induced
by a chronic high fat diet is characterized by an attenuation
of the expression of Glut2 expression in pancreatic beta cell
(38). Glut2 is essential for glucose-stimulated insulin secre-
tion; therefore it could be supposed a similar mechanism
exists in humans as the molecular base of beta-cell lipotoxicity.
According to this view, we can hypothesize that a reduction of
lipotoxicity induced by BPD is a possible mechanism for the
increment of insulin secretion in obese subjects after BPD.
In obese non-diabetic subjects an improvement of beta-cell
function has been reported after a 15 and 25% weight reduc-
tion (39). In accordance with this observation, we found after
a lower weight loss an increase of insulin response to glu-
cose, expressed as insulinogenic index corrected for insulin
resistance, both in diabetic and non-diabetic obese subjects.
Interestingly, this parameter was not different after BPD in the
two groups. This observation can justify the reported high rate
of normalization in the long term, of blood glucose in the dia-
betic obese after BPD (19).
In conclusion, in obese subjects with type 2 diabetes we
observed a reduction of fasting blood glucose and a restoration
of AIR 1 month after BPD, when the subjects are still severely
obese. Selective fat malabsorbtion, obtained by BPD, with the
consequent reduction of gluco and lipotoxicity might be the
mechanism responsible for the normalization of fasting blood
glucose and restoration of AIR.
We thank Mrs Maria Rosa Dagnino for skilful administrative assistance.
This work was supported in part by grants from Fondazione CARIGE and
the University of Genova.
The authors declared no conflict of interest.
© 2008 The Obesity Society
1. Kahn SE. The relative contributions of insulin resistance and beta-cell
dysfunction to the pathophysiology of type 2 diabetes. Diabetologia
2. Zimmet P, Alberti KG, Shaw J. Global and societal implications of the
diabetes epidemic. Nature 2001;414:782–787.
3. Knowler WC, Barrett-Connor E, Fowler SE et al. The Diabetes Prevention
Program Research Group: reduction in the incidence of type 2 diabetes with
lifestyle intervention or metformin. N Engl J Med 2002;346:393–403.
4. Pan XR, Li GW, Hu YH et al. Effects of diet and exercise in preventing
NIDDM in people with impaired glucose tolerance. The Da Qing IGT and
Diabetes Study. Diabetes Care 1997;20:537–544.
5. Tuomilehto J, Lindstrom J, Eriksson JG et al. Prevention of type 2 diabetes
mellitus by changes in lifestyle among subjects with impaired glucose
tolerance. N Engl J Med 2001;344:1343–1350.
obesity | VOLUME 16 NUMBER 1 | JANUARY 2008 81 Download full-text
intervention and prevention
6. Buchwald H, Avidor Y, Braunwald E et al. Bariatric surgery: a systematic
review and meta-analysis. JAMA 2004;292:1724–1737.
7. Scopinaro N, Marinari GM, Camerini GB, Papaia FS, Adami GF. Specific
effects of biliopancreatic diversion on the major components of metabolic
syndrome: a long-term follow-up study. Diabetes Care 2005;28:2406–2411.
8. Mingrone G, DeGaetano A, Greco AV et al. Reversibility of insulin resistance
in obese diabetic patients: role of plasma lipids. Diabetologia 1997;
9. Brunzell JD, Robertson RP, Lerner RL et al. Relationship between fasting
plasma glucose levels and insulin secretion during intravenous glucose
tolerance tests. J Clin Endocrinol Metab 1976;42:222–229.
10. Highes TA, Gwynne JT, Switzer BR, Herbst C, White G. Effects of caloric
restriction and weight loss on glycemic control, insulin release and
resistance, and atherosclerotic risk in obese patients with type II diabetes
mellitus. Am J Med 1984;77:7–17.
11. Polyzogopoulou EV, Kalfarentzos F, Vagenakis AG, Alexandrides TK.
Restoration of euglycemia and normal acute insulin response to glucose
in obese subjects with type 2 diabetes following bariatric surgery. Diabetes
12. Guidone C, Manco M, Valera-Mora E et al. Mechanisms of recovery
from type 2 diabetes after malabsorptive bariatric surgery. Diabetes
13. Expert Committee on the Diagnosis and Classification of Diabetes Mellitus:
Report of the Expert Committee on the Diagnosis and Classification of
Diabetes Mellitus Diabetes Care 1997;20:1183–1197.
14. Scopinaro N, Adami GF, Marinari GM et al. Biliopancreatic diversion.
World J Surg 1998;22:936–946.
15. Alvarsson M, Wajngot A, Cerasi E, Efendic S. K-value and low insulin
secretion in a non-obese white population: predicted glucose tolerance
after 25 years. Diabetologia 2005;48:2262–2268.
16. Matthews DR, Hosker JP, Rudenski AS et al. Homeostasis model
assessment: insulin resistance and beta-cell function from fasting
plasma glucose and insulin concentrations in man. Diabetologia
17. Salani B, Briatore L, Andreghetti G et al. High-molecular weight adiponectin
isoforms increase after biliopancreatic diversion in obese subjects. Obesity
(silver spring) 2006;14:1511–1514.
18. Mari A, Manco M, Guidone C et al. Restoration of normal glucose tolerance
in severely obese patients after bilio-pancreatic diversion: role of insulin
sensitivity and beta cell function. Diabetologia 2006;49:2136–2143.
19. Adami GF, Cordera R, Camerini G, Marinari GM, Scopinaro N.
Long-term normalization of insulin sensitivity following biliopancreatic
diversion for obesity. Int J Obes Relat Metab Disord 2004;28:671–673.
20. Adami GF, Cordera R, Camerini G, Marinari GM, Scopinaro N.
Recovery of insulin sensitivity in obese patients at short term after
biliopancreatic diversion. J Surg Res 2003;113:217–221.
21. Rubino F, Marescaux J. Effect of duodenal-jejunal exclusion in a non-obese
animal model of type 2 diabetes: a new perspective for an old disease.
Ann Surg 2004;239:1–11.
22. Scopinaro N, Marinari GM, Pretolesi F et al. Energy and nitrogen absorption
after biliopancreatic diversion. Obes Surg 2000;10:436–441.
23. Mingrone G, Rosa G, Di Rocco P et al. Skeletal muscle triglycerides lowering
is associated with net improvement of insulin sensitivity, TNF-α reduction
and GLUT4 expression enhancement. Int J Obes Relat Metab Disord
24. Naslund E, Kral JG. Impact of gastric bypass surgery on gut hormones and
glucose homeostasis in type 2 diabetes. Diabetes 2006;55:S92–S97.
25. Valverde I, Puente J, Martin-Duce A et al. Changes in glucagon-like
peptide-1 (GLP-1) secretion after biliopancreatic diversion or vertical banded
gastroplasty in obese subjects. Obes Surg 2005;15:387–397.
26. Rubino F, Forgione A, Cummings DE et al. The mechanism of diabetes
control after gastrointestinal bypass surgery reveals a role of the proximal
small intestine in the pathophysiology of type 2 diabetes. Ann Surg
27. O’Rahilly SP, Nugent Z, Rudenski AS et al. Beta-cell dysfunction, rather than
insulin insensitivity, is the primary defect in familial type 2 diabetes. Lancet
28. Pimenta W, Korytkowski M, Mitrakou A et al. Pancreatic beta-cell
dysfunction as the primary genetic lesion in NIDDM. Evidence from studies
in normal glucose-tolerant individuals with a first-degree NIDDM relative.
29. Weyer C, Hanson K, Bogardus C, Pratley RE. Long-term changes in
insulin action and insulin secretion associated with gain, loss, regain and
maintenance of body weight. Diabetologia 2000;43:36–46.
30. Garcia-Fuentes E, Garcia-Almeida JM, Garcia-Arnes J et al. Morbidly obese
individuals with impaired fasting glucose have a specific pattern of insulin
secretion and sensitivity: effect of weight loss after bariatric surgery.
Obes Surg 2006;16:1179–1188.
31. Toschi E, Camastra S, Sironi AM et al. Effect of acute hyperglycemia on
insulin secretion in humans. Diabetes 2002;51:S130–S133.
32. Vague P, Moulin JP. The defective glucose sensitivity of the B cell in
non insulin dependent diabetes. Improvement after twenty hours of
normoglycaemia. Metabolism 1982;31:139–142.
33. Garvey WT, Olefsky JM, Griffin J, Hamman RF, Koltermann OG. The effect
of insulin treatment on insulin secretion and insulin action in type II diabetes
34. Pratley RE, Weyer C. The role of impaired early insulin secretion in the
pathogenesis of Type II diabetes mellitus. Diabetologia 2001;44:929–945.
35. Seufer J. Leptin effects on pancreatic β-cell gene expression and function.
36. Winzell MS, Nogueiras R, Dieguez C, Ahren B. Dual action of adiponectin on
insulin secretion in insulin-resistant mice. Biochem Biophys Res Commun
37. Greco AV, Mingrone G, Giancaterini A et al. Insulin resistance in morbid
obesity: reversal with intramyocellular fat depletion. Diabetes
38. Ohtsubo K, Takamatsu S, Minowa MT et al. Dietary and genetic control
of glucose transporter 2 glycosylation promotes insulin secretion in
suppressing diabetes. Cell 2005;123:1307–1321.
39. Guldstrand M, Ahren B, Adamson U. Improved beta-cell function after
standardized weight reduction in severely obese subjects.
Am J Physiol Endocrinol Metab 2003;284:E557–E565.