Bariatric Surgery Reduces Risk Factors for Development of Type 2 Diabetes Mellitus in Morbidly Obese,Nondiabetic Patients

Abstract

Background:

Patients with morbid obesity have a high risk of developing type 2 diabetes mellitus (T2DM). Important risk factors include body mass index (BMI), waist circumference, and insulin resistance. In this prospective study, we investigated if preoperative lifestyle changes followed by bariatric surgery could reduce these risk factors.

Methods:

Forty nondiabetic obese patients aged 27–57 years participated. Baseline BMI was 36.1–65.6 kg/m². Fasting glucose, C-peptide, and glycated hemoglobin (HbA1c) were measured at baseline and 1 year after surgery. The patients underwent lifestyle changes for a period of 3 months prior to bariatric surgery and were followed for 1 year after surgery. The correlations between risk factors and weight reduction were assessed by a Pearson test.

Results:

Lifestyle changes resulted in a mean weight reduction of 14.3 kg. One year after bariatric surgery, the patients had a mean reduction in BMI of 17.6. Mean waist circumference was reduced from 136.5 cm to 100.7 cm. At baseline, all 40 patients had a waist circumference >100 cm; 1 year after surgery 18 of 40 patients did. At baseline, 11 out of 40 had insulin resistance (as defined by a homeostasis model score >3.99), whereas 1 year after surgery none of the patients did. There was a statistically significant correlation between change in waist circumference and change in insulin resistance (P<0.02), and between HbA1c and weight loss (P<0.002).

Conclusions:

Our study shows that, in morbidly obese individuals, lifestyle changes followed by bariatric surgery led to a significant weight loss and a reduction in risk factors for development of T2DM.

Introduction

O besity is now a worldwide problem. Morbidly obese patients have an increasing risk of impaired glucose metabolism and insulin-resistance and thereby of developing type 2 diabetes mellitus (T2DM).¹ Bariatric surgery has for the last 2 decades become an approved treatment for morbidly obese patients. Surgery leads to a significantly better weight reduction than intensive conventional therapy, including change of eating habits and increased physical activity.² Especially laparoscopic Roux-en-Y gastric bypass (LRYGB) has proven to be beneficial in treatment of T2DM.^3
–5 The significant weight reduction is caused by several mechanisms. A small ventricular pouch decreases the amount of food that the patient can consume; creating a long alimentary limb results in a reduced energy uptake, and the fact that the antrum of the ventricle and duodenum is bypassed results in changing the brain/gut pathway and thereby the sensation of hunger, satiety, and craving for sweets.^6
–8 Obesity leads to a significant economic burden on the health care system, treatment of T2DM and its complications being one of the major factors contributing to it.^8,9 Many obese patients have undiagnosed T2DM.¹⁰ Diabetes mellitus may lead to impaired renal function, urine incontinence, retinopathy, atherosclerotic disease, and polyneuropathy. Therefore, the aim of the present study was to investigate the effect of lifestyle changes followed by bariatric surgery on risk factors for development of T2DM in nondiabetic obese patients [using waist circumference and homeostasis model assessment of insulin resistance (HOMA-IR score)].

Materials and Methods

Study participants and experimental design

This was a prospective study with 40 morbidly obese nondiabetic patients admitted to the Regional center for treatment of morbid obesity at Nordland Hospital, Norway. The patients were followed from admission to 1 year after bariatric surgery. The study was approved by the regional ethics committee of Northern Norway in accordance with the Helsinki II declaration and by the Norwegian Data Protection Authority. Written informed consent was obtained from all participation patients.

Inclusion criteria were body mass index (kg/m², BMI) ≥40 or BMI ≥35 with co-morbidity, such as hypertension and sleep apnea, but with no overt diabetes and with a normal oral glucose tolerance test (OGTT). The patients underwent lifestyle changes for a mean period of 3 months prior to bariatric surgery and were followed 1 year after surgery. Waist circumference was measured midway between the lateral lower ribs and the iliac crest with the patient in an upright position at first admission and at 1 year after surgery.

Blood sampling

Fasting blood samples were obtained by standard venipuncture on three occasions—at admission, at the time of surgery, and 1 year after surgery. Routine blood analyses were performed at the laboratory of Nordland Hospital. The analyses included an OGTT at first visit and glycated hemoglobin (HbA1c) at all three occasions. In addition, fasting glucose and C-peptide were measured at first admission and after 1 year. C-peptide was analyzed at Aker University Hospital, Oslo. Samples for C-peptide were frozen in aliquots at −80°C and analyzed in batches at the end of the study. For HbA1c, the Tosoh Bioscience HLC-723 G8 (Tokyo, Japan) method was used.

HOMA-IR score was calculated using the HOMA-IR calculator, developed by the “Diabetes Trials Unit” (University of Oxford, UK).¹¹ The HOMA-IR score is a method to assess insulin resistance from fasting glucose and insulin or C-peptide concentration.

Lifestyle changes

Patients had to undergo lifestyle changes preoperatively, resulting in an average weight loss of 10%. The aim of this was to prepare the patients for a life with a small gastric pouch after gastric bypass. Patients received repeated personal guidance concerning change of eating habits and increased physical activity at baseline and by phone consultations with a nutritionist or specially educated nurse every 2 weeks preoperatively. The patients were told to have a meal every 3–4 hours, for a daily total of three main meals and three to four small meals in between. They were advised to eat an energy-restricted diet of 2000 kcal for males and 1500 kcal for women. That included fat content of <30 energy %, complex carbohydrates content of <40–50 energy %, and protein content of <20 energy %. It was also mandatory to participate in a 2-day course focusing on lifestyle changes and on how bariatric surgery would affect daily life. Information and education were given according to the Norwegian guidelines for treatment of morbidly obese patients, and Norwegian guidelines for nutrition given by the Norwegian Ministry of Health and Care Services. The patients were not accepted for surgery before they had achieved a 10% weight loss. It took patients on average 12 weeks to achieve a 10% weight loss.

Surgery

Two surgical methods were used: (1) LRYGB was performed using a standardized procedure by creating a small ventricular pouch of 30 mL, a bileopancreatic limb of 50 cm, and an alimentary limb of 100 cm.¹² This method was used for patients with BMI ≤50. (2) Bileopancreatic diversion with duodenal switch (BPDDS) was performed using a standardized procedure. We created a gastric sleeve using a 32 French probe to measure the diameter of the gastric sleeve, then made an alimentary limb of 150 cm and a common channel of 100 cm.¹² This method was chosen for patients with a BMI >50. One patient received a LRYGB despite a BMI of 51.7. One patient received a BPDDS despite a BMI of 46.7. This patient had lost 14.7 kg prior to the first admission, so the initial BMI of the patient was 51.7. All operations were performed by two experienced bariatric surgeons.

Statistics

Numerical data are presented with mean. Repeated-measures analysis of variance (ANOVA) was used for comparing changes in weight, BMI, and HbA1c during the observation period. A one-sample paired t-test was used for comparing changes in weight, BMI, and HbA1c from baseline to the time of surgery and from the time of surgery to 1 year after surgery. A one-sample paired t-test was also used for comparing HOMA-IR score and waist circumference. Correlation between variables was calculated with a Pearson correlation test. Graphs and analyses were done in PRISM 6 (GraphPad Software Inc., La Jolla, CA).

Results

Baseline characteristics

Baseline characteristics are given in Table 1.

Table 1.

Baseline Characteristics n=40 Patients

	n or mean	Range
LRYGBP/BPDDS	29/11
Males/females	8/32
Age	43.0 year	27–57 year
Weight	136.5 kg	89.5–219 kg
BMI	46.94 kg/cm²	36.10–65.6 kg/cm²
Waist	136.5 cm	107.0–177.0 cm
Fasting glucose	5.46 mmol/L	4.3–6.7 mmol/L
HbA1c	5.81%	5.4–6.6 %
HOMA-IR score	3.46	1.5–7.9

LRYGBP, laparoscopic Roux-en-Y gastric bypass; BPDDS, bileopancreatic diversion with duodenal switch; BMI, body mass index; HOMA-IR score, homeostasis model assessment of insulin resistance.

Effect on weight loss, BMI, and waist circumference

The 3-month lifestyle change resulted in a mean preoperative weight loss of 14.3 kg, (range 12.1–19.5 kg, P<0.0001). One year after surgical intervention, patients had a mean weight loss from baseline of 50.52 kg (range 30.1–85.8 kg, P<0.0001) (Fig. 1A). Correspondingly, BMI was reduced from a mean baseline value of 46.94 kg/m² (range 36.1–65.6 kg/m²) to a mean value of 41.75 kg/m² before surgery (range 33.5–58.7 kg/m², P<0.0001). One year after surgery, mean BMI was 29.31kg/m² (range 22.4–38.2 kg/m², P<0.0001) (Fig. 1B). All patients had a statistically significant reduction in waist circumference from baseline to 1 year after surgery. The mean reduction was 35.8 cm (range 33.0–46.0 cm, P<0.0001) (Fig. 1C).

FIG. 1.

Weight (A), body mass index (BMI) (B), and waist circumference (C) at baseline, time of surgery, and 1 year after surgery. Mean is indicated.

Effects on glucose metabolism

Mean fasting glucose decreased from 5.46 mmol/L at baseline to 4.76 mmol/L 1 year after surgery (P<0.0001) (Fig. 2A). Ten out of 40 patients had a fasting glucose between 6 and 7, possibly indicating impaired glucose tolerance (IGT) or T2DM, but none of the patients had 2-h fasting glucose (2hFG) ≥11.1 mmol/L. Three patients had 2hFG ≥7, whereas one of them had 2hFG of 10.7 mmol/L (data not shown). The patients had a statistically significant reduction in HbA1c %. Mean value decreased from 5.81% at baseline to 5.70 % at time of surgery (P<0.02), and further to 5.46% 1 year after surgery (P<0.0001) (Fig. 2B).

FIG. 2.

Fasting glucose (A) and homeostasis model assessment of insulin resistance (HOMA-IR) score (C) at baseline and 1 year after surgery. Glycated hemoglobin (HbA1c) at baseline, time of surgery, and 1 year after surgery (B). Mean is indicated.

Correspondingly, mean C-peptide value decreased from 1.56 nmol/L at baseline to 0.64 nmol/L 1 year after surgery. Mean reduction was 0.92 nmol/L (range 0.49–3.27 nmol/L, P<0.0001; data not shown). Mean HOMA-IR score reduction from baseline to 1 year after surgery was 2.1 (range 1.1–5.3, P<0.0001) (Fig. 2C).

Correlations

There was a statistically significant correlation between reduction in HOMA-IR score and weight loss from baseline to 1 year after surgery (R ²=0.121, P<0.03) (Fig. 3A). Furthermore, correlation between HOMA-IR score reduction and waist circumference reduction was also statistically significant (R ²=0.148, P<0.02) (Fig. 3B). There was a strong correlation between weight loss and waist circumference reduction (R ²=0.712, P<0.0001; data not shown).

FIG. 3.

Correlation between change in homeostasis model assessment of insulin resistance (HOMA-IR) score and weight (A) and waist circumference (B), respectively, from baseline to 1 year after surgery.

The correlation between preoperative weight loss and preoperative HbA1c reduction was not statistically significant (R ²=0.041, P<0.3) (Fig. 4A). From baseline and from time of surgery to 1 year after surgery, however, the same correlations were statistically significant [R ²=0.10, P<0.05 (Fig. 4B) and R ²=0.247, P<0.002, respectively (Fig.4C)].

FIG. 4.

Correlation between change in glycated hemoglobin (HbA1c) and weight at three different occasions—baseline versus surgery (A), surgery versus 1 year after surgery (B), and baseline versus 1 year after surgery (C).

Discussion

In this study, we have demonstrated how lifestyle changes followed by bariatric surgery reduce risk factors for development of T2DM in nondiabetic patients. The main factor for development of T2DM is increasing body weight and the development of obesity. The relative risk of T2DM increases exponentially with increasing BMI.¹ The true incidence of T2DM in morbidly obese patients has been estimated to 31%, but only a fourth of these were detected by fasting plasma glucose screening.^10,13 In addition, many morbidly obese patients have IGT. IGT is defined as glucose plasma levels of 7.8–11.0 mmol/L 2 h after an OGTT. Fasting glucose levels may be normal or slightly elevated in IGT. The term “prediabetes” is used to define patients with IGT and/or insulin resistance.³ Up to 70% of morbidly obese patients who have “prediabetes” develop T2DM during their lifetime.³ Using fasting C-peptide and fasting glucose to calculate the HOMA-IR score can identify patients in danger of developing T2DM, even if their OGTT is normal.¹¹ There are clinical trials that show a decrease in development of T2DM after lifestyle intervention or treatment with metformin.^14,15 In our study, nondiabetic patients did not (by definition) have IGT, but 11 out of 40 patients had a HOMA-IR score higher than 3.99, which indicates insulin resistance. Prioritizing these patients for lifestyle intervention and bariatric surgery could prevent development of T2DM.

HbA1c has been used to monitor patients suffering from diabetes mellitus. However, the World Health Organization now accepts using HbA1c as a diagnostic criterion for diabetes mellitus.^16,17 HbA1c reflects the blood glucose level over the last 8–12 weeks. Even if the weight loss was 10%, our patients had a limited effect on reduction of HbA1c preoperatively. This can be explained by the short period from admission to surgery, on average only 12 weeks. In previous trials, patients going through conventional treatment for morbid obesity had an average weight loss of 4.3%–10% after 1–2 years.^2,18,19 Conventional treatment included change of lifestyle and eating habits as well as increased physical activity. However, these patients were randomized to conventional therapy or bariatric surgery, and individuals already diagnosed with T2DM were not excluded. Jorgensen et al. did not find a statistically significant reduction in HbA1c 1 year after intervention in a group of nondiabetic obese patients undergoing LRYGBP.²⁰ These results differ from ours. In our study, however, patient`s weight and HbA1c at baseline were higher, weight range was wider, and patients lost more weight during the study period compared to patients in the study by Jorgensen et al. Also, in our study, several patients received the more extensive BPDDS procedure because of baseline BMI higher than 50. The BPDDS procedure leads to a greater weight loss. In our study, 11 out of 40 patients had a baseline BMI higher than 50. However, even if we exclude patients with a baseline BMI higher than 50 from in our study, we still observed a higher weight loss 1 year after surgery than did the Jorgenson study. In our study, a higher weight loss was correlated with a higher reduction in HbA1c.

Waist circumference is also a good predictor (of risk) for development of T2DM.^21

–24 The risk for developing insulin resistance increases at a waist circumference higher than 102 cm in men and higher than 88 cm in women in subjects with a BMI ≥30.^24
–26 Waist circumference reflects the amount of intra-abdominal fatty tissue and thereby the hormonal effect on insulin secretion and action. Intra-abdominal fatty tissue contains larger adipocytes than subcutaneous fatty tissue. The larger the adipocytes, the more dysfunctional they become concerning the antilipolytic effect of insulin.²⁷ Increased insulin resistance in intra-abdominal fatty tissue leads to reduction of glucose uptake compared to subcutaneous fatty tissue.²⁷ Through measurement of plasma glucose, HbA1c, and plasma lipopolysaccharide (LPS) before and after bariatric surgery, several studies have indicated a relationship between obesity, gut microbiota, and development of T2DM.^28
–30 Recently, we have shown a statistically significant correlation between plasma levels of LPS and intra-abdominal fatty tissue volume as well as a significantly increased gradient of bacterial DNA content in adipose tissue compartments with increasing proximity to the gut. Furthermore, bariatric surgery significantly reduced plasma levels of LPS, and the reduction correlated with a reduction in HbA1c.³¹ Because intra-abdominal fatty tissue is the leading factor for an increased waist circumference, these findings underline the importance of waist circumference as a risk factor for development of T2DM.

Our study has some limitations. One is the lack of a control group, but it is difficult to compare patients undergoing bariatric surgery and patients undergoing conventional treatment due to the big difference in achieved weight loss. Furthermore, the study has a limited sample size, which can lead to statistical Type II errors, whereas Type I errors are less likely. The imbalance between female and male participants could be of significance, but knowing that male fat distribution leads to a bigger waist circumference our male-to-female ratio should indicate that our results are not overestimated. Furthermore, waist circumference and HOMA-IR score were measured only two times during the study period. On the other hand, the prospective study design and the fact that the study group was followed for 1 year after surgery strengthen our results.

Conclusion

Our study shows that, in morbidly obese nondiabetic individuals, lifestyle changes followed by bariatric surgery lead to a significant weight loss, a reduction in waist circumference, and reduction in HOMA-IR score. We postulate that lifestyle changes followed by bariatric surgery reduce the probability of developing T2DM. To measure waist circumference is an easy and cheap measurement to perform and should therefore be a part of examination of all obese patients. It is important to identify patients at risk and initiate treatment modalities that reduce their body weight and thereby reduce the risk of developing T2DM.

Footnotes

Acknowledgments

The skillful assistance by the nurses at the Regional Centre for Treatment of Morbid Obesity and Hilde Fure at the Somatic Research Laboratory at Nordland Hospital is greatly acknowledged. This study was supported by Nordland Hospital and research grants from the regional health authorities of Northern Norway.

All authors contributed to the study design. T.K.N. interpreted results of analyses, prepared figures and table, and drafted the manuscript. E.W.N. and K.T.L. edited and revised the manuscript. T.K.N., E.W.N., and K.T.L. approved the final version of manuscript.

Author Disclosure Statement

T.K.N., E.W.N., and K.T.L. state that we have no competing financial interests.

References

Anderson

, Kendall

, Jenkins

. Importance of weight management in type 2 diabetes: Review with meta-analysis of clinical studies. J Am Coll Nutr., 2003; 22:331–339.

Mingrone

, Panunzi

, De

et al. Bariatric surgery versus conventional medical therapy for type 2 diabetes. N Engl J Med, 2012; 366:1577–1585.

Perreault

, Pan

, Mather

et al. Effect of regression from prediabetes to normal glucose regulation on long-term reduction in diabetes risk: Results from the Diabetes Prevention Program Outcomes Study. Lancet, 2012; 379:2243–2251.

Bose

, Teixeira

, Olivan

et al. Weight loss and incretin responsiveness improve glucose control independently after gastric bypass surgery. J Diabetes, 2010; 2:47–55.

Hofso

, Jenssen

, Bollerslev

et al. Beta cell function after weight loss: A clinical trial comparing gastric bypass surgery and intensive lifestyle intervention. Eur J Endocrinol, 2011; 164:231–238.

Ochner

, Kwok

, Conceicao

et al. Selective reduction in neural responses to high calorie foods following gastric bypass surgery. Ann Surg, 2011; 253:502–507.

Park

, Torquati

. Physiology of weight loss surgery. Surg Clin North Am, 2011; 91:1149–1161, vii.

Shamseddeen

, Getty

, Hamdallah

et al. Epidemiology and economic impact of obesity and type 2 diabetes. Surg Clin North Am, 2011; 91:1163–1172, vii.

Withrow

, Alter

. The economic burden of obesity worldwide: A systematic review of the direct costs of obesity. Obes Rev, 2011; 12:131–141.

10.

Hofso

, Jenssen

, Hager

et al. Fasting plasma glucose in the screening for type 2 diabetes in morbidly obese subjects. Obes Surg, 2010; 20:302–307.

11.

Wallace

, Levy

, Matthews

. Use and abuse of HOMA modeling. Diabetes Care, 2004; 27:1487–1495.

12.

Buchwald

. Consensus conference statement bariatric surgery for morbid obesity: Health implications for patients, health professionals, and third-party payers. Surg Obes Relat Dis, 2005; 1:371–381.

13.

Saaristo

, Barengo

, Korpi-Hyovalti

et al. High prevalence of obesity, central obesity and abnormal glucose tolerance in the middle-aged Finnish population. BMC Public Health, 2008; 8:423.

14.

Knowler

, Barrett-Connor

, Fowler

et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med, 2002; 346:393–403.

15.

Tuomilehto

, Lindstrom

, Eriksson

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.

16.

International Expert Committee report on the role of the A1C assay in the diagnosis of diabetes. Diabetes Care, 2009; 32:1327–1334.

17.

Diagnosis and classification of diabetes mellitus. Diabetes Care, 2012; 35,Suppl 1:S64–S71.

18.

Hofso

, Nordstrand

, Johnson

et al. Obesity-related cardiovascular risk factors after weight loss: A clinical trial comparing gastric bypass surgery and intensive lifestyle intervention. Eur J Endocrinol, 2010; 163:735–745.

19.

Dixon

, O'Brien

, Playfair

et al. Adjustable gastric banding and conventional therapy for type 2 diabetes: A randomized controlled trial. JAMA, 2008; 299:316–323.

20.

Jorgensen

, Jacobsen

, Dirksen

et al. Acute and long-term effects of Roux-en-Y gastric bypass on glucose metabolism in subjects with type 2 diabetes and normal glucose tolerance. Am J Physiol Endocrinol Metab, 2012; 303:E122–E131.

21.

Wang

, Rimm

, Stampfer

et al. Comparison of abdominal adiposity and overall obesity in predicting risk of type 2 diabetes among men. Am J Clin Nutr, 2005; 81:555–563.

22.

Vazquez

, Duval

, Jacobs

Jr.

et al. Comparison of body mass index, waist circumference, and waist/hip ratio in predicting incident diabetes: A meta-analysis. Epidemiol Rev, 2007; 29:115–128.

23.

Wei

, Gaskill

, Haffner

et al. Waist circumference as the best predictor of noninsulin dependent diabetes mellitus (NIDDM) compared to body mass index, waist/hip ratio and other anthropometric measurements in Mexican Americans—a 7-year prospective study. Obes Res, 1997; 5:16–23.

24.

Han

, van Leer

, Seidell

et al. Waist circumference action levels in the identification of cardiovascular risk factors: Prevalence study in a random sample. Br Med J, 1995; 311:1401–1405.

25.

Wahrenberg

, Hertel

, Leijonhufvud

et al. Use of waist circumference to predict insulin resistance: Retrospective study. Br Med J, 2005; 330:1363–1364.

26.

Lean

, Han

, Morrison

. Waist circumference as a measure for indicating need for weight management. Br Med J, 1995; 311:158–161.

27.

Ibrahim

. Subcutaneous and visceral adipose tissue: Structural and functional differences. Obes Rev, 2010; 11:11–18.

28.

Furet

, Kong

, Tap

et al. Differential adaptation of human gut microbiota to bariatric surgery-induced weight loss: Links with metabolic and low-grade inflammation markers. Diabetes, 2010; 59:3049–3057.

29.

Vrieze

, Van

, Holleman

et al. Transfer of intestinal microbiota from lean donors increases insulin sensitivity in individuals with metabolic syndrome. Gastroenterology, 2012; 143:913–916.

30.

Monte

, Caruana

, Ghanim

et al. Reduction in endotoxemia, oxidative and inflammatory stress, and insulin resistance after Roux-en-Y gastric bypass surgery in patients with morbid obesity and type 2 diabetes mellitus. Surgery, 2012; 151:587–593.

31.

Troseid

, Nestvold

, Rudi

et al. Plasma lipopolysaccharide is closely associated with glycemic control and abdominal obesity. Diabetes Careonline before printJuly 8, 2013, 10.2337/dc13-0451.