Type 2 Diabetes: A Surgical Type 2 Diabetes: A Surgical Disease???Disease???

The prevalance of obesity and diabetes mellitus is rising The prevalance of obesity and diabetes mellitus is rising & strongly linked to DM with accompanying insulin & strongly linked to DM with accompanying insulin resistanceresistance

Impaired insulin secretion and insulin resistance are Impaired insulin secretion and insulin resistance are both causative factors in the development of Type 2 DMboth causative factors in the development of Type 2 DM

Amelioration of Type 2 diabetes is a proven outcome of Amelioration of Type 2 diabetes is a proven outcome of surgical treatment of obesitysurgical treatment of obesity

Biliopancreatic diversion (BPD) and Roux-en-Y gastric Biliopancreatic diversion (BPD) and Roux-en-Y gastric bypass (RYGBP) are more effective for amelioration of bypass (RYGBP) are more effective for amelioration of DM than other proceduresDM than other procedures May lead to normalization of glycosylated hemoglobin, plasma May lead to normalization of glycosylated hemoglobin, plasma

glucose and insulin in as much as 90-100% of morbidly obese glucose and insulin in as much as 90-100% of morbidly obese patients with DM patients with DM 11

Insulin sensitivity is increased approximately 4-5 fold after RYGB Insulin sensitivity is increased approximately 4-5 fold after RYGB induced weight loss induced weight loss 22

Prevents progression from impaired glucose tolerance to Prevents progression from impaired glucose tolerance to diabetes, by as much as 30 fold diabetes, by as much as 30 fold 22

1.Pacheco D, et al. The effects of duodenal-jejunal exclusion on hormonal regulation of glucose metabolism in Goto-Kakizaki rats. Am J Surgery; 194 (2007):221-2242. Rubino F. Bariatric Surgery:effects on glucose homeostasis. Curr Opin Clin Nutr Metab Care 9:497-507

Historic PerspectiveHistoric Perspective ““Diabetes remission has been reported before Diabetes remission has been reported before

the advent of bariatric surgery as a the advent of bariatric surgery as a serendipitous serendipitous outcome of gastric resections for outcome of gastric resections for peptic ulcer in non obese patients.”peptic ulcer in non obese patients.”

In 1955, In 1955, FriedmanFriedman reported 3 patients with DM reported 3 patients with DM who had poor glycemic control , despite therapy who had poor glycemic control , despite therapy with high daily doses of insulinwith high daily doses of insulin 3-4 days after subtotal gastrectomy all 3 pateints 3-4 days after subtotal gastrectomy all 3 pateints

showed an improvement in their DM with sudden showed an improvement in their DM with sudden reduction in insulin requirementsreduction in insulin requirements

This observation occurred sooner than associated This observation occurred sooner than associated weight lossweight loss

More importantly, these patients later regained their More importantly, these patients later regained their weight without an associated loss of glucose control weight without an associated loss of glucose control or glycosuriaor glycosuria

Rubino F. Bariatric Surgery:effects on glucose homeostasis. Curr Opin Clin Nutr Metab Care 9:497-507

Friedman NM et al. The amelioration of diabetes mellitus following subtotal gastrectomy. Surg Gynecol Obstetr 1955; 100:201-204.

Historic PerspectiveHistoric Perspective BittnerBittner et al. also reported amelioration of et al. also reported amelioration of

diabetes with lowered plasma glucose and diabetes with lowered plasma glucose and insulin after subtotal gastrectomy and insulin after subtotal gastrectomy and gastrointestinal reconstructions that gastrointestinal reconstructions that excluded duodenal passage (B2 and excluded duodenal passage (B2 and RYGB)RYGB)

Conclusion: Plasma glucose and insulin Conclusion: Plasma glucose and insulin fall rapidly and antidiabetic medications fall rapidly and antidiabetic medications can be reduced or stopped shortly after can be reduced or stopped shortly after gastrointestinal bypass interventionsgastrointestinal bypass interventions

Rubino F. Bariatric Surgery:effects on glucose homeostasis. Curr OpiClin Nutr Metab Care 9:497-507

Bittner R. Homeostasis of glucose and gastric resection: the influence of food passage through the duodenum. Z Gastroenterology 1981; 19:698-707.

Should patients with type 2 DM be Should patients with type 2 DM be considered for surgical treatment considered for surgical treatment

regardless of their BMI ?regardless of their BMI ? Current indications for bariatric surgery include Current indications for bariatric surgery include

BMI = or > than 40 kg/mBMI = or > than 40 kg/m2 2 or between 35 and 40 or between 35 and 40 kg/mkg/m22 with obesity-related comorbidities with obesity-related comorbidities

All bariatric operations are performed based on All bariatric operations are performed based on these specific criteria; therefore, the antidiabetic these specific criteria; therefore, the antidiabetic effects of bypass surgery is well documented in effects of bypass surgery is well documented in this population of severely or morbidly obese this population of severely or morbidly obese patientspatients

These procedures occaionally performed in non-These procedures occaionally performed in non-obese individuals obese individuals Mingrone et al. reported a case of BPD for a non obese Mingrone et al. reported a case of BPD for a non obese

female with chylomicronemia whose plasma insulin and female with chylomicronemia whose plasma insulin and blood glucose levels were normalized within 3 monthsblood glucose levels were normalized within 3 months

Noya et al. reported remission of type 2 DM in 9/10 Noya et al. reported remission of type 2 DM in 9/10 moderately obese patients with mean BMI 33, who moderately obese patients with mean BMI 33, who underwent BPDunderwent BPD

DJ Bypass & Glucose DJ Bypass & Glucose MetabolismMetabolism

Bariatric Surgery clearly has an antidiabetic Bariatric Surgery clearly has an antidiabetic effect; thought to be secondary to surgically effect; thought to be secondary to surgically induced weight loss and decreased caloric intakeinduced weight loss and decreased caloric intake

But, how do we explain the finding that glycemic But, how do we explain the finding that glycemic control occurs within days, before significant control occurs within days, before significant weight loss has been achieved???weight loss has been achieved??? Direct effect of the surgical bypass of proximal Direct effect of the surgical bypass of proximal

intestinesintestines Hormonal Regulation of Glucose MetabolismHormonal Regulation of Glucose Metabolism

Insulin, glucagons-like peptide(GLP-1), glucose-Insulin, glucagons-like peptide(GLP-1), glucose-dependent insulinotropic peptide (GIP), glucagon dependent insulinotropic peptide (GIP), glucagon and leptin and leptin Pacheco D, et al. The effects of duodenal-jejunal exclusion on hormonal regulation of

glucose metabolism in Goto-Kakizaki rats. Am J Surgery; 194 (2007):221-224

Animal Model of DJ bypass Animal Model of DJ bypass and Glycemic Controland Glycemic Control

Animal Model of nonobese type 2 diabetes; Goto-Kakizaki Animal Model of nonobese type 2 diabetes; Goto-Kakizaki ratsrats

Twelve (12-14 wk old) rats randomly underwentTwelve (12-14 wk old) rats randomly underwent gastrojejeunal bypass or no interventiongastrojejeunal bypass or no intervention * All fed with same type of diet* All fed with same type of diet * All fed with same amount of diet* All fed with same amount of diet * Pre-op, post op 1 wk & 1 month* Pre-op, post op 1 wk & 1 month weight assessment & fasting glycemiaweight assessment & fasting glycemia * Oral Glucose Tolerance Test performed at each * Oral Glucose Tolerance Test performed at each

time pointtime point * Hormone levels were measured after 20 minutes of * Hormone levels were measured after 20 minutes of

oral oral overloadoverload

Pacheco D, et al. The effects of duodenal-jejunal exclusion on hormonal regulation of glucose metabolism in Goto-Kakizaki rats. Am J Surgery; 194 (2007):221-224

Results of DJ Bypass on Results of DJ Bypass on Glycemic ControlGlycemic Control

Group 1 and Group 2 rats remained the Group 1 and Group 2 rats remained the same weight during the experimentsame weight during the experiment

OGTT improved in DJ bypass groupOGTT improved in DJ bypass group Glucose levels were better at 1 week & 1 Glucose levels were better at 1 week & 1

month after DJ bypass in all times of month after DJ bypass in all times of OGTT (basal, 10 min, 120 min)OGTT (basal, 10 min, 120 min)

Postoroal glucose load levels of glucagon, Postoroal glucose load levels of glucagon, insulin, GLP-1 and GIP remained insulin, GLP-1 and GIP remained unchanged in both groupsunchanged in both groups

In DJ bypass group + significant decrease In DJ bypass group + significant decrease in leptin levels notedin leptin levels noted

Leptin???Leptin???

Adipocyte-derived hormoneAdipocyte-derived hormone In mice, leptin acts as a hormonal In mice, leptin acts as a hormonal

signal on the afferent limb of a negative signal on the afferent limb of a negative feeback loop between the adipose feeback loop between the adipose tissue and hypothammic centerstissue and hypothammic centers

Physiological increase in plasma leptin Physiological increase in plasma leptin has been shown to significantly inhibit has been shown to significantly inhibit glucose-stimulated insulin secretion in glucose-stimulated insulin secretion in vivo and to determine insulin resistancevivo and to determine insulin resistance

Pacheco D, et al. The effects of duodenal-jejunal exclusion on hormonal regulation of glucose metabolism in Goto-Kakizaki rats. Am J Surgery; 194 (2007):221-224

Reversal of Insulin Resistance Reversal of Insulin Resistance by Leptinby Leptin