G. Lynis Dohm

Who would have thought it? An operation proves to be the most effective therapy for adult-onset diabetes mellitus.

ObjectiveThis report documents that the gastric bypass operation provides long-term control for obesity and diabetes. Summary Background DataObesity and diabetes, both notoriously resistant to medical therapy, continue to be two of our most common and serious diseases. MethodsOver the last 14 years, 608 morbidly obese patients underwent gastric bypass, an operation that restricts caloric intake by (1) reducing the functional stomach to approximately 30 mL, (2) delaying gastric emptying with a c. 0.8 to 1.0 cm gastric outlet, and (3) excluding foregut with a 40 to 60 cm Roux-en-Y gastrojejunostomy. Even though many of the patients were seriously ill, the operation was performed with a perioperative mortality and complication rate of 1.5% and 8.5%, respectively. Seventeen of the 608 patients (<3%) were lost to follow-up. ResultsGastric bypass provides durable weight control. Weights fell from a preoperative mean of 304.4 lb (range, 198 to 615 lb) to 192.2 lb (range, 104 to 466) by 1 year and were maintained at 205.4 lb (range, 107 to 512 lb) at 5 years, 206.5 lb (130 to 388 lb) at 10 years, and 204.7 lb (158 to 270 lb) at 14 years.The operation provides long-term control of non-insulin-dependent diabetes mellitus (NIDDM). In those patients with adequate follow-up, 121 of 146 patients (82.9%) with NIDDM and 150 of 152 patients (98.7%) with glucose impairment maintained normal levels of plasma glucose, glycosylated hemoglobin, and insulin. These antidiabetic effects appear to be due primarily to a reduction in caloric intake, suggesting that insulin resistance is a secondary protective effect rather than the initial lesion. In addition to the control of weight and NIDDM, gastric bypass also corrected or alleviated a number of other comorbidities of obesity, including hypertension, sleep apnea, cardiopulmonary failure, arthritis, and infertility.

The gastric bypass operation reduces the progression and mortality of non-insulin-dependent diabetes mellitus.

Of 232 morbidly obese patients with non-insulin-dependent diabetes mellitus referred to East Carolina University between March 5, 1979, and January 1, 1994, 154 had a Roux-en-Y gastric bypass operation and 78 did not undergo surgery because of personal preference or their insurance companys refusal to pay for the procedure. The surgical and the nonoperative (control) groups were comparable in terms of age, weight, body mass index, sex, and percentage with hypertension. The two groups were compared retrospectively to determine differences in survival and the need for medical management of their diabetes. Mean length of follow-up was 9 years in the surgical group and 6.2 years in the control group. The mean glucose levels in the surgical group fell from 187 mg/dl preoperatively and remained less than 140 mg/dl for up to 10 years of follow-up. The percentage of control subjects being treated with oral hypoglycemics or insulin increased from 56.4% at initial contact to 87.5% at last contact, (P=0.0003), whereas the percentage of surgical patients requiring medical management fell from 31.8% preoperatively to 8.6% at last contact (P=0.0001). The mortality rate in the control group was 28% compared to 9% in the surgical group (including perioperative deaths). For every year of follow-up, patients in the control group had a 4.5% chance of dying vs. a 1.0% chance for those in the surgical group. The improvement in the mortality rate in the surgical group was primarily due to a decrease in the number of cardiovascular deaths.

A new paradigm for type 2 diabetes mellitus: could it be a disease of the foregut?

SUMMARY BACKGROUND DATA We previously reported, in a study of 608 patients, that the gastric bypass operation (GB) controls type 2 diabetes mellitus in the morbidly obese patient more effectively than any medical therapy. Further, we showed for the first time that it was possible to reduce the mortality from diabetes; GB reduced the chance of dying from 4.5% per year to 1% per year. This control of diabetes has been ascribed to the weight loss induced by the operation. These studies, in weight-stable women, were designed to determine whether weight loss was really the important factor. METHODS Fasting plasma insulin, fasting plasma glucose, minimal model-derived insulin sensitivity and leptin levels were measured in carefully matched cohorts: six women who had undergone GB and had been stable at their lowered weight 24 to 30 months after surgery versus a control group of six women who did not undergo surgery and were similarly weight-stable. The two groups were matched in age, percentage of fat, body mass index, waist circumference, and aerobic capacity. RESULTS Even though the two groups of patients were closely matched in weight, age, percentage of fat, and even aerobic capacity, and with both groups maintaining stable weights, the surgical group demonstrated significantly lower levels of serum leptin, fasting plasma insulin, and fasting plasma glucose compared to the control group. Similarly, minimal model-derived insulin sensitivity was significantly higher in the surgical group. Finally, self-reported food intake was significantly lower in the surgical group. CONCLUSIONS Weight loss is not the reason why GB controls diabetes mellitus. Instead, bypassing the foregut and reducing food intake produce the profound long-term alterations in glucose metabolism and insulin action. These findings suggest that our current paradigms of type 2 diabetes mellitus deserve review. The critical lesion may lie in abnormal signals from the gut.

Changes in muscle strength muscle fibre size and myofibrillar gene expression after immobilization and retraining in humans

1 Changes in muscle strength, vastus lateralis fibre characteristics and myosin heavy‐chain (MyoHC) gene expression were examined in 48 men and women following 3 weeks of knee immobilization and after 12 weeks of retraining with 1866 eccentric, concentric or mixed contractions. 2 Immobilization reduced eccentric, concentric and isometric strength by 47 %. After 2 weeks of spontaneous recovery there still was an average strength deficit of 11 %. With eccentric and mixed compared with concentric retraining the rate of strength recovery was faster and the eccentric and isometric strength gains greater. 3 Immobilization reduced type I, IIa and IIx muscle fibre areas by 13, 10 and 10 %, respectively and after 2 weeks of spontaneous recovery from immobilization these fibres were 5 % smaller than at baseline. Hypertrophy of type I, IIa and IIx fibres relative to baseline was 10, 16 and 16 % after eccentric and 11, 9 and 10 % after mixed training (all P < 0.05), exceeding the 4, 5 and 5 % gains after concentric training. Type IIa and IIx fibre enlargements were greatest after eccentric training. 4 Total RNA/wet muscle weight and type I, IIa and IIx MyoHC mRNA levels did not change differently after immobilization and retraining. Immobilization downregulated the expression of type I MyoHC mRNA to 0.72‐fold of baseline and exercise training upregulated it to 0.95 of baseline. No changes occurred in type IIa MyoHC mRNA. Immobilization and exercise training upregulated type IIx MyoHC mRNA 2.9‐fold and 1.2‐fold, respectively. For the immobilization segment, type I, IIa and IIx fibre area and type I, IIa and IIx MyoHC mRNA correlated (r= 0.66, r= 0.07 and r=−0.71, respectively). 5 The present data underscore the role muscle lengthening plays in human neuromuscular function and adaptation.

Exercise training increases glucose transporter protein GLUT-4 in skeletal muscle of obese Zucker (fa/fa) rats

The present study examined the level of GLUT‐4 glucose transporter protein in gastrocnemius muscles of 36 week old genetically obese Zucker (fa/fa) rats and their lean (Fa/‐) littermates, and in obese Zucker rats following 18 or 30 weeks of treadmill exercise training. Despite skeletal muscle insulin resistance, the level of GLUT‐4 glucose transporter protein was similar in lean and obese Zucker rats. In contrast, exercise training increased GLUT‐4 protein levels by 1.7 and 2.3 fold above sedentary obese rats. These findings suggest endurance training stimulates expression of skeletal muscle GLUT‐4 protein which may be responsible for the previously observed increase in insulin sensitivity with training.

Leptin opposes insulin's effects on fatty acid partitioning in muscles isolated from obese ob/ob mice

Because muscle triacylglycerol (TAG) accumulation might contribute to insulin resistance in leptin-deficient ob/obmice, we studied the acute (60- to 90-min) effects of leptin and insulin on [14C]glucose and [14C]oleate metabolism in muscles isolated from lean and obese ob/ob mice. In ob/ob soleus, leptin decreased glycogen synthesis 36-46% ( P < 0.05), increased oleate oxidation 26% ( P < 0.05), decreased oleate incorporation into TAG 32% ( P < 0.05), and decreased the oleate partitioning ratio (oleate partitioned into TAG/CO2) 44% ( P < 0.05). Insulin decreased oleate oxidation 31% ( P < 0.05), increased oleate incorporation into TAG 46% ( P< 0.05), and increased the partitioning ratio 125% ( P < 0.01). Adding leptin diminished insulins antioxidative, lipogenic effects. In soleus from lean mice, insulin increased the partitioning ratio 142%, whereas leptin decreased it 51%, as previously reported (Muoio, D. M., G. L. Dohm, F. T. Fiedorek, E. B. Tapscott, and R. A. Coleman. Diabetes 46: 1360-1363, 1997). The phosphatidylinositol 3-kinase inhibitor wortmannin blocked insulins effects on lipid metabolism but only attenuated leptins effects. Increasing glucose concentration from 5 to 10 mM did not affect TAG synthesis, suggesting that insulin-induced lipogenesis is independent of increased glucose uptake. These data indicate that leptin opposes insulins promotion of TAG accumulation in lean and ob/ob muscles. Because acute leptin exposure does not correct insulin resistance in ob/ob muscles, in vivo improvements in glucose homeostasis appear to require other long-term factors, possibly TAG depletion.Because muscle triacylglycerol (TAG) accumulation might contribute to insulin resistance in leptin-deficient ob/ob mice, we studied the acute (60- to 90-min) effects of leptin and insulin on [14C]glucose and [14C]oleate metabolism in muscles isolated from lean and obese ob/ob mice. In ob/ob soleus, leptin decreased glycogen synthesis 36-46% (P < 0.05), increased oleate oxidation 26% (P < 0.05), decreased oleate incorporation into TAG 32% (P < 0.05), and decreased the oleate partitioning ratio (oleate partitioned into TAG/CO2) 44% (P < 0.05). Insulin decreased oleate oxidation 31% (P < 0.05), increased oleate incorporation into TAG 46% (P < 0.05), and increased the partitioning ratio 125% (P < 0.01). Adding leptin diminished insulins antioxidative, lipogenic effects. In soleus from lean mice, insulin increased the partitioning ratio 142%, whereas leptin decreased it 51%, as previously reported (Muoio, D. M. , G. L. Dohm, F. T. Fiedorek, E. B. Tapscott, and R. A. Coleman. Diabetes 46: 1360-1363, 1997). The phosphatidylinositol 3-kinase inhibitor wortmannin blocked insulins effects on lipid metabolism but only attenuated leptins effects. Increasing glucose concentration from 5 to 10 mM did not affect TAG synthesis, suggesting that insulin-induced lipogenesis is independent of increased glucose uptake. These data indicate that leptin opposes insulins promotion of TAG accumulation in lean and ob/ob muscles. Because acute leptin exposure does not correct insulin resistance in ob/ob muscles, in vivo improvements in glucose homeostasis appear to require other long-term factors, possibly TAG depletion.

Mechanism for Improved Insulin Sensitivity after Gastric Bypass Surgery

CONTEXT Surgical treatments of obesity have been shown to induce rapid and prolonged improvements in insulin sensitivity. OBJECTIVE The aim of the study was to investigate the effects of gastric bypass surgery and the mechanisms that explain the improvement in insulin sensitivity. DESIGN We performed a cross-sectional, nonrandomized, controlled study. SETTING This study was conducted jointly between the Departments of Exercise Science and Physiology at East Carolina University in Greenville, North Carolina. SUBJECTS Subjects were recruited into four groups: 1) lean [body mass index (BMI) < 25 kg/m(2); n = 93]; 2) weight-matched (BMI = 25 to 35 kg/m(2); n = 310); 3) morbidly obese (BMI > 35 kg/m(2); n = 43); and 4) postsurgery patients (BMI approximately 30 kg/m(2); n = 40). Postsurgery patients were weight stable 1 yr after surgery. MAIN OUTCOME MEASURES Whole-body insulin sensitivity, muscle glucose transport, and muscle insulin signaling were assessed. RESULTS Postsurgery subjects had insulin sensitivity index values that were similar to the lean and higher than morbidly obese and weight-matched control subjects. Glucose transport was higher in the postsurgery vs. morbidly obese and weight-matched groups. IRS1-pSer(312) in the postsurgery group was lower than morbidly obese and weight-matched groups. Inhibitor kappaBalpha was higher in the postsurgery vs. the morbidly obese and weight-matched controls, indicating reduced inhibitor of kappaB kinase beta activity. CONCLUSIONS Insulin sensitivity and glucose transport are greater in the postsurgery patients than predicted from the weight-matched group, suggesting that improved insulin sensitivity after bypass is due to something other than, or in addition to, weight loss. Improved insulin sensitivity is related to reduced inhibitor of kappaB kinase beta activity and enhanced insulin signaling in muscle.

The molecular mechanism linking muscle fat accumulation to insulin resistance.

Skeletal muscle insulin resistance is a co-morbidity of obesity and a risk factor for the development of type 2 diabetes mellitus. Insulin resistance is associated with the accumulation of intramyocellular lipids. Intramyocellular triacylglycerols do not appear to be the cause of insulin resistance but are more likely to be a marker of other lipid intermediates such as fatty acyl-CoA, ceramides or diacylglycerols. Fatty acyl-CoA, ceramides and diacylglycerols are known to directly alter various aspects of the insulin signalling cascade. Insulin signalling is inhibited by the phosphorylation of serine and threonine residues at the levels of the insulin receptor and insulin receptor substrate 1. Protein kinase C is responsible for the phosphorylation of the serine and threonine residues. Fatty acyl-CoA and diacylglycerols are known to activate protein kinase C. The cause of the intramyocellular accumulation of fatty acyl-CoA and diacylglycerols is unclear at this time. Reduced fatty acid oxidation does not appear to be responsible, as fatty acyl-CoA accumulates in skeletal muscle with a normal fatty acid oxidative capacity. Other potential mechanisms include oversupply of lipids to muscle and/or up regulated fatty acid transport.

Regulation of skeletal muscle UCP-2 and UCP-3 gene expression by exercise and denervation

The factors that regulate gene expression of uncoupling proteins 2 and 3 (UCP-2 and UCP-3) in skeletal muscle are poorly understood, but both genes are clearly responsive to the metabolic state of the organism. Therefore, we tested the hypothesis that denervation and acute and/or chronic exercise (factors that profoundly affect metabolism) would alter UCP-2 and UCP-3 gene expression. For the denervation studies, the sciatic nerve of rat and mouse hindlimb was sectioned in one leg while the contralateral limb served as control. Northern blot analysis revealed that denervation was associated with a 331% increase (P < 0.001) in UCP-3 mRNA and a 200% increase (P < 0. 01) in UCP-2 mRNA levels in rat mixed gastrocnemius (MG) muscle. In contrast, denervation caused a 53% decrease (P < 0.001) in UCP-3 and a 63% increase (P < 0.01) in UCP-2 mRNA levels in mouse MG. After acute exercise (2-h treadmill running), rat UCP-3 mRNA levels were elevated (vs. sedentary control) 252% (P < 0.0001) in white gastrocnemius and 63% (P < 0.05) in red gastrocnemius muscles, whereas UCP-2 levels were unaffected. To a lesser extent, elevations in UCP-3 mRNA (22%; P < 0.01) and UCP-2 mRNA (55%; P < 0.01) levels were observed after acute exercise in the mouse MG. There were no changes in either UCP-2 or UCP-3 mRNA levels after chronic exercise (9 wk of wheel running). These results indicate that acute exercise and denervation regulate gene expression of skeletal muscle UCPs.The factors that regulate gene expression of uncoupling proteins 2 and 3 (UCP-2 and UCP-3) in skeletal muscle are poorly understood, but both genes are clearly responsive to the metabolic state of the organism. Therefore, we tested the hypothesis that denervation and acute and/or chronic exercise (factors that profoundly affect metabolism) would alter UCP-2 and UCP-3 gene expression. For the denervation studies, the sciatic nerve of rat and mouse hindlimb was sectioned in one leg while the contralateral limb served as control. Northern blot analysis revealed that denervation was associated with a 331% increase ( P < 0.001) in UCP-3 mRNA and a 200% increase ( P < 0.01) in UCP-2 mRNA levels in rat mixed gastrocnemius (MG) muscle. In contrast, denervation caused a 53% decrease ( P< 0.001) in UCP-3 and a 63% increase ( P < 0.01) in UCP-2 mRNA levels in mouse MG. After acute exercise (2-h treadmill running), rat UCP-3 mRNA levels were elevated (vs. sedentary control) 252% ( P < 0.0001) in white gastrocnemius and 63% ( P < 0.05) in red gastrocnemius muscles, whereas UCP-2 levels were unaffected. To a lesser extent, elevations in UCP-3 mRNA (22%; P < 0.01) and UCP-2 mRNA (55%; P < 0.01) levels were observed after acute exercise in the mouse MG. There were no changes in either UCP-2 or UCP-3 mRNA levels after chronic exercise (9 wk of wheel running). These results indicate that acute exercise and denervation regulate gene expression of skeletal muscle UCPs.

Diabetes: Have We Got It All Wrong?: Hyperinsulinism as the culprit: surgery provides the evidence

In this “clinical” contribution to the Bench to Clinic Symposia, we will show data to support the hypothesis that fasting hyperinsulinemia is the initial underlying cause of type 2 diabetes mellitus (T2DM) and that the remission of the disease following bariatric surgery may be due to the correction of hyperinsulinemia. The intent of this article is to elicit critical thinking about the pathophysiology of T2DM in view of the effects of surgery and to open debate. If our hypothesis is correct, then more research resources should be focused on the cause(s) of fasting hyperinsulinemia and the therapies that may correct it. The study of diabetes has always focused on glucose. Whether the diagnosis was made by the attraction of flies to urine as described in ancient India in 1552 BC (1), the sweet taste of the urine noted by Shushruta in 400 BC (2), or our current dependence on fasting blood glucose levels, HbA1c, and glucose tolerance curves, the severity of the disease is still measured by the level of hyperglycemia. Similarly, our therapeutic directions also aim, almost exclusively, to reverse the hyperglycemia. In 1921 when Banting and Best reported that a pancreatic extract reversed the soaring glucose levels following a pancreatectomy in a dog, the use of insulin spread rapidly to children and adults alike. By the time Sir Harold Percival Himsworth noted, in 1936, that there were at least two types of diabetes (3), the objectives of T2DM treatment were already set; goals that still continue today. Even though type 1 diabetes mellitus (T1DM) and T2DM are virtually two opposite diseases, i.e., a total lack of insulin production versus abnormally high levels, the therapeutic goals for both entities continue to be the same: lower glucose levels by 1 ) giving insulin, 2 ) increasing insulin production, and/or 3 …