Steven K. Malin

Effects of metformin on weight loss: potential mechanisms

Purpose of reviewDespite the known glucose-lowering effects of metformin, more recent clinical interest lies in its potential as a weight loss drug. Herein, we discuss the potential mechanisms by which metformin decreases appetite and opposes unfavorable fat storage in peripheral tissues. Recent findingsMany individuals struggle to maintain clinically relevant weight loss from lifestyle and bariatric surgery interventions. Long-term follow-up from the Diabetes Prevention Program demonstrates that metformin produces durable weight loss, and decreased food intake by metformin is the primary weight loss mechanism. Although the effect of metformin on appetite is likely to be multifactorial, changes in hypothalamic physiology, including leptin and insulin sensitivity, have been documented. In addition, novel work in obesity highlights the gastrointestinal physiology and circadian rhythm changes by metformin as not only affecting food intake, but also the regulation of fat oxidation and storage in liver, skeletal muscle, and adipose tissue. SummaryMetformin induces modest weight loss in overweight and obese individuals at risk for diabetes. A more detailed understanding of how metformin induces weight loss will likely lead to optimal co-prescription of lifestyle modification with pharmacology for the treatment of obesity independent of diabetes.

Pancreatic β-cell function increases in a linear dose-response manner following exercise training in adults with prediabetes.

Although some studies suggest that a linear dose-response relationship exists between exercise and insulin sensitivity, the exercise dose required to enhance pancreatic β-cell function is unknown. Thirty-five older obese adults with prediabetes underwent a progressive 12-wk supervised exercise intervention (5 days/wk for 60 min at ~85% HRmax). Insulin and C-peptide responses to an OGTT were used to define the first- and second-phase disposition index (DI; β-cell function = glucose-stimulated insulin secretion × clamp-derived insulin sensitivity). Maximum oxygen consumption (Vo2max) and body composition (dual-energy X-ray absorptiometry and computed tomography) were also measured before and after the intervention. Exercise dose was computed using Vo2/heart-rate derived linear regression equations. Subjects expended 474.5 ± 8.8 kcal/session (2,372.5 ± 44.1 kcal/wk) during the intervention and lost ~8% body weight. Exercise increased first- and second-phase DI (P < 0.05), and these changes in DI were linearly related to exercise dose (DIfirst phase: r = 0.54, P < 0.001; DIsecond phase: r = 0.56, P = 0.0005). Enhanced DI was also associated with increased Vo2max (DIfirst phase: r = 0.36, P = 0.04; DIsecond phase: r = 0.41, P < 0.02) but not lower body fat (DIfirst phase: r = -0.21, P = 0.25; DIsecond phase: r = -0.30, P = 0.10) after training. Low baseline DI predicted an increase in DI after the intervention (DIfirst phase: r = -0.37; DIsecond phase: r = -0.41, each P < 0.04). Thus, exercise training plus weight loss increased pancreatic β-cell function in a linear dose-response manner in adults with prediabetes. Our data suggest that higher exercise doses (i.e., >2,000 kcal/wk) are necessary to enhance β-cell function in adults with poor insulin secretion capacity.

Improved acylated ghrelin suppression at 2 years in obese patients with type 2 diabetes: effects of bariatric surgery vs standard medical therapy.

Objective:Roux-en-Y gastric bypass (RYGB) produces more durable glycemic control than sleeve gastrectomy (SG) or intensive medical therapy (IMT). However, the contribution of acylated ghrelin (AG), a gluco-regulatory/appetite hormone, to improve glucose metabolism and body composition in patients with type 2 diabetes (T2D) following RYGB is unknown.Design:STAMPEDE (Surgical Treatment and Medication Potentially Eradicate Diabetes Efficiently) was a prospective, randomized controlled trial.Subjects:Fifty-three (body mass index: 36±3 kg m−2, age: 49±9 years) poorly controlled patients with T2D (HbA1c (glycated hemoglobin): 9.7±2%) were randomized to IMT, IMT+RYGB or IMT+SG and underwent a mixed-meal tolerance test at baseline, 12, and 24 months for evaluation of AG suppression (postprandial minus fasting) and beta-cell function (oral disposition index; glucose-stimulated insulin secretion × Matsuda index). Total/android body fat (dual-energy X-ray absorptiometry) was also assessed.Results:RYGB and SG reduced body fat comparably (15–23 kg) at 12 and 24 months, whereas IMT had no effect. Beta-cell function increased 5.8-fold in RYGB and was greater than IMT at 24 months (P<0.001). However, there was no difference in insulin secretion between SG vs IMT at 24 months (P=0.32). Fasting AG was reduced fourfold following SG (P<0.01) and did not change with RYGB or IMT at 24 months. AG suppression improved more following RYGB than SG or IMT at 24 months (P=0.01 vs SG, P=0.07 vs IMT). At 24 months, AG suppression was associated with increased postprandial glucagon-like peptide-1 (r=−0.32, P<0.02) and decreased android fat (r=0.38; P<0.006).Conclusions:Enhanced AG suppression persists for up to 2 years after RYGB, and this effect is associated with decreased android obesity and improved insulin secretion. Together, these findings suggest that AG suppression is partly responsible for the improved glucose control after RYGB surgery.

Fasting hyperglycaemia blunts the reversal of impaired glucose tolerance after exercise training in obese older adults

Aim: Lifestyle modification, consisting of exercise and weight loss, delays the progression from prediabetes to type 2 diabetes (T2D). However, no study has determined the efficacy of exercise training on glucose metabolism in the different prediabetes subtypes.

Pancreatic β-cell Function Is a Stronger Predictor of Changes in Glycemic Control After an Aerobic Exercise Intervention Than Insulin Sensitivity

CONTEXT Understanding intersubject variability in glycemic control following exercise training will help individualize treatment. OBJECTIVE Our aim was to determine whether this variability is related to training-induced changes in insulin sensitivity or pancreatic β-cell function. DESIGN, SETTING, AND PARTICIPANTS We conducted an observational clinical study of 105 subjects with impaired glucose tolerance or type 2 diabetes. INTERVENTIONS AND MAIN OUTCOME MEASURES Individual subject changes in fitness (VO2max), glycemia (glycosylated hemoglobin, fasting glucose, oral glucose tolerance test), insulin sensitivity (hyperinsulinemic-euglycemic clamp), oral glucose-stimulated insulin secretion (GSIS), and disposition index (DI) were measured following 12 to 16 weeks of aerobic exercise training. Regression analyses were used to identify relationships between variables. RESULTS After training, 86% of subjects increased VO2max and lost weight. Glycosylated hemoglobin, fasting glucose, and 2-hour oral glucose tolerance test were reduced in 69%, 62%, and 68% of subjects, respectively, while insulin sensitivity improved in 90% of the participants. Changes in glycemic control were congruent with changes in GSIS such that 66% of subjects had a reduction in first-phase GSIS, and 46% had reduced second-phase GSIS. Training increased first- and second-phase DI in 83% and 74% of subjects. Training-induced changes in glycemic control were related to changes in GSIS (P < .05), but not insulin sensitivity or DI, and training-induced improvements in glycemic control were largest in subjects with greater pretraining GSIS. CONCLUSIONS Intersubject variability in restoring glycemic control following exercise is explained primarily by changes in insulin secretion. Thus, baseline and training-induced changes in β-cell function may be a key determinant of training-induced improvements in glycemic control.

Exercise training with weight loss and either a high- or low-glycemic index diet reduces metabolic syndrome severity in older adults.

Background: The efficacy of combining carbohydrate quality with exercise on metabolic syndrome risk is unclear. Thus, we determined the effects of exercise training with a low (LoGIx)- or high (HiGIx)-glycemic index diet on the severity of the metabolic syndrome (Z-score). Methods: Twenty-one adults (66.2 ± 1.1 years; BMI = 35.3 ± 0.9 kg/m2) with the metabolic syndrome were randomized to 12 weeks of exercise (60 min/day for 5 days/week at about 85% HRmax) and provided a LoGIx (n = 11) or HiGIx (n = 10) diet. Z-scores were determined from: blood pressure, triglycerides (TGs), high-density lipoproteins (HDLs), fasting plasma glucose (FPG), and waist circumference (WC) before and after the intervention. Body composition, aerobic fitness, insulin resistance, and nonesterfied fatty acid (NEFA) suppression were also assessed. Results: LoGIx and HiGIx diets decreased body mass and insulin resistance and increased aerobic fitness comparably (p < 0.05). LoGIx and HiGIx diets decreased the Z-score similarly as each intervention decreased blood pressure, TGs, FPG and WC (p < 0.05). The HiGIx diet tended to suppress NEFA during insulin stimulation compared with the LoGIx diet (p = 0.06). Conclusions: Our findings highlight that exercise with weight loss reduces the severity of the metabolic syndrome whether individuals were randomized to a HiGIx or a LoGIx diet.

Attenuated improvements in adiponectin and fat loss characterize type 2 diabetes non-remission status after bariatric surgery

To identify the metabolic determinants of type 2 diabetes non‐remission status after bariatric surgery at 12 and 24 months.

Sarcopenia and a physiologically low respiratory quotient in patients with cirrhosis: a prospective controlled study

Patients with cirrhosis have increased gluconeogenesis and fatty acid oxidation that may contribute to a low respiratory quotient (RQ), and this may be linked to sarcopenia and metabolic decompensation when these patients are hospitalized. Therefore, we conducted a prospective study to measure RQ and its impact on skeletal muscle mass, survival, and related complications in hospitalized cirrhotic patients. Fasting RQ and resting energy expenditure (REE) were determined by indirect calorimetry in cirrhotic patients (n = 25), and age, sex, and weight-matched healthy controls (n = 25). Abdominal muscle area was quantified by computed tomography scanning. In cirrhotic patients we also examined the impact of RQ on mortality, repeat hospitalizations, and liver transplantation. Mean RQ in patients with cirrhosis (0.63 ± 0.05) was significantly lower (P < 0.0001) than healthy matched controls (0.84 ± 0.06). Psoas muscle area in cirrhosis (24.0 ± 6.6 cm(2)) was significantly (P < 0.001) lower than in controls (35.9 ± 9.5 cm(2)). RQ correlated with the reduction in psoas muscle area (r(2) = 0.41; P = 0.01). However, in patients with cirrhosis a reduced RQ did not predict short-term survival or risk of developing complications. When REE was normalized to psoas area, energy expenditure was significantly higher (P < 0.001) in patients with cirrhosis (66.7 ± 17.8 kcal/cm(2)) compared with controls (47.7 ± 7.9 kcal/cm(2)). We conclude that hospitalized patients with cirrhosis have RQs well below the traditional lowest physiological value of 0.69, and this metabolic state is accompanied by reduced skeletal muscle area. Although low RQ does not predict short-term mortality in these patients, it may reflect a decompensated metabolic state that requires careful nutritional management with appropriate consideration for preservation of skeletal muscle mass.

β-Cell dysfunction is associated with metabolic syndrome severity in adults.

BACKGROUND Metabolic syndrome is prevalent in adults characterized by increased visceral adiposity and insulin resistance (IR). However, the link between pancreatic β-cell function and metabolic syndrome severity in adults across the glucose spectrum is unknown. We hypothesized that poor β-cell function would independently predict a higher metabolic syndrome Z-score (i.e., severity). METHODS Seventy (12 normal glucose tolerant, 37 prediabetic, 21 type 2 diabetic) obese adults [62.4±1.1 year; 34.6±0.6 kg/m(2); data are mean±standard error of the mean (SEM)] participated in this cross-sectional study. A 2-hr 75-gram oral glucose tolerance test (OGTT) was administered, and insulin and glucose area under the curve was determined for calculations of insulin action. Fasting and glucose-stimulated insulin secretion was calculated using homeostasis model assessment of insulin secretion (HOMA-B) and the insulinogenic index (i.e., I(0-30)/Glc(0-30) or I(60-120)/Glc(60-120)), respectively. Fasting and postprandial insulin sensitivity was assessed by HOMA-IR and the Matsuda Index, respectively. β-cell function was estimated using the disposition index via HOMA-B/HOMA-IR, I(0-30)/Glc(0-30) or I(60-120)/Glc(60-120) × Matsuda Index, which represents basal, first-, and second-phase insulin release, respectively. Body composition (via computerized tomography and dual X-ray absorptiometry) and sex-specific metabolic syndrome Z-scores were calculated from waist circumference, blood pressure, fasting glucose, triglycerides, and high-density lipoproteins. RESULTS Compared to those with normal glucose tolerance, visceral fat and IR were higher and β-cell function was lower in adults with glucose intolerance and type 2 diabetes mellitus. Elevated visceral fat and IR (HOMA-IR and Matsuda Index) correlated with elevated Z-scores (r=0.51, r=0.54, r=-0.49; all P<0.002, respectively). Basal, first-, and second-phase β-cell function correlated with low Z-scores (r=-0.59, r=-0.51, and r=-0.43, all P<0.001). Insulin secretion significantly predicted the Z-score independent of sex, body fat, blood lipids, blood pressure, IR, and glucose metabolism (P<0.005). CONCLUSION β-cell dysfunction is highly correlated with the severity of metabolic syndrome in adults. Future work is warranted to elucidate the mechanism by which cardiometabolic disturbances influence insulin secretion.

Ghrelin suppression is associated with weight loss and insulin action following gastric bypass surgery at 12 months in obese adults with type 2 diabetes

Roux‐en‐Y gastric bypass (RYGB) surgery reverses type 2 diabetes mellitus (T2DM) in approximately 80% of patients. Ghrelin regulates glucose homeostasis, but its role in T2DM remission after RYGB surgery is unclear. Nine obese T2DM subjects underwent a mixed meal tolerance test before and at 1 and 12 months after RYGB surgery. Changes in ghrelin, body weight, glucagon‐like polypeptide‐1 (GLP‐1, glucose tolerance and insulin sensitivity (IS) were measured. At 1 month, body weight, glycaemia and IS were improved, while ghrelin concentrations were reduced (p < 0.05). After 12 months, body weight and fasting glucose were reduced (30 and 16%, respectively; p < 0.05) and IS was enhanced (threefold; p < 0.05). Ghrelin suppression improved by 32% at 12 months (p < 0.05), and this was associated with weight loss (r = 0.72, p = 0.03), enhanced IS (r = −0.78, p = 0.01) and peak postprandial GLP‐1 (r = −0.73, p = 0.03). These data suggest that postprandial ghrelin suppression may be part of the mechanism that contributes to diabetes remission after RYGB surgery.