Diabesity Metabolic dysfunction that ranges from mild blood glucose imbalance to full fledged Type 2 DM Signs Abdominal obesity Low HDL, high LDL, and high triglycerides HTN High blood glucose (F>100l, AIC >5.7 (5.5) Systemic inflammation Tendency to form blood clots
Diabesity Symptoms Sugar cravings, especially after meds Eating sweets that don t relieve cravings Fatigue after meds Frequent urination Increased thirst and appetite Difficulty losing weight Slowed gastric emptying Sexual dysfunction Can be thin- metabolically obese
o 350 million people with DM worldwide, ½ undiagnosed multifactorial causes, but 80% are obese o Obesity plays a role in progression from normal glucose intolerance, to pre diabetes, to type 2 DM o Inadequate compensation of B-cells to an increasingly insulin resistant skeletal muscle and liver characterize Type 2 DM o Patients with pre DM have lost up to 80% of B cell function and have comparable degrees of insulin resistance to patients with clinical Type 2 DM o Adipose tissue is considered a chief culprit in development of multi organ insulin resistance and B cell dysfunction through increased circulatory factors (free fatty acids, leptin, cytokines, etc.) that promote hyperglycemia
o New understanding of pathophysiology of T2DM involve the GI tract (small intestine), kidney and brain play an important role in progression to T2DM o Obesity is considered by major health organizations, although others consider it a side effect of energy imbalance o Current focus placed on efforts to improve weight management and glycemic control to combat increased???? Of CV disease in patients with T2DM o Lifestyle modification directly and successfully induces meaningful weight loss by inducing a negative energy balance o Advances in pharmacological interventions that drive weight loss and improve insulin sensitivity and B cell function o Role of bariatric surgery in algorithm for diabetes therapy
Type 2 DM Lifestyle Modification o Better lifestyle decisions that lead to healthier body weights as obesity is the basic risk factor for T2DM o Sedentary behavior and increased caloric intake are two key factors know to trigger insulin resistance and promote increased insulin secretion o Increased physical activity and low fat diet reduce BW by 5kg for 2 years or beyond lowers diabetic risk by 30-60% o Weight loss 2-5% over 1-4 years reduces AIC.2-.3% o 5 to 10% losses at 1 year are associated with AIC reductions of.6-1.0% o Finnish DPS ->5% weight loss with decreased total fat, increasing fiber, and increasing physical activity (>30 min/day) decreased cumulative incidence of pre diabetes progressing to diabetes by 58%
Type 2 DM Lifestyle Modification o US DPP- exercise 150 min/week and lose 7% body weight led to 58% reduction in new diabetes cases- subjects with most weight loss and met physical activity and diet targets had >90% risk reduction of DM o Consistency of balanced diet (high fiber and low fat) promoting 5-8% weight loss with increased physical activity is a well established strategy for many T2DM o Increased physical activity primary determinate of maintaining weight loss
o Some work shows that not all people with hyperglycemia respond to standard lifestyle interventions o Further work is required to understand why some people with hyperglycemia do not respond to traditional lifestyle modification and to develop the optimal exercise program for diabetic prevention and treatment
Treatment of Type 2 DM- Pharmacology Long term adherence to diet and exercise effect less than 50% AIC<7% no decrease in CV events and may not maintain insulin sensitivity and B cell function. Insulin Sensitizers: A. Metformin- Increases insulin sensitivity through hepatic glucose suppression, opposes glucagon action and stimulates peripheral glucose uptake. Some weight loss that can persist Metformin and lifestyle changes- may enhance?????? or have no effect on exercise improval Improvements in insulin sensitivity and glucose homeostasis
Treatment of Type 2 DM- Pharmacology B. Thiazolidinediones Act on PPAR gamma receptor in adipose tissue, liver, and muscle, and improve/restore pancreatic B cell function. Increase body weight (? mechanism of action) Potent anti adrenergic effects that lower CVD risk and slow progression from pre DM to DM
Insulin Secretogogues and B Cell Function Agonists o Sulfonylureas o Enhance insulin secretion through binding to receptors associated with K channels on B cells. o Risk of hypoglycemia does not preserve pancreatic B cell function and promotes weight gain. o Incretin analogues
DDP IV Inhibitors O DDP IV enzyme that cleaves GLP-1 limit the glucoregulatory benefits of the GLP_1 DDP IV inhibitors increase GLP-1 levels, but not as much as GLP-1 drugs themselves and do not cause weight loss Insulin- basal and prandial Risk of hypoglycemia and weight gain Combination of insulin and oral agents
GLP-1 GLP-1 accounts for 60% of meal stimulated insulin secretion and is important for delay gastric emptying and relieving post prandial glucose levels. GLP-1 Receptor Agonist, e.g. Byetta Victoza and one weekly Trulicity, Bydureon, Tanzeum- Offer greatest benefit on addition to Metformin Potential cause of pancreatitis and pancreatic cancer (?)
Novel Medication o Na-glucose cotransporter 2 Inhibitors block reabsorption of glucose in proximal renal tubule and promote glucose loss in the urine. o Improve glycemic control and blood pressure, and reduction in body weight o Added to Metformin, improves CVD risk factors o Increased risk of genital mycotic infection and lower UTIs.
Weight Loss Agents that Promote Glycemic Benefit Phentermine/ Topiramate- Qsymia Phentermine reduces appetite by stimulating norepinephrine action in the hypothalamus Topiramate lowers food craving, decrease fat storage and increase energy expenditure T2DM- weight loss and decreased A IC levels pre diabetes metabolic syndrome- weight loss and reduced progression to diabetes mellitus
Weight Loss Agents that Promote Glycemic Benefit Orlistato Gastric and pancreatic lipase inhibitor that blocks dietary fat absorption by approximately 30% o Can produce weight loss and reduce progression to T2DM in people with pre diabetes mellitus and lead to weight loss and improved insulin sensitivity in patients with T2DM o Causes fecal urgency, mild fat mal absorption, gas with discharge and malabsorption of fat soluble vitamins
Weight Loss Agents that Promote Glycemic Benefit Lorcaserin (Belviq) o Selective antagonist of serotonin 2C receptor o Reduces appetite and food intake reducing body weight o More, T2DM patients lost >5% of body weight compared to placebo and significant reduction in AIC
Weight Loss Agents that Promote Glycemic Benefit Naltrexone/Bupropion o Targets the mesolimbic dopamine reward system and the hypothalamic melanocortin system to reduce food intake o Significant weight loss and reductions in fat mass and visceral adiposity o T2DM patients experienced greater weight loss and Hg A1C improvements as compared to placebo. Side effects of constipation, headache, vomiting, and dizziness
Management of T2DM with Bariatric Surgery o 9.8-15.8 x the odds of achieving diabetes remission with bariatric surgery compared to conventional Rx. o ADA and IDF have recognized bariatric surgery as effective treatment of T2DM o Not all patients remain in remission 2-5 years post surgery with insulin resistance and B cell dysfunction as key factors in relapse. o Swedish obese subjects follow up study o Remission rates decreased from 72.3% at 2 years to 30.4% at 15 years, with long pre operative T2DM duration, insulin use, poor glycemic control despite oral hypoglycemic agents and microvascular complications all additional indicators of inadequate B cell function
Conclusions o Several therapeutic options will be required to correct varying tissue disturbancesskeletal muscle, liver, adipose tissue, gut, kidney o Treatment earlier on in the disease is likely to preserve B cell function and restore insulin sensitivity for long term glycemic control and CVD risk reduction. o Type 2 DM is related to weight gain combined with the exhaustion of insulin secreting B cells caused by insulin resistance in skeletal muscle, liver, and adipose tissue o Lifestyle modification 1 st line therapy o Intervention aimed at reducing weight and increasing insulin sensitivity (metformin, SGLT2) followed by drugs that enhance insulin secretion o Weight loss with metformin, GLP-1, SGLT2- o Anti obesity drugs adjunctive therapy to diet and exercise