Diabesity. Metabolic dysfunction that ranges from mild blood glucose imbalance to full fledged Type 2 DM Signs

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1 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

2 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

3 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

4 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

5 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%

6 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

7 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

8 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

9 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

10 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

11 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

12 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 (?)

13 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.

14 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

15 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

16 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

17 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

18 Management of T2DM with Bariatric Surgery o 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

19 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

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