Type 2 Diabetes and Prediabetes A New Understanding

Type 2 Diabetes and Prediabetes: A New Understanding of Cause and Treatment Bruce Latham, M. D. Endocrine Specialists Greenville Health System

Objectives for this presentation - Understand the “thrifty genotype and thrifty phenotype” hypothesis as to the origin of insulin receptor signaling pathway mutations in patients with type 2 diabetes - Review the new hypothesis as to the cause of pre-diabetes and type 2 diabetes - Understand why bariatric surgery and extreme diets can reverse type 2 diabetes - Briefly review current research for diagnosis and treatment of type 2 diabetes

Types of Diabetes Type 1 diabetes – autoimmune destruction of beta cells in the islets of Langerhans in the pancreas Type 2 diabetes – chronic hyperglycemia resulting from insulin receptor signaling pathway gene mutations LADA (latent autoimmune diabetes of adulthood) Diabetes due to pancreatic destruction (pancreatitis, pancreatic resection) Other genetic causes (Leprechaunism, MODY, etc)

Definition of pre-diabetes and diabetes Pre-diabetes: Two finger stick glucoses of 100 -125 Hb. A 1 c 5. 7 -6. 4 Post glucola (2 hr) glucose 140 -199 Diabetes: Two finger stick fasting glucoses of 126 or higher Hb. A 1 c 6. 5 or higher Post glucola (2 hr) glucose >200

What causes pre-diabetes and diabetes? Is it obesity? Is it genetics? Is it bad life-style?

One size does not fit all

The Paradox… - 85 percent of diabetics are overweight - but only 30 percent of overweight people have type 2 diabetes and 15 percent of type 2 diabetics have a normal BMI

Obesity is not the cause of diabetes

To understand the cause, we need to review insulin action

Only two organs need insulin to internalize glucose: Skeletal muscle Fat The key: both are involved in energy utilization: Skeletal muscle transforms chemical energy (glucose) to mechanical work on a “as needed” basis. Fat provides free fatty acids (FFA) for conversion to ATP in mitochondria during prolonged periods of energy need or during periods of fasting.

There are over 150 known mutations in the insulin receptor or receptor signaling pathway that lead to insulin resistance. Most mutations are detrimental to the survival of the organism. If this is the case, why are there so many mutations in this signaling pathway?

Hypothesis: These mutations may have once been beneficial to Homo sapiens The “thrifty phenotype” hypothesis The “thrifty genotype” hypothesis

Possible etiology of pre-diabetes and type 2 diabetes “Thrifty genotype” hypothesis

Possible etiology of type 2 diabetes Thrifty phenotype hypothesis Babies with low birth weight (less than 4. 3 kg, especially those less than 2. 5 kg) have a 7 x higher incidence of impaired glucose or Type II diabetes as adults than those who were heaviest at birth. This is thought due to poor fetal nutrition leading to in utero genetic reprogramming for insulin resistance to increase the chance of surviving poor postnatal nutrition.

These adaptations are beneficial if the individual experiences poor nutrition postnatally Example: very low incidence of diabetes in sub. Saharan Africa: poor fetal nutrition + poor postnatal nutrition =no diabetes. These adaptations are most detrimental if the individual has poor fetal nutrition + good postnatal nutrition = high incidence of diabetes, especially if obese as an adolescent or adult

Examples: Pima Indians

Nauru Islanders: “coca-colonization”

Europeans: Until recently incidence was decreasing until “glowing pixels of light” and extreme life spans.

Patients with type 2 diabetes also have a greatly increased risk for NASH (non-alcoholic steatosis and hepatitis; i. e. severe fatty liver and liver failure) In one autopsy series, obesity and/or diabetes was found in 20 of 22 patients who died with NASH.

Prerequisites for development of pre-diabetes and type 2 diabetes - Insulin receptor signaling pathway gene defect - High organ (visceral) fat (liver and pancreas) concentrations. Subcutaneous fat not important.

High organ fat – pancreas and liver High liver fat – leads to impaired down-regulation of gluconeogenesis and glycogenolysis and later, NASH High pancreas fat – (later) decreased insulin production

Interventional Therapies Weight Reduction in patients without diabetes Finnish Diabetes Prevention Study (522 subjects) Diabetes Prevention Study (U. S. ) (3243 subjects) Patients treated with: Regular moderate exercise (2. 5 -3 hrs/wk) “Optimal” diet (low simple carbs, more dietary fiber, less saturated fat) 7% weight loss over 3 years 58% fewer people developed type II diabetes than in the control groups.

Interventional Therapies Weight reduction in patients without diabetes Da Qing trial (577 subjects) Three treatment groups: diet, exercise, or both After 6 years, risk reduction of developing T 2 DM 31%, 46%, and 42%, respectively (Pan XR, et. al. Diabetes Care 1997, 537 -44. )

Interventional Therapies Weight reduction in patients with diabetes • 11 patients with type 2 DM (age 49+/-2. 5; BMI 36; 9 male 2 female). 8 non-diabetic control pts • 600 kcal diet for 8 weeks • Pancreatic and hepatic fat measured by MRI after 1, 4 and 8 weeks. • Insulin suppression of hepatic glucose production, 1 st phase insulin response measured Lim KG et. al. Reversal of type 2 diabetes: normalisation of beta cell function in association with decreased pancreas and liver triacylglycerol. Diabetologia (2011) 54: 2506– 2514

Interventional Therapies Weight reduction in patients with diabetes Results • After 1 week, fasting plasma glucose normalized • Insulin suppression of hepatic glucose improved from 43% to 74%. • Hepatic triacylglycerol fell from 12% to 2. 9% • 1 st phase pancreatic insulin response improved from. 19 nmol/min/m to. 46 nmol/min/m. • Maximal insulin response became supranormal at 8 weeks (1. 36 vs. 1. 15 nmol/min/m controls) • Pancreatic triacylglycerol decreased from 8 to 6. 2 nmol/min/m

Interventional Therapies Weight reduction in patients with diabetes Bariatric surgery 136 studies; 22094 patients. 18% men, 72% women -Mean age 39 years; mean BMI 46. 9 (range 32. 368. 8) -Gastric banding, gastric bypass, gastroplasty, biliopancreatic diversion or duodenal switch Operative mortality. 1% for restrictive procedures, . 5% for gastric bypass, 1. 1% for biliopancreatic diversion or duodenal switch (Buchwald, et. al. JAMA 292, Oct. 13, 2004)

Interventional Therapies Weight Reduction Bariatric surgery Diabetes completely resolved in 76. 8%; resolved or improved in 86%. Hyperlipidemia improved in 70%. Hypertension resolved in 62% or resolved or improved in 78. 5% Sleep apnea resolved in 86% and resolved or improved in 83%.

Interventional Therapies Current Research 2, 4, dinitrophenol • Blocks oxidative phosphorylation in mitochondria • Causes “runaway” consumption of hepatic fat – conversion to heat rather than to ATP • Once used for weight loss; banned in the 1930’s due to deaths from severe hyperthermia • Still abused by some athletes today to promote rapid weight loss

In the Zucker diabetic rat, can treatment with small amounts of 2, 4 dinitrophenol reverse diabetes? When given in very small amounts to these rats, it caused a • 40% reduction in fasting glucose • 50% reduction in plasma insulin concentration • 90% reduction in hepatic diacylglycerol (fatty acids) Perry RJ, et. al. Science. 2015 Mar 13; 347(6227): 1253 -6.

What is the concentration of pancreatic and hepatic fat that is associated with the onset of type 2 diabetes?

So, how does this new information influence day to day treatment algorithms of type 2 diabetes?

Diabetes treatment algorithms are rapidly changing… First, metformin (inhibits hepatic gluconeogenesis; weight neutral) Then…what?

Older therapies: Insulin injections Sulfonylurea oral agents often cause weight gain – leading to increased insulin resistance

Interventional Therapies Newer diabetic medications which cause weight loss: GLP-1 agonists: exenatide (Byetta), liraglutide (Victoza), dulaglutide (Trulicity), etc. SGLT 2 inhibitors: dapagliflozin (Farxiga), canagliflozin (Invokana), empagliflozin (Jardiance)

Take Home Points • Obesity itself does not cause type 2 diabetes. • Type 2 diabetes is the result of an insulin receptor or receptor pathway mutation in some individuals, present from birth. • It is the combination of the mutation – along with visceral fat – that may lead to type 2 diabetes. • The visceral fat content needed to cause type 2 diabetes is not yet known. • Weight loss and exercise can prevent and may reverse diabetes in some if not most individuals.

Take Home Points Prediabetes and type 2 diabetes are diseases of our times. The rapid change in human culture from hunter-gatherers to the agricultural age, and now the industrial age has made a once apparently beneficial mutation in our genetic code a detriment. Because of the rapid nature of our cultural change, we as a species have not had time to adapt to our new environment. Since those of us in western societies no longer eat or exercise as our distant ancestors did, this mutation has left many at risk for cardiovascular disease and type II diabetes.