Unit 4 Exam

Joslin/Allen (early 1900’s)

• Diabetes (usually type 10 was fatal

  • glycosuria

  • hyrerphagia

  • extreme thirst

  • weight loss

  • ketoacidosis

• their hypothesis: body cannot handle incoming nutrients, so we should reduce metabolic burden

  • caloric restriction

• approach: intake vs. urine output

• findings:

  • +intake → glycosuria, +ketonuria

  • fasting → -glycosuria, -ketonuria

  • →”starvation diet”

    • not a cure, nut did extend patient’s lives a few months

• T1D is insulin deficiency

  • cells don’t uptake glucose

  • liver → gluconeogenesis and glycogenolysis

  • lipolysis → ketones

Banting/Best/MacLeod/Collip 1922:

• pancreatic extracts (dogs, rabbits, etc) → T1D

• first major endocrine discovery

1920’s-1930’s

• no drugs

• T2D poorly understood

• caloric restriction the norm

• early recommendations:

  • structured diets (caloric counting)

  • energy balance

• known that weight loss improves glycemia

1930’s-1950’s

• no drugs

• amphetamine derivatives

  • central appetite suppressors

  • effective

  • side effectives:

    • addiction

    • CV problems

    • Psychiatric effects

Mason/Ito 1967

• Roux-en-Y:

  • create a small stomach pouch

  • reroute small intestine

• first patient 1966: lost 30% of her weight in 9 months

1970’s-1990’s

• backlash against drugs/surgery

• focus on behavior, exercise, diet

• findings:

  • modest weight loss

  • high long-term regain

• weight loss is possible, maintenance is not

Metabolic Syndrome

• T2D rates rising

• clinical studies identify cluster:

  • hyperinsulinemia

  • hypertension

  • dyslipidemia

• findings:

  • IR central to T2D

  • introduction of metabolic syndrome

• BMI problems not about willpower

  • metabolic dysfunction

Anti-Diabetics 1970’s-1990’s

• modern diabetes drugs

  • sulfonylureas (increased insulin secretion)

    • stimulates b-cells (Ca²⁺)

  • metformin (increased insulin sensitivity)

    • reduces hepatic glucose output

    • increase hepatic insulin sensitivity

  • no effect on BMI

    • treating glucose not the same as treating obesity

Fen-Phen

• 1990’s: “Lost Decade”

  • Fen-Phen (fenfluramine + phentermine)

    • +serotonin (+satiety), + norepinephrine (+appetite suppression)

    • significant weight loss

    • widely prescribed (millions)

Fen-Phen Problems

• Fen-Phen side affects:

  • heart valves

  • pulmonary hypertension

  • off-target effects: 5-HT receptors → valve thickening

• lawsuits, public/regulatory backlash

• drugs withdrawn

• retrospectively:

  • it worked

  • correctly targeted brain regions

  • but not dafe: receptor specificity matters!

GLP1 Research

• Two directions of GLP1 research occurring in the background:

  • inhibit DPP4, prolong endogenous GLP1

  • find deregulation-resistant GLP1 receptor agonists

    • 1992: eventide discovered

    • approved by FDA in 2005

Pories 1995:

• Context? Approach: long-term follow-up of gastric bypass patients

• findings; high rates of diabetes remission

• interpretation:

  • surgery has metabolic effects?

  • cut-endocrine regulation?

Safer T2D drugs

• UKPDS 34 1998:

  • sulfonylureas work against T2D, but cause weight gain

  • insulin works but also causes weight gain

  • high BMI cohort;

    • randomized to:

      • conventional therapy

      • metformin

      • sulfonylureas, insulin

Metformin Wins

• Findings:

  • all drugs lowered HbA1c

  • only metformin did not cause weight gain

    • reduction in:

      • diabetes-related endpoints

      • all-cause mortality

      • myocardial infarction

Knowler 2002:

• contact:

  • T2D rising

  • risk factors known

• hypothesis: progression to T2D can be prevented:

  • lifestyle?

  • metformin?

• approach:

  • 3200 pre diabetic adults

    • high fasting glucose

    • poor glucose tolerance

    • = high risk for T2D

  • randomized into 3 groups:

    • lifestyle: diet/exercise/weight loss (150min/wk)

    • metformin: 850mg twice daily

    • control: placebo and standard advice

• findings:

  • reduction in diabetes:

    • lifestyle: 58%

    • metformin: 31%

  • lifestyle 2X as effective at preventing diabetes

• interpretation:

  • diabetes is preventable

  • lifestyle is a first-line therapy

  • pre diabetes is a clinical target

• criticism:

  • lifestyle group was highly monitored and coached: not feasible broadly

2012; Stampeded trial

• 150 patients with T2D

• range of BMIs

• randomized to:

  • medical therapy

  • +gastric bypass

  • +sleeve gastrectomy

• primary endpoint: HbA1C <6%

• findings:

  • primary endpoint

    • therapy alone: -12%

    • gastric bypass: -42%

    • sleeve gastrectomy: -37%

  • weight

    • therapy: -5%

    • surgery: -25%

Early 2000’s

• Roux-en-Y dramatically increases GLP1 production

• +PYY

• -ghrelin

• faster nutrient delivery to distal intestine

• +insulin

• =+satiety

Exenatide (2005):

• peptide from Gila monster

• DPP-4-resistant

• GLP1-RA

• AMIGO trial

• Reduced HbA1c, modest weight loss

Liraglutide (2010)

• Manipulations of structure to make it longer-acting

• →GLP1 + fatty acid

• -CV events

• HbA1c

• -weight

GLP1-RAs with modest effects:

• lixisenatide

• albiglutide (dimer fused to albumin)

• dulaglutide (fused to IgG Fc)

Semaglutide (2017):

• injectable and oral formulations

• highly potent,long-acting

• GLP1 + fatty acid

• many trials, all good

  • 15% weight loss

  • strong CV benefit

  • -HBA1c

Tirzepatide (2022)

• dual GIP + GLP1 agonist (“twincretin”)

• 20% weight loss, HbA1c -2.3%

GLP Summary

GLP-1 and children

• AAP 2023 guideline: offer weight-loss drugs to 12yo and older with obesity

GLP-1 and side effects

• Common:

  • GI: nausea, vomitting, diarrhea, constipation, abdominal pain

• pancreatitis, gallbladder disease, hypoglycemia, dehydration

• thyroid tumors in mice

AHA 2024/2026

• treat the BMI and glucose, it fixes everything else

• no longer thought of as a willpower problem

• BMI+T2D

  • GLP1-RA

  • SGLT2 inhibitor (renal glucose excretion)

• T2D prevention:

  • lifestyle: 150 min/week physical activity

• Diet/CVD:

  • behavioral counseling

  • mediterranean-style, low carb

The Problem

• short-term success common

• long-term maintenance hard, rare

• Mann 2007 review:

  • diets produced modest weight loss (~5%)

  • Regained 3-5 years

• Look AHEAD trial (2012)

  • can diet +exercise reduce CV events?

  • 5k adults w/T2D → either:

    • ILI (intensive lifestyle intervention)

      • did lose more weight, had better HbA1c, BP, HDL, TAG

      • But did not significantly reduce CV events

        • early success, hard to maintain

    • Crtl: support/education, not intensive

Liebel 1995:

• energy expenditure reduced after wight loss, hunger increases (promote return to original weight)

• gain? energy expenditure does not increase enough to return to original weight (settling point)

Proietto 2011

• 50 participants, 8wk diet, 1 yr follow-up

• weight regain

• + ghrelin

• - PYY

• -CCK

Food Industry

• Whole/minimally-processed → ultra-processed (UPF)

• shelf-stable products

• hyper-palatability

• food system works to maximize:

  • yield

  • predictable production

  • profit

• U.S. Farm Bill:

  • subsidies, crop insurance, commodity pricing, SNAP

• Big Four:

  • corn, soybeans, wheat, rice

  • subsidized → cheap for manufactures → profitable → UPF

UPF

• industrial formulations

• ~69% of calories in U.S. diet

• additives:

  • override satiety

  • drive repeat consumption

• Fractionation + recombination

  • + absorption (proximal intestine)

  • Matrix effect:

    • UPF refined, essentially pre-digested, rapid glucose absorption